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Mechanistic Hypotheses

4

Lewy-Body PAF with Postganglionic Noradrenergic Lesion

lewy_body_paf CANONICAL

Evidence balance 1 support

Most PAF is a peripheral Lewy body disease: intraneuronal alpha-synuclein aggregates in postganglionic sympathetic neurons cause noradrenergic denervation and very low norepinephrine. This form can phenoconvert to Parkinson disease or dementia with Lewy bodies, but not to MSA.

Pathograph links

Peripheral Autonomic Alpha-Synuclein Aggregation -> Postganglionic Sympathetic Noradrenergic Denervation INDIRECT UNKNOWN INTERMEDIATES Synuclein-laden postganglionic neurons degenerate; the steps from aggregation to neuronal loss are not resolved in PAF.

Peripheral Autonomic Alpha-Synuclein Aggregation -> Noradrenergic Vesicular Storage and Synthesis Defect INDIRECT UNKNOWN INTERMEDIATES

Peripheral Autonomic Alpha-Synuclein Aggregation -> Preganglionic Intermediolateral Column Neuron Loss INDIRECT UNKNOWN INTERMEDIATES

Subclinical Central Catecholaminergic Involvement -> Spread to Central Nervous System (Phenoconversion) INDIRECT UNKNOWN INTERMEDIATES

Show evidence (1 reference)

PMID:34669076 SUPPORT REVIEW SYNTHESIS Human clinical

"Clinical and postmortem data show that the form of PAF that involves sympathetic intraneuronal synucleinopathy and noradrenergic deficiency can phenoconvert to PD or DLB-but not to MSA."

Review of autopsy and clinical data defining the Lewy-body form.

Non-Lewy PAF as Premotor Multiple System Atrophy

prodromal_msa_paf ALTERNATIVE

Evidence balance 4 support

A minority of patients diagnosed with PAF have a preganglionic lesion without the postganglionic noradrenergic lesion: higher supine norepinephrine, normal cardiac sympathetic imaging, preserved smell, younger onset, severe bladder failure, raised CSF neurofilament light chain and an MSA-like seeding profile. These patients are in the premotor phase of MSA rather than having a peripheral Lewy body disease.

Pathograph links

Preganglionic Lesion Without Postganglionic Lewy Pathology -> Preganglionic Intermediolateral Column Neuron Loss INDIRECT UNKNOWN INTERMEDIATES

Preganglionic Lesion Without Postganglionic Lewy Pathology -> Spread to Central Nervous System (Phenoconversion) INDIRECT UNKNOWN INTERMEDIATES

Show evidence (4 references)

PMID:34669076 SUPPORT REVIEW SYNTHESIS Human clinical

"Conversely, PAF without these features leaves open the possibility of premotor MSA."

Defines the non-Lewy form as possible premotor MSA.

PMID:28202694 SUPPORT Human clinical

"Several variables were identified to predict conversion to MSA: (1) mild degree of cardiovagal impairment, (2) preganglionic pattern of sweat loss, (3) severe bladder dysfunction, (4) supine norepinephrine >100 pg/mL, and (5) subtle motor signs at first presentation."

Clinical and biochemical profile of PAF patients who convert to MSA.

PMID:33881777 SUPPORT Human clinical

"NfL at baseline was elevated only in patients who later developed MSA, perfectly separating those from future PD and DLB converters as well as non-converters."

CSF NfL distinguishes future MSA converters.

+ 1 more reference

Catecholaldehyde (DOPAL) Autotoxicity as the Trigger for Aggregation

catecholaldehyde_autotoxicity EMERGING

Evidence balance 2 support 1 no evidence

Aggregation in PAF is not the first event. On this account the initiating step is a shift of dopamine from vesicular stores into the cytoplasm, where monoamine oxidase produces the autotoxic aldehyde DOPAL; DOPAL then oligomerizes alpha-synuclein, and the oligomers further degrade vesicular storage, forming a positive feedback loop that destroys the neuron over a long preclinical period. The hypothesis is attractive for PAF because it explains the cell-type selectivity of the lesion, and because the vesicular storage defect it requires is independently measured in PAF patients. What is missing is any measurement of DOPAL in PAF neurons, and testing in animals has been obstructed by the secondary effects of the drugs used to manipulate the pathway. It is recorded as EMERGING for that reason, and the edges belonging to it are tagged so they can be read separately from the canonical chain.

Pathograph links

Catecholaldehyde (DOPAL) Autotoxicity in Noradrenergic Neurons -> Peripheral Autonomic Alpha-Synuclein Aggregation INDIRECT UNKNOWN INTERMEDIATES DOPAL oligomerizes and quinonizes alpha-synuclein, which is proposed as the proximate chemical cause of aggregation in catecholaminergic neurons. The steps between an oligomer formed in vitro and a Lewy body in a human sympathetic ganglion are not established.

Noradrenergic Vesicular Storage and Synthesis Defect -> Catecholaldehyde (DOPAL) Autotoxicity in Noradrenergic Neurons INDIRECT UNKNOWN INTERMEDIATES Failing vesicular sequestration returns dopamine to the cytoplasm, where monoamine oxidase converts it to DOPAL, so the storage defect feeds the autotoxic step that is proposed to have caused it. This closes a self-reinforcing loop rather than adding a one-way step, and the loop is the form in which the catecholaldehyde hypothesis is stated. The vesicular defect is measured in PAF patients; its consequence for DOPAL levels in those patients is not.

Show evidence (3 references)

PMID:34206133 SUPPORT INDIRECT REVIEW SYNTHESIS In vitro / ex vivo

"DOPAL potently oligomerizes αS, and αS oligomers impede vesicular and mitochondrial functions, shifting the fate of cytoplasmic dopamine toward the MAO-catalyzed formation of DOPAL-destabilizing vicious cycles."

Statement of the hypothesis, including the feedback loop that defines it.

PMID:34206133 NO_EVIDENCE REVIEW SYNTHESIS Other

"there has been insufficient testing of the catecholaldehyde hypothesis in animal models"

The author of the hypothesis records that the animal work needed to test it has not been done, which is why this group is EMERGING rather than ALTERNATIVE. Graded NO_EVIDENCE because the sentence reports no animal result in either direction: it says the experiment is missing, not that it was run and the hypothesis failed.

PMID:35621196 SUPPORT INDIRECT Computational

"The model combines cardiac sympathetic activation with autotoxicity mediated by the dopamine metabolite 3,4-dihydroxyphenylacetaldehyde."

A computational model of cardiac noradrenergic decline built on this mechanism reproduces serial 18F-dopamine PET data from Lewy body disease patients, PAF among them. Agreement of a model with data is indirect support for its mechanism.

Sympathetic-Predominant Body-First Origin of the Pathology

sympathetic_body_first_origin EMERGING

Evidence balance 2 support

Where the pathology starts, as distinct from what makes it start. Postmortem staging of Lewy body disease separates cases whose pathology appears first in peripheral autonomic tissue (body-first) from those where it appears first in the olfactory bulb and amygdala (brain-first), and splits the body-first group again into a vagal-predominant and a sympathetic-predominant subtype in roughly equal numbers. A purely peripheral, sympathetically dominated synucleinopathy, which is what PAF is, fits the sympathetic-predominant subtype, and this would make PAF the clinically isolated form of a distribution pattern that is otherwise observed on its way to Parkinson disease or dementia with Lewy bodies. The evidence is autopsy-based and drawn from cohorts classified as incidental Lewy body disease, PD or DLB; no PAF case series has been staged this way, so the alignment is inferred rather than shown.

Show evidence (2 references)

PMID:40082617 SUPPORT INDIRECT PRIMARY RESULT Human clinical

"we identified two distinct body-first subtypes, one with vagal predominance and another with sympathetic predominance, in equal proportions"

Establishes a sympathetic-predominant peripheral-onset subtype in 302 autopsied Lewy-positive cases. None was a PAF case, which is why this is indirect.

PMID:40082617 SUPPORT INDIRECT PRIMARY RESULT Human clinical

"In body-first LBD, isolated Lewy pathology in the sympathetic PNS is frequent, suggesting that the gut-to-sympathetic propagation route is as important as the vagal gut-to-DMV propagation route."

Isolated sympathetic pathology with no central involvement is the anatomical counterpart of the PAF phenotype, and it is common rather than exceptional.

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Discussions and Knowledge Gaps

7

What starts alpha-synuclein aggregating in peripheral autonomic neurons in PAF, and does the catecholaldehyde DOPAL accumulate in those neurons before the aggregates appear?

KNOWLEDGE GAP OPEN paf_what_initiates_aggregation

Attached to

pathophysiology#Catecholaldehyde (DOPAL) Autotoxicity in Noradrenergic Neurons pathophysiology#Peripheral Autonomic Alpha-Synuclein Aggregation mechanistic_hypotheses#catecholaldehyde_autotoxicity

The entry's canonical chain begins at aggregation, and the aggregation node says the initiating trigger is unknown. The catecholaldehyde node upstream of it rests on cell-free chemistry, postmortem tissue from other Lewy body diseases and a computational model; nothing has measured DOPAL, aldehyde dehydrogenase activity or the DOPAC:DOPAL ratio in sympathetic tissue from patients with PAF. The gap matters for more than completeness, because the two interventions the hypothesis implies - inhibiting monoamine oxidase to make less DOPAL, and antioxidant treatment to stop its oxidation - are both available, and PAF is the one Lewy body disease where the affected neurons are accessible by skin and vein biopsy. The author of the hypothesis lists the PAF form of the question explicitly as unanswered.

Proposed experiments

Catecholaldehyde measurement in biopsied sympathetic tissue from PAF patients

paf_dopal_in_accessible_sympathetic_tissue

Quantify DOPAL, DOPAC, the DOPAC:DOPAL ratio and aldehyde dehydrogenase activity in forearm vein and skin biopsies from patients with PAF, from patients with the non-Lewy preganglionic form, and from controls, in the same samples used to assay tyrosine hydroxylase and VMAT2. The vein-biopsy protocol that established the vesicular storage defect in PAF already yields the tissue; what has not been measured is the aldehyde.

Would support

pathophysiology#Catecholaldehyde (DOPAL) Autotoxicity in Noradrenergic Neurons mechanistic_hypotheses#catecholaldehyde_autotoxicity

Would refute

pathophysiology#Catecholaldehyde (DOPAL) Autotoxicity in Noradrenergic Neurons mechanistic_hypotheses#catecholaldehyde_autotoxicity

Supporting outcome

A raised DOPAL level or a lowered DOPAC:DOPAL ratio in PAF sympathetic tissue, tracking the vesicular storage defect in the same samples, would support the autotoxic step acting in this disease rather than only in vitro.

Refuting outcome

Normal DOPAL handling in sympathetic tissue carrying heavy alpha-synuclein deposits would refute the catecholaldehyde step in PAF and leave aggregation as the entry point of the chain.

Longitudinal catecholaldehyde and vesicular-storage markers across phenoconversion

paf_dopal_longitudinal_prodrome

Follow a PAF cohort already undergoing serial cardiac 18F-dopamine PET and CSF seed amplification, adding catecholaldehyde-pathway markers at each visit, to test whether the aldehyde burden moves before or after the storage defect and the seeding signal. The computational model of this mechanism predicts a specific three-phase order, which makes it falsifiable by serial measurement.

Would support

mechanistic_hypotheses#catecholaldehyde_autotoxicity

Would refute

mechanistic_hypotheses#catecholaldehyde_autotoxicity

Supporting outcome

Aldehyde-pathway change preceding measurable loss of vesicular sequestration, in the order the model predicts, would support the loop running in the direction the hypothesis claims.

Refuting outcome

Aldehyde change appearing only after denervation is established would make it a consequence of the lesion rather than its cause.

Reconstruction of the catecholaldehyde loop in human iPSC-derived sympathetic neurons

paf_dopal_loop_in_ipsc_sympathetic_neurons

Impose the aldehyde burden on the cell type this entry is about. Human pluripotent stem cells are differentiated to postganglionic sympathetic neurons, aldehyde dehydrogenase is inhibited to raise DOPAL without adding it from outside, and alpha-synuclein oligomer load, vesicular norepinephrine storage and stimulated norepinephrine release are measured in the same cultures. The existing cell models of the catecholaldehyde step use a neuroblastoma line, mouse cortical neurons or a glial line, and supply DOPAL in the medium, so neither the affected cell type nor the endogenous route to the aldehyde has been tested; these neurons secrete norepinephrine on activation, which is the quantity PAF loses. A patient-derived line is deliberately not the design here. PAF is sporadic with no causal gene, so an unselected patient line carries no lesion to express, which is why the protocol's established use is a Mendelian autonomic disease rather than this one.

Model systems

Human iPSC-derived postganglionic sympathetic neurons

Sympathetic neurons differentiated from human pluripotent stem cells by way of neural crest, maintained as monocultures or co-cultured with iPSC-derived cardiomyocytes. They carry tyrosine hydroxylase, fire action potentials, secrete norepinephrine on stimulation, and in co-culture drive the beating rate of the myocytes they innervate, so the noradrenergic functions this entry's nodes describe are all directly measurable.

IPSC DERIVED MODEL PMID:32822546 link

human NCBITaxon:9606

iPSC-derived postganglionic sympathetic neuron CL:3000002

Pathograph links

Catecholaldehyde (DOPAL) Autotoxicity in Noradrenergic Neurons measures fidelity: moderate observes: cellular Supplies the cell type the node names, so the aldehyde burden, the oligomer load and the storage defect can be measured in one system and in the right neuron rather than inferred across three unrelated ones.

Limitations: These neurons are weeks old and were never exposed to whatever initiates the disease, so a loop demonstrated in them shows the mechanism can run in a human sympathetic neuron, not that it is what runs in a patient.

Divergences from the human mechanism

cause unrepresented qualifying

PAF has no causal lesion to encode, so the aldehyde burden has to be imposed pharmacologically by inhibiting aldehyde dehydrogenase. The model therefore tests whether the loop can run, and cannot establish that it starts this way in the disease.

temporal scope qualifying

A culture runs for weeks against a disease that takes decades and whose own progression node is measured in years of serial imaging, so an acute aldehyde challenge stands in for chronic accumulation.

boundary omission immaterial

Preganglionic input, the baroreflex arc and the vasculature are outside the model. Immaterial to this experiment, whose claims are confined to events inside the postganglionic neuron.

Readouts

Intraneuronal DOPAL and DOPAC to DOPAL ratio after aldehyde dehydrogenase inhibition

pathophysiology#Catecholaldehyde (DOPAL) Autotoxicity in Noradrenergic Neurons

Direction: INCREASED

Interpretation: Confirms the intended perturbation was achieved from the cell's own dopamine rather than supplied from outside, which is what the existing cell models cannot show.

Alpha-synuclein oligomer load in sympathetic neurons

pathophysiology#Peripheral Autonomic Alpha-Synuclein Aggregation

Direction: INCREASED

Interpretation: Tests whether an endogenously generated aldehyde burden is sufficient to aggregate alpha-synuclein in the cell type that aggregates it in patients.

Vesicular norepinephrine content and stimulated release

pathophysiology#Noradrenergic Vesicular Storage and Synthesis Defect

Direction: DECREASED

Interpretation: The return arm of the loop, measured as the function PAF loses rather than as dopamine leak from a vesicle preparation.

Decision criterion

The three readouts are read in order. An aldehyde rise followed by oligomer accumulation followed by loss of vesicular storage establishes that the loop can run in a human sympathetic neuron. An aldehyde rise with no oligomer accumulation places the burden of the hypothesis back on the cell-free chemistry.

Would support

pathophysiology#Catecholaldehyde (DOPAL) Autotoxicity in Noradrenergic Neurons mechanistic_hypotheses#catecholaldehyde_autotoxicity

Would refute

pathophysiology#Catecholaldehyde (DOPAL) Autotoxicity in Noradrenergic Neurons mechanistic_hypotheses#catecholaldehyde_autotoxicity

Supporting outcome

Oligomer accumulation and loss of vesicular norepinephrine storage following an endogenously generated aldehyde burden, in human sympathetic neurons, would move the catecholaldehyde step off cell-free chemistry and out of the wrong cell types for the first time.

Refuting outcome

A raised aldehyde burden that leaves alpha-synuclein unaggregated and storage intact in the cell type the hypothesis is about would weigh against the step, and would suggest the oligomerisation seen in neuroblastoma and glial lines depends on conditions those systems impose.

Posed by dismech curation (PR #15556) Posed 2026-10-26T00:00:00Z

Show evidence (2 references)

PMID:34206133 SUPPORT REVIEW SYNTHESIS Other

"Do DOPAL and αS ascend together in the periphery in “body-first” PD or PAF?"

The review poses this PAF-specific question in its own list of what the field does not know, which is the gap recorded here.

PMID:34206133 SUPPORT REVIEW SYNTHESIS Other

"The extent to which DOPAL toxicity is mediated by interactions with αS, and vice versa, is poorly understood."

States that the direction of causation between the two upstream nodes is unsettled.

Can alpha-synuclein aggregates taken from human peripheral sympathetic ganglia actually seed and propagate pathology, as the mouse fibril-injection model of PAF assumes?

HUMAN MODEL MISMATCH OPEN paf_peripheral_aggregate_seeding_mismatch

Attached to

pathophysiology#Peripheral Autonomic Alpha-Synuclein Aggregation pathophysiology#Spread to Central Nervous System (Phenoconversion) animal_models#Mouse

The animal model in this entry seeds pathology by injecting synthetic preformed fibrils into the ganglia of mice overexpressing mutant human alpha-synuclein, and the pathology then spreads along autonomic pathways into the central nervous system. That result is the main experimental support for the phenoconversion node. But when Lewy-body aggregates purified from the stellate ganglia of Parkinson disease patients were inoculated into mouse brain, they produced neither pathology nor degeneration, while aggregates from the same patients' substantia nigra did. So the seeding competence demonstrated in the model may be a property of synthetic fibrils in a transgenic host rather than of the human peripheral aggregate the model stands for. This is a mismatch rather than a missing experiment: evidence exists on both sides and points in opposite directions, and what is unresolved is whether the human peripheral aggregate propagates at all.

Proposed experiments

Seeding competence of PAF-derived ganglionic aggregates

paf_ganglion_aggregate_seeding_competence

Purify alpha-synuclein aggregates from sympathetic ganglia of autopsy-confirmed PAF cases, rather than from Parkinson disease cases or from synthetic fibrils, and test them both in seed amplification assays and by inoculation into the ganglia of wild-type and TgM83 mice. The published negative result used Parkinson disease stellate ganglia and inoculated the brain, so it leaves the PAF aggregate and the peripheral route untested.

Would support

pathophysiology#Spread to Central Nervous System (Phenoconversion)

Would refute

pathophysiology#Spread to Central Nervous System (Phenoconversion)

Supporting outcome

Pathology propagating from the injected ganglion in a wild-type host would support peripheral-to-central spread as a mechanism of phenoconversion in PAF, independent of transgene overexpression.

Refuting outcome

A PAF-derived aggregate that seeds in vitro but propagates in no host would make the model's spread result an artefact of synthetic fibrils and would leave phenoconversion unexplained by propagation.

Posed by dismech curation (PR #15556) Posed 2026-10-26T00:00:00Z

Show evidence (3 references)

PMID:29422109 REFUTE PRIMARY RESULT Model organism

"intracerebral inoculation of SG-derived LB into mice did not trigger long-term nigrostriatal neurodegeneration nor α-synuclein pathology"

Human sympathetic-ganglion aggregates failed to seed, in the same assay in which nigral aggregates from the same patients succeeded.

PMID:29422109 REFUTE PRIMARY RESULT Model organism

"Our results argue against a putative pathogenic capacity of peripheral α-synuclein aggregates to promote α-synuclein pathology in the brain, propagate between neuronal networks or induce neurodegeneration."

The authors' own reading of the negative result, which contradicts what the fibril-injection model is taken to show about peripheral-to-central spread.

PMID:32071315 SUPPORT Model organism

"induces spreading of α-Syn pathology only through the autonomic pathway to both the central nervous system (CNS) and the autonomic innervation of peripheral organs bidirectionally"

The other side of the mismatch: synthetic fibrils in the transgenic host do spread.

Has any environmental, occupational or lifestyle exposure been studied as a risk factor for pure autonomic failure?

KNOWLEDGE GAP no_exposure_epidemiology

Attached to

environmental#

This entry carries no environmental section because no exposure study of this disease was found, not because exposures were judged irrelevant. A deep-research sweep of exposure epidemiology across the alpha-synucleinopathies returned substantial literature for Parkinson disease, a single unreplicated case-control study for multiple system atrophy, one multicentre case-control study for isolated REM sleep behaviour disorder and one for dementia with Lewy bodies, and nothing at all for this disease. The gap matters because the exposure findings that do exist do not agree with one another across these diseases: smoking is inversely associated with Parkinson disease, positively associated with isolated REM sleep behaviour disorder and null in dementia with Lewy bodies, and occupational pesticide exposure is positive in Parkinson disease and null in multiple system atrophy under a formal job-exposure matrix. Nothing can therefore be inferred about this disease from its neighbours, and an exposure profile for a condition whose pathology is largely restricted to the peripheral autonomic nervous system would bear directly on whether peripheral-onset disease has a distinct trigger.

Recorded as an absence of evidence rather than as evidence of absence. The searches run were disease-named exposure queries across the synucleinopathies; a dedicated search strategy for this disease, including its synonyms and the older Bradbury-Eggleston designation, has not been run and might surface case series that a cross-disease sweep missed.

Is the noradrenergic failure of PAF carried by surviving neurons that can no longer synthesise or sequester norepinephrine, rather than by loss of those neurons, and does a functional phase precede denervation widely enough to leave anything to rescue?

KNOWLEDGE GAP OPEN paf_functional_deficit_versus_neuronal_loss

Attached to

pathophysiology#Noradrenergic Vesicular Storage and Synthesis Defect pathophysiology#Postganglionic Sympathetic Noradrenergic Denervation mechanistic_hypotheses#catecholaldehyde_autotoxicity

This entry carries both answers and does not choose between them. The denervation node asserts loss of postganglionic sympathetic neurons, while the synthesis and storage node closes by saying sympathetic dysfunction may precede frank denervation - a hedge sitting in a description rather than a recorded question. The two rest on measurements in different tissues. The forearm vein biopsy that found normal norepinephrine transporter abundance alongside very low tyrosine hydroxylase samples a peripheral vein, whereas the 18F-dopamine PET showing lost tracer uptake images the myocardium. Normal transporter in one territory and lost uptake in another is as consistent with regional heterogeneity as with a lesion in living neurons, and this entry cites no study that makes both measurements in the same patients. What hangs on it is whether there is a target at all: a neuron surviving with a synthetic and vesicular deficit can be treated, and a lost one cannot. The question also bears on the catecholaldehyde hypothesis, whose loop requires the vesicular defect to arise in a neuron that is still alive to be damaged by it.

Proposed experiments

Paired sympathetic nerve protein panel and cardiac 18F-dopamine PET in the same patients

paf_paired_vein_biopsy_and_cardiac_pet

Quantify norepinephrine transporter, tyrosine hydroxylase and VMAT2 protein in a forearm vein biopsy, and measure cardiac 18F-dopamine uptake at 8 minutes with the 8-to-25-minute washout slope, in the same patients with PAF at the same visit, and repeat after two years. Pairing the two in one person is what neither existing study does, and it separates the two readings: a functional lesion predicts preserved transporter with preserved uptake and an accelerated washout, while regional independence predicts lost uptake in a patient whose transporter abundance is normal.

Would support

pathophysiology#Noradrenergic Vesicular Storage and Synthesis Defect

Would refute

pathophysiology#Noradrenergic Vesicular Storage and Synthesis Defect

Supporting outcome

Preserved transporter abundance together with preserved 8-minute uptake and an accelerated washout slope in the same patient would place the early lesion in surviving neurons, as a synthesis and sequestration failure rather than as denervation, and would make the deficit a treatment target.

Refuting outcome

Low 8-minute uptake alongside normal transporter abundance in the same patient would show the two measurements report different territories, leaving the storage and synthesis defect unable to account for the systemic norepinephrine deficit the entry attributes to it.

Posed by dismech curation Posed 2026-10-27T00:00:00Z

Show evidence (3 references)

PMID:32372682 SUPPORT INDIRECT REVIEW SYNTHESIS Human clinical

"functional abnormalities in extant residual neurons contribute to the neurotransmitter deficiencies"

States the position this gap asks about, for Lewy body diseases as a class rather than for PAF specifically, which is why it is indirect.

PMID:32372682 SUPPORT INDIRECT REVIEW SYNTHESIS Human clinical

"There is also recent evidence that at least one dysfunction, a vesicular storage defect, is an early abnormality that can precede overt neuronal loss"

The precedence claim on which a treatable window would depend. The cited observation is in Lewy body disease cohorts that included PAF, not in PAF alone.

PMID:29162745 SUPPORT Human clinical

"The finding of normal NET abundance in PAF suggests intact sympathetic nerves but with reduced NE synthesis."

The PAF-specific reading of the vein biopsy, and the one measurement in the entry that argues the nerves are present rather than gone.

Does a stable, purely peripheral PAF exist, or would every case phenoconvert given long enough follow-up?

KNOWLEDGE GAP OPEN paf_is_nonconverting_paf_a_distinct_entity

Attached to

progression#Phenoconversion to a central synucleinopathy mechanistic_hypotheses#lewy_body_paf mechanistic_hypotheses#sympathetic_body_first_origin

The entry records the conversion rate well - about 30 percent of patients, a pooled 5.09 per 100 person-years, with MSA clustering in the first years while Lewy body disorders arrive at a steadier rate. What it cannot say is what the other 70 percent are. If the Lewy body rate is genuinely constant, a cohort followed long enough would see most of them convert, and PAF would be a stage of a central synucleinopathy rather than a disease with an endpoint of its own. The meta-analysis reports that heterogeneity between studies was partly explained by follow-up duration, which is the signature of censoring rather than of a biologically distinct group that never converts. The alternative is that some patients carry a peripherally restricted lesion that never ascends, which is what the sympathetic-predominant body-first hypothesis would predict for a subset, and which the autopsy series behind that hypothesis observed in people who had not been diagnosed with anything. No cohort in this entry distinguishes the two readings, and they differ in what a prognosis should say to a patient diagnosed today.

Proposed experiments

Autopsy-anchored follow-up of long-standing non-converters

paf_long_horizon_nonconverter_cohort

Follow patients who have carried a PAF diagnosis for more than ten years without motor or cognitive signs until death, with brain and peripheral autonomic autopsy, and compare their alpha-synuclein distribution with that of converters and with the incidental Lewy body cases staged as sympathetic-predominant. Clinical follow-up alone cannot settle this, because a patient who dies without motor signs may still carry central pathology; only the autopsy distinguishes a lesion that never ascended from one that ascended without becoming symptomatic.

Would support

mechanistic_hypotheses#sympathetic_body_first_origin

Would refute

mechanistic_hypotheses#sympathetic_body_first_origin

Supporting outcome

Long-standing non-converters whose pathology at autopsy remains confined to peripheral sympathetic tissue would establish a peripherally restricted form, and would make PAF a disease with its own endpoint rather than a stage.

Refuting outcome

Central Lewy pathology in clinically pure long-standing cases would show that ascent is the rule and that non-conversion is a statement about symptoms rather than about distribution, leaving PAF a prodromal stage in every case.

Posed by dismech curation Posed 2026-10-27T00:00:00Z

Show evidence (2 references)

PMID:42081229 SUPPORT REVIEW SYNTHESIS Human clinical

"Heterogeneity was partly explained by follow-up duration."

The meta-analysis attributes part of the between-study spread in conversion rate to how long each cohort was watched, which is what makes censoring the leading explanation for the non-converting majority.

PMID:28093795 SUPPORT Human clinical

"Within 4 years of follow-up, 25 of 74 subjects (34%) developed dementia with Lewy bodies (n = 13), Parkinson disease (n = 6), or multiple system atrophy (n = 6)."

Establishes the scale of the unexplained group: two thirds of this cohort had not converted, over a horizon too short to tell a stable form from an unfinished one.

Can treatment given during the peripheral phase of PAF prevent phenoconversion, and is the peripheral lesion still the right target by the time PAF is diagnosed?

KNOWLEDGE GAP OPEN paf_can_the_prodromal_window_be_intercepted

Attached to

treatments#No Disease-Modifying Therapy pathophysiology#Spread to Central Nervous System (Phenoconversion)

Every treatment in this entry is symptomatic, and the entry records that nothing slows progression or phenoconversion. The field's stated plan is to use PAF as a prodromal population and biomarkers to select who enters a disease-modification trial. Two things already in this entry argue that the target may be wrong. By the time PAF is diagnosed the postganglionic noradrenergic lesion is severe - plasma norepinephrine is very low and cardiac tracer uptake largely gone - so a therapy meant to protect peripheral neurons arrives after most of them are affected, which is the same question the functional-versus-structural gap asks. And a therapy aimed instead at preventing ascent targets propagation, the step this entry's HUMAN_MODEL_MISMATCH discussion records as unproven in PAF, since aggregates from human peripheral tissue failed to seed and only synthetic fibrils spread in the transgenic host. So the prodromal window here is defined clinically, by the absence of motor and cognitive signs, and not by the presence of neurons left to save or of a propagation step shown to occur. Which of the two a trial should target is open, and the choice decides what the endpoint and the enrolment window should be.

Proposed experiments

Biomarker-stratified prevention trial with phenoconversion as the endpoint

paf_biomarker_stratified_prevention_trial

Enrol patients with PAF stratified by the markers this entry already records as predicting the conversion target - supine norepinephrine, cardiac 18F-dopamine pattern, CSF neurofilament light chain and seed amplification - and randomise to an alpha-synuclein-directed agent or placebo with phenoconversion as the primary endpoint. Stratification is not a refinement here but the design: the entry's two subtype hypotheses predict different conversion targets on different timescales, so an unstratified trial pools patients whose event rates and mechanisms differ.

Would support

pathophysiology#Spread to Central Nervous System (Phenoconversion)

Would refute

pathophysiology#Spread to Central Nervous System (Phenoconversion)

Supporting outcome

A reduction in phenoconversion under an alpha-synuclein-directed agent would establish propagation as both real and interruptible in PAF, which no model result currently shows for human peripheral aggregates.

Refuting outcome

No effect on phenoconversion despite engagement of the target would favour central disease arising independently of peripheral spread, and would leave the entry's phenoconversion node without its proposed mechanism.

Posed by dismech curation Posed 2026-10-27T00:00:00Z

Show evidence (3 references)

PMID:42081229 SUPPORT REVIEW SYNTHESIS Other

"providing an invaluable opportunity for early diagnosis and intervention"

The field's statement of the interception plan. Graded OTHER because the sentence is the authors' recommendation rather than a result their analysis measured.

PMID:37843677 SUPPORT Human clinical

"This capability could refine eligibility criteria for entry into disease-modification trials aimed at preventing evolution of PAF to symptomatic central LBDs."

Names preventing evolution to central disease as the intended endpoint, which is the propagation step whose occurrence in PAF is unproven.

PMID:32372682 SUPPORT INDIRECT REVIEW SYNTHESIS Other

"The discovery of specific paths mediating the sick-but-not-dead phenomenon offers novel targets for multi-pronged therapeutic approaches."

States the competing target - the functional deficit in surviving neurons rather than propagation. Graded OTHER as a forward-looking proposal, not a result.

What genetic contribution does PAF have, given that it is consistently described as sporadic and has never been subject to an association study?

KNOWLEDGE GAP OPEN paf_genetic_contribution_to_a_sporadic_disease

Attached to

disease#Pure Autonomic Failure pathophysiology#Peripheral Autonomic Alpha-Synuclein Aggregation

This entry has no genetic section, and that is a decision rather than an omission: the reviews describe PAF as sporadic, and SNCA appears on pathophysiology nodes as the gene of the aggregating protein rather than as a cause. But sporadic is a statement about family history, not about susceptibility, and the related synucleinopathies have common-variant architecture that PAF has not been tested for. A PubMed search for a genome-wide association study of pure autonomic failure returns no records (searched 2026-10-27, pure autonomic failure AND genome-wide association, 0 records; the eleven hits for a broader genetic-association query are reviews, other diseases, or unrelated). The genetic evidence that does touch the PAF phenotype comes from rare monogenic families rather than from PAF cohorts: SNCA triplication produces the cardiac noradrenergic lesion, and E46K carriers include people whose clinical diagnosis is PAF. So whether PAF carries risk alleles, whether GBA or SNCA variants shift which central disease a patient converts to, and whether the non-Lewy preganglionic form has a different architecture are all untested rather than answered. This is a resource gap, not a conceptual one, and it is recorded so the absence is not read as a negative result.

Proposed experiments

Genotyping of PAF cohorts against synucleinopathy risk architecture

paf_targeted_and_genome_wide_genotyping

Genotype the existing multicentre PAF cohorts, which are already assembled for phenoconversion follow-up, for the common variants established in Parkinson disease and dementia with Lewy bodies and for GBA and SNCA, and test both for association with the PAF diagnosis and for association with the conversion target within the cohort. PAF is too rare for a well-powered genome-wide study of its own, so the tractable question is whether known synucleinopathy risk loci are enriched and whether they stratify conversion, which the follow-up data already collected would answer.

Would support

pathophysiology#Peripheral Autonomic Alpha-Synuclein Aggregation

Would refute

pathophysiology#Peripheral Autonomic Alpha-Synuclein Aggregation

Supporting outcome

Enrichment of established synucleinopathy risk alleles in PAF would place the peripheral aggregation lesion inside the same susceptibility architecture as the central Lewy body diseases, and a genotype that predicted the conversion target would give the two subtype hypotheses a genetic correlate.

Refuting outcome

No enrichment at loci well established in Parkinson disease and dementia with Lewy bodies would argue the peripheral form has a distinct susceptibility architecture, and would weaken reading PAF as the peripheral presentation of the same disease process.

Posed by dismech curation Posed 2026-10-27T00:00:00Z

Show evidence (3 references)

PMID:34392300 SUPPORT REVIEW SYNTHESIS Human clinical

"PAF is a sporadic peripheral autonomic neurodegenerative disease that belongs to the group of disorders known as alpha-synucleinopathies."

The sporadic classification this gap starts from, which concerns family history and leaves susceptibility untouched.

PMID:29508456 SUPPORT INDIRECT REVIEW SYNTHESIS Human clinical

"SNCA mutations and multiplications, LRRK2 disease with Lewy bodies as well as other common, sporadic forms of idiopathic PD, MSA, pure autonomic failure, and dementia with Lewy bodies have all been associated with dysautonomia."

Places PAF on the sporadic side of a review whose genetic cases are monogenic families, which is the shape of the available evidence rather than of PAF itself.

PMID:31178336 SUPPORT INDIRECT Human clinical

"We studied 7 E46K-SNCA carriers (3 dementia with Lewy bodies, 2 pure autonomic failure, 1 PD and 1 asymptomatic)"

A monogenic lesion producing the PAF phenotype in two carriers, which shows a genetic route to this phenotype exists while saying nothing about sporadic PAF.

⚙

Pathophysiology

19

Catecholaldehyde (DOPAL) Autotoxicity in Noradrenergic Neurons

Mechanism confidence: Hypothetical

Dopamine that leaks from storage vesicles into the neuronal cytoplasm is deaminated by monoamine oxidase to 3,4-dihydroxyphenylacetaldehyde (DOPAL), an obligate intermediate of dopamine metabolism normally detoxified by aldehyde dehydrogenase. DOPAL binds covalently to the lysine-rich alpha-synuclein molecule and oligomerizes it far more efficiently than dopamine itself does, and the resulting oligomers impair vesicular storage, returning more dopamine to the cytoplasm. This is the catecholaldehyde hypothesis, and it is the step put forward to explain why alpha-synuclein precipitates in catecholaminergic neurons rather than elsewhere. It is placed upstream of aggregation on in vitro, postmortem and computational grounds only: DOPAL has not been measured in sympathetic neurons of living patients, and whether it accumulates in PAF specifically is unresolved.

Catecholaldehyde (DOPAL) Autotoxicity as the Trigger for Aggregation

sympathetic noradrenergic neuron CL:3000002

monoamine oxidase-catalysed deamination of cytoplasmic dopamine GO:0042420 ↑ INCREASED

Experimental models

DOPAL challenge in BE(2)-M17 neuroblastoma cells and primary cortical neurons CELL LINE DOPAL is applied to intact cells and the covalent alpha-synuclein oligomers this node describes are then recovered from inside them, so the node's chemistry is demonstrated in a cellular context rather than only in a tube.

MO3.13 oligodendrocyte and PC12 catecholaldehyde transfer co-culture CO CULTURE Shows the aldehyde crossing from a catecholamine-synthesising cell into a recipient that makes none, and oligomerising alpha-synuclein once inside, so the oligomerising step this node asserts does not require the aldehyde to be made in the same cell.

Downstream

Peripheral Autonomic Alpha-Synuclein Aggregation DOPAL oligomerizes and quinonizes alpha-synuclein, which is proposed as the proximate chemical cause of aggregation in catecholaminergic neurons. The steps between an oligomer formed in vitro and a Lewy body in a human sympathetic ganglion are not established.

Show evidence (3 references)

PMID:34206133 SUPPORT INDIRECT REVIEW SYNTHESIS In vitro / ex vivo

"The catecholaldehyde is produced via oxidative deamination catalyzed by monoamine oxidase (MAO) acting on cytoplasmic dopamine. DOPAL is autotoxic, in that it can harm the same cells in which it is produced."

States the biochemical route to DOPAL and its autotoxicity. Indirect for PAF: the chemistry is established in vitro and in animal tissue, not in patients.

PMID:34206133 SUPPORT INDIRECT REVIEW SYNTHESIS In vitro / ex vivo

"tends to precipitate in catecholaminergic neurons in Lewy body diseases, because DOPAL potently oligomerizes, quinonizes, and aggregates"

This is the reason the node exists: it offers a mechanism for the cell-type selectivity of the aggregation that PAF shares with the other Lewy body diseases.

PMID:31744850 SUPPORT INDIRECT PRIMARY RESULT In vitro / ex vivo

"DOPAL was far more potent than DA both in oligomerizing and forming quinone-protein adducts with (quinonizing) AS."

Cell-free and cultured-cell comparison establishing that the DOPAL route, not spontaneous dopamine oxidation, is the efficient one. No patient tissue involved.

Peripheral Autonomic Alpha-Synuclein Aggregation

Misfolded, phosphorylated alpha-synuclein accumulates as Lewy bodies and Lewy neurites predominantly in peripheral autonomic neurons: sympathetic ganglion neurons and their distal axons in the heart, adrenal region, bladder and skin. CSF seeding assays are positive in nearly all patients, and cutaneous phosphorylated alpha-synuclein is found at every biopsy site. The initiating trigger is unknown. A rare clinically diagnosed case without any synuclein pathology shows that the clinical label is not always a synucleinopathy.

Lewy-Body PAF with Postganglionic Noradrenergic Lesion

sympathetic noradrenergic neuron CL:3000002

SNCA hgnc:11138

inclusion body assembly GO:0070841

sympathetic ganglion UBERON:0001806

Animal models

Ganglionic alpha-synuclein fibril injection in TgM83 mice Mouse partially recapitulates Autonomic-restricted alpha-synuclein pathology with autonomic failure and no motor signs, the defining features of PAF.

Downstream

Postganglionic Sympathetic Noradrenergic Denervation Synuclein-laden postganglionic neurons degenerate; the steps from aggregation to neuronal loss are not resolved in PAF.

Noradrenergic Vesicular Storage and Synthesis Defect

Preganglionic Intermediolateral Column Neuron Loss

Sudomotor Sympathetic Cholinergic Denervation

Pelvic Visceral Autonomic Denervation

Cardiovagal Parasympathetic Impairment

Subclinical Central Catecholaminergic Involvement

Show evidence (7 references)

PMID:34392300 SUPPORT REVIEW SYNTHESIS Human clinical

"Pure autonomic failure (PAF) is a peripheral autonomic neurodegenerative disease caused by alpha-synuclein deposition that is predominantly confined to peripheral autonomic neurons."

Review defining PAF as a peripherally confined alpha-synucleinopathy.

PMID:9255396 SUPPORT Human clinical

"Postmortem findings included typical and atypical Lewy bodies in the substantia nigra, locus ceruleus, substantia innominata, and sympathetic ganglia, as well as in autonomic axons in the epicardial fat, autonomic nerve fascicles in periadrenal adipose tissue, and autonomic nerves in the..."

Autopsy showing Lewy bodies in sympathetic ganglia and distal autonomic axons.

PMID:33881777 SUPPORT Human clinical

"αSyn-PMCA is almost invariably positive in the CSF of patients with PAF establishing this condition as α-synucleinopathy."

CSF seed amplification establishes aggregated alpha-synuclein in vivo.

+ 4 more references

Preganglionic Lesion Without Postganglionic Lewy Pathology

In the minority of patients whose PAF is the premotor phase of MSA, the preganglionic autonomic lesion is not accompanied by postganglionic noradrenergic Lewy pathology. In MSA, insoluble alpha-synuclein is deposited in glia rather than as neuronal Lewy bodies. These patients have higher supine norepinephrine, a preganglionic pattern of sweat loss, severe bladder dysfunction and raised CSF neurofilament light chain, and they go on to MSA.

Non-Lewy PAF as Premotor Multiple System Atrophy

Downstream

Preganglionic Intermediolateral Column Neuron Loss

Spread to Central Nervous System (Phenoconversion)

Show evidence (2 references)

PMID:24095130 SUPPORT REVIEW SYNTHESIS Human clinical

"Insoluble deposits of α-synuclein are found in glia in MSA, whereas they take the form of neuronal cytoplasmic inclusions called Lewy bodies in PAF and PD."

Contrasts the glial synucleinopathy of MSA with neuronal Lewy bodies in PAF.

PMID:34669076 SUPPORT REVIEW SYNTHESIS Human clinical

"Conversely, PAF without these features leaves open the possibility of premotor MSA."

PAF lacking the postganglionic Lewy lesion may be premotor MSA.

Preganglionic Intermediolateral Column Neuron Loss

Sympathetic preganglionic neurons in the thoracic intermediolateral cell column are lost alongside the ganglionic lesion, removing central drive to the sympathetic ganglia. Both pathological forms of PAF are thought to involve this preganglionic lesion.

sympathetic preganglionic neuron CL:0000107

Downstream

Failure of Baroreflex-Mediated Vasoconstriction

Show evidence (3 references)

PMID:9255396 SUPPORT Human clinical

"characterized by autonomic failure without other neurological deficits and histopathologically by cell loss in intermediolateral columns and sympathetic ganglia"

Neuropathological hallmark of preganglionic and ganglionic cell loss.

PMID:27338613 SUPPORT REVIEW SYNTHESIS Human clinical

"Autonomic failure in PAF is caused by neuronal degeneration of pre- and postganglionic sympathetic and parasympathetic neurons in the thoracic spinal cord and paravertebral autonomic ganglia."

Review locating the lesion in pre- and postganglionic autonomic neurons.

PMID:34669076 SUPPORT REVIEW SYNTHESIS Human clinical

"Both PAF phenotypes involve a sympathetic preganglionic lesion, but only Lewy body PAF, PD, and DLB entail a postganglionic noradrenergic lesion."

The preganglionic lesion is shared by Lewy and non-Lewy forms of PAF.

Postganglionic Sympathetic Noradrenergic Denervation

Postganglionic sympathetic noradrenergic terminals are lost from the heart, renal cortex, blood vessels and skin. Cardiac 18F-dopamine and 11C-methylreboxetine PET show reduced noradrenergic innervation, and skin biopsy shows marked postganglionic denervation of autonomic adnexa, in contrast to the largely preserved peripheral innervation of MSA. Denervation is accompanied by length-dependent somatic and autonomic small-fibre loss.

sympathetic noradrenergic neuron CL:3000002

heart UBERON:0000948

Downstream

Deficient Sympathetic Norepinephrine Release

Cardiac Sympathetic Denervation

Adrenoceptor Denervation Supersensitivity

Sympathetic Deprivation with Blunted Erythropoietin Response

Sympathetic Pupillary Deficit Loss of sympathetic innervation of the iris dilator produces the pupillary deficit found on pupillometry.

Show evidence (4 references)

PMID:16269589 SUPPORT Human clinical

"Both the PD+OH group and the PAF group had decreased 6-(18)F-fluorodopamine-derived radioactivity in the heart (P < 0.0001) and renal cortex (P = 0.02 and P = 0.005, respectively)."

PET evidence of cardiac and renal sympathetic denervation in PAF.

PMID:32945121 SUPPORT Human clinical

"PAF entails moderately decreased cardiac sympathetic innervation and a substantial vesicular storage defect in residual nerves."

Combined 11C-MRB and 18F-dopamine PET shows moderate denervation.

PMID:20660924 SUPPORT Human clinical

"MSA patients showed a generally preserved skin autonomic innervation with a significantly higher score than PAF patients showing a marked postganglionic sympathetic denervation."

Skin biopsy shows postganglionic denervation in PAF but not MSA.

+ 1 more reference

Noradrenergic Vesicular Storage and Synthesis Defect

Surviving sympathetic terminals store and synthesize norepinephrine poorly. Forearm vein biopsies show normal norepinephrine transporter but very low tyrosine hydroxylase and reduced VMAT2, with a raised plasma DHPG:NE ratio; PET shows rapid loss of 18F-dopamine from residual cardiac nerves. Sympathetic dysfunction may therefore precede frank denervation.

Catecholaldehyde (DOPAL) Autotoxicity as the Trigger for Aggregation

sympathetic noradrenergic neuron CL:3000002

TH hgnc:11782

norepinephrine biosynthetic process GO:0042421 ↓ DECREASED

Experimental models

DOPAL challenge in BE(2)-M17 neuroblastoma cells and primary cortical neurons CELL LINE Catecholamine escaping from storage vesicles is the quantity this node is about, and it is measured here as a consequence of the aldehyde-driven oligomers rather than assumed. That is the return arm of the loop this entry draws between the storage defect and the catecholaldehyde node.

Downstream

Deficient Sympathetic Norepinephrine Release

Catecholaldehyde (DOPAL) Autotoxicity in Noradrenergic Neurons Failing vesicular sequestration returns dopamine to the cytoplasm, where monoamine oxidase converts it to DOPAL, so the storage defect feeds the autotoxic step that is proposed to have caused it. This closes a self-reinforcing loop rather than adding a one-way step, and the loop is the form in which the catecholaldehyde hypothesis is stated. The vesicular defect is measured in PAF patients; its consequence for DOPAL levels in those patients is not.

Show evidence (2 references)

PMID:29162745 SUPPORT Human clinical

"PAF participants were found to have normal abundance of the NE transporter (NET) protein, together with very low levels of tyrosine hydroxylase (TH) (P<0.0001) and reduced vesicular monoamine transporter 2 (VMAT2) (P<0.05) protein expression compared with control and MSA participants."

Molecular evidence of a synthesis and vesicular storage defect in sympathetic nerves.

PMID:32945121 SUPPORT Human clinical

"The PAF patients had five times faster postinfusion loss of 18 F-DA-derived radioactivity (70 ± 3% vs. 14 ± 8% by 30 minutes, p < 0.0001)."

PET evidence of a vesicular storage defect in residual cardiac nerves.

Deficient Sympathetic Norepinephrine Release

Norepinephrine release from sympathetic terminals is profoundly reduced at rest and fails to rise on standing. Very low supine plasma norepinephrine is the biochemical signature of PAF, distinguishing it from MSA, in which postganglionic neurons are largely spared.

norepinephrine secretion, neurotransmission GO:0061533 ↓ DECREASED

Downstream

Failure of Baroreflex-Mediated Vasoconstriction

Decreased circulating norepinephrine

Show evidence (2 references)

PMID:32945121 SUPPORT Human clinical

"Pure autonomic failure (PAF) is a rare disease characterized by neurogenic orthostatic hypotension (nOH), absence of signs of central neurodegeneration, and profound deficiency of the sympathetic neurotransmitter norepinephrine."

Profound norepinephrine deficiency is a defining feature of PAF.

PMID:24095130 SUPPORT REVIEW SYNTHESIS Human clinical

"pure autonomic failure (PAF), characterized by isolated peripheral autonomic dysfunction and decreased norepinephrine synthesis; multiple system atrophy (MSA) with symptoms of a central Parkinson-like syndrome and normal resting plasma norepinephrine"

Contrasts low norepinephrine in PAF with normal resting norepinephrine in MSA.

Failure of Baroreflex-Mediated Vasoconstriction

On standing, the baroreflex cannot increase sympathetic vasoconstrictor outflow or heart rate, so peripheral resistance and venous return fall and blood pressure drops. The heart-rate rise is blunted relative to the fall in blood pressure, which is the physiological signature that separates neurogenic from non-neurogenic orthostatic hypotension.

baroreflex arterial vasoconstriction on standing GO:0001987 ↓ DECREASED

Downstream

Neurogenic Orthostatic Hypotension

Postprandial Hypotension

Chronotropic Incompetence on Tilt

Cerebral and Muscle Hypoperfusion on Standing

Show evidence (2 references)

PMID:29405350 SUPPORT Human clinical

"Patients with neurogenic OH had twice the fall in systolic blood pressure (SBP; -44 ± 25 vs -21 ± 14 mmHg ... p < 0.0001) but only one-third of the increase in HR of those with nonneurogenic OH (8 ± 8 vs 25 ± 11 beats per minute ... p < 0.0001)."

Quantifies the blunted reflex response in synucleinopathy-related nOH, including PAF.

PMID:39608812 SUPPORT INDIRECT Human clinical

"Autonomic p-syn subscores correlated with orthostatic intolerance ratio on tilt (ρ=0.63, p=0.0004), blood pressure recovery time following Valsalva manoeuvre (r=0.44, p=0.03) and patient-reported orthostatic intolerance (ρ=0.57, p=0.006)."

Cutaneous synuclein burden correlates with failed reflex blood pressure control; correlational, not causal.

Cerebral and Muscle Hypoperfusion on Standing

The upright fall in blood pressure lowers cerebral perfusion and perfusion of shoulder-girdle muscles, producing light-headedness, visual disturbance, syncope, fatigue and the suboccipital coat-hanger pain characteristic of autonomic failure. Symptoms are worse in the morning, in heat, after meals and with exertion, and resolve on lying flat.

Downstream

Syncope

Orthostatic Light-Headedness

Orthostatic Visual Disturbance

Coat-Hanger Neck Pain

Orthostatic Chest Pain

Fatigue

Falls

Show evidence (1 reference)

PMID:10552235 SUPPORT Human clinical

"orthostatic hypotension caused symptoms of cerebral hypoperfusion (syncope, dizziness and visual disturbances); neck pain, presumably due to muscle hypoperfusion, also occurred frequently"

Attributes orthostatic symptoms to cerebral and muscle hypoperfusion in PAF and MSA.

Cardiac Sympathetic Denervation

Loss of cardiac sympathetic nerves reduces the chronotropic and inotropic reserve of the heart. Denervated hearts show an impaired inotropic response to tyramine, which depends on endogenous norepinephrine release, and exaggerated responses to the direct beta-agonist isoproterenol.

heart UBERON:0000948

Downstream

Chronotropic Incompetence on Tilt

Resting Bradycardia Hypothesised: loss of cardiac sympathetic tone is the presumed basis of the slow, steady resting heart rate, but no cited source tests the link directly.

Show evidence (2 references)

PMID:18514012 SUPPORT Human clinical

"Among patients with NOH those with cardiac sympathetic denervation have an impaired inotropic response to tyramine and exaggerated responses to isoproterenol."

Functional consequences of cardiac denervation in PAF and PD with nOH.

PMID:41072204 SUPPORT REVIEW SYNTHESIS Human clinical

"Abnormal MIBG scintigraphy was observed in 33 patients (84.6 %)."

Most clinically diagnosed PAF cases show reduced cardiac MIBG uptake.

Adrenoceptor Denervation Supersensitivity

Chronic loss of sympathetic input, combined with loss of baroreflex buffering, makes patients unusually sensitive to small doses of pressor and beta-adrenergic agents. This shapes treatment: norepinephrine replacers work at low doses, while exaggerated pressor responses contribute to supine hypertension on therapy.

Downstream

Supine Hypertension Heightened sensitivity to pressor agents makes treatment-related rises in supine blood pressure likely; this edge describes supine hypertension on therapy, not its untreated cause.

Show evidence (2 references)

PMID:32979782 SUPPORT REVIEW SYNTHESIS Human clinical

"Denervation hypersensitivity and impairment of baroreflex buffering makes these patients sensitive to small doses of pressor agents."

Review describing the clinical pharmacology consequence of denervation.

PMID:18514012 SUPPORT Human clinical

"For similar heart rate responses, the PD+NOH/PAF group required less isoproterenol (p<0.01) and had lower plasma isoproterenol levels (p<0.01) than did the MSA group."

Direct pharmacological evidence of beta-adrenoceptor supersensitivity in denervated hearts.

Supine Hypertension Mechanism

About half of patients have high blood pressure when lying flat despite very low plasma norepinephrine and suppressed renin. Raised angiotensin II and inappropriate mineralocorticoid receptor activation contribute; the full mechanism in PAF is not known.

Downstream

Supine Hypertension

Show evidence (3 references)

PMID:26644241 SUPPORT BACKGROUND Human clinical

"we recently showed that plasma angiotensin II is elevated and acts at AT1 (angiotensin type 1) receptors to contribute to hypertension in these patients"

Elevated angiotensin II contributes to supine hypertension despite suppressed renin.

PMID:26644241 SUPPORT Human clinical

"These findings suggest that inappropriate mineralocorticoid receptor activation contributes to the hypertension of autonomic failure"

Eplerenone crossover study (7 of 10 patients had PAF) implicating mineralocorticoid receptor activation.

PMID:11927799 SUPPORT REVIEW SYNTHESIS Human clinical

"the cause is not known in patients with pure autonomic failure, who have increased vascular resistance despite very low levels or plasma norepinephrine and renin activity"

States that the mechanism in PAF is unresolved.

Supine Pressure Natriuresis

High supine blood pressure overnight drives pressure natriuresis and diuresis, causing nocturia and overnight volume loss that worsens orthostatic hypotension the next morning.

positive regulation of renal sodium excretion by pressure natriuresis GO:0035819

Downstream

Nocturia

Neurogenic Orthostatic Hypotension Overnight volume loss worsens orthostatic hypotension the following morning.

Show evidence (2 references)

PMID:11927799 SUPPORT REVIEW SYNTHESIS Human clinical

"about one half of these patients also suffer from supine hypertension, which induces pressure natriuresis, worsening orthostatic hypotension"

Describes the supine hypertension to natriuresis to orthostatic hypotension loop.

PMID:36601916 SUPPORT Human clinical

"overnight CPAP lowered nighttime systolic blood pressure (maximal change -23±5 versus placebo -1±7 mmHg; P=0.023) and was associated with lower nighttime diuresis (609±84 versus placebo 1004±160 mL; P=0.004) and improved morning orthostatic tolerance"

Lowering nocturnal pressure reduced diuresis and improved morning orthostatic tolerance, supporting the loop.

Sympathetic Deprivation with Blunted Erythropoietin Response

Chronic sympathetic deprivation is associated with an inappropriately low erythropoietin response and a normocytic anemia that further lowers orthostatic tolerance. The evidence comes from primary autonomic failure generally rather than PAF alone.

Downstream

Normocytic Anemia

Show evidence (1 reference)

PMID:8017744 SUPPORT Human clinical

"In seven of nine patients with autonomic failure who had hemoglobin levels less than 120 g/L, serum erythropoietin levels decreased below the 95% confidence interval corresponding to patients with iron deficiency anemia."

Inappropriately low erythropoietin in anemic patients with primary autonomic failure.

Sudomotor Sympathetic Cholinergic Denervation

Postganglionic sympathetic cholinergic fibres to sweat glands carry alpha-synuclein inclusions and degenerate, producing anhidrosis and impaired thermoregulation.

sympathetic cholinergic neuron CL:3000003

Downstream

Anhidrosis

Thermoregulatory Dysfunction

Show evidence (2 references)

PMID:40053259 SUPPORT Human clinical

"Autonomic testing showed moderate to severe autonomic failure with median composite autonomic score of 6 (IQR 4-8; N = 133) and median percentage anhidrosis of 51% (IQR 3-93%; N = 105)."

Quantifies sudomotor failure in patients who retain the PAF phenotype.

PMID:18805037 SUPPORT Human clinical

"In the PAF patients, both SkVR and SSwR were attenuated."

Both sympathetic sweat and skin vasomotor responses are reduced in PAF.

Pelvic Visceral Autonomic Denervation

Sympathetic and parasympathetic innervation of the bladder, bowel and genital organs is affected, with Lewy bodies found in bladder-wall autonomic nerves. This produces bladder dysfunction, constipation and sexual dysfunction, which usually begin close to the onset of orthostatic hypotension.

parasympathetic neuron CL:0011102 sympathetic neuron CL:0011103

Downstream

Urinary Dysfunction

Constipation

Erectile Dysfunction

Show evidence (2 references)

PMID:9255396 SUPPORT Human clinical

"Sites of autonomic nerve involvement correlated with clinical symptomatology"

In the autopsy case with long-standing urinary symptoms, bladder autonomic nerves carried Lewy bodies.

PMID:38129276 SUPPORT REVIEW SYNTHESIS Human clinical

"Although OH is the primary symptom, the autonomic dysfunction may be more generalised, leading to genitourinary and intestinal dysfunction and sweating disorders."

Review describing generalized autonomic involvement beyond the cardiovascular system.

Cardiovagal Parasympathetic Impairment

Parasympathetic cardiac (vagal) control is also impaired, reducing beat-to-beat heart-rate variation. Mild cardiovagal impairment at presentation is instead a predictor of conversion to MSA, so the degree of cardiovagal failure helps separate peripheral Lewy-body PAF from prodromal MSA.

parasympathetic neuron CL:0011102

Downstream

Decreased Heart Rate Variability

Show evidence (3 references)

PMID:27338613 SUPPORT REVIEW SYNTHESIS Human clinical

"Autonomic failure in PAF is caused by neuronal degeneration of pre- and postganglionic sympathetic and parasympathetic neurons in the thoracic spinal cord and paravertebral autonomic ganglia."

Parasympathetic neurons degenerate alongside sympathetic ones.

PMID:18805037 SUPPORT Human clinical

"CV(R-R) was low in the MSA and PAF patients, but a significant difference was found only between the PAF and control groups."

Reduced R-R interval variation in PAF.

PMID:28202694 SUPPORT Human clinical

"Several variables were identified to predict conversion to MSA: (1) mild degree of cardiovagal impairment"

A milder cardiovagal deficit points toward later MSA.

Subclinical Central Catecholaminergic Involvement

Even without motor signs, Lewy pathology and catecholaminergic loss are found in the substantia nigra and locus coeruleus. Nigral dopaminergic denervation is as severe as in Parkinson disease, but striatal terminals are relatively spared, which may explain the absence of parkinsonism. Hyposmia and REM sleep behaviour disorder are the clinical markers of this central involvement.

Lewy-Body PAF with Postganglionic Noradrenergic Lesion

dopaminergic neuron CL:0000700 noradrenergic neuron CL:0008025

Downstream

Hyposmia

REM Sleep Behavior Disorder

Spread to Central Nervous System (Phenoconversion)

Show evidence (3 references)

PMID:18363034 SUPPORT Human clinical

"Surprisingly, PAF and PD entail similarly severe nigral and overall central dopaminergic denervation. There is more severe loss of striatal dopaminergic terminals in PD than in PAF and more severe loss of sympathetic noradrenergic terminals in PAF than in PD."

PET and postmortem evidence of nigral involvement with striatal sparing in PAF.

PMID:39825743 SUPPORT Human clinical

"High-LR PAF patients showed reduced contrast in the LC and SN compared with controls and low-LR PAF patients, with values similar to PD and DLB."

Neuromelanin MRI shows locus coeruleus and nigral loss in PAF patients at high risk of conversion.

PMID:27757562 SUPPORT Human clinical

"the presence of RBD suggests brainstem involvement in some cases of PAF"

RBD indicates brainstem involvement.

Spread to Central Nervous System (Phenoconversion)

In a subset of patients the synucleinopathy becomes clinically manifest in the CNS, and the diagnosis changes to Parkinson disease, dementia with Lewy bodies or multiple system atrophy. Lewy-body PAF with cardiac noradrenergic denervation converts to Lewy body disease, whereas PAF with preserved postganglionic innervation, higher norepinephrine and an MSA-like CSF seeding profile converts to MSA. RBD is the strongest clinical predictor of any conversion.

Animal models

Ganglionic alpha-synuclein fibril injection in TgM83 mice Mouse partially recapitulates Pathology spreads from autonomic ganglia to the central nervous system.

Show evidence (4 references)

PMID:28093795 SUPPORT Human clinical

"The presence of probable rapid eye movement (REM) sleep behavior disorder was strongly associated with the development of a manifest central nervous system (CNS) synucleinopathy (odds ratio = 7.1)."

RBD predicts conversion to a manifest CNS synucleinopathy.

PMID:37843677 SUPPORT Human clinical

"All 6 patients with low cardiac 18F-dopamine-derived radioactivity who phenoconverted during follow-up developed a central LBD, whereas none of 4 patients with consistently normal 18F-dopamine PET phenoconverted to a central LBD (p = 0.0048), 3 evolving to probable MSA"

Cardiac denervation status predicts the type of conversion.

PMID:33881777 SUPPORT Human clinical

"Both NfL and the magnitude and reaction kinetics of αSyn PMCA faithfully predict which PAF patients will eventually phenoconvert to MSA."

CSF markers predict conversion to MSA.

+ 1 more reference

✶

Histopathology

3

Lewy Bodies in Sympathetic Ganglia and Distal Autonomic Axons

Typical and atypical Lewy bodies in sympathetic ganglia and in distal autonomic axons (epicardial, periadrenal, bladder wall), with Lewy bodies also in substantia nigra and locus coeruleus despite the absence of motor signs.

Show evidence (1 reference)

PMID:9255396 SUPPORT Human clinical

"Systemic autopsy results should be reviewed carefully in patients with PAF, as Lewy bodies in this disease may be seen in distal axons at a great length from their primary cell bodies."

Autopsy finding of distal axonal Lewy bodies in PAF.

Neuronal Loss in Intermediolateral Columns and Sympathetic Ganglia

Show evidence (1 reference)

PMID:9255396 SUPPORT Human clinical

"histopathologically by cell loss in intermediolateral columns and sympathetic ganglia"

Characteristic neuronal loss in PAF.

Cutaneous Phosphorylated Alpha-Synuclein in Autonomic Nerve Fibres VERY_FREQUENT

Phosphorylated alpha-synuclein deposits in dermal autonomic nerves (sweat glands, arrector pili, blood vessels) on punch skin biopsy, with a heavier burden than in MSA and absence in non-synuclein autonomic neuropathies.

Show evidence (2 references)

PMID:39608812 SUPPORT Human clinical

"P-syn was present in 22/22 (100%) PAF biopsies, 19/26 (73%) MSA biopsies and 0/22 (0%) non-synucleinopathy biopsies."

Skin biopsy positivity in PAF, MSA and non-synuclein autonomic failure.

PMID:23390175 SUPPORT Human clinical

"all patients with PAF showed α-synuclein deposits, which were absent in patients with acquired autonomic neuropathy"

Distinguishes PAF from acquired autonomic neuropathy.

⬡

Pathograph

Use Group by to collapse related nodes into one box. Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

●

Phenotypes

24

Blood 1

Normocytic Anemia HP:0001897

Show evidence (2 references)

PMID:8017744 SUPPORT Human clinical

"Anemia was present in 32 of 84 patients (38%; 95% Cl, 27% to 50%)."

Anemia in 38% of patients with primary autonomic failure (a group including but not limited to PAF).

PMID:8017744 SUPPORT Human clinical

"mean corpuscular volume, 89 fL"

Normal MCV indicates a normocytic anemia.

Cardiovascular 8

Neurogenic Orthostatic Hypotension OBLIGATE Orthostatic hypotension due to autonomic dysfunction HP:0004926

Course: PROGRESSIVE

Show evidence (2 references)

ORPHA:441 SUPPORT Other

"HP:0001278 | Orthostatic hypotension | Very frequent (99-80%)"

Orphanet annotates orthostatic hypotension as very frequent.

PMID:34669076 SUPPORT REVIEW SYNTHESIS Human clinical

"PAF is defined clinically by nOH without an identified secondary cause or clinical evidence of motor or cognitive impairment attributable to central nervous system neurodegeneration"

nOH is the defining clinical criterion.

Supine Hypertension FREQUENT HP:0000822

HPO has no supine hypertension term (runoak -i sqlite:obo:hp info "l~supine" returns nothing), so the parent Hypertension is bound and the posture is carried in preferred_term.

Sequelae: Supine Pressure Natriuresis

Show evidence (3 references)

PMID:11927799 SUPPORT REVIEW SYNTHESIS Human clinical

"about one half of these patients also suffer from supine hypertension"

Frequency of supine hypertension in autonomic failure with orthostatic hypotension.

PMID:15633433 SUPPORT Human clinical

"On examination, orthostatic hypotension and supine hypertension were detected in the absence of pharmacological therapy. All the patients presented hypertensive organ disease."

Case series of untreated PAF patients with supine hypertension and organ damage.

PMID:29766366 SUPPORT REVIEW SYNTHESIS Other

"In patients with neurogenic orthostatic hypotension, nSH is defined as systolic BP ≥ 140 mmHg and/or diastolic BP ≥ 90 mmHg, measured after at least 5 min of rest in the supine position."

Consensus definition of neurogenic supine hypertension.

Syncope VERY_FREQUENT Orthostatic syncope HP:0012670

Show evidence (2 references)

PMID:10552235 SUPPORT Human clinical

"The most common posturally related symptoms were dizziness (84% PAF, 83% MSA), syncope (91% PAF, 45% MSA)"

Syncope in 91% of 32 PAF patients.

ORPHA:441 SUPPORT Other

"HP:0001279 | Syncope | Frequent (79-30%)"

Orphanet records syncope as frequent; the questionnaire series reports a higher rate.

Orthostatic Light-Headedness VERY_FREQUENT Presyncope HP:0031972

Show evidence (1 reference)

PMID:10552235 SUPPORT Human clinical

"The most common posturally related symptoms were dizziness (84% PAF, 83% MSA)"

Postural dizziness in 84% of PAF patients.

Postprandial Hypotension HP:0002615

HPO has no postprandial hypotension term (runoak -i sqlite:obo:hp info "l~postprandial" returns only postprandial hyperlactemia, hyperglycemia, fullness and exacerbation), so Hypotension is bound.

Show evidence (1 reference)

PMID:8492945 SUPPORT Human clinical

"After food, supine BP fell in IPD, but to a greater extent in MSA and PAF."

Liquid-meal challenge shows marked postprandial hypotension in PAF.

Chronotropic Incompetence on Tilt HP:0033992

Show evidence (1 reference)

PMID:29405350 SUPPORT Human clinical

"A blunted HR increase during hypotension suggests a neurogenic cause. A ΔHR/ΔSBP ratio < 0.5 bpm/mmHg is diagnostic of neurogenic OH."

Defines the blunted heart-rate response of neurogenic OH.

Resting Bradycardia HP:0001662

Show evidence (2 references)

PMID:24095130 SUPPORT REVIEW SYNTHESIS Human clinical

"A 1925 report by Bradbury and Eggleston first described patients with extreme orthostatic hypotension and a low, steady heart rate."

Historical description of the low steady heart rate.

PMID:28093795 SUPPORT Human clinical

"The small group of patients retaining the pure autonomic failure phenotype had very low plasma norepinephrine levels, slow resting heart rate, no REM sleep behavior disorder, and preserved smell."

Slow resting heart rate marks patients who remain PAF.

Decreased Heart Rate Variability HP:0031861

Show evidence (1 reference)

PMID:18805037 SUPPORT Human clinical

"CV(R-R) was low in the MSA and PAF patients, but a significant difference was found only between the PAF and control groups."

Reduced R-R interval variation (cardiovagal impairment) in PAF.

Digestive 1

Constipation FREQUENT HP:0002019

Show evidence (2 references)

PMID:40053259 SUPPORT Human clinical

"Additional autonomic symptoms included constipation (N = 60; 45%)"

Constipation in 45% of patients who remained PAF.

ORPHA:441 SUPPORT Other

"HP:0002019 | Constipation | Frequent (79-30%)"

Orphanet annotates constipation as frequent.

Endocrine 1

Decreased circulating norepinephrine VERY_FREQUENT Decreased circulating norepinephrine concentration HP:0034874

Show evidence (2 references)

ORPHA:441 SUPPORT Other

"HP:0012099 | Abnormality of circulating catecholamine level | Very frequent (99-80%)"

Orphanet annotates abnormal circulating catecholamines as very frequent.

PMID:40696849 SUPPORT Human clinical

"Patients with PAF had more severe orthostatic hypotension, lower supine plasma noradrenaline, and frequent sympathetic pupillary deficits at initial assessment than MSA and LBD."

Supine noradrenaline is lower in PAF than in MSA or Lewy body disease.

Eye 2

Orthostatic Visual Disturbance FREQUENT Visual impairment HP:0000505

Show evidence (1 reference)

PMID:10552235 SUPPORT Human clinical

"visual disturbances (75% PAF, 53% MSA)"

Postural visual disturbance in 75% of PAF patients.

Sympathetic Pupillary Deficit FREQUENT Abnormal pupillary function HP:0007686

Show evidence (1 reference)

PMID:40696849 SUPPORT Human clinical

"Patients with PAF had more severe orthostatic hypotension, lower supine plasma noradrenaline, and frequent sympathetic pupillary deficits at initial assessment than MSA and LBD."

Pupillometry shows frequent sympathetic deficits in PAF.

Genitourinary 3

Urinary Dysfunction FREQUENT Neurogenic bladder HP:0000011

Show evidence (2 references)

PMID:40053259 SUPPORT Human clinical

"bladder symptoms (N = 78; 59%), which were severe in 50 patients (37.6%) with incontinence or requiring catheterization"

Frequency and severity of bladder dysfunction in patients who remained PAF.

ORPHA:441 SUPPORT Other

"HP:0000020 | Urinary incontinence | Frequent (79-30%)"

Orphanet annotates urinary incontinence as frequent.

Erectile Dysfunction Autonomic erectile dysfunction HP:0008652

Frequency is omitted because sources disagree: Orphanet annotates impotence as occasional, while a Mayo series reports sexual dysfunction (not restricted to men or to erectile failure) in 40%.

Show evidence (2 references)

ORPHA:441 SUPPORT Other

"HP:0000802 | Impotence | Occasional (29-5%)"

Orphanet annotates impotence as occasional.

PMID:40053259 SUPPORT Human clinical

"sexual dysfunction (N = 53; 40%)"

Sexual dysfunction in 40% of patients who remained PAF.

Nocturia HP:0000017

Show evidence (1 reference)

PMID:36601916 SUPPORT INDIRECT Human clinical

"was associated with lower nighttime diuresis (609±84 versus placebo 1004±160 mL; P=0.004)"

Nighttime diuresis of about a litre on placebo, reduced by lowering nocturnal blood pressure, documents pressure-driven nocturnal urine output in autonomic failure.

Head and Neck 1

Hyposmia HP:0004409

Show evidence (2 references)

PMID:19433741 SUPPORT Human clinical

"Hyposmia may be a feature of pure autonomic failure (PAF), but to a lesser degree than that found in Parkinson disease."

UPSIT study of 16 PAF patients.

PMID:19201246 SUPPORT Human clinical

"The PAF group had a low mean UPSIT score (22+/-3), similar to that in PD (20+/-2) and lower than in MSA (31+/-2, p=0.004)."

UPSIT scores in PAF were similar to PD.

Integument 1

Anhidrosis VERY_FREQUENT HP:0000970

Show evidence (2 references)

ORPHA:441 SUPPORT Other

"HP:0000970 | Anhidrosis | Very frequent (99-80%)"

Orphanet annotates anhidrosis as very frequent.

PMID:40053259 SUPPORT Human clinical

"median percentage anhidrosis of 51% (IQR 3-93%; N = 105)"

Thermoregulatory sweat testing quantifies the extent of anhidrosis.

Metabolism 1

Thermoregulatory Dysfunction FREQUENT Abnormality of temperature regulation HP:0004370

Show evidence (1 reference)

PMID:40053259 SUPPORT Human clinical

"thermoregulatory dysfunction (N = 51; 38%)"

Thermoregulatory symptoms in 38% of patients who remained PAF.

Nervous System 2

Falls HP:0002527

Show evidence (1 reference)

PMID:33705537 SUPPORT REVIEW SYNTHESIS Human clinical

"The goal of treatment is not to normalize blood pressure but rather to improve quality of life and prevent syncope and falls by reducing symptoms of cerebral hypoperfusion."

Falls are a principal complication targeted by treatment of nOH in synucleinopathies including PAF.

REM Sleep Behavior Disorder FREQUENT HP:5200291

Show evidence (3 references)

PMID:40053259 SUPPORT Human clinical

"Assessment of dream enactment behavior was completed in 86 patients and endorsed in 45 patients (52%)."

Dream enactment in 52% of assessed patients who remained PAF.

PMID:27757562 SUPPORT Human clinical

"Five out of 8 (63 %) met diagnostic criteria for RBD, confirmed on vPSG."

Polysomnography-confirmed RBD in a small PAF series.

PMID:9598693 REFUTE Human clinical

"RBD remained absent in the remaining six patients with pure autonomic failure."

An early prospective series found no RBD in six PAF patients.

Constitutional 3

Coat-Hanger Neck Pain VERY_FREQUENT HP:0030833

Show evidence (1 reference)

PMID:10552235 SUPPORT Human clinical

"suboccipital/paracervical 'coat-hanger' neck pain (8 l% PAF, 53% MSA)"

Coat-hanger pain in 81% of PAF patients (the source text renders 81 as "8 l").

Orthostatic Chest Pain FREQUENT HP:0100749

Show evidence (1 reference)

PMID:10552235 SUPPORT Human clinical

"Chest pain occurred mainly in patients with PAF (44% PAF, 13% MSA)."

Chest pain in 44% of PAF patients.

Fatigue VERY_FREQUENT HP:0012378

Show evidence (1 reference)

PMID:10552235 SUPPORT Human clinical

"Non-specific symptoms (weakness, lethargy and fatigue) were common in both groups (91% PAF, 85% MSA)"

Non-specific weakness, lethargy and fatigue in 91% of PAF patients.

💊

Medical Actions

14

Patient Education and Physical Countermeasures

Action: patient education and orthostatic countermeasures Ontology label: Behavioral Intervention NCIT:C15184

Platform: Behavioral / lifestyle

First-line management: recognizing and avoiding triggers (heat, large meals, straining, sudden standing, vasoactive drugs), physical counter-manoeuvres, and planning upright activity. The aim is to reduce symptoms rather than normalize blood pressure.

Mechanism Target:

MODULATES Cerebral and Muscle Hypoperfusion on Standing

Show evidence (2 references)

PMID:33705537 SUPPORT REVIEW SYNTHESIS Human clinical

"The first step in the management of NOH is to educate patients on how to avoid high-risk situations and providers to identify medications that trigger or worsen NOH."

Education is the first management step.

PMID:21664375 SUPPORT REVIEW SYNTHESIS Human clinical

"Non-pharmacologic strategies such as physical counter-maneuvers, dietary changes (i.e. high salt diet, rapid water drinking or compression garments) are the first line therapy."

Non-pharmacological measures are first line.

Salt and Fluid Loading with Rapid Water Drinking

Action: dietary salt and water loading Ontology label: Dietary Intervention NCIT:C15447

Platform: Behavioral / lifestyle

Increased salt and fluid intake expands volume, and rapid drinking of about 500 mL of water raises blood pressure within minutes through the osmopressor reflex, which is exaggerated when baroreflex buffering is lost. Useful before standing or meals.

Mechanism Target:

BYPASSES Failure of Baroreflex-Mediated Vasoconstriction

Show evidence (1 reference)

PMID:21048076 SUPPORT REVIEW SYNTHESIS Human clinical

"The osmopressor response can be exploited in the treatment of orthostatic and postprandial hypotension in patients with severe autonomic failure."

Review of the water-drinking pressor response in autonomic failure.

Compression Garments and Abdominal Binder

Action: abdominal compression Ontology label: Compression Therapy NCIT:C157735

Platform: Device

Lower-body and abdominal compression reduces venous pooling, increasing stroke volume and standing blood pressure.

Mechanism Target:

BYPASSES Failure of Baroreflex-Mediated Vasoconstriction

Show evidence (1 reference)

PMID:15241645 SUPPORT Human clinical

"Elastic abdominal binding increased standing blood pressure with 15/6 mmHg (range -3/3 to 36/14, p < 0.05)."

Abdominal binder raised standing blood pressure in neurogenic OH.

Head-Up Tilt Sleeping

Platform: Behavioral / lifestyle

Raising the head of the bed reduces nocturnal supine hypertension and pressure natriuresis and may improve morning orthostatic tolerance. A scoping review judged the evidence weak, from small studies at high risk of bias.

Mechanism Target:

INHIBITS Supine Pressure Natriuresis — Lowering nocturnal supine pressure reduces the overnight pressure natriuresis that depletes volume before morning.

Show evidence (1 reference)

PMID:37626994 SUPPORT REVIEW SYNTHESIS Human clinical

"Orthostatic tolerance was consistently enhanced in OH studies with higher angles (≥12°)"

Scoping review reporting improved orthostatic tolerance with steeper head-up tilt.

Midodrine

Action: Pharmacotherapy NCIT:C15986

Agent: midodrine CHEBI:6933

Platform: Small molecule

Peripheral alpha-1 adrenoceptor agonist (prodrug of desglymidodrine) that acts directly on vascular receptors and so does not require surviving noradrenergic terminals. Taken during the day before upright activity; avoid the supine position for several hours after a dose. Adverse effects include supine hypertension, piloerection and urinary retention.

Mechanism Target:

BYPASSES Deficient Sympathetic Norepinephrine Release — Acts on the vascular receptor downstream of the missing neurotransmitter, so it does not need surviving terminals.

RESTORES Failure of Baroreflex-Mediated Vasoconstriction — Restores vasoconstriction pharmacologically.

Show evidence (3 references)

PMID:9091692 SUPPORT Human clinical

"In the evaluable patients, midodrine resulted in improvements in standing systolic BP at all time points (P<.001 at visits 2, 3, 4, and 5)"

Multicentre randomized trial in neurogenic OH; the abstract gives no breakdown by diagnosis.

PMID:9091692 SUPPORT Human clinical

"The main adverse effects were those of pilomotor reactions, urinary retention, and supine hypertension."

Main adverse effects of midodrine.

PMID:32979782 SUPPORT REVIEW SYNTHESIS Human clinical

"patients with low "sympathetic reserve", i.e., those with peripheral noradrenergic degeneration (pure autonomic failure, Parkinson's disease) and low plasma norepinephrine, tend to respond better to "norepinephrine replacers" (midodrine and droxidopa)"

PAF patients respond best to norepinephrine replacers.

Droxidopa

Action: Pharmacotherapy NCIT:C15986

Agent: droxidopa CHEBI:31524

Platform: Small molecule

Oral synthetic amino acid converted by aromatic L-amino acid decarboxylase to norepinephrine outside noradrenergic terminals, replacing the missing neurotransmitter. Used for symptomatic neurogenic orthostatic hypotension in PD, MSA, PAF and other autonomic neuropathies. Supine blood pressure rises and must be monitored.

Mechanism Target:

BYPASSES Deficient Sympathetic Norepinephrine Release

Show evidence (5 references)

PMID:24944260 SUPPORT Human clinical

"In patients with symptomatic nOH, droxidopa improved symptoms and symptom impact on daily activities, with an associated increase in standing systolic BP, and was generally well tolerated."

Phase 3 trial including PAF patients.

PMID:24944260 SUPPORT Human clinical

"At endpoint, supine systolic BP >180 mm Hg was observed in 4.9% of droxidopa and 2.5% of placebo recipients."

Supine hypertension risk on droxidopa.

PMID:28494751 SUPPORT Human clinical

"Droxidopa improved virtually all nOH symptom scores compared with placebo, significantly reducing OHQ composite score (-2.68 ± 2.20 vs -1.82 ± 2.34 units; P < 0.001)"

Pooled analysis of the three randomized trials (n = 460) behind approval for primary autonomic failure. The same analysis bounds its own claim: the trials assessed 2 to 10 weeks of treatment, and the authors note that a longer trial was then underway to confirm efficacy beyond that period, so this result does not establish durable benefit.

+ 2 more references

Fludrocortisone

Action: Pharmacotherapy NCIT:C15986

Agent: fludrocortisone CHEBI:50885

Platform: Small molecule

Mineralocorticoid that expands plasma volume through renal sodium retention. It raises blood pressure in both supine and standing positions, so it can worsen supine hypertension and should be used with caution.

Mechanism Target:

INHIBITS Neurogenic Orthostatic Hypotension — Expanded plasma volume raises standing blood pressure without restoring sympathetic function or vasoconstriction.

ACTIVATES Supine Hypertension Mechanism — Raises supine blood pressure too, so it worsens supine hypertension.

Show evidence (3 references)

PMID:21664375 SUPPORT REVIEW SYNTHESIS Human clinical

"these interventions should be aimed at increasing intravascular volume either by promoting water and salt retention (fludrocortisone) or by increasing red blood cell mass when anemia is present (recombinant erythropoietin)"

Fludrocortisone as a volume expander.

PMID:15633433 SUPPORT Human clinical

"Salt-retaining steroid fludrocortisone, also, used to treat orthostatic hypotension, increases blood pressure both in supine and in standing position."

Fludrocortisone worsens supine as well as standing blood pressure.

PMID:33705537 SUPPORT REVIEW SYNTHESIS Human clinical

"Volume expanders (fludrocortisone and desmopressin) should be used with caution."

Caution with volume expanders.

Pyridostigmine

Action: Pharmacotherapy NCIT:C15986

Agent: pyridostigmine CHEBI:8665

Platform: Small molecule

Acetylcholinesterase inhibitor that enhances ganglionic transmission and so amplifies residual sympathetic outflow mainly when upright, with little effect on supine blood pressure. It is more effective with preserved sympathetic reserve, and therefore less so in PAF than in MSA or mild disease.

Mechanism Target:

MODULATES Deficient Sympathetic Norepinephrine Release — Amplifies residual ganglionic traffic so surviving postganglionic terminals release more norepinephrine on standing; limited in PAF because most terminals are lost.

Show evidence (3 references)

PMID:16476804 SUPPORT Human clinical

"Pairwise comparison showed significant reduction by pyridostigmine alone (BP fall of 27.6 mm Hg vs 34.0 mm Hg with placebo; P = .04)"

Crossover trial in neurogenic OH; the abstract gives no breakdown by diagnosis.

PMID:16476804 SUPPORT Human clinical

"No significant differences were seen in the supine BP, either systolic (P = .36) or diastolic (P = .85)."

No worsening of supine blood pressure.

PMID:33705537 SUPPORT REVIEW SYNTHESIS Human clinical

"Drugs that enhance residual sympathetic tone (pyridostigmine and atomoxetine) are more effective in patients with mild disease and in MSA patients with spared postganglionic fibers."

Reduced expected efficacy in PAF with postganglionic loss.

Atomoxetine

Action: Pharmacotherapy NCIT:C15986

Agent: atomoxetine CHEBI:127342

Platform: Small molecule

Norepinephrine transporter inhibitor that raises synaptic norepinephrine from residual sympathetic terminals. Acute doses raised upright blood pressure more than midodrine, but a four-week randomized trial showed no symptomatic benefit over placebo. Enhancers of residual sympathetic tone are expected to work better with preserved postganglionic fibres, although supine plasma norepinephrine alone did not predict the pressor response.

Mechanism Target:

MODULATES Deficient Sympathetic Norepinephrine Release

Show evidence (4 references)

PMID:25185131 SUPPORT Human clinical

"In contrast, atomoxetine produced a greater pressor response in upright systolic blood pressure (means difference=7.5 mm Hg; 95% CI, 0.6 to 15; P=0.03) compared with midodrine."

Acute pressor efficacy in severe autonomic failure.

PMID:39294522 REFUTE Human clinical

"We found no differences in the OHQ composite score between atomoxetine and placebo at 2 weeks (-0.3 ± 1.7 versus -0.4 ± 1.5; P = 0.806) and 4 weeks (-0.6 ± 2.4 versus -0.5 ± 1.6; P = 0.251)."

Four-week randomized crossover trial showed no symptomatic benefit (41% of participants had PAF).

PMID:34176285 SUPPORT Human clinical

"Nevertheless, our results showed that plasma NE is not a good predictor of response."

Supine norepinephrine did not predict the atomoxetine pressor response.

+ 1 more reference

Ampreloxetine

Action: Pharmacotherapy NCIT:C15986

Agent: ampreloxetine CHEBI:757112

Platform: Small molecule

Investigational once-daily selective norepinephrine reuptake inhibitor that raises synaptic norepinephrine from residual sympathetic terminals. A phase 2 trial in neurogenic orthostatic hypotension raised seated blood pressure with little effect on supine pressure. The phase 3 SEQUOIA and REDWOOD trials, which enrolled PAF as well as PD and MSA patients, missed their primary endpoints. A prespecified MSA subgroup analysis showed maintained symptom benefit on secondary endpoints after randomized withdrawal; the trials were powered only for the full population, and no PAF-specific result has been reported. Like atomoxetine, it is expected to help least in PAF, where those neurons are lost. It is not approved.

Mechanism Target:

MODULATES Deficient Sympathetic Norepinephrine Release

Show evidence (4 references)

PMID:34657222 SUPPORT Human clinical

"Seated blood pressure increased 15.7 mmHg 4 h after ampreloxetine and decreased 14.2 mmHg after placebo [least squares mean difference (95% CI) 29.9 mmHg (7.6-52.3); P = 0.0112]."

One-day randomized placebo-controlled phase of a 34-patient phase 2 trial; the abstract gives no breakdown by diagnosis.

PMID:42475649 REFUTE Human clinical

"Both SEQUOIA and REDWOOD did not meet their primary endpoints."

The phase 3 programme enrolled patients with PD, PAF or MSA and failed its primary endpoints in the full population.

PMID:42475649 SUPPORT Human clinical

"The trials enrolled participants aged 30 years or older with PD, PAF, or MSA and symptomatic nOH."

Confirms PAF patients were part of the phase 3 trial population.

+ 1 more reference

Recombinant Erythropoietin

Action: Pharmacotherapy NCIT:C15986

Agent: epoetin alfa NCIT:C2695

Platform: Protein replacement

Corrects the normocytic anemia of autonomic failure at low doses, increasing red cell mass and orthostatic tolerance.

Mechanism Target:

BYPASSES Sympathetic Deprivation with Blunted Erythropoietin Response

Show evidence (1 reference)

PMID:8017744 SUPPORT Human clinical

"Therapy with recombinant erythropoietin improved mean hemoglobin levels (from 108 to 133 g/L) in all patients treated (n = 5) at relatively low doses (25 to 50 units/kg body weight, subcutaneously, three times a week)."

Open-label erythropoietin corrected anemia in autonomic failure.

Nocturnal Treatment of Supine Hypertension

Action: Pharmacotherapy NCIT:C15986

Agent: nitroglycerin CHEBI:28787 eplerenone CHEBI:31547

Platform: Small molecule

Avoiding the supine position during the day, head-up tilt at night, and a short-acting antihypertensive at bedtime (for example transdermal nitroglycerin, or the mineralocorticoid antagonist eplerenone) lower nocturnal blood pressure without worsening daytime orthostatic hypotension.

Mechanism Target:

INHIBITS Supine Hypertension Mechanism

Show evidence (4 references)

PMID:11927799 SUPPORT REVIEW SYNTHESIS Human clinical

"During the day, avoiding the supine position is often all that is required. Short-acting vasodilators (e.g., transdermal nitroglycerin) can be used during the night."

Management approach to supine hypertension.

PMID:28050656 SUPPORT REVIEW SYNTHESIS Other

"provides essential recommendations based upon best available evidence as well as expert opinion for the (1) screening, (2) diagnosis, (3) treatment of nOH, and (4) diagnosis and treatment of associated supine hypertension"

American Autonomic Society and National Parkinson Foundation consensus recommendations, which explicitly include pure autonomic failure.

PMID:26644241 SUPPORT Human clinical

"Eplerenone maximally reduced supine systolic blood pressure by 32±6 mm Hg at 8 hours after administration (versus 8±10 mm Hg placebo, P=0.016), with no effect on nocturia"

Eplerenone lowered supine blood pressure in a crossover study (7 of 10 PAF).

+ 1 more reference

Nocturnal Continuous Positive Airway Pressure

Platform: Device

Overnight CPAP lowers supine blood pressure through a Valsalva-like reduction in cardiac output, reducing nocturnal diuresis and improving morning orthostatic tolerance.

Mechanism Target:

INHIBITS Supine Pressure Natriuresis

Show evidence (1 reference)

PMID:36601916 SUPPORT Human clinical

"overnight CPAP lowered nighttime systolic blood pressure (maximal change -23±5 versus placebo -1±7 mmHg; P=0.023) and was associated with lower nighttime diuresis (609±84 versus placebo 1004±160 mL; P=0.004) and improved morning orthostatic tolerance"

Two-night crossover study in autonomic failure.

No Disease-Modifying Therapy

Platform: Other

No treatment slows or prevents progression or phenoconversion. Biomarker stratification (cardiac imaging, CSF seeding and NfL, olfaction, RBD) is being developed to select prodromal patients for future disease-modification trials.

Show evidence (2 references)

PMID:27338613 SUPPORT REVIEW SYNTHESIS Human clinical

"There is currently no specific treatment to stop progression in PAF."

No disease-modifying therapy exists.

PMID:37843677 SUPPORT Human clinical

"This capability could refine eligibility criteria for entry into disease-modification trials aimed at preventing evolution of PAF to symptomatic central LBDs."

Prognostic biomarkers aim at future trials.

🔬

Biochemical Markers

5

Supine plasma norepinephrine (Decreased)

Pathograph Readouts

Readout of Deficient Sympathetic Norepinephrine Release Positive

Plasma norepinephrine at rest reflects postganglionic noradrenergic integrity.

Show evidence (1 reference)

PMID:34176285 SUPPORT BACKGROUND Human clinical

"Plasma norepinephrine (NE) levels while resting supine, a biomarker of the integrity of sympathetic post-ganglionic neurons, are frequently normal in MSA but low in PAF and PD."

Supine plasma NE as a readout of postganglionic integrity.

Predicts Spread to Central Nervous System (Phenoconversion) Threshold dependent

Higher supine norepinephrine predicts conversion, particularly to MSA.

Show evidence (1 reference)

PMID:40696849 SUPPORT Human clinical

"50/194 (26%) with PAF phenoconverted to MSA or LBD after a median of 13 years, with normal pupils, heart rate response to deep breathing ≥ 10 bpm, and supine plasma noradrenaline ≥ 200 pg/mL predicting future phenoconversion to MSA or LBD"

Supine noradrenaline threshold predicting phenoconversion.

Show evidence (1 reference)

PMID:28093795 SUPPORT Human clinical

"The small group of patients retaining the pure autonomic failure phenotype had very low plasma norepinephrine levels"

Very low plasma norepinephrine characterizes stable PAF.

Plasma DHPG to norepinephrine ratio (Increased)

Pathograph Readouts

Readout of Noradrenergic Vesicular Storage and Synthesis Defect Positive

A raised ratio indicates intraneuronal norepinephrine metabolism exceeding vesicular sequestration.

Show evidence (1 reference)

PMID:29162745 SUPPORT Human clinical

"The finding of elevated plasma ratio of DHPG:NE and reduced VMAT2 in PAF indicates a shift towards intraneuronal NE metabolism over sequestration in sympathetic nerves"

Links the ratio to the vesicular storage defect.

Show evidence (1 reference)

PMID:29162745 SUPPORT Human clinical

"These findings were associated with a significantly higher ratio of plasma 3,4-dihydroxyphenylglycol (DHPG):NE in PAF participants when compared with controls (P<0.05)."

Raised DHPG:NE ratio in PAF.

CSF alpha-synuclein seeding activity (Present)

Pathograph Readouts

Readout of Peripheral Autonomic Alpha-Synuclein Aggregation Present/absent

A positive seeding assay indicates aggregated alpha-synuclein; an MSA-like kinetic profile predicts conversion to MSA.

Show evidence (1 reference)

PMID:33881777 SUPPORT Human clinical

"The PMCA reaction was markedly different in five samples with maximum fluorescence and reaction kinetics previously described in MSA patients; all of these patients later developed MSA."

Seeding kinetics distinguish future MSA converters.

Show evidence (1 reference)

PMID:33881777 SUPPORT Human clinical

"ASyn-PMCA was positive in all but two cases (94%)."

CSF seeding is positive in nearly all PAF patients.

CSF neurofilament light chain (Increased only in future MSA converters)

Pathograph Readouts

Predicts Spread to Central Nervous System (Phenoconversion) Positive

Elevated CSF NfL at baseline predicts conversion to MSA.

Show evidence (1 reference)

PMID:33881777 SUPPORT Human clinical

"NfL at baseline was elevated only in patients who later developed MSA, perfectly separating those from future PD and DLB converters as well as non-converters."

CSF NfL separates future MSA converters.

Show evidence (1 reference)

PMID:33881777 SUPPORT Human clinical

"NfL at baseline was elevated only in patients who later developed MSA"

CSF NfL is normal in stable PAF and raised in prodromal MSA.

Serum erythropoietin (Inappropriately low for hemoglobin)

Pathograph Readouts

Readout of Sympathetic Deprivation with Blunted Erythropoietin Response Negative

Low erythropoietin relative to anemia reflects loss of sympathetic drive to erythropoietin production.

Show evidence (1 reference)

PMID:8017744 SUPPORT Human clinical

"In seven of nine patients with autonomic failure who had hemoglobin levels less than 120 g/L, serum erythropoietin levels decreased below the 95% confidence interval corresponding to patients with iron deficiency anemia."

Low erythropoietin in anemic autonomic failure patients.

Show evidence (1 reference)

PMID:8017744 SUPPORT Human clinical

"No relation was found between serum erythropoietin and blood hemoglobin levels."

Erythropoietin does not rise appropriately with falling hemoglobin.

🔬

Diagnosis

7

Head-up tilt or active stand blood pressure testing

Orthostatic hypotension is a sustained fall of at least 20 mmHg systolic or 10 mmHg diastolic blood pressure within 3 minutes of standing or head-up tilt. A blunted heart-rate rise (change in heart rate divided by change in systolic pressure below 0.5 bpm/mmHg) identifies a neurogenic cause. Supine blood pressure is measured at the same session to detect supine hypertension.

Systolic blood pressure LOINC:8480-6

Show evidence (2 references)

PMID:28717053 SUPPORT REVIEW SYNTHESIS Human clinical

"Tilt table (head-up) testing is probably the test most commonly used to establish the diagnosis. However, simple office testing is also useful, such as having the patient stand after lying supine with blood pressure monitoring."

Tilt-table and active-stand testing establish the diagnosis.

PMID:29405350 SUPPORT Human clinical

"A ΔHR/ΔSBP ratio of 0.492 bpm/mmHg had excellent sensitivity (91.3%) and specificity (88.4%) to distinguish between patients with neurogenic from nonneurogenic OH (area under the curve = 0.96, p < 0.0001)."

Heart-rate-to-blood-pressure ratio cut-off for neurogenic OH.

Autonomic reflex screen and thermoregulatory sweat testing

Cardiovagal, adrenergic and sudomotor testing quantifies the extent of autonomic failure. A postganglionic sweat-loss pattern fits PAF, whereas a preganglionic pattern and mild cardiovagal impairment predict conversion to MSA.

Show evidence (2 references)

PMID:28202694 SUPPORT Human clinical

"Several variables were identified to predict conversion to MSA: (1) mild degree of cardiovagal impairment, (2) preganglionic pattern of sweat loss"

Autonomic testing patterns that predict MSA conversion.

PMID:31307617 SUPPORT REVIEW SYNTHESIS Human clinical

"We focus on various neurophysiological tests that may be used to evaluate the function of the peripheral autonomic nervous system including quantitative sudomotor axon reflex testing, thermoregulatory sweat testing, and others."

Review of the autonomic test battery used in PAF.

Supine and standing plasma catecholamines

Very low supine plasma norepinephrine with little rise on standing supports a postganglionic lesion and distinguishes PAF from MSA.

Plasma norepinephrine LOINC:14852-8

Show evidence (1 reference)

PMID:40696849 SUPPORT Human clinical

"Patients with PAF had more severe orthostatic hypotension, lower supine plasma noradrenaline, and frequent sympathetic pupillary deficits at initial assessment than MSA and LBD."

Supine plasma noradrenaline is lower in PAF than in MSA or Lewy body disease, which is what makes the measurement discriminating.

Skin biopsy for phosphorylated alpha-synuclein

Punch biopsy immunohistochemistry detects phosphorylated alpha-synuclein in cutaneous autonomic nerves in essentially all patients with PAF, separating it from acquired autonomic neuropathies; a high total score separates PAF from MSA.

skin biopsy NCIT:C51692

Show evidence (2 references)

PMID:38506839 SUPPORT Human clinical

"98.2% (54 of 55) with MSA, 96.0% (48 of 50) with DLB, and 100% (22 of 22) with PAF; 3.3% (4 of 120) of controls had cutaneous phosphorylated α-synuclein detected."

Thirty-site blinded Synuclein-One study positivity rates.

PMID:39608812 SUPPORT Human clinical

"Total p-syn score >3 distinguished PAF from MSA with 100% specificity and 82% sensitivity."

Quantitative score separates PAF from MSA.

Cardiac sympathetic neuroimaging

Cardiac 18F-dopamine PET or 123I-MIBG scintigraphy shows sympathetic denervation in most patients; preserved uptake raises the possibility of prodromal MSA.

positron emission tomography NCIT:C17007

Show evidence (1 reference)

PMID:37843677 SUPPORT Human clinical

"Since cardiac 18F-dopamine-derived radioactivity usually is low in LBDs and usually is normal in MSA, we hypothesized that patients with PAF with low cardiac 18F-dopamine-derived radioactivity would be more likely to phenoconvert to a central LBD than to MSA."

Rationale for cardiac PET in classifying PAF.

CSF alpha-synuclein seed amplification and neurofilament light chain

CSF seeding assays confirm a synucleinopathy, and an MSA-like seeding profile or raised NfL identifies prodromal MSA.

lumbar puncture NCIT:C15327

CSF neurofilament light chain LOINC:100996-8

Show evidence (1 reference)

PMID:33881777 SUPPORT Human clinical

"This finding has important implications not only for prognostication, but also for future trials of disease modifying therapies, allowing for differentiation of MSA from Lewy body synucleinopathies before motor symptoms develop."

CSF testing separates prodromal MSA from Lewy body forms.

Polysomnography and olfactory testing for central risk markers

Video-polysomnography confirms RBD and smell identification testing detects hyposmia; both stratify the risk and direction of phenoconversion. A stricter UPSIT threshold improves the specificity of the MDS prodromal MSA criteria in PAF.

polysomnography NCIT:C114185

Show evidence (2 references)

PMID:42444112 SUPPORT Human clinical

"Applying a stricter olfactory threshold improved specificity (90%-97%) and PPV (53%-83%), with a modest reduction in sensitivity (to 83%)."

Olfactory testing refines prodromal MSA criteria in PAF.

PMID:27757562 SUPPORT Human clinical

"Five out of 8 (63 %) met diagnostic criteria for RBD, confirmed on vPSG."

Polysomnography confirms RBD in PAF.

🩻

Imaging Findings

4

Reduced Cardiac Sympathetic Innervation on 18F-Dopamine PET

Low myocardial 18F-dopamine-derived radioactivity indicates cardiac noradrenergic denervation. Low uptake predicts conversion to Lewy body disease, while normal uptake points toward MSA.

Modality: PET Diagnostic

Location: heart UBERON:0000948

Show evidence (2 references)

PMID:16269589 SUPPORT Human clinical

"Both the PD+OH group and the PAF group had decreased 6-(18)F-fluorodopamine-derived radioactivity in the heart (P < 0.0001)"

Cardiac PET shows reduced sympathetic innervation in PAF.

PMID:37843677 SUPPORT Human clinical

"Cardiac 18F-dopamine PET can predict the type of phenoconversion of PAF."

Prognostic value of cardiac PET.

Reduced Cardiac MIBG Uptake VERY_FREQUENT

Modality: Other

Location: heart UBERON:0000948

123I-MIBG myocardial scintigraphy (planar or SPECT).

Show evidence (1 reference)

PMID:41072204 SUPPORT REVIEW SYNTHESIS Human clinical

"MIBG scintigraphy showed abnormal cardiac uptake in most patients with clinical PAF. Conversely, preserved MIBG uptake may be associated with a high probability of phenoconversion, particularly to MSA."

Systematic review of 39 cases.

Abnormal Dopamine Transporter SPECT Before Phenoconversion

DaTSCAN is abnormal in a subset of patients years before motor signs, and most of them go on to a more widespread synucleinopathy.

Modality: SPECT

Show evidence (1 reference)

PMID:40397689 SUPPORT Human clinical

"Overall, 39% of patients had abnormal DaTSCAN results up to 7 years before phenoconversion, with 84% of these patients progressing to more widespread synucleinopathy."

Prodromal striatal dopaminergic deficit on DaTSCAN.

Reduced Neuromelanin MRI Signal in Locus Coeruleus and Substantia Nigra

Seen in PAF patients at high risk of conversion, with values similar to PD and DLB.

Modality: MRI

Show evidence (1 reference)

PMID:39825743 SUPPORT Human clinical

"High-LR PAF patients showed reduced contrast in the LC and SN compared with controls and low-LR PAF patients, with values similar to PD and DLB."

Neuromelanin-sensitive MRI evidence of early central involvement.

📈

Progression

3

Adult-onset insidious autonomic failure

Age: Middle to late adulthood (pooled mean onset about 63 years)

Onset is insidious in adulthood or old age. Most non-orthostatic autonomic symptoms begin close to the onset of orthostatic hypotension, while dream enactment behaviour tends to appear years later.

Show evidence (3 references)

ORPHA:441 SUPPORT Other

"Age of onset: Elderly"

Orphanet records elderly (and adult) onset.

PMID:42081229 SUPPORT REVIEW SYNTHESIS Human clinical

"A total of 9 studies comprising 900 individuals with PAF (mean ... age at onset, 63.1 ... years; 63.8% male) were included."

Pooled mean age at onset across nine longitudinal cohorts.

PMID:40053259 SUPPORT Human clinical

"Median time to dream enactment behavior onset from orthostatic hypotension was 7.00 years (1.55-13.50). Other autonomic symptoms tended to occur near orthostatic hypotension."

Timeline of symptom onset in patients who retained the PAF phenotype.

Chronic progressive peripheral autonomic failure

Duration: Years to decades; median survival about 15 years from orthostatic symptom onset

Autonomic failure worsens on repeat testing. Survival is longer than in the other synucleinopathies and depends mainly on age and orthostatic hypotension severity. Many patients retain the pure phenotype until death.

Show evidence (4 references)

PMID:40397689 SUPPORT Human clinical

"Median survival of patients with PAF was 15 years from orthostatic symptoms onset and was mostly influenced by age and the severity of orthostatic hypotension."

Largest single-centre natural-history cohort (n=281, median 10 years follow-up).

PMID:40397689 SUPPORT Human clinical

"repeat testing indicated worsening of autonomic failure during the disease course"

Autonomic failure progresses over time.

PMID:40053259 SUPPORT Human clinical

"Of 202 patients, 133 remained pure autonomic failure with median follow-up time of 9.05 years"

A majority of patients keep the PAF phenotype over prolonged follow-up.

+ 1 more reference

Phenoconversion to a central synucleinopathy

Duration: About 5 percent per year in pooled data (12 percent per year in one prospective cohort)

Roughly a quarter to a third of patients presenting with PAF develop Parkinson disease, dementia with Lewy bodies or multiple system atrophy. Conversion to MSA clusters in the first years of follow-up, whereas conversion to Lewy body disorders occurs at a steadier rate. The annual-risk estimates differ between the eight-centre prospective cohort and the meta-analysis.

Show evidence (6 references)

PMID:42081229 SUPPORT REVIEW SYNTHESIS Human clinical

"270 of 900 individuals with PAF (30%) experienced phenoconversion to a central α-synucleinopathy (12% to MSA, 11% to DLB, 7% to PD) with a pooled incidence rate of 5.09 per 100 person-years"

Meta-analysis of nine longitudinal studies.

PMID:42081229 SUPPORT REVIEW SYNTHESIS Human clinical

"Phenoconversion rates for MSA (pooled incidence rate, 1.96; 95% CI, 1.29-2.99) were highest in the first years of follow-up, whereas Lewy body disorders showed more constant phenoconversion rates"

Different temporal profiles for MSA versus Lewy body conversion.

PMID:38366572 SUPPORT Human clinical

"Patients with PAF have an estimated 12% (95% CI: 9-15%) per year annual risk following study entry of phenoconverting to a manifest CNS synucleinopathy."

Eight-centre prospective cohort estimate of annual conversion risk.

+ 3 more references

📊

Prevalence

1

Europe

Point prevalence 1–9 per 1,000,000

Orphanet point-prevalence class 1-9 / 1,000,000 for Europe. The source column of that Orphanet row reads "PMID:2007", which is not a usable citation, so only the Orphanet class itself is cited. No population-based incidence study was found.

Show evidence (1 reference)

ORPHA:441 SUPPORT Other

"1-9 / 1 000 000 | Europe | Point prevalence"

Orphanet epidemiology row giving the European point-prevalence class.

⚖️

Clinical Burden

High

Neurogenic orthostatic hypotension is disabling, causing recurrent syncope, falls and inability to stand for long, and is frequently complicated by supine hypertension that constrains treatment. About a third of patients go on to a central synucleinopathy. Survival is nonetheless longer than in MSA, PD or DLB.

Show evidence (2 references)

PMID:28717053 SUPPORT REVIEW SYNTHESIS Human clinical

"Patients experience symptomatic hypotension that requires them to sit, squat or lie down to prevent syncope."

Describes the day-to-day functional burden of orthostatic hypotension.

PMID:34176285 SUPPORT BACKGROUND Human clinical

"nOH results in cerebral hypoperfusion7 with lightheadedness, dizziness, syncope, and falls8 all being common symptoms, which contribute to morbidity, disability, and death in this population."

Links nOH to morbidity, disability and death in synucleinopathies including PAF.

🔀

Differential Diagnoses

6

Conditions with similar clinical presentations that must be differentiated from Pure Autonomic Failure:

Multiple system atrophy MONDO:0007803

Distinguishing Features

Central (preganglionic) lesion with preserved postganglionic innervation
Normal or near-normal supine plasma norepinephrine
Normal cardiac sympathetic imaging and preserved smell
Parkinsonism or cerebellar ataxia appear later; premotor MSA can present exactly as PAF

Show evidence (2 references)

PMID:24095130 SUPPORT REVIEW SYNTHESIS Human clinical

"Cardiac sympathetic innervation is generally intact in MSA but decreased or absent in Parkinson's disease with autonomic failure and PAF."

Cardiac innervation differs between MSA and PAF.

PMID:19201246 SUPPORT Human clinical

"The PAF group had a low mean UPSIT score (22+/-3), similar to that in PD (20+/-2) and lower than in MSA (31+/-2, p=0.004)."

Smell is better preserved in MSA than in PAF.

Parkinson disease with autonomic failure MONDO:0005180

Distinguishing Features

Shares postganglionic noradrenergic denervation with PAF
Parkinsonism with marked striatal dopaminergic terminal loss

Show evidence (1 reference)

PMID:18363034 SUPPORT Human clinical

"Parkinsonism appears to reflect striatal dopamine deficiency rather than loss of nigral dopaminergic neurons per se."

Striatal deficiency distinguishes PD from PAF.

Dementia with Lewy bodies MONDO:0007488

Distinguishing Features

Cognitive decline with fluctuations and hallucinations
PAF may be its autonomic prodrome

Show evidence (1 reference)

PMID:28093795 SUPPORT Human clinical

"Patients presenting with pure autonomic failure are at high risk of phenoconverting to a manifest CNS synucleinopathy."

PAF can evolve into DLB, PD or MSA.

Diabetic autonomic neuropathy Not Yet Curated MONDO:0001299

Distinguishing Features

Secondary autonomic neuropathy with an identified cause (diabetes mellitus)
No cutaneous phosphorylated alpha-synuclein on skin biopsy

Show evidence (2 references)

PMID:34392300 SUPPORT REVIEW SYNTHESIS Human clinical

"Peripheral autonomic manifestations are similar to those seen in other autonomic neuropathies, particularly, diabetic autonomic neuropathy, amyloid polyneuropathy, and autoimmune autonomic neuropathies."

Names diabetic autonomic neuropathy as a principal mimic.

PMID:23390175 SUPPORT Human clinical

"all patients with PAF showed α-synuclein deposits, which were absent in patients with acquired autonomic neuropathy"

Skin synuclein separates PAF from acquired autonomic neuropathies.

Autoimmune autonomic ganglionopathy MONDO:0016499

Distinguishing Features

Acquired autonomic neuropathy that mimics the peripheral autonomic picture of PAF
No cutaneous phosphorylated alpha-synuclein on skin biopsy

Show evidence (3 references)

PMID:34392300 SUPPORT REVIEW SYNTHESIS Human clinical

"Peripheral autonomic manifestations are similar to those seen in other autonomic neuropathies, particularly, diabetic autonomic neuropathy, amyloid polyneuropathy, and autoimmune autonomic neuropathies."

Lists the main peripheral autonomic neuropathy mimics.

PMID:23390175 SUPPORT Human clinical

"all patients with PAF showed α-synuclein deposits, which were absent in patients with acquired autonomic neuropathy"

Skin synuclein separates PAF from acquired autonomic neuropathies.

PMID:39608812 SUPPORT Human clinical

"P-syn was present in 22/22 (100%) PAF biopsies, 19/26 (73%) MSA biopsies and 0/22 (0%) non-synucleinopathy biopsies."

Non-synucleinopathy autonomic failure was skin-synuclein negative.

Amyloid autonomic polyneuropathy MONDO:0007100

Distinguishing Features

Autonomic neuropathy that mimics the peripheral autonomic picture of PAF
No cutaneous phosphorylated alpha-synuclein on skin biopsy

Show evidence (3 references)

PMID:34392300 SUPPORT REVIEW SYNTHESIS Human clinical

"Peripheral autonomic manifestations are similar to those seen in other autonomic neuropathies, particularly, diabetic autonomic neuropathy, amyloid polyneuropathy, and autoimmune autonomic neuropathies."

Amyloid polyneuropathy is a key differential.

PMID:23390175 SUPPORT Human clinical

"all patients with PAF showed α-synuclein deposits, which were absent in patients with acquired autonomic neuropathy"

Skin synuclein separates PAF from acquired autonomic neuropathies.

PMID:39608812 SUPPORT Human clinical

"P-syn was present in 22/22 (100%) PAF biopsies, 19/26 (73%) MSA biopsies and 0/22 (0%) non-synucleinopathy biopsies."

Non-synucleinopathy autonomic failure was skin-synuclein negative.

🔬

Clinical Trials

2

NCT03750552 PHASE_III COMPLETED

SEQUOIA, the 4-week parallel-group phase 3 trial of ampreloxetine in symptomatic neurogenic orthostatic hypotension due to primary autonomic failure, enrolling PAF alongside Parkinson disease and multiple system atrophy. It did not meet its primary endpoint.

Target Phenotypes: Neurogenic orthostatic hypotension HP:0001278

Show evidence (1 reference)

clinicaltrials:NCT03750552 SUPPORT Other

"A Phase 3 study to evaluate efficacy, safety, and tolerability of ampreloxetine (TD-9855) in subjects with primary autonomic failures (MSA, PD, or PAF) and symptomatic nOH with up to 4 weeks of treatment."

Registry record establishing the trial's design and that PAF was an eligible diagnosis.

NCT03829657 PHASE_III TERMINATED

REDWOOD, the 22-week randomized withdrawal phase 3 trial of ampreloxetine in the same population, terminated early by the sponsor after SEQUOIA missed its endpoint. Its own primary endpoint was not met; a prespecified MSA subgroup analysis was reported separately.

Target Phenotypes: Neurogenic orthostatic hypotension HP:0001278

Show evidence (2 references)

clinicaltrials:NCT03829657 SUPPORT Other

"A Phase 3, 22-week, Multi-center, Randomized Withdrawal Study of ampreloxetine in Treating Symptomatic Neurogenic Orthostatic Hypotension in Subjects with Primary Autonomic Failure"

Registry record establishing the trial's design and population.

PMID:42475649 SUPPORT Human clinical

"After SEQUOIA did not meet the primary endpoint, REDWOOD was early terminated by the sponsor"

Source for the TERMINATED status and its reason.

🧫

Experimental Models

2

DOPAL challenge in BE(2)-M17 neuroblastoma cells and primary cortical neurons CELL_LINE

The non-animal system behind the catecholaldehyde step of this entry. DOPAL added to the medium forms covalent oligomers with alpha-synuclein inside the cell, and those oligomers permeabilise cholesterol-containing membranes, damage synaptic vesicles and let dopamine escape into the cytoplasm, where it is converted to more DOPAL. It is the experiment that makes the vicious cycle drawn in this entry's pathograph measurable rather than inferred, and it works on endogenous as well as overexpressed alpha-synuclein. It is not a model of PAF. The cells are a neuroblastoma line and mouse cortical neurons rather than sympathetic noradrenergic neurons, no patient material is involved, and the catecholamine that leaks is dopamine rather than norepinephrine.

Organism

human NCBITaxon:9606

Cell source

Human BE(2)-M17 neuroblastoma cells overexpressing mCherry-tagged alpha-synuclein, with mouse primary cortical neurons carrying only endogenous alpha-synuclein as the non-overexpressing comparison, both exposed to exogenous DOPAL. HEK293T cells overexpressing alpha-synuclein-EGFP are the paper's negative arm: they supply the mass-spectrometric characterisation of the modified protein, but oligomers were not detected in them. An isolated synaptic-vesicle preparation is assayed alongside the intact cells.

Culture

Two-dimensional monolayer culture, with an accompanying isolated synaptic-vesicle preparation

Publication

PMID:28084443

Pathograph links

Catecholaldehyde (DOPAL) Autotoxicity in Noradrenergic Neurons perturbs fidelity: moderate observes: molecular DOPAL is applied to intact cells and the covalent alpha-synuclein oligomers this node describes are then recovered from inside them, so the node's chemistry is demonstrated in a cellular context rather than only in a tube.

Limitations: DOPAL is supplied from outside at fixed concentrations, so the node's claim that it accumulates because dopamine leaks from storage vesicles and is deaminated in the cytoplasm is assumed by the design rather than tested by it.

Divergences from the human mechanism

cause unrepresented qualifying

The node's upstream cause is vesicular leak followed by monoamine oxidase deamination of cytoplasmic dopamine. Here the aldehyde is pipetted into the medium, so neither the leak nor the enzymatic step is in the model, and the exposure cannot be titrated to a physiological cytoplasmic concentration.

boundary omission qualifying

A sympathetic noradrenergic neuron is outside the model. Its distinguishing features - dopamine beta-hydroxylase inside the vesicle, norepinephrine rather than dopamine as the stored transmitter, and the aldehyde dehydrogenase complement of that cell type - are exactly what the node invokes to explain why catecholaminergic neurons are selectively affected.

species mismatch qualifying

The non-overexpressing arm uses mouse cortical neurons, and the species gap bears on this link because the endogenous-alpha-synuclein claim rests on that arm alone. Both human lines overexpress a tagged construct, and in the HEK293T line no oligomers were detected at all, so there is no human result showing the reaction on endogenous protein at endogenous abundance. The substrate in the neurons is the mouse protein rather than the human one, and those neurons were exposed to 20 or 50 micromolar DOPAL against 100 micromolar in the human lines, so the two arms are not interchangeable on dose either.

Readouts

Covalent alpha-synuclein oligomer formation after DOPAL exposure

Direction: INCREASED

Interpretation: Oligomeric alpha-synuclein species appear on western blot in DOPAL-treated cells and not in untreated ones, in both the overexpressing line and neurons carrying only endogenous protein.

Show evidence (1 reference)

PMID:28084443 SUPPORT PRIMARY RESULT In vitro / ex vivo

"is able to induce aS oligomerization in immortalized cell lines, and in primary neurons"

The measurement behind this readout, in both cell systems.

Noradrenergic Vesicular Storage and Synthesis Defect partially recapitulates fidelity: low observes: cellular Catecholamine escaping from storage vesicles is the quantity this node is about, and it is measured here as a consequence of the aldehyde-driven oligomers rather than assumed. That is the return arm of the loop this entry draws between the storage defect and the catecholaldehyde node.

Limitations: The transmitter that leaks is dopamine from a neuroblastoma line and from cortical neurons, not norepinephrine from a sympathetic neuron, and vesicular monoamine transporter density and tyrosine hydroxylase content - the two measurements that define this node in patients - are not reported.

Divergences from the human mechanism

proxy quantity qualifying

Dopamine leak from synaptic vesicles stands in for failure of norepinephrine sequestration in a sympathetic varicosity. The direction of the defect is the same; the transmitter, the vesicle population and the cell are not.

boundary omission qualifying

Dopamine beta-hydroxylase and the noradrenergic vesicle itself lie outside the model, so nothing here bears on the reduced vesicular norepinephrine synthesis that this node also asserts.

species mismatch qualifying

The in-cell evidence that oligomers damage synaptic vesicles is the electron microscopy of mouse primary neurons, where the readily releasable pool shrinks and vesicles per synapse fall from about 71 to 49 and 38 with rising DOPAL. The human arm contributes the pHluorin permeabilisation result and the dopamine-leak assay is cell-free, so the structural measurement of vesicle loss has no human counterpart here.

Readouts

Dopamine leak from synaptic vesicles

Direction: INCREASED

Interpretation: Alpha-synuclein-DOPAL oligomers permeabilise vesicle membranes and release stored dopamine, in isolated vesicles and in cells.

Show evidence (2 references)

PMID:28084443 SUPPORT PRIMARY RESULT In vitro / ex vivo

"aS-DOPAL oligomers can induce dopamine leak in an in vitro model of synaptic vesicles and in cellular models"

The measured leak, which is the step that closes the loop back onto the aldehyde node.

+ 1 more reference

Show evidence (1 reference)

PMID:28084443 SUPPORT PRIMARY RESULT In vitro / ex vivo

"DOPAL can target both overexpressed aS and endogenous aS, and it is able to induce aS oligomerization in immortalized cell lines, and in primary neurons"

Establishes the system and that the effect does not depend on overexpression, which is what makes it usable as evidence about an endogenous mechanism.

MO3.13 oligodendrocyte and PC12 catecholaldehyde transfer co-culture CO_CULTURE

A catecholamine-free recipient cell used as a clean background for the aldehyde. It answers a question the single-cell systems cannot: whether DOPAL made in one cell reaches another and oligomerises alpha-synuclein there. It was built to explain glial inclusions in multiple system atrophy, so for PAF it bears on the chemistry and the transmissibility and not on the cell type, and the entry's other MO3.13 result on DOPAL-driven quinonisation of intracellular proteins comes from the same laboratory.

Organism

human NCBITaxon:9606

Cell source

Human MO3.13 oligodendrocyte and glioblastoma lines, which contain neither catecholamines nor alpha-synuclein of their own, co-incubated with dopamine-producing rat PC12 cells or exposed to DOPAL directly, with recombinant wild-type or A53T alpha-synuclein supplied in the medium.

Culture

Two-dimensional co-incubation of two cell lines in shared medium

Publication

PMID:26777075

Pathograph links

Catecholaldehyde (DOPAL) Autotoxicity in Noradrenergic Neurons perturbs fidelity: low observes: molecular Shows the aldehyde crossing from a catecholamine-synthesising cell into a recipient that makes none, and oligomerising alpha-synuclein once inside, so the oligomerising step this node asserts does not require the aldehyde to be made in the same cell.

Limitations: The recipient is a glial line chosen for the multiple system atrophy question, and neither alpha-synuclein nor the catecholamine is endogenous to it, so the model reproduces the reaction and not the cell in which this entry places it.

Divergences from the human mechanism

boundary omission qualifying

The sympathetic noradrenergic neuron is absent, and so is the intracellular origin of the aldehyde. Alpha-synuclein is added from outside rather than expressed, so the model cannot speak to the concentrations either species reaches in the affected neuron.

proxy quantity qualifying

An oligodendrocyte taking up extracellular alpha-synuclein stands in for a peripheral noradrenergic neuron aggregating its own. The cell-type selectivity that this node exists to explain is therefore not something the model can test.

species mismatch immaterial

The dopamine-producing partner in the transfer arm is a rat PC12 line. Immaterial to the claim, because the arm with DOPAL added directly to the human cells gives the same result.

Show evidence (1 reference)

PMID:26777075 SUPPORT PRIMARY RESULT In vitro / ex vivo

"DOPAL is transmissible to glial cells and enhances intracellular oligomerization of AS"

The system's own conclusion, and the reason it is recorded here rather than folded into the single-cell model above.

🐁

Animal Models

1

Ganglionic alpha-synuclein fibril injection in TgM83 mice

Preformed alpha-synuclein fibrils injected into the stellate and celiac ganglia of TgM83 mice spread only along autonomic pathways, to the central nervous system and bidirectionally to the autonomic innervation of peripheral organs. The mice develop orthostatic hypotension, constipation, hypohidrosis and hyposmia without motor dysfunction.

Species

Mouse

Genotype

TgM83+/- (human SNCA A53T transgene, hemizygous)

Publication

PMID:32071315

Pathograph links

Peripheral Autonomic Alpha-Synuclein Aggregation partially recapitulates fidelity: moderate observes: organism Autonomic-restricted alpha-synuclein pathology with autonomic failure and no motor signs, the defining features of PAF.

Limitations: Pathology is seeded by injected fibrils into mice overexpressing mutant human alpha-synuclein, whereas human PAF is sporadic with no SNCA variant, and the seeded pathology also reaches the central nervous system.

Divergences from the human mechanism

cause unrepresented qualifying

Aggregation is started by injecting preformed fibrils into ganglia of mice overexpressing A53T human alpha-synuclein. In the sporadic human disease the protein is wild type at normal dosage and the initiating trigger is unknown, so the model cannot speak to why aggregation begins.

species mismatch qualifying

Orthostatic hypotension and hypohidrosis are measured in mice, whose postural cardiovascular load differs greatly from upright humans.

Show evidence (1 reference)

PMID:32071315 SUPPORT Model organism

"In parallel, the mice develop autonomic dysfunction, featured by orthostatic hypotension, constipation, hypohidrosis and hyposmia, without motor dysfunction."

The model reproduces autonomic failure without motor features.

Spread to Central Nervous System (Phenoconversion) partially recapitulates fidelity: low observes: organism Pathology spreads from autonomic ganglia to the central nervous system.

Limitations: Central spread was shown histologically without the motor or cognitive phenotype of a phenoconverted disease, and the model has not been shown to separate Lewy-type from MSA-type conversion.

Divergences from the human mechanism

proxy quantity qualifying

The model's quantity is the histological presence of alpha-synuclein pathology in central regions. The node's quantity is clinical phenoconversion to Parkinson disease or dementia with Lewy bodies, which is a diagnosis made on motor or cognitive features the mice never develop. Central pathology stands in for a clinical event, and the proportion of PAF patients with central pathology who would ever convert is not something this model can report.

cause unrepresented qualifying

Spread is initiated by synthetic preformed fibrils in a host overexpressing A53T human alpha-synuclein. Aggregates purified from human sympathetic ganglia have failed to seed pathology in mouse brain, so whether the human peripheral aggregate propagates as this model's fibrils do is unsettled; see the paf_peripheral_aggregate_seeding_mismatch discussion.

Show evidence (1 reference)

PMID:32071315 SUPPORT Model organism

"induces spreading of α-Syn pathology only through the autonomic pathway to both the central nervous system (CNS) and the autonomic innervation of peripheral organs bidirectionally"

Autonomic-to-central spread of seeded pathology.

{ }

Source YAML

click to show

name: Pure Autonomic Failure
creation_date: '2026-10-24T00:18:00Z'
description: >-
  Pure autonomic failure (PAF; Bradbury-Eggleston syndrome, idiopathic orthostatic
  hypotension) is a rare, sporadic, slowly progressive adult-onset alpha-synucleinopathy
  in which misfolded alpha-synuclein accumulates predominantly in peripheral autonomic
  neurons. Degeneration and dysfunction of postganglionic sympathetic noradrenergic
  neurons cause a profound deficit in norepinephrine synthesis and release, so that
  baroreflex-mediated vasoconstriction fails on standing. The clinical picture is
  dominated by disabling neurogenic orthostatic hypotension, often with paradoxical
  supine hypertension, accompanied by bladder, bowel, sexual and sudomotor failure, but
  without motor or cognitive signs of central neurodegeneration. PAF is frequently a
  prodromal state: about a third of patients phenoconvert to Parkinson disease,
  dementia with Lewy bodies, or multiple system atrophy over several years of
  follow-up. Treatment is symptomatic and aimed at orthostatic symptoms; no
  disease-modifying therapy exists.
category: Complex
synonyms:
- Bradbury-Eggleston syndrome
- idiopathic orthostatic hypotension
- PAF
- pure dysautonomia
parents:
- Synucleinopathy
- Autonomic Nervous System Disorder
- Neurodegenerative Disease
disease_term:
  preferred_term: pure autonomic failure
  term:
    id: MONDO:0018608
    label: pure autonomic failure
prevalence:
- population: Europe
  measure_type: POINT_PREVALENCE
  prevalence_class: BAND_1_9_PER_1000000
  notes: >-
    Orphanet point-prevalence class 1-9 / 1,000,000 for Europe. The source column of
    that Orphanet row reads "PMID:2007", which is not a usable citation, so only the
    Orphanet class itself is cited. No population-based incidence study was found.
  evidence:
  - reference: ORPHA:441
    reference_title: "Pure autonomic failure"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "1-9 / 1 000 000 | Europe | Point prevalence"
    explanation: Orphanet epidemiology row giving the European point-prevalence class.
progression:
- phase: Adult-onset insidious autonomic failure
  age_range: Middle to late adulthood (pooled mean onset about 63 years)
  notes: >-
    Onset is insidious in adulthood or old age. Most non-orthostatic autonomic symptoms
    begin close to the onset of orthostatic hypotension, while dream enactment behaviour
    tends to appear years later.
  evidence:
  - reference: ORPHA:441
    reference_title: "Pure autonomic failure"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Age of onset: Elderly"
    explanation: Orphanet records elderly (and adult) onset.
  - reference: PMID:42081229
    reference_title: "Phenoconversion in Pure Autonomic Failure: A Systematic Review and Meta-Analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "A total of 9 studies comprising 900 individuals with PAF (mean ... age at onset, 63.1 ... years; 63.8% male) were included."
    explanation: Pooled mean age at onset across nine longitudinal cohorts.
  - reference: PMID:40053259
    reference_title: "The phenotype of \"pure\" autonomic failure."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Median time to dream enactment behavior onset from orthostatic hypotension was 7.00 years (1.55-13.50). Other autonomic symptoms tended to occur near orthostatic hypotension."
    explanation: Timeline of symptom onset in patients who retained the PAF phenotype.
- phase: Chronic progressive peripheral autonomic failure
  duration: Years to decades; median survival about 15 years from orthostatic symptom onset
  notes: >-
    Autonomic failure worsens on repeat testing. Survival is longer than in the other
    synucleinopathies and depends mainly on age and orthostatic hypotension severity.
    Many patients retain the pure phenotype until death.
  evidence:
  - reference: PMID:40397689
    reference_title: "Pure autonomic failure: a natural history study of the Queen Square cohort."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Median survival of patients with PAF was 15 years from orthostatic symptoms onset and was mostly influenced by age and the severity of orthostatic hypotension."
    explanation: Largest single-centre natural-history cohort (n=281, median 10 years follow-up).
  - reference: PMID:40397689
    reference_title: "Pure autonomic failure: a natural history study of the Queen Square cohort."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "repeat testing indicated worsening of autonomic failure during the disease course"
    explanation: Autonomic failure progresses over time.
  - reference: PMID:40053259
    reference_title: "The phenotype of \"pure\" autonomic failure."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Of 202 patients, 133 remained pure autonomic failure with median follow-up time of 9.05 years"
    explanation: A majority of patients keep the PAF phenotype over prolonged follow-up.
  - reference: PMID:27338613
    reference_title: "Pure Autonomic Failure."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "The prognosis for survival of PAF is better than for the other synucleinopathies."
    explanation: Review comparing prognosis across synucleinopathies.
- phase: Phenoconversion to a central synucleinopathy
  duration: About 5 percent per year in pooled data (12 percent per year in one prospective cohort)
  notes: >-
    Roughly a quarter to a third of patients presenting with PAF develop Parkinson
    disease, dementia with Lewy bodies or multiple system atrophy. Conversion to MSA
    clusters in the first years of follow-up, whereas conversion to Lewy body disorders
    occurs at a steadier rate. The annual-risk estimates differ between the
    eight-centre prospective cohort and the meta-analysis.
  evidence:
  - reference: PMID:42081229
    reference_title: "Phenoconversion in Pure Autonomic Failure: A Systematic Review and Meta-Analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "270 of 900 individuals with PAF (30%) experienced phenoconversion to a central α-synucleinopathy (12% to MSA, 11% to DLB, 7% to PD) with a pooled incidence rate of 5.09 per 100 person-years"
    explanation: Meta-analysis of nine longitudinal studies.
  - reference: PMID:42081229
    reference_title: "Phenoconversion in Pure Autonomic Failure: A Systematic Review and Meta-Analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Phenoconversion rates for MSA (pooled incidence rate, 1.96; 95% CI, 1.29-2.99) were highest in the first years of follow-up, whereas Lewy body disorders showed more constant phenoconversion rates"
    explanation: Different temporal profiles for MSA versus Lewy body conversion.
  - reference: PMID:38366572
    reference_title: "Phenoconversion in pure autonomic failure: a multicentre prospective longitudinal cohort study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients with PAF have an estimated 12% (95% CI: 9-15%) per year annual risk following study entry of phenoconverting to a manifest CNS synucleinopathy."
    explanation: Eight-centre prospective cohort estimate of annual conversion risk.
  - reference: PMID:28093795
    reference_title: "Natural history of pure autonomic failure: A United States prospective cohort."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Within 4 years of follow-up, 25 of 74 subjects (34%) developed dementia with Lewy bodies (n = 13), Parkinson disease (n = 6), or multiple system atrophy (n = 6)."
    explanation: US prospective cohort phenoconversion rate.
  - reference: PMID:32546656
    reference_title: "Predicting phenoconversion in pure autonomic failure."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Among 275 patients with PAF at presentation, 67 (24%) phenoconverted to a synucleinopathy with motor or cognitive involvement"
    explanation: Mayo Clinic retrospective cohort conversion rate.
  - reference: PMID:40397689
    reference_title: "Pure autonomic failure: a natural history study of the Queen Square cohort."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Of these, 33% (91) converted to a more widespread synucleinopathy, and 41% (115) died during follow-up, of whom 53% (61) retained a PAF phenotype."
    explanation: Queen Square cohort conversion and mortality.
clinical_burden:
  burden_level: HIGH
  rationale: >-
    Neurogenic orthostatic hypotension is disabling, causing recurrent syncope, falls
    and inability to stand for long, and is frequently complicated by supine
    hypertension that constrains treatment. About a third of patients go on to a central
    synucleinopathy. Survival is nonetheless longer than in MSA, PD or DLB.
  evidence:
  - reference: PMID:28717053
    reference_title: "Pure autonomic failure."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Patients experience symptomatic hypotension that requires them to sit, squat or lie down to prevent syncope."
    explanation: Describes the day-to-day functional burden of orthostatic hypotension.
  - reference: PMID:34176285
    reference_title: "Predictors of the Pressor Response to the Norepinephrine Transporter Inhibitor, Atomoxetine, in Neurogenic Orthostatic Hypotension."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "nOH results in cerebral hypoperfusion7 with lightheadedness, dizziness, syncope, and falls8 all being common symptoms, which contribute to morbidity, disability, and death in this population."
    explanation: Links nOH to morbidity, disability and death in synucleinopathies including PAF.
pathophysiology:
- name: Catecholaldehyde (DOPAL) Autotoxicity in Noradrenergic Neurons
  description: >-
    Dopamine that leaks from storage vesicles into the neuronal cytoplasm is deaminated
    by monoamine oxidase to 3,4-dihydroxyphenylacetaldehyde (DOPAL), an obligate
    intermediate of dopamine metabolism normally detoxified by aldehyde dehydrogenase.
    DOPAL binds covalently to the lysine-rich alpha-synuclein molecule and oligomerizes
    it far more efficiently than dopamine itself does, and the resulting oligomers
    impair vesicular storage, returning more dopamine to the cytoplasm. This is the
    catecholaldehyde hypothesis, and it is the step put forward to explain why
    alpha-synuclein precipitates in catecholaminergic neurons rather than elsewhere.
    It is placed upstream of aggregation on in vitro, postmortem and computational
    grounds only: DOPAL has not been measured in sympathetic neurons of living
    patients, and whether it accumulates in PAF specifically is unresolved.
  biological_scale: MOLECULAR
  mechanism_confidence: HYPOTHETICAL
  cell_types:
  - preferred_term: sympathetic noradrenergic neuron
    term:
      id: CL:3000002
      label: sympathetic noradrenergic neuron
  biological_processes:
  - preferred_term: monoamine oxidase-catalysed deamination of cytoplasmic dopamine
    modifier: INCREASED
    term:
      id: GO:0042420
      label: dopamine catabolic process
  chemical_entities:
  - preferred_term: 3,4-dihydroxyphenylacetaldehyde (DOPAL)
    modifier: INCREASED
    term:
      id: CHEBI:27978
      label: 3,4-dihydroxyphenylacetaldehyde
  evidence:
  - reference: PMID:34206133
    reference_title: "The Catecholaldehyde Hypothesis for the Pathogenesis of Catecholaminergic Neurodegeneration: What We Know and What We Do Not Know."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: IN_VITRO
    quote_role: REVIEW_SYNTHESIS
    snippet: "The catecholaldehyde is produced via oxidative deamination catalyzed by monoamine oxidase (MAO) acting on cytoplasmic dopamine. DOPAL is autotoxic, in that it can harm the same cells in which it is produced."
    explanation: >-
      States the biochemical route to DOPAL and its autotoxicity. Indirect for PAF: the
      chemistry is established in vitro and in animal tissue, not in patients.
  - reference: PMID:34206133
    reference_title: "The Catecholaldehyde Hypothesis for the Pathogenesis of Catecholaminergic Neurodegeneration: What We Know and What We Do Not Know."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: IN_VITRO
    quote_role: REVIEW_SYNTHESIS
    snippet: "tends to precipitate in catecholaminergic neurons in Lewy body diseases, because DOPAL potently oligomerizes, quinonizes, and aggregates"
    explanation: >-
      This is the reason the node exists: it offers a mechanism for the cell-type
      selectivity of the aggregation that PAF shares with the other Lewy body diseases.
  - reference: PMID:31744850
    reference_title: "3,4-Dihydroxyphenylacetaldehyde Is More Efficient than Dopamine in Oligomerizing and Quinonizing α-Synuclein."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: "DOPAL was far more potent than DA both in oligomerizing and forming quinone-protein adducts with (quinonizing) AS."
    explanation: >-
      Cell-free and cultured-cell comparison establishing that the DOPAL route, not
      spontaneous dopamine oxidation, is the efficient one. No patient tissue involved.
  downstream:
  - target: Peripheral Autonomic Alpha-Synuclein Aggregation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      DOPAL oligomerizes and quinonizes alpha-synuclein, which is proposed as the
      proximate chemical cause of aggregation in catecholaminergic neurons. The steps
      between an oligomer formed in vitro and a Lewy body in a human sympathetic
      ganglion are not established.
    hypothesis_groups:
    - catecholaldehyde_autotoxicity
    evidence:
    - reference: PMID:32372682
      reference_title: "\"Sick-but-not-dead\": multiple paths to catecholamine deficiency in Lewy body diseases."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: IN_VITRO
      quote_role: REVIEW_SYNTHESIS
      snippet: "DOPAL potently oligomerizes, aggregates, and forms quinone-protein adducts with (\u201cquinonizes\u201d) AS and many other intra-cellular proteins"
      explanation: >-
        States the proposed chemical step from DOPAL to aggregated alpha-synuclein in a
        review that treats PAF as one of the diseases concerned.
- name: Peripheral Autonomic Alpha-Synuclein Aggregation
  description: >-
    Misfolded, phosphorylated alpha-synuclein accumulates as Lewy bodies and Lewy
    neurites predominantly in peripheral autonomic neurons: sympathetic ganglion
    neurons and their distal axons in the heart, adrenal region, bladder and skin. CSF
    seeding assays are positive in nearly all patients, and cutaneous phosphorylated
    alpha-synuclein is found at every biopsy site. The initiating trigger is unknown.
    A rare clinically diagnosed case without any synuclein pathology shows that the
    clinical label is not always a synucleinopathy.
  biological_scale: MOLECULAR
  conforms_to: "loss_of_proteostasis#Misfolded-Protein Aggregation"
  cell_types:
  - preferred_term: sympathetic noradrenergic neuron
    term:
      id: CL:3000002
      label: sympathetic noradrenergic neuron
  biological_processes:
  - preferred_term: inclusion body assembly
    term:
      id: GO:0070841
      label: inclusion body assembly
  genes:
  - preferred_term: SNCA
    term:
      id: hgnc:11138
      label: SNCA
  locations:
  - preferred_term: sympathetic ganglion
    term:
      id: UBERON:0001806
      label: sympathetic ganglion
  evidence:
  - reference: PMID:34392300
    reference_title: "Pure autonomic failure and the differential diagnosis of autonomic peripheral neuropathies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Pure autonomic failure (PAF) is a peripheral autonomic neurodegenerative disease caused by alpha-synuclein deposition that is predominantly confined to peripheral autonomic neurons."
    explanation: Review defining PAF as a peripherally confined alpha-synucleinopathy.
  - reference: PMID:9255396
    reference_title: "The distribution of Lewy bodies in pure autonomic failure: autopsy findings and review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Postmortem findings included typical and atypical Lewy bodies in the substantia nigra, locus ceruleus, substantia innominata, and sympathetic ganglia, as well as in autonomic axons in the epicardial fat, autonomic nerve fascicles in periadrenal adipose tissue, and autonomic nerves in the muscularis of the urinary bladder."
    explanation: Autopsy showing Lewy bodies in sympathetic ganglia and distal autonomic axons.
  - reference: PMID:33881777
    reference_title: "Alpha-Synuclein Oligomers and Neurofilament Light Chain Predict Phenoconversion of Pure Autonomic Failure."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "αSyn-PMCA is almost invariably positive in the CSF of patients with PAF establishing this condition as α-synucleinopathy."
    explanation: CSF seed amplification establishes aggregated alpha-synuclein in vivo.
  - reference: PMID:26606657
    reference_title: "Skin nerve misfolded α-synuclein in pure autonomic failure and Parkinson disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "abnormal α-synuclein deposits were found in all analyzed skin samples in PAF but in only 49% of samples with a higher positivity rate at the proximal site in IPD"
    explanation: Diffuse peripheral nerve alpha-synuclein deposition in PAF.
  - reference: PMID:31178336
    reference_title: "Small fiber neuropathy and phosphorylated alpha-synuclein in the skin of E46K-SNCA mutation carriers."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "All E46K-SNCA carriers had moderate to severe p-synuclein deposits and small fiber neurodegeneration in different epidermal and dermal structures including nerve fascicles and glands, especially in carriers with Pure Autonomic Failure"
    explanation: >-
      Two carriers of the pathogenic SNCA E46K variant presented as PAF and had the
      heaviest cutaneous phosphorylated alpha-synuclein, so altered alpha-synuclein is
      sufficient to produce a PAF phenotype. Sporadic PAF carries no such variant, which
      makes this indirect support for the aggregation node.
  - reference: PMID:14736756
    reference_title: "Association between cardiac denervation and parkinsonism caused by alpha-synuclein gene triplication."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "These results indicate that both parkinsonism and cardiac sympathetic denervation can result from an excess of normal synuclein."
    explanation: >-
      In the SNCA-triplication (Iowa) kindred, cardiac sympathetic denervation
      cosegregates with the triplication, linking alpha-synuclein excess to the
      noradrenergic lesion PAF shares; the affected members had parkinsonism, not PAF.
  - reference: PMID:28188385
    reference_title: "Pure autonomic failure without synucleinopathy."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "In pure autonomic failure, sympathetic noradrenergic denervation can occur without concurrent Lewy bodies or alpha-synuclein deposition in the brain or sympathetic ganglion tissue."
    explanation: >-
      A single autopsied clinically diagnosed PAF case had sympathetic denervation with
      no alpha-synuclein pathology, so the aggregation node does not hold for every
      patient carrying the clinical label.
  downstream:
  - target: Postganglionic Sympathetic Noradrenergic Denervation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Synuclein-laden postganglionic neurons degenerate; the steps from aggregation to
      neuronal loss are not resolved in PAF.
    hypothesis_groups:
    - lewy_body_paf
  - target: Noradrenergic Vesicular Storage and Synthesis Defect
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - lewy_body_paf
  - target: Preganglionic Intermediolateral Column Neuron Loss
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - lewy_body_paf
  - target: Sudomotor Sympathetic Cholinergic Denervation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:23390175
      reference_title: "Skin sympathetic fiber α-synuclein deposits: a potential biomarker for pure autonomic failure."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Colocalization study disclosed α-synuclein neuritic inclusions in the postganglionic sympathetic adrenergic and cholinergic nerve fibers."
      explanation: Places alpha-synuclein inclusions in cholinergic (sudomotor) as well as adrenergic fibres.
  - target: Pelvic Visceral Autonomic Denervation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Cardiovagal Parasympathetic Impairment
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Subclinical Central Catecholaminergic Involvement
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: Preganglionic Lesion Without Postganglionic Lewy Pathology
  description: >-
    In the minority of patients whose PAF is the premotor phase of MSA, the
    preganglionic autonomic lesion is not accompanied by postganglionic noradrenergic
    Lewy pathology. In MSA, insoluble alpha-synuclein is deposited in glia rather than
    as neuronal Lewy bodies. These patients have higher supine norepinephrine, a
    preganglionic pattern of sweat loss, severe bladder dysfunction and raised CSF
    neurofilament light chain, and they go on to MSA.
  biological_scale: CELLULAR
  notes: >-
    No cell type is bound: the glial alpha-synuclein pathology of MSA is documented in
    established MSA, not in patients who still carry the PAF diagnosis.
  evidence:
  - reference: PMID:24095130
    reference_title: "Pure autonomic failure."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Insoluble deposits of α-synuclein are found in glia in MSA, whereas they take the form of neuronal cytoplasmic inclusions called Lewy bodies in PAF and PD."
    explanation: Contrasts the glial synucleinopathy of MSA with neuronal Lewy bodies in PAF.
  - reference: PMID:34669076
    reference_title: "Different phenoconversion pathways in pure autonomic failure with versus without Lewy bodies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Conversely, PAF without these features leaves open the possibility of premotor MSA."
    explanation: PAF lacking the postganglionic Lewy lesion may be premotor MSA.
  downstream:
  - target: Preganglionic Intermediolateral Column Neuron Loss
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - prodromal_msa_paf
    evidence:
    - reference: PMID:34669076
      reference_title: "Different phenoconversion pathways in pure autonomic failure with versus without Lewy bodies."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: "Both PAF phenotypes involve a sympathetic preganglionic lesion, but only Lewy body PAF, PD, and DLB entail a postganglionic noradrenergic lesion."
      explanation: The non-Lewy form carries the preganglionic lesion without the postganglionic one.
  - target: Spread to Central Nervous System (Phenoconversion)
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - prodromal_msa_paf
    evidence:
    - reference: PMID:33881777
      reference_title: "Alpha-Synuclein Oligomers and Neurofilament Light Chain Predict Phenoconversion of Pure Autonomic Failure."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The PMCA reaction was markedly different in five samples with maximum fluorescence and reaction kinetics previously described in MSA patients; all of these patients later developed MSA."
      explanation: An MSA-type seeding profile at PAF presentation precedes conversion to MSA.
- name: Preganglionic Intermediolateral Column Neuron Loss
  conforms_to: "neurogenic_orthostatic_hypotension#Central Baroreflex Efferent Pathway Degeneration"
  description: >-
    Sympathetic preganglionic neurons in the thoracic intermediolateral cell column are
    lost alongside the ganglionic lesion, removing central drive to the sympathetic
    ganglia. Both pathological forms of PAF are thought to involve this preganglionic
    lesion.
  biological_scale: TISSUE
  cell_types:
  - preferred_term: sympathetic preganglionic neuron
    term:
      id: CL:0000107
      label: autonomic neuron
  notes: >-
    CL has no sympathetic preganglionic neuron class (runoak -i ols:cl info
    "l~preganglionic" returns nothing). CL:0011103 sympathetic neuron is defined as
    primarily adrenergic and so does not fit cholinergic preganglionic neurons; the
    broader autonomic neuron is bound instead.
  evidence:
  - reference: PMID:9255396
    reference_title: "The distribution of Lewy bodies in pure autonomic failure: autopsy findings and review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "characterized by autonomic failure without other neurological deficits and histopathologically by cell loss in intermediolateral columns and sympathetic ganglia"
    explanation: Neuropathological hallmark of preganglionic and ganglionic cell loss.
  - reference: PMID:27338613
    reference_title: "Pure Autonomic Failure."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Autonomic failure in PAF is caused by neuronal degeneration of pre- and postganglionic sympathetic and parasympathetic neurons in the thoracic spinal cord and paravertebral autonomic ganglia."
    explanation: Review locating the lesion in pre- and postganglionic autonomic neurons.
  - reference: PMID:34669076
    reference_title: "Different phenoconversion pathways in pure autonomic failure with versus without Lewy bodies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Both PAF phenotypes involve a sympathetic preganglionic lesion, but only Lewy body PAF, PD, and DLB entail a postganglionic noradrenergic lesion."
    explanation: The preganglionic lesion is shared by Lewy and non-Lewy forms of PAF.
  downstream:
  - target: Failure of Baroreflex-Mediated Vasoconstriction
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
- name: Postganglionic Sympathetic Noradrenergic Denervation
  conforms_to: "neurogenic_orthostatic_hypotension#Postganglionic Noradrenergic Denervation"
  description: >-
    Postganglionic sympathetic noradrenergic terminals are lost from the heart, renal
    cortex, blood vessels and skin. Cardiac 18F-dopamine and 11C-methylreboxetine PET
    show reduced noradrenergic innervation, and skin biopsy shows marked postganglionic
    denervation of autonomic adnexa, in contrast to the largely preserved peripheral
    innervation of MSA. Denervation is accompanied by length-dependent somatic and
    autonomic small-fibre loss.
  biological_scale: TISSUE
  cell_types:
  - preferred_term: sympathetic noradrenergic neuron
    term:
      id: CL:3000002
      label: sympathetic noradrenergic neuron
  locations:
  - preferred_term: heart
    term:
      id: UBERON:0000948
      label: heart
  evidence:
  - reference: PMID:16269589
    reference_title: "Cardiac and extracardiac sympathetic denervation in Parkinson's disease with orthostatic hypotension and in pure autonomic failure."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Both the PD+OH group and the PAF group had decreased 6-(18)F-fluorodopamine-derived radioactivity in the heart (P < 0.0001) and renal cortex (P = 0.02 and P = 0.005, respectively)."
    explanation: PET evidence of cardiac and renal sympathetic denervation in PAF.
  - reference: PMID:32945121
    reference_title: "Cardiac sympathetic innervation and vesicular storage in pure autonomic failure."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "PAF entails moderately decreased cardiac sympathetic innervation and a substantial vesicular storage defect in residual nerves."
    explanation: Combined 11C-MRB and 18F-dopamine PET shows moderate denervation.
  - reference: PMID:20660924
    reference_title: "Autonomic innervation in multiple system atrophy and pure autonomic failure."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "MSA patients showed a generally preserved skin autonomic innervation with a significantly higher score than PAF patients showing a marked postganglionic sympathetic denervation."
    explanation: Skin biopsy shows postganglionic denervation in PAF but not MSA.
  - reference: PMID:26606657
    reference_title: "Skin nerve misfolded α-synuclein in pure autonomic failure and Parkinson disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "PAF and IPD showed length-dependent somatic and autonomic small fiber loss, more severely expressed in patients with higher p-syn load."
    explanation: Fibre loss scales with phosphorylated alpha-synuclein burden.
  downstream:
  - target: Deficient Sympathetic Norepinephrine Release
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:28717053
      reference_title: "Pure autonomic failure."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: "These lesions are responsible for defects in the synthesis and release of norepinephrine from sympathetic nerve terminals, resulting in significant hypotension."
      explanation: Review linking the peripheral lesions to deficient norepinephrine release and hypotension.
  - target: Cardiac Sympathetic Denervation
    causal_link_type: DIRECT
  - target: Adrenoceptor Denervation Supersensitivity
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
  - target: Sympathetic Deprivation with Blunted Erythropoietin Response
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
  - target: Sympathetic Pupillary Deficit
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Loss of sympathetic innervation of the iris dilator produces the pupillary deficit
      found on pupillometry.
- name: Noradrenergic Vesicular Storage and Synthesis Defect
  description: >-
    Surviving sympathetic terminals store and synthesize norepinephrine poorly. Forearm
    vein biopsies show normal norepinephrine transporter but very low tyrosine
    hydroxylase and reduced VMAT2, with a raised plasma DHPG:NE ratio; PET shows rapid
    loss of 18F-dopamine from residual cardiac nerves. Sympathetic dysfunction may
    therefore precede frank denervation.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: sympathetic noradrenergic neuron
    term:
      id: CL:3000002
      label: sympathetic noradrenergic neuron
  biological_processes:
  - preferred_term: norepinephrine biosynthetic process
    modifier: DECREASED
    term:
      id: GO:0042421
      label: norepinephrine biosynthetic process
  genes:
  - preferred_term: TH
    term:
      id: hgnc:11782
      label: TH
  evidence:
  - reference: PMID:29162745
    reference_title: "Does sympathetic dysfunction occur before denervation in pure autonomic failure?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "PAF participants were found to have normal abundance of the NE transporter (NET) protein, together with very low levels of tyrosine hydroxylase (TH) (P<0.0001) and reduced vesicular monoamine transporter 2 (VMAT2) (P<0.05) protein expression compared with control and MSA participants."
    explanation: Molecular evidence of a synthesis and vesicular storage defect in sympathetic nerves.
  - reference: PMID:32945121
    reference_title: "Cardiac sympathetic innervation and vesicular storage in pure autonomic failure."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The PAF patients had five times faster postinfusion loss of 18 F-DA-derived radioactivity (70 ± 3% vs. 14 ± 8% by 30 minutes, p < 0.0001)."
    explanation: PET evidence of a vesicular storage defect in residual cardiac nerves.
  downstream:
  - target: Deficient Sympathetic Norepinephrine Release
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:29162745
      reference_title: "Does sympathetic dysfunction occur before denervation in pure autonomic failure?"
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The finding of normal NET abundance in PAF suggests intact sympathetic nerves but with reduced NE synthesis."
      explanation: Reduced synthesis in intact nerves contributes to the norepinephrine deficit.
  - target: Catecholaldehyde (DOPAL) Autotoxicity in Noradrenergic Neurons
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Failing vesicular sequestration returns dopamine to the cytoplasm, where monoamine
      oxidase converts it to DOPAL, so the storage defect feeds the autotoxic step that
      is proposed to have caused it. This closes a self-reinforcing loop rather than
      adding a one-way step, and the loop is the form in which the catecholaldehyde
      hypothesis is stated. The vesicular defect is measured in PAF patients; its
      consequence for DOPAL levels in those patients is not.
    hypothesis_groups:
    - catecholaldehyde_autotoxicity
    evidence:
    - reference: PMID:32372682
      reference_title: "\"Sick-but-not-dead\": multiple paths to catecholamine deficiency in Lewy body diseases."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: IN_VITRO
      quote_role: REVIEW_SYNTHESIS
      snippet: "DOPAL-induced AS oligomers impede vesicular functions (Plotegher et al., 2017), which could set the stage for a damaging positive feedback loop, destroying the neurons and resulting in a variety of clinical manifestations including parkinsonism and sympathetic neurocirculatory failure."
      explanation: >-
        States the feedback loop, and names sympathetic neurocirculatory failure, the
        clinical syndrome of PAF, as one of its outcomes.
    - reference: PMID:32372682
      reference_title: "\"Sick-but-not-dead\": multiple paths to catecholamine deficiency in Lewy body diseases."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: "In PD and PAF, there is accelerated loss of myocardial 18F-DA-derived radioactivity"
      explanation: >-
        The vesicular leak that supplies cytoplasmic dopamine is demonstrated in PAF
        patients by PET, which is what makes the upstream limb of the loop more than an
        extrapolation from other diseases.
- name: Deficient Sympathetic Norepinephrine Release
  conforms_to: "neurogenic_orthostatic_hypotension#Deficient Norepinephrine Release at the Neurovascular Junction"
  description: >-
    Norepinephrine release from sympathetic terminals is profoundly reduced at rest and
    fails to rise on standing. Very low supine plasma norepinephrine is the biochemical
    signature of PAF, distinguishing it from MSA, in which postganglionic neurons are
    largely spared.
  biological_scale: CELLULAR
  biological_processes:
  - preferred_term: norepinephrine secretion, neurotransmission
    modifier: DECREASED
    term:
      id: GO:0061533
      label: norepinephrine secretion, neurotransmission
  chemical_entities:
  - preferred_term: norepinephrine
    term:
      id: CHEBI:33569
      label: noradrenaline
  evidence:
  - reference: PMID:32945121
    reference_title: "Cardiac sympathetic innervation and vesicular storage in pure autonomic failure."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Pure autonomic failure (PAF) is a rare disease characterized by neurogenic orthostatic hypotension (nOH), absence of signs of central neurodegeneration, and profound deficiency of the sympathetic neurotransmitter norepinephrine."
    explanation: Profound norepinephrine deficiency is a defining feature of PAF.
  - reference: PMID:24095130
    reference_title: "Pure autonomic failure."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "pure autonomic failure (PAF), characterized by isolated peripheral autonomic dysfunction and decreased norepinephrine synthesis; multiple system atrophy (MSA) with symptoms of a central Parkinson-like syndrome and normal resting plasma norepinephrine"
    explanation: Contrasts low norepinephrine in PAF with normal resting norepinephrine in MSA.
  downstream:
  - target: Failure of Baroreflex-Mediated Vasoconstriction
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:34176285
      reference_title: "Predictors of the Pressor Response to the Norepinephrine Transporter Inhibitor, Atomoxetine, in Neurogenic Orthostatic Hypotension."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: BACKGROUND
      snippet: "all synucleinopathies can manifest with neurogenic orthostatic hypotension (nOH) because of blunted baroreflex-mediated sympathetic activation and impaired vasoconstriction"
      explanation: States the step from sympathetic failure to impaired vasoconstriction.
  - target: Decreased circulating norepinephrine
    causal_link_type: DIRECT
- name: Failure of Baroreflex-Mediated Vasoconstriction
  conforms_to: "neurogenic_orthostatic_hypotension#Failure of Baroreflex-Mediated Vasoconstriction"
  description: >-
    On standing, the baroreflex cannot increase sympathetic vasoconstrictor outflow or
    heart rate, so peripheral resistance and venous return fall and blood pressure
    drops. The heart-rate rise is blunted relative to the fall in blood pressure, which
    is the physiological signature that separates neurogenic from non-neurogenic
    orthostatic hypotension.
  biological_scale: ORGANISM
  biological_processes:
  - preferred_term: baroreflex arterial vasoconstriction on standing
    modifier: DECREASED
    term:
      id: GO:0001987
      label: vasoconstriction of artery involved in baroreceptor response to lowering of systemic arterial blood pressure
  evidence:
  - reference: PMID:29405350
    reference_title: "Orthostatic heart rate changes in patients with autonomic failure caused by neurodegenerative synucleinopathies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients with neurogenic OH had twice the fall in systolic blood pressure (SBP; -44 ± 25 vs -21 ± 14 mmHg ... p < 0.0001) but only one-third of the increase in HR of those with nonneurogenic OH (8 ± 8 vs 25 ± 11 beats per minute ... p < 0.0001)."
    explanation: Quantifies the blunted reflex response in synucleinopathy-related nOH, including PAF.
  - reference: PMID:39608812
    reference_title: "Cutaneous phosphorylated-synuclein: an early diagnostic biomarker for pure autonomic failure."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Autonomic p-syn subscores correlated with orthostatic intolerance ratio on tilt (ρ=0.63, p=0.0004), blood pressure recovery time following Valsalva manoeuvre (r=0.44, p=0.03) and patient-reported orthostatic intolerance (ρ=0.57, p=0.006)."
    explanation: Cutaneous synuclein burden correlates with failed reflex blood pressure control; correlational, not causal.
  downstream:
  - target: Neurogenic Orthostatic Hypotension
    causal_link_type: DIRECT
  - target: Postprandial Hypotension
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
  - target: Chronotropic Incompetence on Tilt
    causal_link_type: DIRECT
  - target: Cerebral and Muscle Hypoperfusion on Standing
    causal_link_type: DIRECT
- name: Cerebral and Muscle Hypoperfusion on Standing
  conforms_to: "neurogenic_orthostatic_hypotension#Orthostatic Fall in Blood Pressure with Cerebral Hypoperfusion"
  description: >-
    The upright fall in blood pressure lowers cerebral perfusion and perfusion of
    shoulder-girdle muscles, producing light-headedness, visual disturbance, syncope,
    fatigue and the suboccipital coat-hanger pain characteristic of autonomic failure.
    Symptoms are worse in the morning, in heat, after meals and with exertion, and
    resolve on lying flat.
  biological_scale: ORGANISM
  evidence:
  - reference: PMID:10552235
    reference_title: "Symptoms associated with orthostatic hypotension in pure autonomic failure and multiple system atrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "orthostatic hypotension caused symptoms of cerebral hypoperfusion (syncope, dizziness and visual disturbances); neck pain, presumably due to muscle hypoperfusion, also occurred frequently"
    explanation: Attributes orthostatic symptoms to cerebral and muscle hypoperfusion in PAF and MSA.
  downstream:
  - target: Syncope
    causal_link_type: DIRECT
  - target: Orthostatic Light-Headedness
    causal_link_type: DIRECT
  - target: Orthostatic Visual Disturbance
    causal_link_type: DIRECT
  - target: Coat-Hanger Neck Pain
    causal_link_type: DIRECT
  - target: Orthostatic Chest Pain
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Fatigue
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Falls
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:34176285
      reference_title: "Predictors of the Pressor Response to the Norepinephrine Transporter Inhibitor, Atomoxetine, in Neurogenic Orthostatic Hypotension."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: BACKGROUND
      snippet: "nOH results in cerebral hypoperfusion7 with lightheadedness, dizziness, syncope, and falls8 all being common symptoms"
      explanation: Links cerebral hypoperfusion to falls in nOH.
- name: Cardiac Sympathetic Denervation
  description: >-
    Loss of cardiac sympathetic nerves reduces the chronotropic and inotropic reserve
    of the heart. Denervated hearts show an impaired inotropic response to tyramine,
    which depends on endogenous norepinephrine release, and exaggerated responses to
    the direct beta-agonist isoproterenol.
  biological_scale: TISSUE
  locations:
  - preferred_term: heart
    term:
      id: UBERON:0000948
      label: heart
  evidence:
  - reference: PMID:18514012
    reference_title: "Functional effects of cardiac sympathetic denervation in neurogenic orthostatic hypotension."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Among patients with NOH those with cardiac sympathetic denervation have an impaired inotropic response to tyramine and exaggerated responses to isoproterenol."
    explanation: Functional consequences of cardiac denervation in PAF and PD with nOH.
  - reference: PMID:41072204
    reference_title: "Cardiac MIBG scintigraphy in pure autonomic failure: A systematic review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Abnormal MIBG scintigraphy was observed in 33 patients (84.6 %)."
    explanation: Most clinically diagnosed PAF cases show reduced cardiac MIBG uptake.
  downstream:
  - target: Chronotropic Incompetence on Tilt
    causal_link_type: DIRECT
  - target: Resting Bradycardia
    causal_link_type: UNKNOWN
    description: >-
      Hypothesised: loss of cardiac sympathetic tone is the presumed basis of the slow,
      steady resting heart rate, but no cited source tests the link directly.
- name: Adrenoceptor Denervation Supersensitivity
  conforms_to: "neurogenic_orthostatic_hypotension#Adrenoceptor Denervation Supersensitivity"
  description: >-
    Chronic loss of sympathetic input, combined with loss of baroreflex buffering, makes
    patients unusually sensitive to small doses of pressor and beta-adrenergic agents.
    This shapes treatment: norepinephrine replacers work at low doses, while exaggerated
    pressor responses contribute to supine hypertension on therapy.
  biological_scale: CELLULAR
  evidence:
  - reference: PMID:32979782
    reference_title: "Pharmacologic treatment of orthostatic hypotension."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Denervation hypersensitivity and impairment of baroreflex buffering makes these patients sensitive to small doses of pressor agents."
    explanation: Review describing the clinical pharmacology consequence of denervation.
  - reference: PMID:18514012
    reference_title: "Functional effects of cardiac sympathetic denervation in neurogenic orthostatic hypotension."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "For similar heart rate responses, the PD+NOH/PAF group required less isoproterenol (p<0.01) and had lower plasma isoproterenol levels (p<0.01) than did the MSA group."
    explanation: Direct pharmacological evidence of beta-adrenoceptor supersensitivity in denervated hearts.
  downstream:
  - target: Supine Hypertension
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Heightened sensitivity to pressor agents makes treatment-related rises in supine
      blood pressure likely; this edge describes supine hypertension on therapy, not its
      untreated cause.
    evidence:
    - reference: PMID:32979782
      reference_title: "Pharmacologic treatment of orthostatic hypotension."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: "Denervation hypersensitivity and impairment of baroreflex buffering makes these patients sensitive to small doses of pressor agents."
      explanation: Pressor sensitivity underlies exaggerated blood pressure responses to therapy.
    - reference: PMID:9091692
      reference_title: "Efficacy of midodrine vs placebo in neurogenic orthostatic hypotension. A randomized, double-blind multicenter study. Midodrine Study Group."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: "The main adverse effects were those of pilomotor reactions, urinary retention, and supine hypertension."
      explanation: Supine hypertension is a principal adverse effect of a pressor agent in neurogenic OH.
- name: Supine Hypertension Mechanism
  conforms_to: "neurogenic_orthostatic_hypotension#Neurogenic Supine Hypertension"
  description: >-
    About half of patients have high blood pressure when lying flat despite very low
    plasma norepinephrine and suppressed renin. Raised angiotensin II and inappropriate
    mineralocorticoid receptor activation contribute; the full mechanism in PAF is not
    known.
  biological_scale: ORGANISM
  evidence:
  - reference: PMID:26644241
    reference_title: "Mineralocorticoid Receptor Activation Contributes to the Supine Hypertension of Autonomic Failure."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "we recently showed that plasma angiotensin II is elevated and acts at AT1 (angiotensin type 1) receptors to contribute to hypertension in these patients"
    explanation: Elevated angiotensin II contributes to supine hypertension despite suppressed renin.
  - reference: PMID:26644241
    reference_title: "Mineralocorticoid Receptor Activation Contributes to the Supine Hypertension of Autonomic Failure."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These findings suggest that inappropriate mineralocorticoid receptor activation contributes to the hypertension of autonomic failure"
    explanation: Eplerenone crossover study (7 of 10 patients had PAF) implicating mineralocorticoid receptor activation.
  - reference: PMID:11927799
    reference_title: "Diagnosis and treatment of supine hypertension in autonomic failure patients with orthostatic hypotension."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "the cause is not known in patients with pure autonomic failure, who have increased vascular resistance despite very low levels or plasma norepinephrine and renin activity"
    explanation: States that the mechanism in PAF is unresolved.
  downstream:
  - target: Supine Hypertension
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: Supine Pressure Natriuresis
  conforms_to: "neurogenic_orthostatic_hypotension#Nocturnal Pressure Natriuresis and Volume Depletion"
  description: >-
    High supine blood pressure overnight drives pressure natriuresis and diuresis,
    causing nocturia and overnight volume loss that worsens orthostatic hypotension the
    next morning.
  biological_scale: ORGANISM
  biological_processes:
  - preferred_term: positive regulation of renal sodium excretion by pressure natriuresis
    term:
      id: GO:0035819
      label: positive regulation of renal sodium excretion by pressure natriuresis
  evidence:
  - reference: PMID:11927799
    reference_title: "Diagnosis and treatment of supine hypertension in autonomic failure patients with orthostatic hypotension."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "about one half of these patients also suffer from supine hypertension, which induces pressure natriuresis, worsening orthostatic hypotension"
    explanation: Describes the supine hypertension to natriuresis to orthostatic hypotension loop.
  - reference: PMID:36601916
    reference_title: "Continuous Positive Airway Pressure for the Treatment of Supine Hypertension and Orthostatic Hypotension in Autonomic Failure."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "overnight CPAP lowered nighttime systolic blood pressure (maximal change -23±5 versus placebo -1±7 mmHg; P=0.023) and was associated with lower nighttime diuresis (609±84 versus placebo 1004±160 mL; P=0.004) and improved morning orthostatic tolerance"
    explanation: Lowering nocturnal pressure reduced diuresis and improved morning orthostatic tolerance, supporting the loop.
  downstream:
  - target: Nocturia
    causal_link_type: DIRECT
  - target: Neurogenic Orthostatic Hypotension
    causal_link_type: DIRECT
    description: Overnight volume loss worsens orthostatic hypotension the following morning.
- name: Sympathetic Deprivation with Blunted Erythropoietin Response
  description: >-
    Chronic sympathetic deprivation is associated with an inappropriately low
    erythropoietin response and a normocytic anemia that further lowers orthostatic
    tolerance. The evidence comes from primary autonomic failure generally rather than
    PAF alone.
  biological_scale: ORGANISM
  evidence:
  - reference: PMID:8017744
    reference_title: "The anemia of primary autonomic failure and its reversal with recombinant erythropoietin."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In seven of nine patients with autonomic failure who had hemoglobin levels less than 120 g/L, serum erythropoietin levels decreased below the 95% confidence interval corresponding to patients with iron deficiency anemia."
    explanation: Inappropriately low erythropoietin in anemic patients with primary autonomic failure.
  downstream:
  - target: Normocytic Anemia
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
- name: Sudomotor Sympathetic Cholinergic Denervation
  description: >-
    Postganglionic sympathetic cholinergic fibres to sweat glands carry alpha-synuclein
    inclusions and degenerate, producing anhidrosis and impaired thermoregulation.
  biological_scale: TISSUE
  cell_types:
  - preferred_term: sympathetic cholinergic neuron
    term:
      id: CL:3000003
      label: sympathetic cholinergic neuron
  evidence:
  - reference: PMID:40053259
    reference_title: "The phenotype of \"pure\" autonomic failure."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Autonomic testing showed moderate to severe autonomic failure with median composite autonomic score of 6 (IQR 4-8; N = 133) and median percentage anhidrosis of 51% (IQR 3-93%; N = 105)."
    explanation: Quantifies sudomotor failure in patients who retain the PAF phenotype.
  - reference: PMID:18805037
    reference_title: "Differences in skin sympathetic involvements between two chronic autonomic disorders: multiple system atrophy and pure autonomic failure."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In the PAF patients, both SkVR and SSwR were attenuated."
    explanation: Both sympathetic sweat and skin vasomotor responses are reduced in PAF.
  downstream:
  - target: Anhidrosis
    causal_link_type: DIRECT
  - target: Thermoregulatory Dysfunction
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
- name: Pelvic Visceral Autonomic Denervation
  description: >-
    Sympathetic and parasympathetic innervation of the bladder, bowel and genital organs
    is affected, with Lewy bodies found in bladder-wall autonomic nerves. This produces
    bladder dysfunction, constipation and sexual dysfunction, which usually begin close
    to the onset of orthostatic hypotension.
  biological_scale: TISSUE
  cell_types:
  - preferred_term: parasympathetic neuron
    term:
      id: CL:0011102
      label: parasympathetic neuron
  - preferred_term: sympathetic neuron
    term:
      id: CL:0011103
      label: sympathetic neuron
  evidence:
  - reference: PMID:9255396
    reference_title: "The distribution of Lewy bodies in pure autonomic failure: autopsy findings and review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Sites of autonomic nerve involvement correlated with clinical symptomatology"
    explanation: In the autopsy case with long-standing urinary symptoms, bladder autonomic nerves carried Lewy bodies.
  - reference: PMID:38129276
    reference_title: "An overview on pure autonomic failure."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Although OH is the primary symptom, the autonomic dysfunction may be more generalised, leading to genitourinary and intestinal dysfunction and sweating disorders."
    explanation: Review describing generalized autonomic involvement beyond the cardiovascular system.
  downstream:
  - target: Urinary Dysfunction
    causal_link_type: DIRECT
  - target: Constipation
    causal_link_type: DIRECT
  - target: Erectile Dysfunction
    causal_link_type: DIRECT
- name: Cardiovagal Parasympathetic Impairment
  description: >-
    Parasympathetic cardiac (vagal) control is also impaired, reducing beat-to-beat
    heart-rate variation. Mild cardiovagal impairment at presentation is instead a
    predictor of conversion to MSA, so the degree of cardiovagal failure helps separate
    peripheral Lewy-body PAF from prodromal MSA.
  biological_scale: TISSUE
  cell_types:
  - preferred_term: parasympathetic neuron
    term:
      id: CL:0011102
      label: parasympathetic neuron
  evidence:
  - reference: PMID:27338613
    reference_title: "Pure Autonomic Failure."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Autonomic failure in PAF is caused by neuronal degeneration of pre- and postganglionic sympathetic and parasympathetic neurons in the thoracic spinal cord and paravertebral autonomic ganglia."
    explanation: Parasympathetic neurons degenerate alongside sympathetic ones.
  - reference: PMID:18805037
    reference_title: "Differences in skin sympathetic involvements between two chronic autonomic disorders: multiple system atrophy and pure autonomic failure."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "CV(R-R) was low in the MSA and PAF patients, but a significant difference was found only between the PAF and control groups."
    explanation: Reduced R-R interval variation in PAF.
  - reference: PMID:28202694
    reference_title: "Pure autonomic failure: Predictors of conversion to clinical CNS involvement."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Several variables were identified to predict conversion to MSA: (1) mild degree of cardiovagal impairment"
    explanation: A milder cardiovagal deficit points toward later MSA.
  downstream:
  - target: Decreased Heart Rate Variability
    causal_link_type: DIRECT
- name: Subclinical Central Catecholaminergic Involvement
  description: >-
    Even without motor signs, Lewy pathology and catecholaminergic loss are found in the
    substantia nigra and locus coeruleus. Nigral dopaminergic denervation is as severe
    as in Parkinson disease, but striatal terminals are relatively spared, which may
    explain the absence of parkinsonism. Hyposmia and REM sleep behaviour disorder are
    the clinical markers of this central involvement.
  biological_scale: TISSUE
  cell_types:
  - preferred_term: dopaminergic neuron
    term:
      id: CL:0000700
      label: dopaminergic neuron
  - preferred_term: noradrenergic neuron
    term:
      id: CL:0008025
      label: noradrenergic neuron
  evidence:
  - reference: PMID:18363034
    reference_title: "Central dopamine deficiency in pure autonomic failure."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Surprisingly, PAF and PD entail similarly severe nigral and overall central dopaminergic denervation. There is more severe loss of striatal dopaminergic terminals in PD than in PAF and more severe loss of sympathetic noradrenergic terminals in PAF than in PD."
    explanation: PET and postmortem evidence of nigral involvement with striatal sparing in PAF.
  - reference: PMID:39825743
    reference_title: "Central Involvement in Pure Autonomic Failure: Insights from Neuromelanin-Sensitive Magnetic Resonance Imaging and (18)F-Fluorodopa-Positron Emission Tomography."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "High-LR PAF patients showed reduced contrast in the LC and SN compared with controls and low-LR PAF patients, with values similar to PD and DLB."
    explanation: Neuromelanin MRI shows locus coeruleus and nigral loss in PAF patients at high risk of conversion.
  - reference: PMID:27757562
    reference_title: "A case series of REM sleep behavior disorder in pure autonomic failure."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the presence of RBD suggests brainstem involvement in some cases of PAF"
    explanation: RBD indicates brainstem involvement.
  downstream:
  - target: Hyposmia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: REM Sleep Behavior Disorder
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Spread to Central Nervous System (Phenoconversion)
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - lewy_body_paf
- name: Spread to Central Nervous System (Phenoconversion)
  description: >-
    In a subset of patients the synucleinopathy becomes clinically manifest in the CNS,
    and the diagnosis changes to Parkinson disease, dementia with Lewy bodies or
    multiple system atrophy. Lewy-body PAF with cardiac noradrenergic denervation
    converts to Lewy body disease, whereas PAF with preserved postganglionic
    innervation, higher norepinephrine and an MSA-like CSF seeding profile converts to
    MSA. RBD is the strongest clinical predictor of any conversion.
  biological_scale: ORGANISM
  evidence:
  - reference: PMID:28093795
    reference_title: "Natural history of pure autonomic failure: A United States prospective cohort."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The presence of probable rapid eye movement (REM) sleep behavior disorder was strongly associated with the development of a manifest central nervous system (CNS) synucleinopathy (odds ratio = 7.1)."
    explanation: RBD predicts conversion to a manifest CNS synucleinopathy.
  - reference: PMID:37843677
    reference_title: "Cardiac (18)F-dopamine positron emission tomography predicts the type of phenoconversion of pure autonomic failure."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All 6 patients with low cardiac 18F-dopamine-derived radioactivity who phenoconverted during follow-up developed a central LBD, whereas none of 4 patients with consistently normal 18F-dopamine PET phenoconverted to a central LBD (p = 0.0048), 3 evolving to probable MSA"
    explanation: Cardiac denervation status predicts the type of conversion.
  - reference: PMID:33881777
    reference_title: "Alpha-Synuclein Oligomers and Neurofilament Light Chain Predict Phenoconversion of Pure Autonomic Failure."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Both NfL and the magnitude and reaction kinetics of αSyn PMCA faithfully predict which PAF patients will eventually phenoconvert to MSA."
    explanation: CSF markers predict conversion to MSA.
  - reference: PMID:42081229
    reference_title: "Phenoconversion in Pure Autonomic Failure: A Systematic Review and Meta-Analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Hyposmia was the only predictor with diagnostic value to distinguish between those with phenoconversion to PD and DLB (hyposmia pooled risk ratio, 1.88; 95% CI, 1.26-2.97) and MSA, although rapid eye movement sleep behavior disorder (RBD) and subtle motor signs were consistent predictors of phenoconversion to any central α-synucleinopathy."
    explanation: Pooled predictors of conversion and of its direction.
mechanistic_hypotheses:
- hypothesis_group_id: lewy_body_paf
  hypothesis_label: Lewy-Body PAF with Postganglionic Noradrenergic Lesion
  status: CANONICAL
  description: >-
    Most PAF is a peripheral Lewy body disease: intraneuronal alpha-synuclein
    aggregates in postganglionic sympathetic neurons cause noradrenergic denervation and
    very low norepinephrine. This form can phenoconvert to Parkinson disease or dementia
    with Lewy bodies, but not to MSA.
  evidence:
  - reference: PMID:34669076
    reference_title: "Different phenoconversion pathways in pure autonomic failure with versus without Lewy bodies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Clinical and postmortem data show that the form of PAF that involves sympathetic intraneuronal synucleinopathy and noradrenergic deficiency can phenoconvert to PD or DLB-but not to MSA."
    explanation: Review of autopsy and clinical data defining the Lewy-body form.
- hypothesis_group_id: prodromal_msa_paf
  hypothesis_label: Non-Lewy PAF as Premotor Multiple System Atrophy
  status: ALTERNATIVE
  description: >-
    A minority of patients diagnosed with PAF have a preganglionic lesion without the
    postganglionic noradrenergic lesion: higher supine norepinephrine, normal cardiac
    sympathetic imaging, preserved smell, younger onset, severe bladder failure, raised
    CSF neurofilament light chain and an MSA-like seeding profile. These patients are in
    the premotor phase of MSA rather than having a peripheral Lewy body disease.
  evidence:
  - reference: PMID:34669076
    reference_title: "Different phenoconversion pathways in pure autonomic failure with versus without Lewy bodies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Conversely, PAF without these features leaves open the possibility of premotor MSA."
    explanation: Defines the non-Lewy form as possible premotor MSA.
  - reference: PMID:28202694
    reference_title: "Pure autonomic failure: Predictors of conversion to clinical CNS involvement."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Several variables were identified to predict conversion to MSA: (1) mild degree of cardiovagal impairment, (2) preganglionic pattern of sweat loss, (3) severe bladder dysfunction, (4) supine norepinephrine >100 pg/mL, and (5) subtle motor signs at first presentation."
    explanation: Clinical and biochemical profile of PAF patients who convert to MSA.
  - reference: PMID:33881777
    reference_title: "Alpha-Synuclein Oligomers and Neurofilament Light Chain Predict Phenoconversion of Pure Autonomic Failure."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "NfL at baseline was elevated only in patients who later developed MSA, perfectly separating those from future PD and DLB converters as well as non-converters."
    explanation: CSF NfL distinguishes future MSA converters.
  - reference: PMID:35790426
    reference_title: "Diagnosing Premotor Multiple System Atrophy: Natural History and Autonomic Testing in an Autopsy-Confirmed Cohort."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A third (5/15) were initially diagnosed with pure autonomic failure (PAF) before evolving into MSA. All these patients had normal supine plasma noradrenaline levels (332.0 ± 120.3 pg/mL) with no rise on head-up tilt (0.1 ± 0.3 pg/mL)."
    explanation: >-
      Autopsy-confirmed MSA cases first diagnosed as PAF had normal supine
      noradrenaline, the preserved-postganglionic profile that defines this hypothesis.
- hypothesis_group_id: catecholaldehyde_autotoxicity
  hypothesis_label: Catecholaldehyde (DOPAL) Autotoxicity as the Trigger for Aggregation
  status: EMERGING
  description: >-
    Aggregation in PAF is not the first event. On this account the initiating step is a
    shift of dopamine from vesicular stores into the cytoplasm, where monoamine oxidase
    produces the autotoxic aldehyde DOPAL; DOPAL then oligomerizes alpha-synuclein, and
    the oligomers further degrade vesicular storage, forming a positive feedback loop
    that destroys the neuron over a long preclinical period. The hypothesis is
    attractive for PAF because it explains the cell-type selectivity of the lesion, and
    because the vesicular storage defect it requires is independently measured in PAF
    patients. What is missing is any measurement of DOPAL in PAF neurons, and testing in
    animals has been obstructed by the secondary effects of the drugs used to
    manipulate the pathway. It is recorded as EMERGING for that reason, and the edges
    belonging to it are tagged so they can be read separately from the canonical chain.
  evidence:
  - reference: PMID:34206133
    reference_title: "The Catecholaldehyde Hypothesis for the Pathogenesis of Catecholaminergic Neurodegeneration: What We Know and What We Do Not Know."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: IN_VITRO
    quote_role: REVIEW_SYNTHESIS
    snippet: "DOPAL potently oligomerizes αS, and αS oligomers impede vesicular and mitochondrial functions, shifting the fate of cytoplasmic dopamine toward the MAO-catalyzed formation of DOPAL-destabilizing vicious cycles."
    explanation: Statement of the hypothesis, including the feedback loop that defines it.
  - reference: PMID:34206133
    reference_title: "The Catecholaldehyde Hypothesis for the Pathogenesis of Catecholaminergic Neurodegeneration: What We Know and What We Do Not Know."
    supports: NO_EVIDENCE
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "there has been insufficient testing of the catecholaldehyde hypothesis in animal models"
    explanation: >-
      The author of the hypothesis records that the animal work needed to test it has
      not been done, which is why this group is EMERGING rather than ALTERNATIVE. Graded
      NO_EVIDENCE because the sentence reports no animal result in either direction: it
      says the experiment is missing, not that it was run and the hypothesis failed.
  - reference: PMID:35621196
    reference_title: "Modeling the Progression of Cardiac Catecholamine Deficiency in Lewy Body Diseases."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: COMPUTATIONAL
    snippet: "The model combines cardiac sympathetic activation with autotoxicity mediated by the dopamine metabolite 3,4-dihydroxyphenylacetaldehyde."
    explanation: >-
      A computational model of cardiac noradrenergic decline built on this mechanism
      reproduces serial 18F-dopamine PET data from Lewy body disease patients, PAF
      among them. Agreement of a model with data is indirect support for its mechanism.
- hypothesis_group_id: sympathetic_body_first_origin
  hypothesis_label: Sympathetic-Predominant Body-First Origin of the Pathology
  status: EMERGING
  description: >-
    Where the pathology starts, as distinct from what makes it start. Postmortem
    staging of Lewy body disease separates cases whose pathology appears first in
    peripheral autonomic tissue (body-first) from those where it appears first in the
    olfactory bulb and amygdala (brain-first), and splits the body-first group again
    into a vagal-predominant and a sympathetic-predominant subtype in roughly equal
    numbers. A purely peripheral, sympathetically dominated synucleinopathy, which is
    what PAF is, fits the sympathetic-predominant subtype, and this would make PAF the
    clinically isolated form of a distribution pattern that is otherwise observed on
    its way to Parkinson disease or dementia with Lewy bodies. The evidence is
    autopsy-based and drawn from cohorts classified as incidental Lewy body disease,
    PD or DLB; no PAF case series has been staged this way, so the alignment is
    inferred rather than shown.
  evidence:
  - reference: PMID:40082617
    reference_title: Sympathetic and parasympathetic subtypes of body-first Lewy body disease observed in postmortem tissue from prediagnostic individuals.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "we identified two distinct body-first subtypes, one with vagal predominance and another with sympathetic predominance, in equal proportions"
    explanation: >-
      Establishes a sympathetic-predominant peripheral-onset subtype in 302 autopsied
      Lewy-positive cases. None was a PAF case, which is why this is indirect.
  - reference: PMID:40082617
    reference_title: Sympathetic and parasympathetic subtypes of body-first Lewy body disease observed in postmortem tissue from prediagnostic individuals.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "In body-first LBD, isolated Lewy pathology in the sympathetic PNS is frequent, suggesting that the gut-to-sympathetic propagation route is as important as the vagal gut-to-DMV propagation route."
    explanation: >-
      Isolated sympathetic pathology with no central involvement is the anatomical
      counterpart of the PAF phenotype, and it is common rather than exceptional.
phenotypes:
- name: Neurogenic Orthostatic Hypotension
  category: Cardiovascular
  frequency: OBLIGATE
  diagnostic: true
  description: >-
    A sustained fall in blood pressure on standing or head-up tilt with a blunted
    heart-rate response, typically severe enough to cause syncope. It is the defining
    feature of the disease.
  phenotype_term:
    preferred_term: Neurogenic orthostatic hypotension
    term:
      id: HP:0004926
      label: Orthostatic hypotension due to autonomic dysfunction
    clinical_course: PROGRESSIVE
  evidence:
  - reference: ORPHA:441
    reference_title: "Pure autonomic failure"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001278 | Orthostatic hypotension | Very frequent (99-80%)"
    explanation: Orphanet annotates orthostatic hypotension as very frequent.
  - reference: PMID:34669076
    reference_title: "Different phenoconversion pathways in pure autonomic failure with versus without Lewy bodies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "PAF is defined clinically by nOH without an identified secondary cause or clinical evidence of motor or cognitive impairment attributable to central nervous system neurodegeneration"
    explanation: nOH is the defining clinical criterion.
- name: Supine Hypertension
  category: Cardiovascular
  frequency: FREQUENT
  description: >-
    Systolic blood pressure of 140 mmHg or more (or diastolic 90 mmHg or more) when
    supine, falling on standing. It occurs in about half of patients without treatment
    and is worsened by pressor drugs; untreated it may cause hypertensive organ damage.
  phenotype_term:
    preferred_term: Neurogenic supine hypertension
    term:
      id: HP:0000822
      label: Hypertension
  notes: >-
    HPO has no supine hypertension term (runoak -i sqlite:obo:hp info "l~supine" returns
    nothing), so the parent Hypertension is bound and the posture is carried in
    preferred_term.
  sequelae:
  - target: Supine Pressure Natriuresis
  evidence:
  - reference: PMID:11927799
    reference_title: "Diagnosis and treatment of supine hypertension in autonomic failure patients with orthostatic hypotension."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "about one half of these patients also suffer from supine hypertension"
    explanation: Frequency of supine hypertension in autonomic failure with orthostatic hypotension.
  - reference: PMID:15633433
    reference_title: "[Orthostatic hypotension and supine hypertension in pure autonomic failure]."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "On examination, orthostatic hypotension and supine hypertension were detected in the absence of pharmacological therapy. All the patients presented hypertensive organ disease."
    explanation: Case series of untreated PAF patients with supine hypertension and organ damage.
  - reference: PMID:29766366
    reference_title: "Consensus statement on the definition of neurogenic supine hypertension in cardiovascular autonomic failure by the American Autonomic Society (AAS) and the European Federation of Autonomic Societies (EFAS) : Endorsed by the European Academy of Neurology (EAN) and the European Society of Hypertension (ESH)."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "In patients with neurogenic orthostatic hypotension, nSH is defined as systolic BP ≥ 140 mmHg and/or diastolic BP ≥ 90 mmHg, measured after at least 5 min of rest in the supine position."
    explanation: Consensus definition of neurogenic supine hypertension.
- name: Syncope
  category: Cardiovascular
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Orthostatic syncope
    term:
      id: HP:0012670
      label: Orthostatic syncope
  evidence:
  - reference: PMID:10552235
    reference_title: "Symptoms associated with orthostatic hypotension in pure autonomic failure and multiple system atrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The most common posturally related symptoms were dizziness (84% PAF, 83% MSA), syncope (91% PAF, 45% MSA)"
    explanation: Syncope in 91% of 32 PAF patients.
  - reference: ORPHA:441
    reference_title: "Pure autonomic failure"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001279 | Syncope | Frequent (79-30%)"
    explanation: Orphanet records syncope as frequent; the questionnaire series reports a higher rate.
- name: Orthostatic Light-Headedness
  category: Neurological
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Orthostatic dizziness and light-headedness
    term:
      id: HP:0031972
      label: Presyncope
  evidence:
  - reference: PMID:10552235
    reference_title: "Symptoms associated with orthostatic hypotension in pure autonomic failure and multiple system atrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The most common posturally related symptoms were dizziness (84% PAF, 83% MSA)"
    explanation: Postural dizziness in 84% of PAF patients.
- name: Orthostatic Visual Disturbance
  category: Neurological
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Visual disturbance on standing
    term:
      id: HP:0000505
      label: Visual impairment
  evidence:
  - reference: PMID:10552235
    reference_title: "Symptoms associated with orthostatic hypotension in pure autonomic failure and multiple system atrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "visual disturbances (75% PAF, 53% MSA)"
    explanation: Postural visual disturbance in 75% of PAF patients.
- name: Coat-Hanger Neck Pain
  category: Musculoskeletal
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Suboccipital and paracervical coat-hanger pain on standing
    term:
      id: HP:0030833
      label: Neck pain
  evidence:
  - reference: PMID:10552235
    reference_title: "Symptoms associated with orthostatic hypotension in pure autonomic failure and multiple system atrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "suboccipital/paracervical 'coat-hanger' neck pain (8 l% PAF, 53% MSA)"
    explanation: Coat-hanger pain in 81% of PAF patients (the source text renders 81 as "8 l").
- name: Orthostatic Chest Pain
  category: Cardiovascular
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Orthostatic chest pain
    term:
      id: HP:0100749
      label: Chest pain
  evidence:
  - reference: PMID:10552235
    reference_title: "Symptoms associated with orthostatic hypotension in pure autonomic failure and multiple system atrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Chest pain occurred mainly in patients with PAF (44% PAF, 13% MSA)."
    explanation: Chest pain in 44% of PAF patients.
- name: Fatigue
  category: Constitutional
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Fatigue
    term:
      id: HP:0012378
      label: Fatigue
  evidence:
  - reference: PMID:10552235
    reference_title: "Symptoms associated with orthostatic hypotension in pure autonomic failure and multiple system atrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Non-specific symptoms (weakness, lethargy and fatigue) were common in both groups (91% PAF, 85% MSA)"
    explanation: Non-specific weakness, lethargy and fatigue in 91% of PAF patients.
- name: Falls
  category: Neurological
  phenotype_term:
    preferred_term: Falls
    term:
      id: HP:0002527
      label: Falls
  evidence:
  - reference: PMID:33705537
    reference_title: "Neurogenic Orthostatic Hypotension. Lessons From Synucleinopathies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "The goal of treatment is not to normalize blood pressure but rather to improve quality of life and prevent syncope and falls by reducing symptoms of cerebral hypoperfusion."
    explanation: Falls are a principal complication targeted by treatment of nOH in synucleinopathies including PAF.
- name: Postprandial Hypotension
  category: Cardiovascular
  description: >-
    Blood pressure falls after meals, both supine and on tilt, unmasking or worsening
    orthostatic hypotension.
  phenotype_term:
    preferred_term: Postprandial hypotension
    term:
      id: HP:0002615
      label: Hypotension
  notes: >-
    HPO has no postprandial hypotension term (runoak -i sqlite:obo:hp info
    "l~postprandial" returns only postprandial hyperlactemia, hyperglycemia, fullness and
    exacerbation), so Hypotension is bound.
  evidence:
  - reference: PMID:8492945
    reference_title: "Cardiovascular and hormonal responses to liquid food challenge in idiopathic Parkinson's disease, multiple system atrophy, and pure autonomic failure."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "After food, supine BP fell in IPD, but to a greater extent in MSA and PAF."
    explanation: Liquid-meal challenge shows marked postprandial hypotension in PAF.
- name: Chronotropic Incompetence on Tilt
  category: Cardiovascular
  description: >-
    Heart rate rises little during the orthostatic fall in blood pressure; a
    heart-rate-to-systolic-pressure change ratio below 0.5 bpm/mmHg indicates a
    neurogenic cause.
  phenotype_term:
    preferred_term: Blunted orthostatic heart-rate response
    term:
      id: HP:0033992
      label: Chronotropic incompetence
  evidence:
  - reference: PMID:29405350
    reference_title: "Orthostatic heart rate changes in patients with autonomic failure caused by neurodegenerative synucleinopathies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A blunted HR increase during hypotension suggests a neurogenic cause. A ΔHR/ΔSBP ratio < 0.5 bpm/mmHg is diagnostic of neurogenic OH."
    explanation: Defines the blunted heart-rate response of neurogenic OH.
- name: Resting Bradycardia
  category: Cardiovascular
  description: >-
    A slow, steady resting heart rate was part of the original Bradbury-Eggleston
    description and characterizes patients who keep the PAF phenotype.
  phenotype_term:
    preferred_term: Slow steady resting heart rate
    term:
      id: HP:0001662
      label: Bradycardia
  evidence:
  - reference: PMID:24095130
    reference_title: "Pure autonomic failure."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "A 1925 report by Bradbury and Eggleston first described patients with extreme orthostatic hypotension and a low, steady heart rate."
    explanation: Historical description of the low steady heart rate.
  - reference: PMID:28093795
    reference_title: "Natural history of pure autonomic failure: A United States prospective cohort."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The small group of patients retaining the pure autonomic failure phenotype had very low plasma norepinephrine levels, slow resting heart rate, no REM sleep behavior disorder, and preserved smell."
    explanation: Slow resting heart rate marks patients who remain PAF.
- name: Decreased Heart Rate Variability
  category: Cardiovascular
  phenotype_term:
    preferred_term: Decreased heart rate variability
    term:
      id: HP:0031861
      label: Decreased heart rate variability
  evidence:
  - reference: PMID:18805037
    reference_title: "Differences in skin sympathetic involvements between two chronic autonomic disorders: multiple system atrophy and pure autonomic failure."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "CV(R-R) was low in the MSA and PAF patients, but a significant difference was found only between the PAF and control groups."
    explanation: Reduced R-R interval variation (cardiovagal impairment) in PAF.
- name: Decreased circulating norepinephrine
  category: Laboratory
  frequency: VERY_FREQUENT
  diagnostic: true
  phenotype_term:
    preferred_term: Low supine plasma norepinephrine
    term:
      id: HP:0034874
      label: Decreased circulating norepinephrine concentration
  evidence:
  - reference: ORPHA:441
    reference_title: "Pure autonomic failure"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0012099 | Abnormality of circulating catecholamine level | Very frequent (99-80%)"
    explanation: Orphanet annotates abnormal circulating catecholamines as very frequent.
  - reference: PMID:40696849
    reference_title: "Multimodal Autonomic Biomarkers Predict Phenoconversion in Pure Autonomic Failure."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients with PAF had more severe orthostatic hypotension, lower supine plasma noradrenaline, and frequent sympathetic pupillary deficits at initial assessment than MSA and LBD."
    explanation: Supine noradrenaline is lower in PAF than in MSA or Lewy body disease.
- name: Sympathetic Pupillary Deficit
  category: Neurological
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Sympathetic pupillary deficit
    term:
      id: HP:0007686
      label: Abnormal pupillary function
  evidence:
  - reference: PMID:40696849
    reference_title: "Multimodal Autonomic Biomarkers Predict Phenoconversion in Pure Autonomic Failure."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients with PAF had more severe orthostatic hypotension, lower supine plasma noradrenaline, and frequent sympathetic pupillary deficits at initial assessment than MSA and LBD."
    explanation: Pupillometry shows frequent sympathetic deficits in PAF.
- name: Anhidrosis
  category: Dermatological
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Anhidrosis
    term:
      id: HP:0000970
      label: Anhidrosis
  evidence:
  - reference: ORPHA:441
    reference_title: "Pure autonomic failure"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000970 | Anhidrosis | Very frequent (99-80%)"
    explanation: Orphanet annotates anhidrosis as very frequent.
  - reference: PMID:40053259
    reference_title: "The phenotype of \"pure\" autonomic failure."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "median percentage anhidrosis of 51% (IQR 3-93%; N = 105)"
    explanation: Thermoregulatory sweat testing quantifies the extent of anhidrosis.
- name: Thermoregulatory Dysfunction
  category: Constitutional
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Thermoregulatory dysfunction
    term:
      id: HP:0004370
      label: Abnormality of temperature regulation
  evidence:
  - reference: PMID:40053259
    reference_title: "The phenotype of \"pure\" autonomic failure."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "thermoregulatory dysfunction (N = 51; 38%)"
    explanation: Thermoregulatory symptoms in 38% of patients who remained PAF.
- name: Urinary Dysfunction
  category: Genitourinary
  frequency: FREQUENT
  description: >-
    Bladder symptoms occur in most patients; severe dysfunction with incontinence or
    catheterization is present in over a third and is a predictor of conversion to MSA.
  phenotype_term:
    preferred_term: Neurogenic bladder dysfunction
    term:
      id: HP:0000011
      label: Neurogenic bladder
  evidence:
  - reference: PMID:40053259
    reference_title: "The phenotype of \"pure\" autonomic failure."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "bladder symptoms (N = 78; 59%), which were severe in 50 patients (37.6%) with incontinence or requiring catheterization"
    explanation: Frequency and severity of bladder dysfunction in patients who remained PAF.
  - reference: ORPHA:441
    reference_title: "Pure autonomic failure"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000020 | Urinary incontinence | Frequent (79-30%)"
    explanation: Orphanet annotates urinary incontinence as frequent.
- name: Constipation
  category: Gastrointestinal
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Constipation
    term:
      id: HP:0002019
      label: Constipation
  evidence:
  - reference: PMID:40053259
    reference_title: "The phenotype of \"pure\" autonomic failure."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Additional autonomic symptoms included constipation (N = 60; 45%)"
    explanation: Constipation in 45% of patients who remained PAF.
  - reference: ORPHA:441
    reference_title: "Pure autonomic failure"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002019 | Constipation | Frequent (79-30%)"
    explanation: Orphanet annotates constipation as frequent.
- name: Erectile Dysfunction
  category: Genitourinary
  phenotype_term:
    preferred_term: Sexual and erectile dysfunction
    term:
      id: HP:0008652
      label: Autonomic erectile dysfunction
  notes: >-
    Frequency is omitted because sources disagree: Orphanet annotates impotence as
    occasional, while a Mayo series reports sexual dysfunction (not restricted to men or
    to erectile failure) in 40%.
  evidence:
  - reference: ORPHA:441
    reference_title: "Pure autonomic failure"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000802 | Impotence | Occasional (29-5%)"
    explanation: Orphanet annotates impotence as occasional.
  - reference: PMID:40053259
    reference_title: "The phenotype of \"pure\" autonomic failure."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "sexual dysfunction (N = 53; 40%)"
    explanation: Sexual dysfunction in 40% of patients who remained PAF.
- name: Nocturia
  category: Genitourinary
  phenotype_term:
    preferred_term: Nocturia from supine pressure natriuresis
    term:
      id: HP:0000017
      label: Nocturia
  evidence:
  - reference: PMID:36601916
    reference_title: "Continuous Positive Airway Pressure for the Treatment of Supine Hypertension and Orthostatic Hypotension in Autonomic Failure."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "was associated with lower nighttime diuresis (609±84 versus placebo 1004±160 mL; P=0.004)"
    explanation: >-
      Nighttime diuresis of about a litre on placebo, reduced by lowering nocturnal blood
      pressure, documents pressure-driven nocturnal urine output in autonomic failure.
- name: Normocytic Anemia
  category: Hematological
  description: >-
    Anemia with inappropriately low erythropoietin. The 38% figure comes from a mixed
    primary autonomic failure cohort, so no PAF-specific frequency is recorded.
  phenotype_term:
    preferred_term: Normocytic anemia with low erythropoietin
    term:
      id: HP:0001897
      label: Normocytic anemia
  evidence:
  - reference: PMID:8017744
    reference_title: "The anemia of primary autonomic failure and its reversal with recombinant erythropoietin."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Anemia was present in 32 of 84 patients (38%; 95% Cl, 27% to 50%)."
    explanation: Anemia in 38% of patients with primary autonomic failure (a group including but not limited to PAF).
  - reference: PMID:8017744
    reference_title: "The anemia of primary autonomic failure and its reversal with recombinant erythropoietin."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "mean corpuscular volume, 89 fL"
    explanation: Normal MCV indicates a normocytic anemia.
- name: Hyposmia
  category: Neurological
  description: >-
    Reduced smell identification, milder than in Parkinson disease in one series and
    similar in another; it predicts conversion to Lewy body disease rather than MSA.
  phenotype_term:
    preferred_term: Hyposmia
    term:
      id: HP:0004409
      label: Hyposmia
  evidence:
  - reference: PMID:19433741
    reference_title: "Hyposmia in pure autonomic failure."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Hyposmia may be a feature of pure autonomic failure (PAF), but to a lesser degree than that found in Parkinson disease."
    explanation: UPSIT study of 16 PAF patients.
  - reference: PMID:19201246
    reference_title: "Olfactory dysfunction in pure autonomic failure: Implications for the pathogenesis of Lewy body diseases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The PAF group had a low mean UPSIT score (22+/-3), similar to that in PD (20+/-2) and lower than in MSA (31+/-2, p=0.004)."
    explanation: UPSIT scores in PAF were similar to PD.
- name: REM Sleep Behavior Disorder
  category: Neurological
  frequency: FREQUENT
  description: >-
    Dream enactment behaviour is endorsed by about half of patients, usually years after
    the onset of orthostatic hypotension, and strongly predicts phenoconversion. An
    early small series found none, so the frequency depends on case selection.
  phenotype_term:
    preferred_term: REM sleep behavior disorder
    term:
      id: HP:5200291
      label: REM sleep behavior disorder
  evidence:
  - reference: PMID:40053259
    reference_title: "The phenotype of \"pure\" autonomic failure."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Assessment of dream enactment behavior was completed in 86 patients and endorsed in 45 patients (52%)."
    explanation: Dream enactment in 52% of assessed patients who remained PAF.
  - reference: PMID:27757562
    reference_title: "A case series of REM sleep behavior disorder in pure autonomic failure."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Five out of 8 (63 %) met diagnostic criteria for RBD, confirmed on vPSG."
    explanation: Polysomnography-confirmed RBD in a small PAF series.
  - reference: PMID:9598693
    reference_title: "REM sleep behaviour disorder differentiates pure autonomic failure from multiple system atrophy with autonomic failure."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "RBD remained absent in the remaining six patients with pure autonomic failure."
    explanation: An early prospective series found no RBD in six PAF patients.
histopathology:
- name: Lewy Bodies in Sympathetic Ganglia and Distal Autonomic Axons
  description: >-
    Typical and atypical Lewy bodies in sympathetic ganglia and in distal autonomic
    axons (epicardial, periadrenal, bladder wall), with Lewy bodies also in substantia
    nigra and locus coeruleus despite the absence of motor signs.
  diagnostic: true
  evidence:
  - reference: PMID:9255396
    reference_title: "The distribution of Lewy bodies in pure autonomic failure: autopsy findings and review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Systemic autopsy results should be reviewed carefully in patients with PAF, as Lewy bodies in this disease may be seen in distal axons at a great length from their primary cell bodies."
    explanation: Autopsy finding of distal axonal Lewy bodies in PAF.
- name: Neuronal Loss in Intermediolateral Columns and Sympathetic Ganglia
  evidence:
  - reference: PMID:9255396
    reference_title: "The distribution of Lewy bodies in pure autonomic failure: autopsy findings and review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "histopathologically by cell loss in intermediolateral columns and sympathetic ganglia"
    explanation: Characteristic neuronal loss in PAF.
- name: Cutaneous Phosphorylated Alpha-Synuclein in Autonomic Nerve Fibres
  description: >-
    Phosphorylated alpha-synuclein deposits in dermal autonomic nerves (sweat glands,
    arrector pili, blood vessels) on punch skin biopsy, with a heavier burden than in
    MSA and absence in non-synuclein autonomic neuropathies.
  diagnostic: true
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:39608812
    reference_title: "Cutaneous phosphorylated-synuclein: an early diagnostic biomarker for pure autonomic failure."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "P-syn was present in 22/22 (100%) PAF biopsies, 19/26 (73%) MSA biopsies and 0/22 (0%) non-synucleinopathy biopsies."
    explanation: Skin biopsy positivity in PAF, MSA and non-synuclein autonomic failure.
  - reference: PMID:23390175
    reference_title: "Skin sympathetic fiber α-synuclein deposits: a potential biomarker for pure autonomic failure."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "all patients with PAF showed α-synuclein deposits, which were absent in patients with acquired autonomic neuropathy"
    explanation: Distinguishes PAF from acquired autonomic neuropathy.
imaging_findings:
- name: Reduced Cardiac Sympathetic Innervation on 18F-Dopamine PET
  modality: PET
  diagnostic: true
  description: >-
    Low myocardial 18F-dopamine-derived radioactivity indicates cardiac noradrenergic
    denervation. Low uptake predicts conversion to Lewy body disease, while normal uptake
    points toward MSA.
  located_in:
    preferred_term: heart
    term:
      id: UBERON:0000948
      label: heart
  evidence:
  - reference: PMID:16269589
    reference_title: "Cardiac and extracardiac sympathetic denervation in Parkinson's disease with orthostatic hypotension and in pure autonomic failure."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Both the PD+OH group and the PAF group had decreased 6-(18)F-fluorodopamine-derived radioactivity in the heart (P < 0.0001)"
    explanation: Cardiac PET shows reduced sympathetic innervation in PAF.
  - reference: PMID:37843677
    reference_title: "Cardiac (18)F-dopamine positron emission tomography predicts the type of phenoconversion of pure autonomic failure."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Cardiac 18F-dopamine PET can predict the type of phenoconversion of PAF."
    explanation: Prognostic value of cardiac PET.
- name: Reduced Cardiac MIBG Uptake
  modality: OTHER
  notes: 123I-MIBG myocardial scintigraphy (planar or SPECT).
  frequency: VERY_FREQUENT
  located_in:
    preferred_term: heart
    term:
      id: UBERON:0000948
      label: heart
  evidence:
  - reference: PMID:41072204
    reference_title: "Cardiac MIBG scintigraphy in pure autonomic failure: A systematic review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "MIBG scintigraphy showed abnormal cardiac uptake in most patients with clinical PAF. Conversely, preserved MIBG uptake may be associated with a high probability of phenoconversion, particularly to MSA."
    explanation: Systematic review of 39 cases.
- name: Abnormal Dopamine Transporter SPECT Before Phenoconversion
  modality: SPECT
  description: >-
    DaTSCAN is abnormal in a subset of patients years before motor signs, and most of
    them go on to a more widespread synucleinopathy.
  evidence:
  - reference: PMID:40397689
    reference_title: "Pure autonomic failure: a natural history study of the Queen Square cohort."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Overall, 39% of patients had abnormal DaTSCAN results up to 7 years before phenoconversion, with 84% of these patients progressing to more widespread synucleinopathy."
    explanation: Prodromal striatal dopaminergic deficit on DaTSCAN.
- name: Reduced Neuromelanin MRI Signal in Locus Coeruleus and Substantia Nigra
  modality: MRI
  description: Seen in PAF patients at high risk of conversion, with values similar to PD and DLB.
  evidence:
  - reference: PMID:39825743
    reference_title: "Central Involvement in Pure Autonomic Failure: Insights from Neuromelanin-Sensitive Magnetic Resonance Imaging and (18)F-Fluorodopa-Positron Emission Tomography."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "High-LR PAF patients showed reduced contrast in the LC and SN compared with controls and low-LR PAF patients, with values similar to PD and DLB."
    explanation: Neuromelanin-sensitive MRI evidence of early central involvement.
biochemical:
- name: Supine plasma norepinephrine
  presence: Decreased
  biomarker_term:
    preferred_term: plasma norepinephrine
    term:
      id: CHEBI:33569
      label: noradrenaline
  loinc_term:
    id: LOINC:14852-8
    label: Norepinephrine [Moles/volume] in Plasma
  notes: >-
    Very low supine values are typical of PAF. Published conversion thresholds are
    stated in mass units: supine norepinephrine above 100 pg/mL (Mayo) and at or above
    200 pg/mL (London cohorts) predict phenoconversion, especially to MSA. They are
    recorded here as prose rather than interpretation bands because the bound LOINC code
    is the molar plasma norepinephrine code.
  readouts:
  - target: Deficient Sympathetic Norepinephrine Release
    relationship: READOUT_OF
    direction: POSITIVE
    interpretation: Plasma norepinephrine at rest reflects postganglionic noradrenergic integrity.
    evidence:
    - reference: PMID:34176285
      reference_title: "Predictors of the Pressor Response to the Norepinephrine Transporter Inhibitor, Atomoxetine, in Neurogenic Orthostatic Hypotension."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: BACKGROUND
      snippet: "Plasma norepinephrine (NE) levels while resting supine, a biomarker of the integrity of sympathetic post-ganglionic neurons, are frequently normal in MSA but low in PAF and PD."
      explanation: Supine plasma NE as a readout of postganglionic integrity.
  - target: Spread to Central Nervous System (Phenoconversion)
    relationship: PREDICTS
    direction: THRESHOLD_DEPENDENT
    interpretation: Higher supine norepinephrine predicts conversion, particularly to MSA.
    evidence:
    - reference: PMID:40696849
      reference_title: "Multimodal Autonomic Biomarkers Predict Phenoconversion in Pure Autonomic Failure."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "50/194 (26%) with PAF phenoconverted to MSA or LBD after a median of 13 years, with normal pupils, heart rate response to deep breathing ≥ 10 bpm, and supine plasma noradrenaline ≥ 200 pg/mL predicting future phenoconversion to MSA or LBD"
      explanation: Supine noradrenaline threshold predicting phenoconversion.
  evidence:
  - reference: PMID:28093795
    reference_title: "Natural history of pure autonomic failure: A United States prospective cohort."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The small group of patients retaining the pure autonomic failure phenotype had very low plasma norepinephrine levels"
    explanation: Very low plasma norepinephrine characterizes stable PAF.
- name: Plasma DHPG to norepinephrine ratio
  presence: Increased
  biomarker_term:
    preferred_term: 3,4-dihydroxyphenylglycol to norepinephrine ratio
  readouts:
  - target: Noradrenergic Vesicular Storage and Synthesis Defect
    relationship: READOUT_OF
    direction: POSITIVE
    interpretation: A raised ratio indicates intraneuronal norepinephrine metabolism exceeding vesicular sequestration.
    evidence:
    - reference: PMID:29162745
      reference_title: "Does sympathetic dysfunction occur before denervation in pure autonomic failure?"
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The finding of elevated plasma ratio of DHPG:NE and reduced VMAT2 in PAF indicates a shift towards intraneuronal NE metabolism over sequestration in sympathetic nerves"
      explanation: Links the ratio to the vesicular storage defect.
  evidence:
  - reference: PMID:29162745
    reference_title: "Does sympathetic dysfunction occur before denervation in pure autonomic failure?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These findings were associated with a significantly higher ratio of plasma 3,4-dihydroxyphenylglycol (DHPG):NE in PAF participants when compared with controls (P<0.05)."
    explanation: Raised DHPG:NE ratio in PAF.
- name: CSF alpha-synuclein seeding activity
  presence: Present
  biomarker_term:
    preferred_term: CSF alpha-synuclein seed amplification (PMCA)
  readouts:
  - target: Peripheral Autonomic Alpha-Synuclein Aggregation
    relationship: READOUT_OF
    direction: PRESENT_ABSENT
    interpretation: A positive seeding assay indicates aggregated alpha-synuclein; an MSA-like kinetic profile predicts conversion to MSA.
    evidence:
    - reference: PMID:33881777
      reference_title: "Alpha-Synuclein Oligomers and Neurofilament Light Chain Predict Phenoconversion of Pure Autonomic Failure."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The PMCA reaction was markedly different in five samples with maximum fluorescence and reaction kinetics previously described in MSA patients; all of these patients later developed MSA."
      explanation: Seeding kinetics distinguish future MSA converters.
  evidence:
  - reference: PMID:33881777
    reference_title: "Alpha-Synuclein Oligomers and Neurofilament Light Chain Predict Phenoconversion of Pure Autonomic Failure."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "ASyn-PMCA was positive in all but two cases (94%)."
    explanation: CSF seeding is positive in nearly all PAF patients.
- name: CSF neurofilament light chain
  presence: Increased only in future MSA converters
  loinc_term:
    id: LOINC:100996-8
    label: Neurofilament light chain [Mass/volume] in Cerebral spinal fluid
  readouts:
  - target: Spread to Central Nervous System (Phenoconversion)
    relationship: PREDICTS
    direction: POSITIVE
    interpretation: Elevated CSF NfL at baseline predicts conversion to MSA.
    evidence:
    - reference: PMID:33881777
      reference_title: "Alpha-Synuclein Oligomers and Neurofilament Light Chain Predict Phenoconversion of Pure Autonomic Failure."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "NfL at baseline was elevated only in patients who later developed MSA, perfectly separating those from future PD and DLB converters as well as non-converters."
      explanation: CSF NfL separates future MSA converters.
  evidence:
  - reference: PMID:33881777
    reference_title: "Alpha-Synuclein Oligomers and Neurofilament Light Chain Predict Phenoconversion of Pure Autonomic Failure."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "NfL at baseline was elevated only in patients who later developed MSA"
    explanation: CSF NfL is normal in stable PAF and raised in prodromal MSA.
- name: Serum erythropoietin
  presence: Inappropriately low for hemoglobin
  biomarker_term:
    preferred_term: serum erythropoietin
  readouts:
  - target: Sympathetic Deprivation with Blunted Erythropoietin Response
    relationship: READOUT_OF
    direction: NEGATIVE
    interpretation: Low erythropoietin relative to anemia reflects loss of sympathetic drive to erythropoietin production.
    evidence:
    - reference: PMID:8017744
      reference_title: "The anemia of primary autonomic failure and its reversal with recombinant erythropoietin."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "In seven of nine patients with autonomic failure who had hemoglobin levels less than 120 g/L, serum erythropoietin levels decreased below the 95% confidence interval corresponding to patients with iron deficiency anemia."
      explanation: Low erythropoietin in anemic autonomic failure patients.
  evidence:
  - reference: PMID:8017744
    reference_title: "The anemia of primary autonomic failure and its reversal with recombinant erythropoietin."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "No relation was found between serum erythropoietin and blood hemoglobin levels."
    explanation: Erythropoietin does not rise appropriately with falling hemoglobin.
diagnosis:
- name: Head-up tilt or active stand blood pressure testing
  description: >-
    Orthostatic hypotension is a sustained fall of at least 20 mmHg systolic or 10 mmHg
    diastolic blood pressure within 3 minutes of standing or head-up tilt. A blunted
    heart-rate rise (change in heart rate divided by change in systolic pressure below
    0.5 bpm/mmHg) identifies a neurogenic cause. Supine blood pressure is measured at
    the same session to detect supine hypertension.
  measurements:
  - preferred_term: Systolic blood pressure
    term:
      id: LOINC:8480-6
      label: Systolic blood pressure
  evidence:
  - reference: PMID:28717053
    reference_title: "Pure autonomic failure."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Tilt table (head-up) testing is probably the test most commonly used to establish the diagnosis. However, simple office testing is also useful, such as having the patient stand after lying supine with blood pressure monitoring."
    explanation: Tilt-table and active-stand testing establish the diagnosis.
  - reference: PMID:29405350
    reference_title: "Orthostatic heart rate changes in patients with autonomic failure caused by neurodegenerative synucleinopathies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A ΔHR/ΔSBP ratio of 0.492 bpm/mmHg had excellent sensitivity (91.3%) and specificity (88.4%) to distinguish between patients with neurogenic from nonneurogenic OH (area under the curve = 0.96, p < 0.0001)."
    explanation: Heart-rate-to-blood-pressure ratio cut-off for neurogenic OH.
- name: Autonomic reflex screen and thermoregulatory sweat testing
  description: >-
    Cardiovagal, adrenergic and sudomotor testing quantifies the extent of autonomic
    failure. A postganglionic sweat-loss pattern fits PAF, whereas a preganglionic
    pattern and mild cardiovagal impairment predict conversion to MSA.
  evidence:
  - reference: PMID:28202694
    reference_title: "Pure autonomic failure: Predictors of conversion to clinical CNS involvement."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Several variables were identified to predict conversion to MSA: (1) mild degree of cardiovagal impairment, (2) preganglionic pattern of sweat loss"
    explanation: Autonomic testing patterns that predict MSA conversion.
  - reference: PMID:31307617
    reference_title: "Pure autonomic failure."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "We focus on various neurophysiological tests that may be used to evaluate the function of the peripheral autonomic nervous system including quantitative sudomotor axon reflex testing, thermoregulatory sweat testing, and others."
    explanation: Review of the autonomic test battery used in PAF.
- name: Supine and standing plasma catecholamines
  description: >-
    Very low supine plasma norepinephrine with little rise on standing supports a
    postganglionic lesion and distinguishes PAF from MSA.
  measurements:
  - preferred_term: Plasma norepinephrine
    term:
      id: LOINC:14852-8
      label: Norepinephrine [Moles/volume] in Plasma
  evidence:
  - reference: PMID:40696849
    reference_title: "Multimodal Autonomic Biomarkers Predict Phenoconversion in Pure Autonomic Failure."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients with PAF had more severe orthostatic hypotension, lower supine plasma noradrenaline, and frequent sympathetic pupillary deficits at initial assessment than MSA and LBD."
    explanation: Supine plasma noradrenaline is lower in PAF than in MSA or Lewy body disease, which is what makes the measurement discriminating.
- name: Skin biopsy for phosphorylated alpha-synuclein
  description: >-
    Punch biopsy immunohistochemistry detects phosphorylated alpha-synuclein in
    cutaneous autonomic nerves in essentially all patients with PAF, separating it from
    acquired autonomic neuropathies; a high total score separates PAF from MSA.
  diagnosis_term:
    preferred_term: skin biopsy
    term:
      id: NCIT:C51692
      label: Skin Biopsy
  evidence:
  - reference: PMID:38506839
    reference_title: "Skin Biopsy Detection of Phosphorylated α-Synuclein in Patients With Synucleinopathies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "98.2% (54 of 55) with MSA, 96.0% (48 of 50) with DLB, and 100% (22 of 22) with PAF; 3.3% (4 of 120) of controls had cutaneous phosphorylated α-synuclein detected."
    explanation: Thirty-site blinded Synuclein-One study positivity rates.
  - reference: PMID:39608812
    reference_title: "Cutaneous phosphorylated-synuclein: an early diagnostic biomarker for pure autonomic failure."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Total p-syn score >3 distinguished PAF from MSA with 100% specificity and 82% sensitivity."
    explanation: Quantitative score separates PAF from MSA.
- name: Cardiac sympathetic neuroimaging
  description: >-
    Cardiac 18F-dopamine PET or 123I-MIBG scintigraphy shows sympathetic denervation in
    most patients; preserved uptake raises the possibility of prodromal MSA.
  diagnosis_term:
    preferred_term: positron emission tomography
    term:
      id: NCIT:C17007
      label: Positron Emission Tomography
  evidence:
  - reference: PMID:37843677
    reference_title: "Cardiac (18)F-dopamine positron emission tomography predicts the type of phenoconversion of pure autonomic failure."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Since cardiac 18F-dopamine-derived radioactivity usually is low in LBDs and usually is normal in MSA, we hypothesized that patients with PAF with low cardiac 18F-dopamine-derived radioactivity would be more likely to phenoconvert to a central LBD than to MSA."
    explanation: Rationale for cardiac PET in classifying PAF.
- name: CSF alpha-synuclein seed amplification and neurofilament light chain
  description: >-
    CSF seeding assays confirm a synucleinopathy, and an MSA-like seeding profile or
    raised NfL identifies prodromal MSA.
  diagnosis_term:
    preferred_term: lumbar puncture
    term:
      id: NCIT:C15327
      label: Lumbar Puncture
  measurements:
  - preferred_term: CSF neurofilament light chain
    term:
      id: LOINC:100996-8
      label: Neurofilament light chain [Mass/volume] in Cerebral spinal fluid
  evidence:
  - reference: PMID:33881777
    reference_title: "Alpha-Synuclein Oligomers and Neurofilament Light Chain Predict Phenoconversion of Pure Autonomic Failure."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This finding has important implications not only for prognostication, but also for future trials of disease modifying therapies, allowing for differentiation of MSA from Lewy body synucleinopathies before motor symptoms develop."
    explanation: CSF testing separates prodromal MSA from Lewy body forms.
- name: Polysomnography and olfactory testing for central risk markers
  description: >-
    Video-polysomnography confirms RBD and smell identification testing detects
    hyposmia; both stratify the risk and direction of phenoconversion. A stricter UPSIT
    threshold improves the specificity of the MDS prodromal MSA criteria in PAF.
  diagnosis_term:
    preferred_term: polysomnography
    term:
      id: NCIT:C114185
      label: Polysomnography
  evidence:
  - reference: PMID:42444112
    reference_title: "Prospective Validation of the Movement Disorder Society Prodromal Multiple System Atrophy Criteria in Pure Autonomic Failure."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Applying a stricter olfactory threshold improved specificity (90%-97%) and PPV (53%-83%), with a modest reduction in sensitivity (to 83%)."
    explanation: Olfactory testing refines prodromal MSA criteria in PAF.
  - reference: PMID:27757562
    reference_title: "A case series of REM sleep behavior disorder in pure autonomic failure."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Five out of 8 (63 %) met diagnostic criteria for RBD, confirmed on vPSG."
    explanation: Polysomnography confirms RBD in PAF.
differential_diagnoses:
- name: Multiple system atrophy
  disease_term:
    preferred_term: multiple system atrophy
    term:
      id: MONDO:0007803
      label: multiple system atrophy
  distinguishing_features:
  - Central (preganglionic) lesion with preserved postganglionic innervation
  - Normal or near-normal supine plasma norepinephrine
  - Normal cardiac sympathetic imaging and preserved smell
  - Parkinsonism or cerebellar ataxia appear later; premotor MSA can present exactly as PAF
  evidence:
  - reference: PMID:24095130
    reference_title: "Pure autonomic failure."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Cardiac sympathetic innervation is generally intact in MSA but decreased or absent in Parkinson's disease with autonomic failure and PAF."
    explanation: Cardiac innervation differs between MSA and PAF.
  - reference: PMID:19201246
    reference_title: "Olfactory dysfunction in pure autonomic failure: Implications for the pathogenesis of Lewy body diseases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The PAF group had a low mean UPSIT score (22+/-3), similar to that in PD (20+/-2) and lower than in MSA (31+/-2, p=0.004)."
    explanation: Smell is better preserved in MSA than in PAF.
- name: Parkinson disease with autonomic failure
  disease_term:
    preferred_term: Parkinson disease
    term:
      id: MONDO:0005180
      label: Parkinson disease
  distinguishing_features:
  - Shares postganglionic noradrenergic denervation with PAF
  - Parkinsonism with marked striatal dopaminergic terminal loss
  evidence:
  - reference: PMID:18363034
    reference_title: "Central dopamine deficiency in pure autonomic failure."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Parkinsonism appears to reflect striatal dopamine deficiency rather than loss of nigral dopaminergic neurons per se."
    explanation: Striatal deficiency distinguishes PD from PAF.
- name: Dementia with Lewy bodies
  disease_term:
    preferred_term: Lewy body dementia
    term:
      id: MONDO:0007488
      label: Lewy body dementia
  distinguishing_features:
  - Cognitive decline with fluctuations and hallucinations
  - PAF may be its autonomic prodrome
  evidence:
  - reference: PMID:28093795
    reference_title: "Natural history of pure autonomic failure: A United States prospective cohort."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients presenting with pure autonomic failure are at high risk of phenoconverting to a manifest CNS synucleinopathy."
    explanation: PAF can evolve into DLB, PD or MSA.
- name: Diabetic autonomic neuropathy
  disease_term:
    preferred_term: diabetic autonomic neuropathy
    term:
      id: MONDO:0001299
      label: diabetic autonomic neuropathy
  distinguishing_features:
  - Secondary autonomic neuropathy with an identified cause (diabetes mellitus)
  - No cutaneous phosphorylated alpha-synuclein on skin biopsy
  evidence:
  - reference: PMID:34392300
    reference_title: "Pure autonomic failure and the differential diagnosis of autonomic peripheral neuropathies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Peripheral autonomic manifestations are similar to those seen in other autonomic neuropathies, particularly, diabetic autonomic neuropathy, amyloid polyneuropathy, and autoimmune autonomic neuropathies."
    explanation: Names diabetic autonomic neuropathy as a principal mimic.
  - reference: PMID:23390175
    reference_title: "Skin sympathetic fiber α-synuclein deposits: a potential biomarker for pure autonomic failure."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "all patients with PAF showed α-synuclein deposits, which were absent in patients with acquired autonomic neuropathy"
    explanation: Skin synuclein separates PAF from acquired autonomic neuropathies.
- name: Autoimmune autonomic ganglionopathy
  disease_term:
    preferred_term: autoimmune autonomic ganglionopathy
    term:
      id: MONDO:0016499
      label: autoimmune autonomic ganglionopathy
  distinguishing_features:
  - Acquired autonomic neuropathy that mimics the peripheral autonomic picture of PAF
  - No cutaneous phosphorylated alpha-synuclein on skin biopsy
  evidence:
  - reference: PMID:34392300
    reference_title: "Pure autonomic failure and the differential diagnosis of autonomic peripheral neuropathies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Peripheral autonomic manifestations are similar to those seen in other autonomic neuropathies, particularly, diabetic autonomic neuropathy, amyloid polyneuropathy, and autoimmune autonomic neuropathies."
    explanation: Lists the main peripheral autonomic neuropathy mimics.
  - reference: PMID:23390175
    reference_title: "Skin sympathetic fiber α-synuclein deposits: a potential biomarker for pure autonomic failure."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "all patients with PAF showed α-synuclein deposits, which were absent in patients with acquired autonomic neuropathy"
    explanation: Skin synuclein separates PAF from acquired autonomic neuropathies.
  - reference: PMID:39608812
    reference_title: "Cutaneous phosphorylated-synuclein: an early diagnostic biomarker for pure autonomic failure."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "P-syn was present in 22/22 (100%) PAF biopsies, 19/26 (73%) MSA biopsies and 0/22 (0%) non-synucleinopathy biopsies."
    explanation: Non-synucleinopathy autonomic failure was skin-synuclein negative.
- name: Amyloid autonomic polyneuropathy
  disease_term:
    preferred_term: familial amyloid neuropathy
    term:
      id: MONDO:0007100
      label: familial amyloid neuropathy
  distinguishing_features:
  - Autonomic neuropathy that mimics the peripheral autonomic picture of PAF
  - No cutaneous phosphorylated alpha-synuclein on skin biopsy
  evidence:
  - reference: PMID:34392300
    reference_title: "Pure autonomic failure and the differential diagnosis of autonomic peripheral neuropathies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Peripheral autonomic manifestations are similar to those seen in other autonomic neuropathies, particularly, diabetic autonomic neuropathy, amyloid polyneuropathy, and autoimmune autonomic neuropathies."
    explanation: Amyloid polyneuropathy is a key differential.
  - reference: PMID:23390175
    reference_title: "Skin sympathetic fiber α-synuclein deposits: a potential biomarker for pure autonomic failure."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "all patients with PAF showed α-synuclein deposits, which were absent in patients with acquired autonomic neuropathy"
    explanation: Skin synuclein separates PAF from acquired autonomic neuropathies.
  - reference: PMID:39608812
    reference_title: "Cutaneous phosphorylated-synuclein: an early diagnostic biomarker for pure autonomic failure."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "P-syn was present in 22/22 (100%) PAF biopsies, 19/26 (73%) MSA biopsies and 0/22 (0%) non-synucleinopathy biopsies."
    explanation: Non-synucleinopathy autonomic failure was skin-synuclein negative.
treatments:
- name: Patient Education and Physical Countermeasures
  description: >-
    First-line management: recognizing and avoiding triggers (heat, large meals,
    straining, sudden standing, vasoactive drugs), physical counter-manoeuvres, and
    planning upright activity. The aim is to reduce symptoms rather than normalize blood
    pressure.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: patient education and orthostatic countermeasures
    term:
      id: NCIT:C15184
      label: Behavioral Intervention
  target_mechanisms:
  - target: Cerebral and Muscle Hypoperfusion on Standing
    treatment_effect: MODULATES
  evidence:
  - reference: PMID:33705537
    reference_title: "Neurogenic Orthostatic Hypotension. Lessons From Synucleinopathies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "The first step in the management of NOH is to educate patients on how to avoid high-risk situations and providers to identify medications that trigger or worsen NOH."
    explanation: Education is the first management step.
  - reference: PMID:21664375
    reference_title: "Pharmacotherapy of autonomic failure."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Non-pharmacologic strategies such as physical counter-maneuvers, dietary changes (i.e. high salt diet, rapid water drinking or compression garments) are the first line therapy."
    explanation: Non-pharmacological measures are first line.
- name: Salt and Fluid Loading with Rapid Water Drinking
  description: >-
    Increased salt and fluid intake expands volume, and rapid drinking of about 500 mL
    of water raises blood pressure within minutes through the osmopressor reflex, which
    is exaggerated when baroreflex buffering is lost. Useful before standing or meals.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: dietary salt and water loading
    term:
      id: NCIT:C15447
      label: Dietary Intervention
  target_mechanisms:
  - target: Failure of Baroreflex-Mediated Vasoconstriction
    treatment_effect: BYPASSES
  evidence:
  - reference: PMID:21048076
    reference_title: "The osmopressor response to water drinking."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "The osmopressor response can be exploited in the treatment of orthostatic and postprandial hypotension in patients with severe autonomic failure."
    explanation: Review of the water-drinking pressor response in autonomic failure.
- name: Compression Garments and Abdominal Binder
  description: >-
    Lower-body and abdominal compression reduces venous pooling, increasing stroke
    volume and standing blood pressure.
  therapeutic_modality: DEVICE
  treatment_term:
    preferred_term: abdominal compression
    term:
      id: NCIT:C157735
      label: Compression Therapy
  target_mechanisms:
  - target: Failure of Baroreflex-Mediated Vasoconstriction
    treatment_effect: BYPASSES
  evidence:
  - reference: PMID:15241645
    reference_title: "Use of lower abdominal compression to combat orthostatic hypotension in patients with autonomic dysfunction."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Elastic abdominal binding increased standing blood pressure with 15/6 mmHg (range -3/3 to 36/14, p < 0.05)."
    explanation: Abdominal binder raised standing blood pressure in neurogenic OH.
- name: Head-Up Tilt Sleeping
  description: >-
    Raising the head of the bed reduces nocturnal supine hypertension and pressure
    natriuresis and may improve morning orthostatic tolerance. A scoping review judged
    the evidence weak, from small studies at high risk of bias.
  therapeutic_modality: BEHAVIORAL
  target_mechanisms:
  - target: Supine Pressure Natriuresis
    treatment_effect: INHIBITS
    description: >-
      Lowering nocturnal supine pressure reduces the overnight pressure
      natriuresis that depletes volume before morning.
  evidence:
  - reference: PMID:37626994
    reference_title: "The Impact of Head-Up Tilt Sleeping on Orthostatic Tolerance: A Scoping Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Orthostatic tolerance was consistently enhanced in OH studies with higher angles (≥12°)"
    explanation: Scoping review reporting improved orthostatic tolerance with steeper head-up tilt.
- name: Midodrine
  description: >-
    Peripheral alpha-1 adrenoceptor agonist (prodrug of desglymidodrine) that acts
    directly on vascular receptors and so does not require surviving noradrenergic
    terminals. Taken during the day before upright activity; avoid the supine position
    for several hours after a dose. Adverse effects include supine hypertension,
    piloerection and urinary retention.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: midodrine
      term:
        id: CHEBI:6933
        label: midodrine
  target_mechanisms:
  - target: Deficient Sympathetic Norepinephrine Release
    treatment_effect: BYPASSES
    description: >-
      Acts on the vascular receptor downstream of the missing neurotransmitter,
      so it does not need surviving terminals.
  - target: Failure of Baroreflex-Mediated Vasoconstriction
    treatment_effect: RESTORES
    description: >-
      Restores vasoconstriction pharmacologically.
  evidence:
  - reference: PMID:9091692
    reference_title: "Efficacy of midodrine vs placebo in neurogenic orthostatic hypotension. A randomized, double-blind multicenter study. Midodrine Study Group."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In the evaluable patients, midodrine resulted in improvements in standing systolic BP at all time points (P<.001 at visits 2, 3, 4, and 5)"
    explanation: Multicentre randomized trial in neurogenic OH; the abstract gives no breakdown by diagnosis.
  - reference: PMID:9091692
    reference_title: "Efficacy of midodrine vs placebo in neurogenic orthostatic hypotension. A randomized, double-blind multicenter study. Midodrine Study Group."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The main adverse effects were those of pilomotor reactions, urinary retention, and supine hypertension."
    explanation: Main adverse effects of midodrine.
  - reference: PMID:32979782
    reference_title: "Pharmacologic treatment of orthostatic hypotension."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "patients with low \"sympathetic reserve\", i.e., those with peripheral noradrenergic degeneration (pure autonomic failure, Parkinson's disease) and low plasma norepinephrine, tend to respond better to \"norepinephrine replacers\" (midodrine and droxidopa)"
    explanation: PAF patients respond best to norepinephrine replacers.
- name: Droxidopa
  description: >-
    Oral synthetic amino acid converted by aromatic L-amino acid decarboxylase to
    norepinephrine outside noradrenergic terminals, replacing the missing
    neurotransmitter. Used for symptomatic neurogenic orthostatic hypotension in PD,
    MSA, PAF and other autonomic neuropathies. Supine blood pressure rises and must be
    monitored.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: droxidopa
      term:
        id: CHEBI:31524
        label: droxidopa
  target_mechanisms:
  - target: Deficient Sympathetic Norepinephrine Release
    treatment_effect: BYPASSES
  evidence:
  - reference: PMID:24944260
    reference_title: "Droxidopa for neurogenic orthostatic hypotension: a randomized, placebo-controlled, phase 3 trial."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In patients with symptomatic nOH, droxidopa improved symptoms and symptom impact on daily activities, with an associated increase in standing systolic BP, and was generally well tolerated."
    explanation: Phase 3 trial including PAF patients.
  - reference: PMID:24944260
    reference_title: "Droxidopa for neurogenic orthostatic hypotension: a randomized, placebo-controlled, phase 3 trial."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "At endpoint, supine systolic BP >180 mm Hg was observed in 4.9% of droxidopa and 2.5% of placebo recipients."
    explanation: Supine hypertension risk on droxidopa.
  - reference: PMID:28494751
    reference_title: "Integrated analysis of droxidopa trials for neurogenic orthostatic hypotension."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Droxidopa improved virtually all nOH symptom scores compared with placebo, significantly reducing OHQ composite score (-2.68 ± 2.20 vs -1.82 ± 2.34 units; P < 0.001)"
    explanation: >-
      Pooled analysis of the three randomized trials (n = 460) behind approval for
      primary autonomic failure. The same analysis bounds its own claim: the trials
      assessed 2 to 10 weeks of treatment, and the authors note that a longer trial was
      then underway to confirm efficacy beyond that period, so this result does not
      establish durable benefit.
  - reference: PMID:27538531
    reference_title: "Analysis of number needed to treat for droxidopa in patients with symptomatic neurogenic orthostatic hypotension."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The NNT for droxidopa for improvement in OHSA Item 1 was <10. The NNH for adverse events (AEs) leading to discontinuation in the pooled studies was 81."
    explanation: Number needed to treat and to harm from the pooled trials, which included PAF.
  - reference: PMID:25350981
    reference_title: "Randomized withdrawal study of patients with symptomatic neurogenic orthostatic hypotension responsive to droxidopa."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "In summary, this randomized withdrawal droxidopa study failed to meet its primary efficacy end point."
    explanation: The randomized withdrawal trial missed its primary dizziness endpoint, although secondary and post hoc measures favoured droxidopa.
- name: Fludrocortisone
  description: >-
    Mineralocorticoid that expands plasma volume through renal sodium retention. It
    raises blood pressure in both supine and standing positions, so it can worsen supine
    hypertension and should be used with caution.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: fludrocortisone
      term:
        id: CHEBI:50885
        label: fludrocortisone
  target_mechanisms:
  - target: Neurogenic Orthostatic Hypotension
    treatment_effect: INHIBITS
    description: >-
      Expanded plasma volume raises standing blood pressure without restoring
      sympathetic function or vasoconstriction.
  - target: Supine Hypertension Mechanism
    treatment_effect: ACTIVATES
    description: >-
      Raises supine blood pressure too, so it worsens supine hypertension.
  evidence:
  - reference: PMID:21664375
    reference_title: "Pharmacotherapy of autonomic failure."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "these interventions should be aimed at increasing intravascular volume either by promoting water and salt retention (fludrocortisone) or by increasing red blood cell mass when anemia is present (recombinant erythropoietin)"
    explanation: Fludrocortisone as a volume expander.
  - reference: PMID:15633433
    reference_title: "[Orthostatic hypotension and supine hypertension in pure autonomic failure]."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Salt-retaining steroid fludrocortisone, also, used to treat orthostatic hypotension, increases blood pressure both in supine and in standing position."
    explanation: Fludrocortisone worsens supine as well as standing blood pressure.
  - reference: PMID:33705537
    reference_title: "Neurogenic Orthostatic Hypotension. Lessons From Synucleinopathies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Volume expanders (fludrocortisone and desmopressin) should be used with caution."
    explanation: Caution with volume expanders.
- name: Pyridostigmine
  description: >-
    Acetylcholinesterase inhibitor that enhances ganglionic transmission and so amplifies
    residual sympathetic outflow mainly when upright, with little effect on supine blood
    pressure. It is more effective with preserved sympathetic reserve, and therefore
    less so in PAF than in MSA or mild disease.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: pyridostigmine
      term:
        id: CHEBI:8665
        label: Pyridostigmine
  target_mechanisms:
  - target: Deficient Sympathetic Norepinephrine Release
    treatment_effect: MODULATES
    description: >-
      Amplifies residual ganglionic traffic so surviving postganglionic
      terminals release more norepinephrine on standing; limited in PAF
      because most terminals are lost.
  evidence:
  - reference: PMID:16476804
    reference_title: "Pyridostigmine treatment trial in neurogenic orthostatic hypotension."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Pairwise comparison showed significant reduction by pyridostigmine alone (BP fall of 27.6 mm Hg vs 34.0 mm Hg with placebo; P = .04)"
    explanation: Crossover trial in neurogenic OH; the abstract gives no breakdown by diagnosis.
  - reference: PMID:16476804
    reference_title: "Pyridostigmine treatment trial in neurogenic orthostatic hypotension."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "No significant differences were seen in the supine BP, either systolic (P = .36) or diastolic (P = .85)."
    explanation: No worsening of supine blood pressure.
  - reference: PMID:33705537
    reference_title: "Neurogenic Orthostatic Hypotension. Lessons From Synucleinopathies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Drugs that enhance residual sympathetic tone (pyridostigmine and atomoxetine) are more effective in patients with mild disease and in MSA patients with spared postganglionic fibers."
    explanation: Reduced expected efficacy in PAF with postganglionic loss.
- name: Atomoxetine
  description: >-
    Norepinephrine transporter inhibitor that raises synaptic norepinephrine from
    residual sympathetic terminals. Acute doses raised upright blood pressure more than
    midodrine, but a four-week randomized trial showed no symptomatic benefit over
    placebo. Enhancers of residual sympathetic tone are expected to work better with
    preserved postganglionic fibres, although supine plasma norepinephrine alone did not
    predict the pressor response.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: atomoxetine
      term:
        id: CHEBI:127342
        label: atomoxetine
  target_mechanisms:
  - target: Deficient Sympathetic Norepinephrine Release
    treatment_effect: MODULATES
  evidence:
  - reference: PMID:25185131
    reference_title: "Efficacy of atomoxetine versus midodrine for the treatment of orthostatic hypotension in autonomic failure."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In contrast, atomoxetine produced a greater pressor response in upright systolic blood pressure (means difference=7.5 mm Hg; 95% CI, 0.6 to 15; P=0.03) compared with midodrine."
    explanation: Acute pressor efficacy in severe autonomic failure.
  - reference: PMID:39294522
    reference_title: "Atomoxetine on neurogenic orthostatic hypotension: a randomized, double-blind, placebo-controlled crossover trial."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "We found no differences in the OHQ composite score between atomoxetine and placebo at 2 weeks (-0.3 ± 1.7 versus -0.4 ± 1.5; P = 0.806) and 4 weeks (-0.6 ± 2.4 versus -0.5 ± 1.6; P = 0.251)."
    explanation: Four-week randomized crossover trial showed no symptomatic benefit (41% of participants had PAF).
  - reference: PMID:34176285
    reference_title: "Predictors of the Pressor Response to the Norepinephrine Transporter Inhibitor, Atomoxetine, in Neurogenic Orthostatic Hypotension."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Nevertheless, our results showed that plasma NE is not a good predictor of response."
    explanation: Supine norepinephrine did not predict the atomoxetine pressor response.
  - reference: PMID:33705537
    reference_title: "Neurogenic Orthostatic Hypotension. Lessons From Synucleinopathies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Drugs that enhance residual sympathetic tone (pyridostigmine and atomoxetine) are more effective in patients with mild disease and in MSA patients with spared postganglionic fibers."
    explanation: Expected lower efficacy where postganglionic fibres are lost, as in PAF.
- name: Ampreloxetine
  description: >-
    Investigational once-daily selective norepinephrine reuptake inhibitor that raises
    synaptic norepinephrine from residual sympathetic terminals. A phase 2 trial in
    neurogenic orthostatic hypotension raised seated blood pressure with little effect
    on supine pressure. The phase 3 SEQUOIA and REDWOOD trials, which enrolled PAF as
    well as PD and MSA patients, missed their primary endpoints. A prespecified MSA
    subgroup analysis showed maintained symptom benefit on secondary endpoints after
    randomized withdrawal; the trials were powered only for the full population, and no
    PAF-specific result has been reported. Like atomoxetine, it is expected to help
    least in PAF, where those neurons are lost. It is not approved.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: ampreloxetine
      term:
        id: CHEBI:757112
        label: ampreloxetine
  target_mechanisms:
  - target: Deficient Sympathetic Norepinephrine Release
    treatment_effect: MODULATES
  evidence:
  - reference: PMID:34657222
    reference_title: "Safety and efficacy of ampreloxetine in symptomatic neurogenic orthostatic hypotension: a phase 2 trial."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Seated blood pressure increased 15.7 mmHg 4 h after ampreloxetine and decreased 14.2 mmHg after placebo [least squares mean difference (95% CI) 29.9 mmHg (7.6-52.3); P = 0.0112]."
    explanation: One-day randomized placebo-controlled phase of a 34-patient phase 2 trial; the abstract gives no breakdown by diagnosis.
  - reference: PMID:42475649
    reference_title: "Mechanism-Based Therapy With Ampreloxetine for Neurogenic Orthostatic Hypotension in Multiple System Atrophy: A Randomized Withdrawal Trial."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "Both SEQUOIA and REDWOOD did not meet their primary endpoints."
    explanation: >-
      The phase 3 programme enrolled patients with PD, PAF or MSA and failed its
      primary endpoints in the full population.
  - reference: PMID:42475649
    reference_title: "Mechanism-Based Therapy With Ampreloxetine for Neurogenic Orthostatic Hypotension in Multiple System Atrophy: A Randomized Withdrawal Trial."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The trials enrolled participants aged 30 years or older with PD, PAF, or MSA and symptomatic nOH."
    explanation: Confirms PAF patients were part of the phase 3 trial population.
  - reference: PMID:42475649
    reference_title: "Mechanism-Based Therapy With Ampreloxetine for Neurogenic Orthostatic Hypotension in Multiple System Atrophy: A Randomized Withdrawal Trial."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the trials were only statistically powered based on the full population analysis (PD, MSA, and PAF) and not for individual diagnoses"
    explanation: >-
      The basis for saying no PAF-specific efficacy result exists. The programme reported
      only an MSA subgroup, and was not powered for any single diagnosis, so nothing here
      measures the drug in PAF either way.
- name: Recombinant Erythropoietin
  description: >-
    Corrects the normocytic anemia of autonomic failure at low doses, increasing red
    cell mass and orthostatic tolerance.
  therapeutic_modality: PROTEIN_REPLACEMENT
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: epoetin alfa
      term:
        id: NCIT:C2695
        label: Epoetin Alfa
  target_mechanisms:
  - target: Sympathetic Deprivation with Blunted Erythropoietin Response
    treatment_effect: BYPASSES
  evidence:
  - reference: PMID:8017744
    reference_title: "The anemia of primary autonomic failure and its reversal with recombinant erythropoietin."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Therapy with recombinant erythropoietin improved mean hemoglobin levels (from 108 to 133 g/L) in all patients treated (n = 5) at relatively low doses (25 to 50 units/kg body weight, subcutaneously, three times a week)."
    explanation: Open-label erythropoietin corrected anemia in autonomic failure.
- name: Nocturnal Treatment of Supine Hypertension
  description: >-
    Avoiding the supine position during the day, head-up tilt at night, and a
    short-acting antihypertensive at bedtime (for example transdermal nitroglycerin, or
    the mineralocorticoid antagonist eplerenone) lower nocturnal blood pressure without
    worsening daytime orthostatic hypotension.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: nitroglycerin
      term:
        id: CHEBI:28787
        label: nitroglycerin
    - preferred_term: eplerenone
      term:
        id: CHEBI:31547
        label: eplerenone
  target_mechanisms:
  - target: Supine Hypertension Mechanism
    treatment_effect: INHIBITS
  evidence:
  - reference: PMID:11927799
    reference_title: "Diagnosis and treatment of supine hypertension in autonomic failure patients with orthostatic hypotension."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "During the day, avoiding the supine position is often all that is required. Short-acting vasodilators (e.g., transdermal nitroglycerin) can be used during the night."
    explanation: Management approach to supine hypertension.
  - reference: PMID:28050656
    reference_title: "The recommendations of a consensus panel for the screening, diagnosis, and treatment of neurogenic orthostatic hypotension and associated supine hypertension."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "provides essential recommendations based upon best available evidence as well as expert opinion for the (1) screening, (2) diagnosis, (3) treatment of nOH, and (4) diagnosis and treatment of associated supine hypertension"
    explanation: American Autonomic Society and National Parkinson Foundation consensus recommendations, which explicitly include pure autonomic failure.
  - reference: PMID:26644241
    reference_title: "Mineralocorticoid Receptor Activation Contributes to the Supine Hypertension of Autonomic Failure."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Eplerenone maximally reduced supine systolic blood pressure by 32±6 mm Hg at 8 hours after administration (versus 8±10 mm Hg placebo, P=0.016), with no effect on nocturia"
    explanation: Eplerenone lowered supine blood pressure in a crossover study (7 of 10 PAF).
  - reference: PMID:33687577
    reference_title: "Management Strategies for Comorbid Supine Hypertension in Patients with Neurogenic Orthostatic Hypotension."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Because nOH and nSH are hemodynamically opposed, therapies to treat one condition may exacerbate the other."
    explanation: Why supine hypertension treatment is confined to the night and balanced against daytime orthostatic hypotension.
- name: Nocturnal Continuous Positive Airway Pressure
  description: >-
    Overnight CPAP lowers supine blood pressure through a Valsalva-like reduction in
    cardiac output, reducing nocturnal diuresis and improving morning orthostatic
    tolerance.
  therapeutic_modality: DEVICE
  target_mechanisms:
  - target: Supine Pressure Natriuresis
    treatment_effect: INHIBITS
  evidence:
  - reference: PMID:36601916
    reference_title: "Continuous Positive Airway Pressure for the Treatment of Supine Hypertension and Orthostatic Hypotension in Autonomic Failure."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "overnight CPAP lowered nighttime systolic blood pressure (maximal change -23±5 versus placebo -1±7 mmHg; P=0.023) and was associated with lower nighttime diuresis (609±84 versus placebo 1004±160 mL; P=0.004) and improved morning orthostatic tolerance"
    explanation: Two-night crossover study in autonomic failure.
- name: No Disease-Modifying Therapy
  description: >-
    No treatment slows or prevents progression or phenoconversion. Biomarker
    stratification (cardiac imaging, CSF seeding and NfL, olfaction, RBD) is being
    developed to select prodromal patients for future disease-modification trials.
  therapeutic_modality: OTHER
  evidence:
  - reference: PMID:27338613
    reference_title: "Pure Autonomic Failure."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "There is currently no specific treatment to stop progression in PAF."
    explanation: No disease-modifying therapy exists.
  - reference: PMID:37843677
    reference_title: "Cardiac (18)F-dopamine positron emission tomography predicts the type of phenoconversion of pure autonomic failure."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This capability could refine eligibility criteria for entry into disease-modification trials aimed at preventing evolution of PAF to symptomatic central LBDs."
    explanation: Prognostic biomarkers aim at future trials.
clinical_trials:
- name: NCT03750552
  description: >-
    SEQUOIA, the 4-week parallel-group phase 3 trial of ampreloxetine in symptomatic
    neurogenic orthostatic hypotension due to primary autonomic failure, enrolling PAF
    alongside Parkinson disease and multiple system atrophy. It did not meet its
    primary endpoint.
  phase: PHASE_III
  status: COMPLETED
  target_phenotypes:
  - preferred_term: Neurogenic orthostatic hypotension
    term:
      id: HP:0001278
      label: Orthostatic hypotension
  evidence:
  - reference: clinicaltrials:NCT03750552
    reference_title: "A Phase 3, 4-week, Multicenter, Randomized, Double-blind, Placebo-controlled, Parallel-group Study of TD-9855 in Treating Symptomatic Neurogenic Orthostatic Hypotension in Subjects With Primary Autonomic Failure"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "A Phase 3 study to evaluate efficacy, safety, and tolerability of ampreloxetine (TD-9855) in subjects with primary autonomic failures (MSA, PD, or PAF) and symptomatic nOH with up to 4 weeks of treatment."
    explanation: Registry record establishing the trial's design and that PAF was an eligible diagnosis.
- name: NCT03829657
  description: >-
    REDWOOD, the 22-week randomized withdrawal phase 3 trial of ampreloxetine in the
    same population, terminated early by the sponsor after SEQUOIA missed its endpoint.
    Its own primary endpoint was not met; a prespecified MSA subgroup analysis was
    reported separately.
  phase: PHASE_III
  status: TERMINATED
  target_phenotypes:
  - preferred_term: Neurogenic orthostatic hypotension
    term:
      id: HP:0001278
      label: Orthostatic hypotension
  evidence:
  - reference: clinicaltrials:NCT03829657
    reference_title: "A Phase 3, 22-week, Multi-center, Randomized Withdrawal Study of TD-9855 in Treating Symptomatic Neurogenic Orthostatic Hypotension in Subjects With Primary Autonomic Failure"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "A Phase 3, 22-week, Multi-center, Randomized Withdrawal Study of ampreloxetine in Treating Symptomatic Neurogenic Orthostatic Hypotension in Subjects with Primary Autonomic Failure"
    explanation: Registry record establishing the trial's design and population.
  - reference: PMID:42475649
    reference_title: "Mechanism-Based Therapy With Ampreloxetine for Neurogenic Orthostatic Hypotension in Multiple System Atrophy: A Randomized Withdrawal Trial."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "After SEQUOIA did not meet the primary endpoint, REDWOOD was early terminated by the sponsor"
    explanation: Source for the TERMINATED status and its reason.
animal_models:
- name: Ganglionic alpha-synuclein fibril injection in TgM83 mice
  species: Mouse
  genotype: TgM83+/- (human SNCA A53T transgene, hemizygous)
  description: >-
    Preformed alpha-synuclein fibrils injected into the stellate and celiac ganglia
    of TgM83 mice spread only along autonomic pathways, to the central nervous system
    and bidirectionally to the autonomic innervation of peripheral organs. The mice
    develop orthostatic hypotension, constipation, hypohidrosis and hyposmia without
    motor dysfunction.
  publication: PMID:32071315
  modeled_mechanisms:
  - target: Peripheral Autonomic Alpha-Synuclein Aggregation
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: ORGANISM
    description: >-
      Autonomic-restricted alpha-synuclein pathology with autonomic failure and no
      motor signs, the defining features of PAF.
    limitations: >-
      Pathology is seeded by injected fibrils into mice overexpressing mutant human
      alpha-synuclein, whereas human PAF is sporadic with no SNCA variant, and the
      seeded pathology also reaches the central nervous system.
    divergences:
    - divergence_type: CAUSE_UNREPRESENTED
      materiality: QUALIFYING
      description: >-
        Aggregation is started by injecting preformed fibrils into ganglia of mice
        overexpressing A53T human alpha-synuclein. In the sporadic human disease the
        protein is wild type at normal dosage and the initiating trigger is unknown,
        so the model cannot speak to why aggregation begins.
    - divergence_type: SPECIES_MISMATCH
      materiality: QUALIFYING
      description: >-
        Orthostatic hypotension and hypohidrosis are measured in mice, whose
        postural cardiovascular load differs greatly from upright humans.
    evidence:
    - reference: PMID:32071315
      reference_title: "Autonomic ganglionic injection of α-synuclein fibrils as a model of pure autonomic failure α-synucleinopathy."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "In parallel, the mice develop autonomic dysfunction, featured by orthostatic hypotension, constipation, hypohidrosis and hyposmia, without motor dysfunction."
      explanation: The model reproduces autonomic failure without motor features.
  - target: Spread to Central Nervous System (Phenoconversion)
    relationship: PARTIALLY_RECAPITULATES
    fidelity: LOW
    model_scale: ORGANISM
    description: Pathology spreads from autonomic ganglia to the central nervous system.
    limitations: >-
      Central spread was shown histologically without the motor or cognitive
      phenotype of a phenoconverted disease, and the model has not been shown to
      separate Lewy-type from MSA-type conversion.
    divergences:
    - divergence_type: PROXY_QUANTITY
      materiality: QUALIFYING
      description: >-
        The model's quantity is the histological presence of alpha-synuclein pathology
        in central regions. The node's quantity is clinical phenoconversion to
        Parkinson disease or dementia with Lewy bodies, which is a diagnosis made on
        motor or cognitive features the mice never develop. Central pathology stands in
        for a clinical event, and the proportion of PAF patients with central pathology
        who would ever convert is not something this model can report.
    - divergence_type: CAUSE_UNREPRESENTED
      materiality: QUALIFYING
      description: >-
        Spread is initiated by synthetic preformed fibrils in a host overexpressing A53T
        human alpha-synuclein. Aggregates purified from human sympathetic ganglia have
        failed to seed pathology in mouse brain, so whether the human peripheral
        aggregate propagates as this model's fibrils do is unsettled; see the
        paf_peripheral_aggregate_seeding_mismatch discussion.
    evidence:
    - reference: PMID:32071315
      reference_title: "Autonomic ganglionic injection of α-synuclein fibrils as a model of pure autonomic failure α-synucleinopathy."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "induces spreading of α-Syn pathology only through the autonomic pathway to both the central nervous system (CNS) and the autonomic innervation of peripheral organs bidirectionally"
      explanation: Autonomic-to-central spread of seeded pathology.
experimental_models:
- name: DOPAL challenge in BE(2)-M17 neuroblastoma cells and primary cortical neurons
  experimental_model_type: CELL_LINE
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  cell_source: >-
    Human BE(2)-M17 neuroblastoma cells overexpressing mCherry-tagged alpha-synuclein,
    with mouse primary cortical neurons carrying only endogenous alpha-synuclein as the
    non-overexpressing comparison, both exposed to exogenous DOPAL. HEK293T cells
    overexpressing alpha-synuclein-EGFP are the paper's negative arm: they supply the
    mass-spectrometric characterisation of the modified protein, but oligomers were not
    detected in them. An isolated synaptic-vesicle preparation is assayed alongside the
    intact cells.
  cell_types:
  - preferred_term: BE(2)-M17 neuroblastoma cell
    term:
      id: CL:0000031
      label: neuroblast (sensu Vertebrata)
  - preferred_term: mouse primary cortical neuron
    term:
      id: CL:0000540
      label: neuron
  conditions:
  - Exogenous DOPAL exposure at 20 and 50 micromolar in the mouse primary neurons
  - Exogenous DOPAL exposure at 100 micromolar in the human overexpressing lines
  - Preformed alpha-synuclein-DOPAL oligomers at 2 micromolar for the cellular
    permeabilisation experiments
  - Alpha-synuclein overexpression, and endogenous alpha-synuclein alone
  culture_system: Two-dimensional monolayer culture, with an accompanying isolated synaptic-vesicle
    preparation
  publication: PMID:28084443
  description: >-
    The non-animal system behind the catecholaldehyde step of this entry. DOPAL added to
    the medium forms covalent oligomers with alpha-synuclein inside the cell, and those
    oligomers permeabilise cholesterol-containing membranes, damage synaptic vesicles and
    let dopamine escape into the cytoplasm, where it is converted to more DOPAL. It is
    the experiment that makes the vicious cycle drawn in this entry's pathograph
    measurable rather than inferred, and it works on endogenous as well as overexpressed
    alpha-synuclein. It is not a model of PAF. The cells are a neuroblastoma line and
    mouse cortical neurons rather than sympathetic noradrenergic neurons, no patient
    material is involved, and the catecholamine that leaks is dopamine rather than
    norepinephrine.
  evidence:
  - reference: PMID:28084443
    reference_title: DOPAL derived alpha-synuclein oligomers impair synaptic vesicles physiological
      function.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: DOPAL can target both overexpressed aS and endogenous aS, and it is able to
      induce aS oligomerization in immortalized cell lines, and in primary neurons
    explanation: >-
      Establishes the system and that the effect does not depend on overexpression, which
      is what makes it usable as evidence about an endogenous mechanism.
  modeled_mechanisms:
  - target: Catecholaldehyde (DOPAL) Autotoxicity in Noradrenergic Neurons
    relationship: PERTURBS
    fidelity: MODERATE
    model_scale: MOLECULAR
    description: >-
      DOPAL is applied to intact cells and the covalent alpha-synuclein oligomers this
      node describes are then recovered from inside them, so the node's chemistry is
      demonstrated in a cellular context rather than only in a tube.
    limitations: >-
      DOPAL is supplied from outside at fixed concentrations, so the node's claim that it
      accumulates because dopamine leaks from storage vesicles and is deaminated in the
      cytoplasm is assumed by the design rather than tested by it.
    divergences:
    - divergence_type: CAUSE_UNREPRESENTED
      materiality: QUALIFYING
      description: >-
        The node's upstream cause is vesicular leak followed by monoamine oxidase
        deamination of cytoplasmic dopamine. Here the aldehyde is pipetted into the
        medium, so neither the leak nor the enzymatic step is in the model, and the
        exposure cannot be titrated to a physiological cytoplasmic concentration.
    - divergence_type: BOUNDARY_OMISSION
      materiality: QUALIFYING
      description: >-
        A sympathetic noradrenergic neuron is outside the model. Its distinguishing
        features - dopamine beta-hydroxylase inside the vesicle, norepinephrine rather
        than dopamine as the stored transmitter, and the aldehyde dehydrogenase
        complement of that cell type - are exactly what the node invokes to explain why
        catecholaminergic neurons are selectively affected.
    - divergence_type: SPECIES_MISMATCH
      materiality: QUALIFYING
      description: >-
        The non-overexpressing arm uses mouse cortical neurons, and the species gap bears
        on this link because the endogenous-alpha-synuclein claim rests on that arm alone.
        Both human lines overexpress a tagged construct, and in the HEK293T line no
        oligomers were detected at all, so there is no human result showing the reaction
        on endogenous protein at endogenous abundance. The substrate in the neurons is the
        mouse protein rather than the human one, and those neurons were exposed to 20 or
        50 micromolar DOPAL against 100 micromolar in the human lines, so the two arms are
        not interchangeable on dose either.
    readouts:
    - name: Covalent alpha-synuclein oligomer formation after DOPAL exposure
      target: Catecholaldehyde (DOPAL) Autotoxicity in Noradrenergic Neurons
      direction: INCREASED
      interpretation: >-
        Oligomeric alpha-synuclein species appear on western blot in DOPAL-treated cells
        and not in untreated ones, in both the overexpressing line and neurons carrying
        only endogenous protein.
      evidence:
      - reference: PMID:28084443
        reference_title: DOPAL derived alpha-synuclein oligomers impair synaptic vesicles
          physiological function.
        supports: SUPPORT
        evidence_source: IN_VITRO
        quote_role: PRIMARY_RESULT
        snippet: is able to induce aS oligomerization in immortalized cell lines, and in
          primary neurons
        explanation: The measurement behind this readout, in both cell systems.
  - target: Noradrenergic Vesicular Storage and Synthesis Defect
    relationship: PARTIALLY_RECAPITULATES
    fidelity: LOW
    model_scale: CELLULAR
    description: >-
      Catecholamine escaping from storage vesicles is the quantity this node is about, and
      it is measured here as a consequence of the aldehyde-driven oligomers rather than
      assumed. That is the return arm of the loop this entry draws between the storage
      defect and the catecholaldehyde node.
    limitations: >-
      The transmitter that leaks is dopamine from a neuroblastoma line and from cortical
      neurons, not norepinephrine from a sympathetic neuron, and vesicular monoamine
      transporter density and tyrosine hydroxylase content - the two measurements that
      define this node in patients - are not reported.
    divergences:
    - divergence_type: PROXY_QUANTITY
      materiality: QUALIFYING
      description: >-
        Dopamine leak from synaptic vesicles stands in for failure of norepinephrine
        sequestration in a sympathetic varicosity. The direction of the defect is the
        same; the transmitter, the vesicle population and the cell are not.
    - divergence_type: BOUNDARY_OMISSION
      materiality: QUALIFYING
      description: >-
        Dopamine beta-hydroxylase and the noradrenergic vesicle itself lie outside the
        model, so nothing here bears on the reduced vesicular norepinephrine synthesis
        that this node also asserts.
    - divergence_type: SPECIES_MISMATCH
      materiality: QUALIFYING
      description: >-
        The in-cell evidence that oligomers damage synaptic vesicles is the electron
        microscopy of mouse primary neurons, where the readily releasable pool shrinks and
        vesicles per synapse fall from about 71 to 49 and 38 with rising DOPAL. The human
        arm contributes the pHluorin permeabilisation result and the dopamine-leak assay
        is cell-free, so the structural measurement of vesicle loss has no human
        counterpart here.
    readouts:
    - name: Dopamine leak from synaptic vesicles
      target: Noradrenergic Vesicular Storage and Synthesis Defect
      direction: INCREASED
      interpretation: >-
        Alpha-synuclein-DOPAL oligomers permeabilise vesicle membranes and release stored
        dopamine, in isolated vesicles and in cells.
      evidence:
      - reference: PMID:28084443
        reference_title: DOPAL derived alpha-synuclein oligomers impair synaptic vesicles
          physiological function.
        supports: SUPPORT
        evidence_source: IN_VITRO
        quote_role: PRIMARY_RESULT
        snippet: aS-DOPAL oligomers can induce dopamine leak in an in vitro model of synaptic
          vesicles and in cellular models
        explanation: The measured leak, which is the step that closes the loop back onto
          the aldehyde node.
      - reference: PMID:28084443
        reference_title: DOPAL derived alpha-synuclein oligomers impair synaptic vesicles
          physiological function.
        supports: SUPPORT
        evidence_source: IN_VITRO
        quote_role: PRIMARY_RESULT
        snippet: DOPAL-induced aS oligomer formation in neurons is associated with damage
          of synaptic vesicles
        explanation: Ties the vesicle damage to the oligomers rather than to DOPAL exposure
          generally.
- name: MO3.13 oligodendrocyte and PC12 catecholaldehyde transfer co-culture
  experimental_model_type: CO_CULTURE
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  cell_source: >-
    Human MO3.13 oligodendrocyte and glioblastoma lines, which contain neither
    catecholamines nor alpha-synuclein of their own, co-incubated with
    dopamine-producing rat PC12 cells or exposed to DOPAL directly, with recombinant
    wild-type or A53T alpha-synuclein supplied in the medium.
  cell_types:
  - preferred_term: MO3.13 oligodendrocyte
    term:
      id: CL:0000128
      label: oligodendrocyte
  - preferred_term: PC12 pheochromocytoma cell
    term:
      id: CL:0000166
      label: chromaffin cell
  conditions:
  - Co-incubation with dopamine-producing PC12 cells
  - Exogenous DOPAL exposure
  - Wild-type and A53T alpha-synuclein supplied extracellularly
  culture_system: Two-dimensional co-incubation of two cell lines in shared medium
  publication: PMID:26777075
  description: >-
    A catecholamine-free recipient cell used as a clean background for the aldehyde. It
    answers a question the single-cell systems cannot: whether DOPAL made in one cell
    reaches another and oligomerises alpha-synuclein there. It was built to explain glial
    inclusions in multiple system atrophy, so for PAF it bears on the chemistry and the
    transmissibility and not on the cell type, and the entry's other MO3.13 result on
    DOPAL-driven quinonisation of intracellular proteins comes from the same laboratory.
  evidence:
  - reference: PMID:26777075
    reference_title: DOPAL is transmissible to and oligomerizes alpha-synuclein in human
      glial cells.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: DOPAL is transmissible to glial cells and enhances intracellular oligomerization
      of AS
    explanation: >-
      The system's own conclusion, and the reason it is recorded here rather than folded
      into the single-cell model above.
  modeled_mechanisms:
  - target: Catecholaldehyde (DOPAL) Autotoxicity in Noradrenergic Neurons
    relationship: PERTURBS
    fidelity: LOW
    model_scale: MOLECULAR
    description: >-
      Shows the aldehyde crossing from a catecholamine-synthesising cell into a recipient
      that makes none, and oligomerising alpha-synuclein once inside, so the oligomerising
      step this node asserts does not require the aldehyde to be made in the same cell.
    limitations: >-
      The recipient is a glial line chosen for the multiple system atrophy question, and
      neither alpha-synuclein nor the catecholamine is endogenous to it, so the model
      reproduces the reaction and not the cell in which this entry places it.
    divergences:
    - divergence_type: BOUNDARY_OMISSION
      materiality: QUALIFYING
      description: >-
        The sympathetic noradrenergic neuron is absent, and so is the intracellular origin
        of the aldehyde. Alpha-synuclein is added from outside rather than expressed, so
        the model cannot speak to the concentrations either species reaches in the
        affected neuron.
    - divergence_type: PROXY_QUANTITY
      materiality: QUALIFYING
      description: >-
        An oligodendrocyte taking up extracellular alpha-synuclein stands in for a
        peripheral noradrenergic neuron aggregating its own. The cell-type selectivity
        that this node exists to explain is therefore not something the model can test.
    - divergence_type: SPECIES_MISMATCH
      materiality: IMMATERIAL
      description: >-
        The dopamine-producing partner in the transfer arm is a rat PC12 line. Immaterial
        to the claim, because the arm with DOPAL added directly to the human cells gives
        the same result.
discussions:
- discussion_id: paf_what_initiates_aggregation
  prompt: >-
    What starts alpha-synuclein aggregating in peripheral autonomic neurons in PAF, and
    does the catecholaldehyde DOPAL accumulate in those neurons before the aggregates
    appear?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Catecholaldehyde (DOPAL) Autotoxicity in Noradrenergic Neurons
  - pathophysiology#Peripheral Autonomic Alpha-Synuclein Aggregation
  - mechanistic_hypotheses#catecholaldehyde_autotoxicity
  rationale: >-
    The entry's canonical chain begins at aggregation, and the aggregation node says the
    initiating trigger is unknown. The catecholaldehyde node upstream of it rests on
    cell-free chemistry, postmortem tissue from other Lewy body diseases and a
    computational model; nothing has measured DOPAL, aldehyde dehydrogenase activity or
    the DOPAC:DOPAL ratio in sympathetic tissue from patients with PAF. The gap matters
    for more than completeness, because the two interventions the hypothesis implies -
    inhibiting monoamine oxidase to make less DOPAL, and antioxidant treatment to stop
    its oxidation - are both available, and PAF is the one Lewy body disease where the
    affected neurons are accessible by skin and vein biopsy. The author of the
    hypothesis lists the PAF form of the question explicitly as unanswered.
  posed_by: "dismech curation (PR #15556)"
  posed_date: '2026-10-26T00:00:00Z'
  evidence:
  - reference: PMID:34206133
    reference_title: "The Catecholaldehyde Hypothesis for the Pathogenesis of Catecholaminergic Neurodegeneration: What We Know and What We Do Not Know."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "Do DOPAL and αS ascend together in the periphery in \u201cbody-first\u201d PD or PAF?"
    explanation: >-
      The review poses this PAF-specific question in its own list of what the field does
      not know, which is the gap recorded here.
  - reference: PMID:34206133
    reference_title: "The Catecholaldehyde Hypothesis for the Pathogenesis of Catecholaminergic Neurodegeneration: What We Know and What We Do Not Know."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "The extent to which DOPAL toxicity is mediated by interactions with αS, and vice versa, is poorly understood."
    explanation: States that the direction of causation between the two upstream nodes is unsettled.
  proposed_experiments:
  - experiment_id: paf_dopal_in_accessible_sympathetic_tissue
    name: Catecholaldehyde measurement in biopsied sympathetic tissue from PAF patients
    description: >-
      Quantify DOPAL, DOPAC, the DOPAC:DOPAL ratio and aldehyde dehydrogenase activity
      in forearm vein and skin biopsies from patients with PAF, from patients with the
      non-Lewy preganglionic form, and from controls, in the same samples used to assay
      tyrosine hydroxylase and VMAT2. The vein-biopsy protocol that established the
      vesicular storage defect in PAF already yields the tissue; what has not been
      measured is the aldehyde.
    would_support:
    - pathophysiology#Catecholaldehyde (DOPAL) Autotoxicity in Noradrenergic Neurons
    - mechanistic_hypotheses#catecholaldehyde_autotoxicity
    supporting_outcome:
    - A raised DOPAL level or a lowered DOPAC:DOPAL ratio in PAF sympathetic tissue, tracking the vesicular storage defect in the same samples, would support the autotoxic step acting in this disease rather than only in vitro.
    would_refute:
    - pathophysiology#Catecholaldehyde (DOPAL) Autotoxicity in Noradrenergic Neurons
    - mechanistic_hypotheses#catecholaldehyde_autotoxicity
    refuting_outcome:
    - Normal DOPAL handling in sympathetic tissue carrying heavy alpha-synuclein deposits would refute the catecholaldehyde step in PAF and leave aggregation as the entry point of the chain.
  - experiment_id: paf_dopal_longitudinal_prodrome
    name: Longitudinal catecholaldehyde and vesicular-storage markers across phenoconversion
    description: >-
      Follow a PAF cohort already undergoing serial cardiac 18F-dopamine PET and CSF
      seed amplification, adding catecholaldehyde-pathway markers at each visit, to test
      whether the aldehyde burden moves before or after the storage defect and the
      seeding signal. The computational model of this mechanism predicts a specific
      three-phase order, which makes it falsifiable by serial measurement.
    would_support:
    - mechanistic_hypotheses#catecholaldehyde_autotoxicity
    supporting_outcome:
    - Aldehyde-pathway change preceding measurable loss of vesicular sequestration, in the order the model predicts, would support the loop running in the direction the hypothesis claims.
    would_refute:
    - mechanistic_hypotheses#catecholaldehyde_autotoxicity
    refuting_outcome:
    - Aldehyde change appearing only after denervation is established would make it a consequence of the lesion rather than its cause.
  - experiment_id: paf_dopal_loop_in_ipsc_sympathetic_neurons
    name: Reconstruction of the catecholaldehyde loop in human iPSC-derived sympathetic
      neurons
    description: >-
      Impose the aldehyde burden on the cell type this entry is about. Human pluripotent
      stem cells are differentiated to postganglionic sympathetic neurons, aldehyde
      dehydrogenase is inhibited to raise DOPAL without adding it from outside, and
      alpha-synuclein oligomer load, vesicular norepinephrine storage and stimulated
      norepinephrine release are measured in the same cultures. The existing cell models
      of the catecholaldehyde step use a neuroblastoma line, mouse cortical neurons or a
      glial line, and supply DOPAL in the medium, so neither the affected cell type nor
      the endogenous route to the aldehyde has been tested; these neurons secrete
      norepinephrine on activation, which is the quantity PAF loses. A patient-derived
      line is deliberately not the design here. PAF is sporadic with no causal gene, so an
      unselected patient line carries no lesion to express, which is why the protocol's
      established use is a Mendelian autonomic disease rather than this one.
    model_systems:
    - name: Human iPSC-derived postganglionic sympathetic neurons
      description: >-
        Sympathetic neurons differentiated from human pluripotent stem cells by way of
        neural crest, maintained as monocultures or co-cultured with iPSC-derived
        cardiomyocytes. They carry tyrosine hydroxylase, fire action potentials, secrete
        norepinephrine on stimulation, and in co-culture drive the beating rate of the
        myocytes they innervate, so the noradrenergic functions this entry's nodes describe
        are all directly measurable.
      experimental_model_type: IPSC_DERIVED_MODEL
      organism:
        preferred_term: human
        term:
          id: NCBITaxon:9606
          label: Homo sapiens
      cell_types:
      - preferred_term: iPSC-derived postganglionic sympathetic neuron
        term:
          id: CL:3000002
          label: sympathetic noradrenergic neuron
      culture_system: >-
        Feeder-free monolayer differentiation through neural crest, with an optional
        neurocardiac co-culture arm against iPSC-derived cardiomyocytes
      publication: PMID:32822546
      evidence:
      - reference: PMID:32822546
        reference_title: Functional coculture of sympathetic neurons and cardiomyocytes
          derived from human-induced pluripotent stem cells.
        supports: SUPPORT
        evidence_source: IN_VITRO
        quote_role: PRIMARY_RESULT
        snippet: secreted norepinephrine upon activation, and generated synaptic and action
          currents
        explanation: >-
          Establishes that the platform reports stimulated norepinephrine release, the
          function whose failure defines this disease.
      - reference: PMID:30702809
        reference_title: Autonomic Neurons with Sympathetic Character Derived From Human
          Pluripotent Stem Cells.
        supports: SUPPORT
        evidence_source: IN_VITRO
        quote_role: PRIMARY_RESULT
        snippet: the character of postganglionic sympathetic neurons from human pluripotent
          stem cells
        explanation: The differentiation protocol, which targets the postganglionic neuron
          that bears the lesion in PAF.
      - reference: PMID:30702809
        reference_title: Autonomic Neurons with Sympathetic Character Derived From Human
          Pluripotent Stem Cells.
        supports: SUPPORT
        evidence_source: IN_VITRO
        quote_role: PRIMARY_RESULT
        snippet: This protocol has been used to generate autonomic neurons from healthy
          embryonic stem cells as well as from patient-derived induced pluripotent stem
          cells
        explanation: >-
          Records that the platform has carried patient lines before, which is what makes
          the design feasible rather than speculative.
      modeled_mechanisms:
      - target: Catecholaldehyde (DOPAL) Autotoxicity in Noradrenergic Neurons
        relationship: MEASURES
        fidelity: MODERATE
        model_scale: CELLULAR
        description: >-
          Supplies the cell type the node names, so the aldehyde burden, the oligomer load
          and the storage defect can be measured in one system and in the right neuron
          rather than inferred across three unrelated ones.
        limitations: >-
          These neurons are weeks old and were never exposed to whatever initiates the
          disease, so a loop demonstrated in them shows the mechanism can run in a human
          sympathetic neuron, not that it is what runs in a patient.
        divergences:
        - divergence_type: CAUSE_UNREPRESENTED
          materiality: QUALIFYING
          description: >-
            PAF has no causal lesion to encode, so the aldehyde burden has to be imposed
            pharmacologically by inhibiting aldehyde dehydrogenase. The model therefore
            tests whether the loop can run, and cannot establish that it starts this way in
            the disease.
        - divergence_type: TEMPORAL_SCOPE
          materiality: QUALIFYING
          description: >-
            A culture runs for weeks against a disease that takes decades and whose own
            progression node is measured in years of serial imaging, so an acute aldehyde
            challenge stands in for chronic accumulation.
        - divergence_type: BOUNDARY_OMISSION
          materiality: IMMATERIAL
          description: >-
            Preganglionic input, the baroreflex arc and the vasculature are outside the
            model. Immaterial to this experiment, whose claims are confined to events
            inside the postganglionic neuron.
    readouts:
    - name: Intraneuronal DOPAL and DOPAC to DOPAL ratio after aldehyde dehydrogenase inhibition
      target: pathophysiology#Catecholaldehyde (DOPAL) Autotoxicity in Noradrenergic Neurons
      direction: INCREASED
      interpretation: >-
        Confirms the intended perturbation was achieved from the cell's own dopamine rather
        than supplied from outside, which is what the existing cell models cannot show.
    - name: Alpha-synuclein oligomer load in sympathetic neurons
      target: pathophysiology#Peripheral Autonomic Alpha-Synuclein Aggregation
      direction: INCREASED
      interpretation: >-
        Tests whether an endogenously generated aldehyde burden is sufficient to aggregate
        alpha-synuclein in the cell type that aggregates it in patients.
    - name: Vesicular norepinephrine content and stimulated release
      target: pathophysiology#Noradrenergic Vesicular Storage and Synthesis Defect
      direction: DECREASED
      interpretation: >-
        The return arm of the loop, measured as the function PAF loses rather than as
        dopamine leak from a vesicle preparation.
    decision_criterion: >-
      The three readouts are read in order. An aldehyde rise followed by oligomer
      accumulation followed by loss of vesicular storage establishes that the loop can run
      in a human sympathetic neuron. An aldehyde rise with no oligomer accumulation places
      the burden of the hypothesis back on the cell-free chemistry.
    would_support:
    - pathophysiology#Catecholaldehyde (DOPAL) Autotoxicity in Noradrenergic Neurons
    - mechanistic_hypotheses#catecholaldehyde_autotoxicity
    supporting_outcome:
    - >-
      Oligomer accumulation and loss of vesicular norepinephrine storage following an
      endogenously generated aldehyde burden, in human sympathetic neurons, would move the
      catecholaldehyde step off cell-free chemistry and out of the wrong cell types for the
      first time.
    would_refute:
    - pathophysiology#Catecholaldehyde (DOPAL) Autotoxicity in Noradrenergic Neurons
    - mechanistic_hypotheses#catecholaldehyde_autotoxicity
    refuting_outcome:
    - >-
      A raised aldehyde burden that leaves alpha-synuclein unaggregated and storage intact
      in the cell type the hypothesis is about would weigh against the step, and would
      suggest the oligomerisation seen in neuroblastoma and glial lines depends on
      conditions those systems impose.
- discussion_id: paf_peripheral_aggregate_seeding_mismatch
  prompt: >-
    Can alpha-synuclein aggregates taken from human peripheral sympathetic ganglia
    actually seed and propagate pathology, as the mouse fibril-injection model of PAF
    assumes?
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  attaches_to:
  - pathophysiology#Peripheral Autonomic Alpha-Synuclein Aggregation
  - pathophysiology#Spread to Central Nervous System (Phenoconversion)
  - animal_models#Mouse
  rationale: >-
    The animal model in this entry seeds pathology by injecting synthetic preformed
    fibrils into the ganglia of mice overexpressing mutant human alpha-synuclein, and
    the pathology then spreads along autonomic pathways into the central nervous
    system. That result is the main experimental support for the phenoconversion node.
    But when Lewy-body aggregates purified from the stellate ganglia of Parkinson
    disease patients were inoculated into mouse brain, they produced neither pathology
    nor degeneration, while aggregates from the same patients' substantia nigra did.
    So the seeding competence demonstrated in the model may be a property of synthetic
    fibrils in a transgenic host rather than of the human peripheral aggregate the
    model stands for. This is a mismatch rather than a missing experiment: evidence
    exists on both sides and points in opposite directions, and what is unresolved is
    whether the human peripheral aggregate propagates at all.
  posed_by: "dismech curation (PR #15556)"
  posed_date: '2026-10-26T00:00:00Z'
  evidence:
  - reference: PMID:29422109
    reference_title: "Lack of pathogenic potential of peripheral α-synuclein aggregates from Parkinson's disease patients."
    supports: REFUTE
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    snippet: "intracerebral inoculation of SG-derived LB into mice did not trigger long-term nigrostriatal neurodegeneration nor α-synuclein pathology"
    explanation: >-
      Human sympathetic-ganglion aggregates failed to seed, in the same assay in which
      nigral aggregates from the same patients succeeded.
  - reference: PMID:29422109
    reference_title: "Lack of pathogenic potential of peripheral α-synuclein aggregates from Parkinson's disease patients."
    supports: REFUTE
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    snippet: "Our results argue against a putative pathogenic capacity of peripheral α-synuclein aggregates to promote α-synuclein pathology in the brain, propagate between neuronal networks or induce neurodegeneration."
    explanation: >-
      The authors' own reading of the negative result, which contradicts what the
      fibril-injection model is taken to show about peripheral-to-central spread.
  - reference: PMID:32071315
    reference_title: "Autonomic ganglionic injection of α-synuclein fibrils as a model of pure autonomic failure α-synucleinopathy."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "induces spreading of α-Syn pathology only through the autonomic pathway to both the central nervous system (CNS) and the autonomic innervation of peripheral organs bidirectionally"
    explanation: "The other side of the mismatch: synthetic fibrils in the transgenic host do spread."
  proposed_experiments:
  - experiment_id: paf_ganglion_aggregate_seeding_competence
    name: Seeding competence of PAF-derived ganglionic aggregates
    description: >-
      Purify alpha-synuclein aggregates from sympathetic ganglia of autopsy-confirmed
      PAF cases, rather than from Parkinson disease cases or from synthetic fibrils, and
      test them both in seed amplification assays and by inoculation into the ganglia of
      wild-type and TgM83 mice. The published negative result used Parkinson disease
      stellate ganglia and inoculated the brain, so it leaves the PAF aggregate and the
      peripheral route untested.
    would_support:
    - pathophysiology#Spread to Central Nervous System (Phenoconversion)
    supporting_outcome:
    - Pathology propagating from the injected ganglion in a wild-type host would support peripheral-to-central spread as a mechanism of phenoconversion in PAF, independent of transgene overexpression.
    would_refute:
    - pathophysiology#Spread to Central Nervous System (Phenoconversion)
    refuting_outcome:
    - A PAF-derived aggregate that seeds in vitro but propagates in no host would make the model's spread result an artefact of synthetic fibrils and would leave phenoconversion unexplained by propagation.
- discussion_id: no_exposure_epidemiology
  kind: KNOWLEDGE_GAP
  attaches_to:
  - environmental#
  prompt: >-
    Has any environmental, occupational or lifestyle exposure been studied as a
    risk factor for pure autonomic failure?
  rationale: >-
    This entry carries no environmental section because no exposure study of
    this disease was found, not because exposures were judged irrelevant. A
    deep-research sweep of exposure epidemiology across the
    alpha-synucleinopathies returned substantial literature for Parkinson
    disease, a single unreplicated case-control study for multiple system
    atrophy, one multicentre case-control study for isolated REM sleep
    behaviour disorder and one for dementia with Lewy bodies, and nothing at
    all for this disease. The gap matters because the exposure findings that do
    exist do not agree with one another across these diseases: smoking is
    inversely associated with Parkinson disease, positively associated with
    isolated REM sleep behaviour disorder and null in dementia with Lewy
    bodies, and occupational pesticide exposure is positive in Parkinson
    disease and null in multiple system atrophy under a formal job-exposure
    matrix. Nothing can therefore be inferred about this disease from its
    neighbours, and an exposure profile for a condition whose pathology is
    largely restricted to the peripheral autonomic nervous system would bear
    directly on whether peripheral-onset disease has a distinct trigger.
  notes: >-
    Recorded as an absence of evidence rather than as evidence of absence. The
    searches run were disease-named exposure queries across the
    synucleinopathies; a dedicated search strategy for this disease, including
    its synonyms and the older Bradbury-Eggleston designation, has not been
    run and might surface case series that a cross-disease sweep missed.
- discussion_id: paf_functional_deficit_versus_neuronal_loss
  prompt: >-
    Is the noradrenergic failure of PAF carried by surviving neurons that can no longer
    synthesise or sequester norepinephrine, rather than by loss of those neurons, and
    does a functional phase precede denervation widely enough to leave anything to
    rescue?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Noradrenergic Vesicular Storage and Synthesis Defect
  - pathophysiology#Postganglionic Sympathetic Noradrenergic Denervation
  - mechanistic_hypotheses#catecholaldehyde_autotoxicity
  rationale: >-
    This entry carries both answers and does not choose between them. The denervation
    node asserts loss of postganglionic sympathetic neurons, while the synthesis and
    storage node closes by saying sympathetic dysfunction may precede frank denervation
    - a hedge sitting in a description rather than a recorded question. The two rest on
    measurements in different tissues. The forearm vein biopsy that found normal
    norepinephrine transporter abundance alongside very low tyrosine hydroxylase samples
    a peripheral vein, whereas the 18F-dopamine PET showing lost tracer uptake images
    the myocardium. Normal transporter in one territory and lost uptake in another is as
    consistent with regional heterogeneity as with a lesion in living neurons, and this
    entry cites no study that makes both measurements in the same patients. What hangs
    on it is whether there is a target at all: a neuron surviving with a synthetic and
    vesicular deficit can be treated, and a lost one cannot. The question also bears on
    the catecholaldehyde hypothesis, whose loop requires the vesicular defect to arise
    in a neuron that is still alive to be damaged by it.
  posed_by: dismech curation
  posed_date: '2026-10-27T00:00:00Z'
  evidence:
  - reference: PMID:32372682
    reference_title: "\"Sick-but-not-dead\": multiple paths to catecholamine deficiency in Lewy body diseases."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "functional abnormalities in extant residual neurons contribute to the neurotransmitter deficiencies"
    explanation: >-
      States the position this gap asks about, for Lewy body diseases as a class rather
      than for PAF specifically, which is why it is indirect.
  - reference: PMID:32372682
    reference_title: "\"Sick-but-not-dead\": multiple paths to catecholamine deficiency in Lewy body diseases."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "There is also recent evidence that at least one dysfunction, a vesicular storage defect, is an early abnormality that can precede overt neuronal loss"
    explanation: >-
      The precedence claim on which a treatable window would depend. The cited
      observation is in Lewy body disease cohorts that included PAF, not in PAF alone.
  - reference: PMID:29162745
    reference_title: "Does sympathetic dysfunction occur before denervation in pure autonomic failure?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The finding of normal NET abundance in PAF suggests intact sympathetic nerves but with reduced NE synthesis."
    explanation: >-
      The PAF-specific reading of the vein biopsy, and the one measurement in the entry
      that argues the nerves are present rather than gone.
  proposed_experiments:
  - experiment_id: paf_paired_vein_biopsy_and_cardiac_pet
    name: Paired sympathetic nerve protein panel and cardiac 18F-dopamine PET in the same patients
    description: >-
      Quantify norepinephrine transporter, tyrosine hydroxylase and VMAT2 protein in a
      forearm vein biopsy, and measure cardiac 18F-dopamine uptake at 8 minutes with the
      8-to-25-minute washout slope, in the same patients with PAF at the same visit, and
      repeat after two years. Pairing the two in one person is what neither existing
      study does, and it separates the two readings: a functional lesion predicts
      preserved transporter with preserved uptake and an accelerated washout, while
      regional independence predicts lost uptake in a patient whose transporter
      abundance is normal.
    would_support:
    - pathophysiology#Noradrenergic Vesicular Storage and Synthesis Defect
    supporting_outcome:
    - Preserved transporter abundance together with preserved 8-minute uptake and an accelerated washout slope in the same patient would place the early lesion in surviving neurons, as a synthesis and sequestration failure rather than as denervation, and would make the deficit a treatment target.
    would_refute:
    - pathophysiology#Noradrenergic Vesicular Storage and Synthesis Defect
    refuting_outcome:
    - Low 8-minute uptake alongside normal transporter abundance in the same patient would show the two measurements report different territories, leaving the storage and synthesis defect unable to account for the systemic norepinephrine deficit the entry attributes to it.
- discussion_id: paf_is_nonconverting_paf_a_distinct_entity
  prompt: >-
    Does a stable, purely peripheral PAF exist, or would every case phenoconvert given
    long enough follow-up?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - progression#Phenoconversion to a central synucleinopathy
  - mechanistic_hypotheses#lewy_body_paf
  - mechanistic_hypotheses#sympathetic_body_first_origin
  rationale: >-
    The entry records the conversion rate well - about 30 percent of patients, a pooled
    5.09 per 100 person-years, with MSA clustering in the first years while Lewy body
    disorders arrive at a steadier rate. What it cannot say is what the other 70 percent
    are. If the Lewy body rate is genuinely constant, a cohort followed long enough
    would see most of them convert, and PAF would be a stage of a central
    synucleinopathy rather than a disease with an endpoint of its own. The meta-analysis
    reports that heterogeneity between studies was partly explained by follow-up
    duration, which is the signature of censoring rather than of a biologically distinct
    group that never converts. The alternative is that some patients carry a
    peripherally restricted lesion that never ascends, which is what the
    sympathetic-predominant body-first hypothesis would predict for a subset, and which
    the autopsy series behind that hypothesis observed in people who had not been
    diagnosed with anything. No cohort in this entry distinguishes the two readings, and
    they differ in what a prognosis should say to a patient diagnosed today.
  posed_by: dismech curation
  posed_date: '2026-10-27T00:00:00Z'
  evidence:
  - reference: PMID:42081229
    reference_title: "Phenoconversion in Pure Autonomic Failure: A Systematic Review and Meta-Analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Heterogeneity was partly explained by follow-up duration."
    explanation: >-
      The meta-analysis attributes part of the between-study spread in conversion rate to
      how long each cohort was watched, which is what makes censoring the leading
      explanation for the non-converting majority.
  - reference: PMID:28093795
    reference_title: "Natural history of pure autonomic failure: A United States prospective cohort."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Within 4 years of follow-up, 25 of 74 subjects (34%) developed dementia with Lewy bodies (n = 13), Parkinson disease (n = 6), or multiple system atrophy (n = 6)."
    explanation: >-
      Establishes the scale of the unexplained group: two thirds of this cohort had not
      converted, over a horizon too short to tell a stable form from an unfinished one.
  proposed_experiments:
  - experiment_id: paf_long_horizon_nonconverter_cohort
    name: Autopsy-anchored follow-up of long-standing non-converters
    description: >-
      Follow patients who have carried a PAF diagnosis for more than ten years without
      motor or cognitive signs until death, with brain and peripheral autonomic autopsy,
      and compare their alpha-synuclein distribution with that of converters and with
      the incidental Lewy body cases staged as sympathetic-predominant. Clinical
      follow-up alone cannot settle this, because a patient who dies without motor signs
      may still carry central pathology; only the autopsy distinguishes a lesion that
      never ascended from one that ascended without becoming symptomatic.
    would_support:
    - mechanistic_hypotheses#sympathetic_body_first_origin
    supporting_outcome:
    - Long-standing non-converters whose pathology at autopsy remains confined to peripheral sympathetic tissue would establish a peripherally restricted form, and would make PAF a disease with its own endpoint rather than a stage.
    would_refute:
    - mechanistic_hypotheses#sympathetic_body_first_origin
    refuting_outcome:
    - Central Lewy pathology in clinically pure long-standing cases would show that ascent is the rule and that non-conversion is a statement about symptoms rather than about distribution, leaving PAF a prodromal stage in every case.
- discussion_id: paf_can_the_prodromal_window_be_intercepted
  prompt: >-
    Can treatment given during the peripheral phase of PAF prevent phenoconversion, and
    is the peripheral lesion still the right target by the time PAF is diagnosed?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - treatments#No Disease-Modifying Therapy
  - pathophysiology#Spread to Central Nervous System (Phenoconversion)
  rationale: >-
    Every treatment in this entry is symptomatic, and the entry records that nothing
    slows progression or phenoconversion. The field's stated plan is to use PAF as a
    prodromal population and biomarkers to select who enters a disease-modification
    trial. Two things already in this entry argue that the target may be wrong. By the
    time PAF is diagnosed the postganglionic noradrenergic lesion is severe - plasma
    norepinephrine is very low and cardiac tracer uptake largely gone - so a therapy
    meant to protect peripheral neurons arrives after most of them are affected, which
    is the same question the functional-versus-structural gap asks. And a therapy aimed
    instead at preventing ascent targets propagation, the step this entry's
    HUMAN_MODEL_MISMATCH discussion records as unproven in PAF, since aggregates from
    human peripheral tissue failed to seed and only synthetic fibrils spread in the
    transgenic host. So the prodromal window here is defined clinically, by the absence
    of motor and cognitive signs, and not by the presence of neurons left to save or of
    a propagation step shown to occur. Which of the two a trial should target is open,
    and the choice decides what the endpoint and the enrolment window should be.
  posed_by: dismech curation
  posed_date: '2026-10-27T00:00:00Z'
  evidence:
  - reference: PMID:42081229
    reference_title: "Phenoconversion in Pure Autonomic Failure: A Systematic Review and Meta-Analysis."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "providing an invaluable opportunity for early diagnosis and intervention"
    explanation: >-
      The field's statement of the interception plan. Graded OTHER because the sentence
      is the authors' recommendation rather than a result their analysis measured.
  - reference: PMID:37843677
    reference_title: "Cardiac (18)F-dopamine positron emission tomography predicts the type of phenoconversion of pure autonomic failure."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This capability could refine eligibility criteria for entry into disease-modification trials aimed at preventing evolution of PAF to symptomatic central LBDs."
    explanation: >-
      Names preventing evolution to central disease as the intended endpoint, which is
      the propagation step whose occurrence in PAF is unproven.
  - reference: PMID:32372682
    reference_title: "\"Sick-but-not-dead\": multiple paths to catecholamine deficiency in Lewy body diseases."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "The discovery of specific paths mediating the sick-but-not-dead phenomenon offers novel targets for multi-pronged therapeutic approaches."
    explanation: >-
      States the competing target - the functional deficit in surviving neurons rather
      than propagation. Graded OTHER as a forward-looking proposal, not a result.
  proposed_experiments:
  - experiment_id: paf_biomarker_stratified_prevention_trial
    name: Biomarker-stratified prevention trial with phenoconversion as the endpoint
    description: >-
      Enrol patients with PAF stratified by the markers this entry already records as
      predicting the conversion target - supine norepinephrine, cardiac 18F-dopamine
      pattern, CSF neurofilament light chain and seed amplification - and randomise to an
      alpha-synuclein-directed agent or placebo with phenoconversion as the primary
      endpoint. Stratification is not a refinement here but the design: the entry's two
      subtype hypotheses predict different conversion targets on different timescales,
      so an unstratified trial pools patients whose event rates and mechanisms differ.
    would_support:
    - pathophysiology#Spread to Central Nervous System (Phenoconversion)
    supporting_outcome:
    - A reduction in phenoconversion under an alpha-synuclein-directed agent would establish propagation as both real and interruptible in PAF, which no model result currently shows for human peripheral aggregates.
    would_refute:
    - pathophysiology#Spread to Central Nervous System (Phenoconversion)
    refuting_outcome:
    - No effect on phenoconversion despite engagement of the target would favour central disease arising independently of peripheral spread, and would leave the entry's phenoconversion node without its proposed mechanism.
- discussion_id: paf_genetic_contribution_to_a_sporadic_disease
  prompt: >-
    What genetic contribution does PAF have, given that it is consistently described as
    sporadic and has never been subject to an association study?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - disease#Pure Autonomic Failure
  - pathophysiology#Peripheral Autonomic Alpha-Synuclein Aggregation
  rationale: >-
    This entry has no genetic section, and that is a decision rather than an omission:
    the reviews describe PAF as sporadic, and SNCA appears on pathophysiology nodes as
    the gene of the aggregating protein rather than as a cause. But sporadic is a
    statement about family history, not about susceptibility, and the related
    synucleinopathies have common-variant architecture that PAF has not been tested for.
    A PubMed search for a genome-wide association study of pure autonomic failure
    returns no records (searched 2026-10-27, pure autonomic failure AND genome-wide
    association, 0 records; the eleven hits for a broader genetic-association query are
    reviews, other diseases, or unrelated). The genetic evidence that does touch the PAF
    phenotype comes from rare monogenic families rather than from PAF cohorts: SNCA
    triplication produces the cardiac noradrenergic lesion, and E46K carriers include
    people whose clinical diagnosis is PAF. So whether PAF carries risk alleles, whether
    GBA or SNCA variants shift which central disease a patient converts to, and whether
    the non-Lewy preganglionic form has a different architecture are all untested rather
    than answered. This is a resource gap, not a conceptual one, and it is recorded so
    the absence is not read as a negative result.
  posed_by: dismech curation
  posed_date: '2026-10-27T00:00:00Z'
  evidence:
  - reference: PMID:34392300
    reference_title: "Pure autonomic failure and the differential diagnosis of autonomic peripheral neuropathies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "PAF is a sporadic peripheral autonomic neurodegenerative disease that belongs to the group of disorders known as alpha-synucleinopathies."
    explanation: >-
      The sporadic classification this gap starts from, which concerns family history and
      leaves susceptibility untouched.
  - reference: PMID:29508456
    reference_title: Autonomic dysfunction in genetic forms of synucleinopathies.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "SNCA mutations and multiplications, LRRK2 disease with Lewy bodies as well as other common, sporadic forms of idiopathic PD, MSA, pure autonomic failure, and dementia with Lewy bodies have all been associated with dysautonomia."
    explanation: >-
      Places PAF on the sporadic side of a review whose genetic cases are monogenic
      families, which is the shape of the available evidence rather than of PAF itself.
  - reference: PMID:31178336
    reference_title: "Small fiber neuropathy and phosphorylated alpha-synuclein in the skin of E46K-SNCA mutation carriers."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "We studied 7 E46K-SNCA carriers (3 dementia with Lewy bodies, 2 pure autonomic failure, 1 PD and 1 asymptomatic)"
    explanation: >-
      A monogenic lesion producing the PAF phenotype in two carriers, which shows a
      genetic route to this phenotype exists while saying nothing about sporadic PAF.
  proposed_experiments:
  - experiment_id: paf_targeted_and_genome_wide_genotyping
    name: Genotyping of PAF cohorts against synucleinopathy risk architecture
    description: >-
      Genotype the existing multicentre PAF cohorts, which are already assembled for
      phenoconversion follow-up, for the common variants established in Parkinson
      disease and dementia with Lewy bodies and for GBA and SNCA, and test both for
      association with the PAF diagnosis and for association with the conversion target
      within the cohort. PAF is too rare for a well-powered genome-wide study of its
      own, so the tractable question is whether known synucleinopathy risk loci are
      enriched and whether they stratify conversion, which the follow-up data already
      collected would answer.
    would_support:
    - pathophysiology#Peripheral Autonomic Alpha-Synuclein Aggregation
    supporting_outcome:
    - Enrichment of established synucleinopathy risk alleles in PAF would place the peripheral aggregation lesion inside the same susceptibility architecture as the central Lewy body diseases, and a genotype that predicted the conversion target would give the two subtype hypotheses a genetic correlate.
    would_refute:
    - pathophysiology#Peripheral Autonomic Alpha-Synuclein Aggregation
    refuting_outcome:
    - No enrichment at loci well established in Parkinson disease and dementia with Lewy bodies would argue the peripheral form has a distinct susceptibility architecture, and would weaken reading PAF as the peripheral presentation of the same disease process.
notes: >-
  PAF is sporadic and has no causal gene; SNCA is recorded on pathophysiology nodes as
  the gene of the aggregating protein, not as a genetic cause. Rare pathogenic SNCA
  lesions (the E46K variant, gene triplication) can produce PAF or its cardiac
  noradrenergic lesion and are cited as indirect evidence on the aggregation node.

📚

References & Deep Research

Deep Research

2

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (3)

Record the absence of any exposure epidemiology as a knowledge gap · 2026-10-25T01:33:56Z · View source

Added a discussions block with one KNOWLEDGE_GAP entry recording that no environmental, occupational or lifestyle exposure has been studied as a risk factor for this disease. This entry has no environmental section because the exposure sweep across the alpha-synucleinopathies returned nothing at all for it, not because exposures were judged irrelevant. The gap is recorded as an absence of evidence rather than evidence of absence, and attaches to environmental# as an intentionally empty section. The reason it is worth recording is that the exposure findings which do exist disagree across these diseases: smoking is inversely associated with Parkinson disease, positively associated with isolated REM sleep behaviour disorder and null in dementia with Lewy bodies, and occupational pesticide exposure is positive in Parkinson disease and null in multiple system atrophy under a job-exposure matrix. Nothing can be inferred about this disease from its neighbours, so the absence is a real gap rather than a formality. The note states the limit of the search honestly: these were disease-named exposure queries run across the synucleinopathies, and a dedicated strategy for this disease including the older Bradbury-Eggleston designation has not been run. Provider: OpenScientist (autonomous mode, 5 iterations, 52 citations, 20 minutes). The report is committed at research/Alpha_Synucleinopathies-environmental-exposures-deep-research-openscientist.md with its citations sidecar and HTML/PDF artifacts. Falcon was unavailable for this run (the configured Edison key returns 403), so no second provider corroborates it. Every quoted sentence was read from the cached abstract in references_cache/ rather than from the report, and several of the report's figures were corrected or qualified against source in the process. The report was treated as a lead throughout.

Add OpenScientist deep research and integrate new evidence · 2026-10-24T20:49:48Z · View source

Ran OpenScientist deep research on the entry (research/Pure_Autonomic_Failure-deep-research-openscientist.md, with its final_report artifacts). This is the first independent provider report for PAF: the earlier report was a Claude Code fallback after Falcon returned 403 and drew on references already cached in the curation worktree. Report checks: 30/30 references resolved, 22/22 quotes valid, 24 on topic. Report mentions PAF 60 times; preflight-dr returned SKIP because MONDO records no causal gene, and a manual identity check confirmed the report is about PAF. Term validation flagged 9 mislabelled CURIEs (for example NCIT:C66878 given as droxidopa is lapatinib ditosylate; HP:0012694 given as supine hypertension is enlarged thalamic volume; ORPHA:95429 given as the PAF Orphanet ID, which is ORPHA:441). None of the report's CURIEs were bound. Additions, each with exact snippets from cached abstracts: - Aggregation node: SNCA E46K carriers presenting as PAF with heavy cutaneous p-synuclein (PMID:31178336) and SNCA-triplication cosegregation of cardiac denervation (PMID:14736756), both graded INDIRECT. - prodromal_msa_paf hypothesis: Queen Square autopsy cohort where 5/15 nonmotor-onset MSA cases were first diagnosed PAF and all had normal supine noradrenaline (PMID:35790426). - Droxidopa: pooled 3-trial analysis (PMID:28494751), including its 2-10 week duration caveat, and NNT/NNH (PMID:27538531). - New treatment Ampreloxetine: phase 2 SUPPORT (PMID:34657222) plus REFUTE from the phase 3 SEQUOIA/REDWOOD programme that enrolled PAF and missed its primary endpoints (PMID:42475649). The report described only the positive phase 2 result; the phase 3 paper was found by a separate PubMed search. - Supine hypertension treatment: nOH/nSH trade-off review (PMID:33687577). - New animal_models block: ganglionic fibril injection in TgM83 mice (PMID:32071315), PARTIALLY_RECAPITULATES the aggregation node and, at LOW fidelity, CNS spread, with typed CAUSE_UNREPRESENTED and SPECIES_MISMATCH divergences. - notes: removed the statement that no dedicated PAF animal model exists, which PMID:32071315 contradicts. Validation: just validate, validate-terms, validate-disorders all pass; 195/195 snippets verified; entity refs, causal targets, snippet grading, duplicate keys, enum values and the whole-tree gates pass; 24/24 phenotypes causally connected.

Create: Pure_Autonomic_Failure · 2026-10-24T00:59:51Z · View source

New entry for pure autonomic failure (MONDO:0018608). No stub existed; the disease was mentioned only in the Multiple_System_Atrophy notes and as an Autoimmune_Autonomic_Ganglionopathy differential. Deep research: falcon was requested but Edison returned 403 (authentication) on both the run and the provider health probe. The run was repeated with the recipe's --fallback, which produced research/Pure_Autonomic_Failure-deep-research-claude_code.md (frontmatter records requested_provider falcon, fell_back true). That report states it was written from the abstracts already cached in this worktree, so its agreement with the entry is not independent corroboration. Its reference validation was 59/59 resolved and 13/13 quotes valid; preflight-dr returned SKIP because MONDO records no causal gene, and a manual identity check found the report is about PAF (SNCA, TH and SLC18A2 noradrenergic biology). The evidence base was assembled directly from PubMed searches (natural history, phenoconversion, biomarkers, skin biopsy, CSF seeding, cardiac imaging, treatment trials, supine hypertension) plus Orphanet ORPHA:441. Curated: two-hypothesis pathograph (Lewy-body PAF with postganglionic noradrenergic lesion; non-Lewy PAF as premotor MSA), with 24 phenotypes all causally connected; progression with phenoconversion rates from a meta-analysis and four cohorts; histopathology, imaging, biochemical readouts (plasma norepinephrine, DHPG:NE ratio, CSF seeding, CSF NfL, erythropoietin), diagnostics, differentials and 13 treatments including supine hypertension management. A REFUTE item records the autopsied PAF case without synuclein pathology (PMID:28188385). An independent subagent review before the PR led to: HP:0004370 instead of Heat intolerance, HP:0000505 instead of Blurred vision, CL:0000107 for preganglionic neurons, a prodromal-MSA root node, removal of unsupported differential features, a renamed erythropoietin node, and dropped frequencies not supported for PAF specifically. Validation: just validate passes (schema, terms, references); count-verified-snippets 181/181; check-entity-refs, check-causal-targets, check-enum-values, check-duplicate-keys, check-block-scalar-comments clean; list-disconnected-phenotypes 24/24. check-genereviews: NO_CHAPTER (non-Mendelian).

Claude Code ▸

Pure Autonomic Failure (PAF): Research Report

claude-opus-5-5 2026-10-23T17:39:03.907495

Pure Autonomic Failure (PAF): Research Report

MONDO:0018608 · ORPHA:441 · MeSH D054970 · ICD-11 8D84 · ICD-10 G90.8 (Orphanet maps this as "Narrower") · UMLS C0393911 · GARD 10428 Report prepared 2026-10-23. Evidence comes from the abstracts and full texts already cached for this entry in references_cache/. Ontology CURIEs were checked against the repository's term caches (cache/*/terms.csv); terms that were not in the cache are marked "lookup needed".

1. Disease information

Overview

Pure autonomic failure (PAF) is a rare, sporadic, adult-onset neurodegenerative disease of the peripheral autonomic nervous system. It is classed as an α-synucleinopathy. Its defining feature is chronic neurogenic orthostatic hypotension (nOH) with no identified secondary cause and no motor or cognitive signs of central neurodegeneration.

PAF has no causal gene, and no OMIM entry is recorded. It is not a Mendelian disease. Orphanet records its inheritance as "Not applicable". Its molecular substrate is aggregated α-synuclein, the protein encoded by SNCA (hgnc:11138). That makes SNCA the disease protein, not a germline causal gene, and this report found no source naming a PAF-specific variant.

Orphanet definition: "A rare sporadic neurodegenerative disease characterized by slowly progressive symptoms of orthostatic hypotension (OH), and other symptoms of generalised dysautonomia related to the impairment of the sympathetic component of the autonomic nervous system." (ORPHA:441)
"Pure autonomic failure (PAF) is a rare sporadic neurodegenerative autonomic disorder characterized by slowly progressive pan autonomic failure without other features of neurologic dysfunctions." (PMID:27338613, 2016 review)
Historical description: "A 1925 report by Bradbury and Eggleston first described patients with extreme orthostatic hypotension and a low, steady heart rate." (PMID:24095130)

Synonyms

Bradbury-Eggleston syndrome, idiopathic orthostatic hypotension, PAF, pure dysautonomia, and "pure idiopatic dysautonomia" (Orphanet's own spelling). Older literature also uses "asympathicotonic orthostatic hypotension" (PMID:34669076).

Nature of the data

Nearly all of the evidence is aggregated at the disease level: multicentre cohorts, single-centre retrospective series, autopsy case reports, and consensus statements. There are no EHR-derived phenotype profiles.

A conceptual caveat

PAF is diagnosed clinically, and autopsy and neurochemical data show that the clinical label covers two separate conditions (PMID:34669076, Goldstein 2021):

"This approach lumps together two nOH syndromes that are pathologically and neurochemically distinct. One is characterized by intraneuronal cytoplasmic alpha-synuclein aggregates (i.e., Lewy bodies) and degeneration of postganglionic sympathetic neurons, as in PD and DLB; the other is not, as in MSA."

One autopsied clinically diagnosed PAF case had no synuclein pathology anywhere (PMID:28188385):

"In pure autonomic failure, sympathetic noradrenergic denervation can occur without concurrent Lewy bodies or alpha-synuclein deposition in the brain or sympathetic ganglion tissue."

2. Etiology

Factor	Evidence
Primary cause	Idiopathic neurodegeneration with misfolded α-synuclein deposited mainly in peripheral autonomic neurons. "PAF is a peripheral autonomic neurodegenerative disease caused by alpha-synuclein deposition that is predominantly confined to peripheral autonomic neurons." (PMID:34392300)
Genetic risk	No causal genes, susceptibility loci, or GWAS signals specific to PAF were found in the cached literature. Orphanet: inheritance "Not applicable".
Environmental risk	None established. This report found no toxin, occupational, or infectious exposure linked to PAF.
Demographics	Age is the main correlate: onset is in adulthood or old age. Men predominate in pooled data (63.8% male; PMID:42081229), although one small Stanford series was 63% female (PMID:27757562).
Protective factors	None documented.
Gene–environment interaction	No data.

The prion-like spreading model is the leading mechanistic hypothesis for the whole synucleinopathy family. It is cited as background in PMID:28093795: "α-Syn spreads from cell-to-cell in a 'prion-like fashion.'" No PAF-specific trigger has been identified.

3. Phenotypes

Onset is in adulthood. The course is chronic and slowly progressive, and repeat testing shows worsening autonomic failure over time (PMID:40397689).

Phenotype	HPO (cache-verified)	Frequency / data	Source
Orthostatic hypotension (neurogenic, severe)	HP:0001278	Defining; Orphanet: very frequent (99–80%). Neurogenic OH: SBP fall −44 ± 25 mmHg with HR rise of only 8 ± 8 bpm (synucleinopathy cohort)	ORPHA:441; PMID:29405350
Syncope	HP:0001279	91% of PAF patients	PMID:10552235
Dizziness / light-headedness	lookup needed	84%	PMID:10552235
Visual disturbance on standing	HP:0000505 (Visual impairment; may be too coarse)	75%	PMID:10552235
"Coat-hanger" suboccipital/paracervical neck pain	HP:0030833 Neck pain	81%	PMID:10552235
Chest pain (orthostatic)	HP:0100749	44% (versus 13% in MSA)	PMID:10552235
Fatigue, weakness, lethargy	HP:0012378	91%	PMID:10552235
Supine hypertension	lookup needed	"at least half"; "affects most patients"	PMID:11927799; PMID:26644241; PMID:36601916
Nocturia / nocturnal pressure natriuresis	HP:0000017	Mechanistically linked to supine hypertension	PMID:11927799; PMID:36601916
Postprandial hypotension	lookup needed	Supine BP falls after a meal in PAF but not in controls	PMID:8492945
Anhidrosis / hypohidrosis	HP:0000970 / HP:0000966	Orphanet: very frequent. Median 51% body-surface anhidrosis (IQR 3–93%) in stable PAF	ORPHA:441; PMID:40053259
Bladder symptoms / urinary incontinence	HP:0000020; HP:0000016 (retention)	59%; severe (catheter or incontinence) in 37.6%	PMID:40053259
Constipation	HP:0002019	45%	PMID:40053259
Sexual dysfunction / erectile dysfunction	HP:0100639; HP:0000802	40%	PMID:40053259
Thermoregulatory dysfunction / heat intolerance	HP:0002046	38%	PMID:40053259
REM sleep behavior disorder / dream enactment	HP:5200291	52% endorsed (median 7 years after OH onset); 5 of 8 confirmed by vPSG. An earlier 1998 series of 6 found none.	PMID:40053259; PMID:27757562; PMID:9598693
Hyposmia	HP:0004409	Mean UPSIT 22 ± 3 (similar to PD, lower than MSA); a second study found it milder than in PD	PMID:19201246; PMID:19433741
Bradycardia / slow steady heart rate	HP:0001662	Typical of patients who keep the PAF phenotype	PMID:28093795; PMID:24095130
Low plasma norepinephrine	HP:0012099 (parent term)	Very frequent; "very low plasma norepinephrine levels"	ORPHA:441; PMID:28093795
Anemia (normocytic, low erythropoietin)	HP:0001903	38% of 84 patients with primary autonomic failure	PMID:8017744
Sympathetic pupillary deficit	HP:0007686	Frequent in PAF compared with MSA and LBD	PMID:40696849
Left ventricular hypertrophy (from supine hypertension)	HP:0001712	Reported in supine hypertension; hypertensive organ disease in a 3-case series	PMID:11927799; PMID:15633433

Aggravating factors and quality of life. "Postural symptoms (mainly dizziness and neck pain) were worse in the morning and with warm temperature, straining, exertion, arm movements and food ingestion" (PMID:10552235). Compensatory palpitations and sweating were absent. Patients may only be able to stand for minutes at a time (PMID:21664375; PMID:25185131). Falls and syncope drive disability (PMID:33705537).

4. Genetic and molecular information

Causal genes: none. This is a sporadic, non-Mendelian disease.
Disease protein: α-synuclein (SNCA, hgnc:11138), present as phosphorylated or misfolded aggregates. CSF α-syn seeding assays (PMCA) are positive in 94% of PAF patients (PMID:33881777).
Molecular deficits in noradrenergic terminals. Forearm vein biopsies show "normal abundance of the NE transporter (NET) protein, together with very low levels of tyrosine hydroxylase (TH)... and reduced vesicular monoamine transporter 2 (VMAT2)" (PMID:29162745). The relevant genes are TH (hgnc:11782), SLC18A2/VMAT2 (lookup needed), and SLC6A2/NET (hgnc:11048).
Variants, allele frequencies, ClinVar entries, modifiers, epigenetics, chromosomal abnormalities: none reported in the sources reviewed. No ClinGen gene–disease validity applies.

5. Environmental information

No established environmental, lifestyle, or infectious cause. Factors that aggravate symptoms (not causes) are heat, meals, straining, exertion, and vasoactive drugs such as alpha-blockers (PMID:10552235; PMID:32979782; PMID:28717053).

6. Mechanism and pathophysiology

Ordered causal chain

Initiating event (unknown). α-Synuclein misfolds and aggregates in peripheral autonomic neurons. The trigger is unknown, and prion-like spread is a hypothesis carried over from the synucleinopathy literature rather than something shown in PAF.
This leads to Lewy bodies and neurites in sympathetic ganglia and distal autonomic axons, and degeneration of preganglionic intermediolateral-column neurons and postganglionic sympathetic neurons. PMID:9255396: "histopathologically by cell loss in intermediolateral columns and sympathetic ganglia"; Lewy bodies were found "in sympathetic ganglia, as well as in autonomic axons in the epicardial fat... and autonomic nerves in the muscularis of the urinary bladder." PMID:27338613: "neuronal degeneration of pre- and postganglionic sympathetic and parasympathetic neurons in the thoracic spinal cord and paravertebral autonomic ganglia."
Branch: the non-Lewy form, a preganglionic lesion only, carries a risk of premotor MSA (PMID:34669076).
This results in postganglionic noradrenergic denervation plus a vesicular storage defect in the surviving nerves. "PAF entails moderately decreased cardiac sympathetic innervation and a substantial vesicular storage defect in residual nerves" (PMID:32945121). Denervation is widespread, affecting the heart and renal cortex (PMID:16269589), and skin, where p-syn is found "in the postganglionic sympathetic adrenergic and cholinergic nerve fibers" (PMID:23390175).
This leads to failure of norepinephrine synthesis and release. TH is low and VMAT2 reduced (PMID:29162745). The lesions "are responsible for defects in the synthesis and release of norepinephrine from sympathetic nerve terminals, resulting in significant hypotension" (PMID:28717053). Plasma NE is very low.
This results in failed baroreflex-mediated vasoconstriction on standing, giving neurogenic OH with a blunted heart-rate response (ΔHR/ΔSBP < 0.5 bpm/mmHg; PMID:29405350). Peripheral resistance is not maintained. PMID:39608812 infers that "P-syn deposition on autonomic nerves may impair control of total peripheral resistance giving rise to symptomatic orthostatic hypotension."
Cerebral and muscle hypoperfusion follow, producing syncope, dizziness, visual disturbance, and coat-hanger pain (PMID:10552235).
Parallel branches from denervation:
Denervation supersensitivity of β-adrenoceptors and pressor sensitivity: "supersensitivity of cardiac beta-adrenoreceptors" (PMID:18514012). This underlies exaggerated responses to pressor drugs and to the water-drinking osmopressor reflex (PMID:21048076).
Supine hypertension. The mechanism is incompletely understood. Plasma renin is suppressed, but angiotensin II is elevated and mineralocorticoid receptors are activated (PMID:26644241). Supine hypertension then drives nocturnal pressure natriuresis, which leads to volume depletion and worse morning OH (PMID:11927799), and also LVH.
Loss of sympathetic drive to erythropoiesis, giving low erythropoietin and anemia (PMID:8017744; the authors' hypothesis is that "the sympathetic nervous system stimulates erythropoiesis").
Sudomotor, bladder, bowel, and sexual dysfunction from involvement of the cholinergic sympathetic and parasympathetic pathways.
Central spread in a subset (phenoconversion). Nigral dopaminergic loss is already present: "PAF and PD entail similarly severe nigral and overall central dopaminergic denervation," with the striatum relatively spared (PMID:18363034). Neuromelanin MRI shows loss in the locus ceruleus and substantia nigra in high-risk PAF (PMID:39825743). Hyposmia and RBD are central markers. Progression leads to PD, DLB, or MSA (see §8).

Checklist mapping

Cell types (cache-verified CL): sympathetic neuron CL:0011103; noradrenergic neuron CL:0008025; cholinergic neuron CL:0000108; dopaminergic neuron CL:0000700. A preganglionic neuron term needs lookup.
Processes (GO terms still need lookup; none were verified here): norepinephrine biosynthesis, catecholamine secretion and storage (vesicular monoamine transport), protein aggregation, baroreflex blood-pressure regulation, neuron death.
Chemicals (CHEBI): noradrenaline CHEBI:33569.
Immune involvement: none described.
Molecular profiling: no transcriptomic, proteomic, or single-cell PAF datasets were found in the cached sources. CSF NfL is elevated only in patients who later convert to MSA (PMID:33881777).

7. Anatomical structures affected

Primary: the peripheral autonomic nervous system. This means the sympathetic ganglia (UBERON term lookup needed), the thoracic intermediolateral column, and postganglionic fibres.
End organs (UBERON, cache-verified): heart UBERON:0000948 (cardiac denervation); kidney UBERON:0002113 (renal cortex); skin of body UBERON:0002097 and sweat gland UBERON:0001820; urinary bladder (lookup needed).
Central nervous system (subclinical or in converters): substantia nigra UBERON:0002038 and locus ceruleus UBERON:0002148 (PMID:9255396; PMID:18363034; PMID:39825743).
Subcellular: neuronal cytoplasmic inclusions (Lewy bodies) and synaptic or secretory vesicles (the storage defect).
Distribution: symmetric and length-dependent, with small-fibre loss (PMID:26606657). In PAF, p-syn is found at every biopsy site: "the site of analysis is irrelevant in PAF."

8. Temporal development

Onset: insidious, in adulthood or old age. Pooled mean onset age is 63.1 ± 4.3 years (PMID:42081229). At enrollment in the US cohort, patients were 68 years old (median) and had had autonomic failure for 5 years (PMID:28093795). Most non-OH autonomic symptoms begin near OH onset, while RBD comes later (median 7 years; PMID:40053259).
Course: chronic and progressive, with no remission.
Phenoconversion (the central prognostic issue):

Study	n	Follow-up	Converted	Breakdown
US consortium (PMID:28093795)	74	≤4 y	34%	DLB 13, PD 6, MSA 6
Mayo retrospective (PMID:28202694)	78 assessable of 318	≥3 y	12% of possible PAF	MSA 22, PD/DLB 11
Mayo (PMID:32546656)	275	—	24%	MSA 34, PD/DLB 33
8-centre prospective (PMID:38366572; NCT01799915)	149	mean 3 y	33%	PD 42%, DLB 35%, MSA 23%; ~12% per year
Queen Square (PMID:40397689)	281	median 10 y	33%	53% of deaths still had the PAF phenotype
UK multimodal (PMID:40696849)	194	median 13 y	26%	MSA or LBD
Meta-analysis (PMID:42081229)	900 (9 studies)	6.4 y	30%	MSA 12%, DLB 11%, PD 7%; 5.09 per 100 person-years

The meta-analysis concludes that "PAF may be a prodromal presentation of PD, DLB, or MSA with phenoconversion incidence rates similar to those of RBD." MSA conversions cluster in the early years, while Lewy body conversions occur at a steady rate. Note that the annual-risk estimates differ: about 12% per year in PMID:38366572 against about 5% per year in the pooled analysis.

Critical window: the pre-motor phase is the opportunity for disease-modifying trials (PMID:37843677; PMID:42444112).

9. Inheritance and population

Inheritance: sporadic, not applicable (ORPHA:441). There is no penetrance, anticipation, founder effect, or carrier-frequency data.
Prevalence: Orphanet gives a point-prevalence class of 1–9 per 1,000,000 (Europe). The source field in that row reads "PMID:2007", which looks malformed and should be checked before citing. No population-based incidence study was found.
Sex: male predominance in pooled cohorts (63.8%; PMID:42081229). In the Queen Square cohort, male sex was associated with conversion to Lewy body disease (PMID:40397689).
Geography and ethnicity: no data. Cohorts are mainly from the US and UK.

10. Diagnostics

Clinical criteria. OH is defined as a sustained fall of ≥20 mmHg systolic or ≥10 mmHg diastolic blood pressure within 3 minutes of standing or tilt (consensus statement, PMID:21431947). PAF additionally requires no secondary cause and no motor or cognitive CNS features (1996 consensus criteria, as cited in PMID:40696849). Neurogenic supine hypertension is defined as SBP ≥140 and/or DBP ≥90 mmHg after 5 minutes supine (PMID:29766366). Screening and treatment recommendations: PMID:28050656.

Test	Finding in PAF	Source
Tilt table / active stand	nOH; ΔHR/ΔSBP < 0.492 bpm/mmHg (sensitivity 91.3%, specificity 88.4%)	PMID:29405350
Supine plasma norepinephrine	Very low. Values >100 pg/mL (Mayo) or ≥200 pg/mL (UK, Queen Square) predict conversion	PMID:28093795; PMID:28202694; PMID:40696849
Cardiac ¹⁸F-dopamine PET / ¹²³I-MIBG	Denervated. MIBG abnormal in 84.6% of 39 cases. Low cardiac ¹⁸F-dopamine predicts conversion to LBD; normal uptake points toward MSA	PMID:16269589; PMID:41072204; PMID:37843677
Skin biopsy for phosphorylated α-synuclein	Positive in 100% (22 of 22) in Synuclein-One versus 3.3% of controls. A total p-syn score >3 separates PAF from MSA (specificity 100%, sensitivity 82%). Absent in acquired autonomic neuropathies	PMID:38506839; PMID:39608812; PMID:23390175; PMID:26606657
Skin autonomic innervation, sympathetic skin responses	Marked postganglionic denervation, whereas skin innervation is preserved in MSA	PMID:20660924; PMID:18805037
CSF α-syn PMCA and NfL	PMCA positive in 94%. An MSA-like seeding profile or raised NfL predicts MSA	PMID:33881777
Autonomic reflex screen / thermoregulatory sweat test	Moderate to severe failure. A preganglionic sweat-loss pattern predicts MSA	PMID:40053259; PMID:28202694
Smell test (UPSIT)	Hyposmia, which points toward PD/DLB conversion	PMID:19201246; PMID:42081229
DaTSCAN, FDOPA-PET, neuromelanin MRI	Abnormal DaTSCAN in 39% of patients up to 7 years before conversion	PMID:40397689; PMID:39825743
Polysomnography	RBD confirmation	PMID:27757562
Pupillometry	Sympathetic deficits. Normal pupils predict conversion	PMID:40696849

Genetic testing: not indicated for PAF itself. It can be used to exclude mimics.

Differential diagnosis: prodromal MSA, PD or DLB with OH, autoimmune autonomic ganglionopathy, amyloid and diabetic autonomic neuropathy, and non-neurogenic OH from volume depletion, anemia, or polypharmacy (PMID:34392300; PMID:29405350). The MDS prodromal-MSA criteria are 92–100% sensitive in PAF but only 56–67% specific. Requiring UPSIT >28 raises specificity to 90–97% (PMID:42444112).

Screening: no population or newborn screening exists.

11. Outcome and prognosis

Survival: median 15 years from orthostatic symptom onset, driven mainly by age and OH severity (PMID:40397689). In that cohort, 41% died during follow-up. Survival is better than in the other synucleinopathies (PMID:27338613; PMID:24095130).
Patients who stay "pure" have very low NE, a slow resting heart rate, no RBD, and preserved smell (PMID:28093795). "not all patients with pure autonomic failure will develop motor or cognitive symptoms, even with prolonged follow-up" (PMID:40053259).
Predictors of conversion to MSA: younger onset, severe bladder dysfunction, preserved smell, HR rise on tilt >10 bpm, higher NE, preganglionic anhidrosis, subtle motor signs, CSF NfL (PMID:28093795; PMID:38366572; PMID:33881777).
Predictors of conversion to PD/DLB: hyposmia, blunted tilt HR response (HR 6.1 for PD), RBD, low cardiac ¹⁸F-dopamine, male sex, older age (PMID:38366572; PMID:37843677; PMID:40397689).
Predictor of any conversion: RBD (odds ratio 7.1; PMID:28093795).
Complications: syncope, falls, injury, supine hypertension with end-organ damage (LVH, transient ischemic attack in one case series), anemia (PMID:15633433; PMID:11927799; PMID:8017744).

12. Treatment

There is no disease-modifying therapy: "There is currently no specific treatment to stop progression in PAF" (PMID:27338613). The goal of treatment is to relieve symptoms, not to normalize blood pressure (PMID:33705537).

Choosing a drug. Patients with low "sympathetic reserve", which includes PAF, "tend to respond better to 'norepinephrine replacers' (midodrine and droxidopa)" (PMID:32979782).

Intervention	Mechanism	Evidence	Suggested NCIT / CHEBI
Non-pharmacologic: avoid triggers, high salt and fluid intake, counter-maneuvers, compression garments	Volume and venous return	First-line (PMID:21664375; PMID:28050656)	Supportive Care NCIT:C15747
Abdominal binder (40 mmHg)	Raises stroke volume	Standing BP +15/6 mmHg (PMID:15241645)	—
Rapid water drinking (~500 mL)	Osmopressor reflex	PMID:21048076	—
Head-up tilt sleeping	Reduces nocturnal natriuresis	Scoping review (PMID:37626994)	—
Midodrine	α1-agonist (direct vasoconstriction)	RCT, n=171: improved standing SBP and symptoms; adverse effects include supine hypertension, piloerection, urinary retention (PMID:9091692)	Pharmacotherapy NCIT:C15986 + CHEBI:6933
Droxidopa	Norepinephrine prodrug	Phase 3: OHQ composite +0.90 (p=0.003), standing SBP +11.2 mmHg (PMID:24944260). Withdrawal trial missed its primary endpoint (PMID:25350981)	CHEBI:31524
Fludrocortisone	Volume expansion (mineralocorticoid)	Use with caution (PMID:33705537; PMID:15633433)	CHEBI:50885
Pyridostigmine	Ganglionic enhancer	Reduced standing diastolic BP fall with no supine rise (PMID:16476804). Better suited to preserved reserve	CHEBI:8665
Atomoxetine	NET inhibitor	Acutely beat midodrine (PMID:25185131), but a 4-week RCT showed no benefit over placebo (PMID:39294522). Response depends on residual sympathetic tone (PMID:34176285)	CHEBI:127342
Recombinant erythropoietin	Corrects anemia	Hb 108 → 133 g/L in 5 of 5 patients (PMID:8017744)	—
Supine hypertension: avoid lying flat in the daytime, short-acting nighttime antihypertensives (e.g., transdermal nitroglycerin)	—	PMID:11927799	—
Eplerenone (night dose)	Mineralocorticoid receptor antagonist	Supine SBP −32 mmHg (crossover, n=10, 7 with PAF) (PMID:26644241)	CHEBI:31547
CPAP (8–12 cmH₂O overnight)	Valsalva-like fall in cardiac output	Night SBP −23 mmHg, less nocturia, better morning orthostatic tolerance (PMID:36601916)	—

Pharmacogenomics: none described.
Gene, cell, and RNA therapies: none.
Trials: registered work is mostly observational, e.g., NCT01799915 (natural history) and NCT04700722 (Synuclein-One). Phenoconversion biomarkers are being developed specifically to select patients for future disease-modification trials (PMID:37843677; PMID:42444112).

13. Prevention

Primary prevention: none is possible, because the cause is unknown.
Secondary prevention: early detection through skin p-syn and autonomic testing, and stratifying conversion risk for trial enrollment.
Tertiary prevention: fall and syncope prevention through education about triggers and medications (PMID:33705537); treating supine hypertension to prevent LVH and nocturnal natriuresis (PMID:11927799; PMID:29766366).
Genetic counseling: not applicable, since PAF is sporadic.
Vaccination, public-health, and environmental measures: not applicable.

14. Other species and natural disease

No naturally occurring PAF in animals was found in the cached literature, and there is no relevant OMIA entry. Not applicable for transmission or zoonosis.

15. Model organisms

There is no dedicated PAF animal model in the reviewed sources.

Related models: sinoaortic-denervated mice, which model loss of baroreflex buffering, show the osmopressor response. Trpv4 is implicated in that response (PMID:21048076, review, MODEL_ORGANISM).
What a model would need to capture: a peripherally restricted synucleinopathy with postganglionic noradrenergic degeneration and spared striatum. The SNCA-based models of the wider synucleinopathy literature were not reviewed here, and none in the cached sources was shown to reproduce PAF specifically. This is a candidate KNOWLEDGE_GAP / HUMAN_MODEL_MISMATCH.

Notes for knowledge-base curation

Lump/split: a single Disease entry seems right. Two candidate subtypes or hypotheses could be modelled: Lewy-body PAF (postganglionic, converts to PD/DLB) and non-Lewy PAF (preganglionic, possible premotor MSA) (PMID:34669076; PMID:28188385; PMID:37843677).
Do not add genetic: causal genes. SNCA belongs on pathophysiology nodes (aggregation) as the disease protein.
Wire every phenotype into the pathograph. OH should be the hub, with branches to cerebral hypoperfusion (syncope, dizziness, visual symptoms), muscle hypoperfusion (neck pain), supine hypertension → nocturia/LVH, and denervation → anemia.
Conformance target: check just list-modules for an α-synuclein aggregation or autonomic module before adding one.
CURIEs still to look up: HP terms for supine hypertension, dizziness, and postprandial hypotension; UBERON terms for sympathetic ganglion, intermediolateral column, and urinary bladder; a CL term for preganglionic neuron; all GO process terms; HGNC for SLC18A2.
Orphanet epidemiology source: the "PMID:2007" source in the ORPHA:441 epidemiology row looks malformed. Do not cite it as a PMID.

Reference Validation

Checked with linkml-reference-validator 0.3.0.

Outcome	Count
References checked	59
Resolved	59
Unresolved (possible confabulation)	0
Unverifiable	0
Quoted claims checked	13
Quoted claims found in source	13
Quoted claims not found in source	0
References weighed for topical relevance	59
On topic	52
Off topic	0

All extracted references resolved successfully.

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Outcome	Count
Terms checked	43
Resolved	42
Unresolved (possible confabulation)	0
Obsolete	0
Unverifiable	1
Terms whose name was checked	17
Terms named correctly	3
Terms named as a different term	7
Terms whose name is worth a second look	7

Terms the report names something else

These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:

HP:0012378 (1 mention) - the report calls it "Fatigue, weakness, lethargy"; HP calls it Fatigue
HP:0000017 (1 mention) - the report calls it "Nocturia / nocturnal pressure natriuresis"; HP calls it Nocturia
HP:0001662 (1 mention) - the report calls it "Bradycardia / slow steady heart rate"; HP calls it Bradycardia
HP:0012099 (1 mention) - the report calls it "parent term"; HP calls it Abnormal circulating catecholamine concentration
HP:0001903 (1 mention) - the report calls it "Anemia (normocytic, low erythropoietin)"; HP calls it Anemia
UBERON:0000948 (1 mention) - the report calls it "cardiac denervation"; UBERON calls it heart
UBERON:0002113 (1 mention) - the report calls it "renal cortex"; UBERON calls it kidney

Terms whose name is worth a second look

The report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:

HP:0001278 (1 mention) - the report calls it "Orthostatic hypotension (neurogenic, severe)"; HP calls it Orthostatic hypotension
HP:0000505 (1 mention) - the report calls it "Visual impairment; may be too coarse"; HP calls it Visual impairment
HP:0100749 (1 mention) - the report calls it "Chest pain (orthostatic)"; HP calls it Chest pain
HP:0002046 (1 mention) - the report calls it "Thermoregulatory dysfunction / heat intolerance"; HP calls it Heat intolerance
HP:5200291 (1 mention) - the report calls it "REM sleep behavior disorder / dream enactment"; HP calls it REM sleep behavior disorder
HP:0007686 (1 mention) - the report calls it "Sympathetic pupillary deficit"; HP calls it Abnormal pupillary function
HP:0001712 (1 mention) - the report calls it "Left ventricular hypertrophy (from supine hypertension)"; HP calls it Left ventricular hypertrophy

Prefixes with no resolver

Terms carrying these prefixes were not checked either way, because no configured ontology covers them. An unrecognised prefix may name an ontology this run could not reach as easily as one that does not exist, so nothing here is evidence of fabrication: ORPHA.

OpenScientist ▸

Pure Autonomic Failure (MONDO:0018608) — Comprehensive Disease Characteristics Report

openscientist-autonomous 29 citations 2026-10-24T13:32:26.700060

Pure Autonomic Failure (MONDO:0018608) — Comprehensive Disease Characteristics Report

Summary

Pure Autonomic Failure (PAF; Bradbury–Eggleston syndrome) is a rare, sporadic, adult/late-onset peripheral α-synucleinopathy. It has no Mendelian causal gene; its central causal protein is α-synuclein, encoded by SNCA (HGNC:11138; chromosome 4q22.1), which misfolds and aggregates as Lewy-body-type neuronal cytoplasmic inclusions predominantly within the peripheral autonomic nervous system — postganglionic sympathetic neurons, sympathetic ganglia, the intermediolateral columns of the spinal cord, and distal autonomic axons of the heart and bladder. The resulting degeneration and biochemical dysfunction of noradrenergic neurons (tyrosine-hydroxylase depletion, impaired vesicular catecholamine storage, postganglionic denervation) produces a profound norepinephrine deficiency and the hallmark clinical feature of neurogenic orthostatic hypotension (nOH), together with genitourinary, gastrointestinal, and sudomotor autonomic failure. Although PAF is historically regarded as an isolated condition, it is now understood as a localized/prodromal synucleinopathy: approximately 30% of patients phenoconvert over ~6 years to a central synucleinopathy — multiple system atrophy (MSA), dementia with Lewy bodies (DLB), or Parkinson's disease (PD).

Diagnosis rests on autonomic function testing demonstrating neurogenic OH, low supine plasma norepinephrine without orthostatic rise, cutaneous phosphorylated α-synuclein on skin biopsy, CSF α-synuclein seed-amplification assays (αSyn-PMCA), and reduced cardiac sympathetic imaging (¹²³I-MIBG scintigraphy). There is no disease-modifying therapy; management is symptomatic and pathophysiology-guided — non-pharmacologic measures (salt/fluid loading, compression garments, physical counter-maneuvers, head-up sleeping) plus norepinephrine-replacing drugs (midodrine, droxidopa), which are preferred in PAF because of its low peripheral sympathetic reserve, balanced carefully against comorbid neurogenic supine hypertension.

This report synthesizes 11 confirmed findings and 37 reviewed papers across all 15 requested sections. The strongest, best-supported conclusions are: (1) PAF is molecularly an α-synucleinopathy with a peripheral noradrenergic lesion; (2) the biochemical signature is tyrosine-hydroxylase deficiency with relatively preserved norepinephrine transporter; (3) roughly one-third of patients phenoconvert, with identifiable clinical and biomarker predictors; and (4) droxidopa and midodrine are the evidence-supported, pathophysiology-matched therapies for the orthostatic hypotension.

1. Disease Information

Overview. PAF is a chronic, slowly progressive degenerative disorder of the autonomic nervous system characterized by isolated (at onset) autonomic failure in the absence of other neurological deficits. The cardinal manifestation is neurogenic orthostatic hypotension. Pathologically it is defined by predominantly peripheral deposition of α-synuclein and degeneration of postganglionic sympathetic neurons (PMID: 31515103; PMID: 24095130).

"Pathologically, PAF is characterized by predominantly peripheral deposition of α-synuclein." — PMID: 31515103

"characterized by isolated peripheral autonomic dysfunction and decreased norepinephrine synthesis" — PMID: 24095130

Key identifiers. - MONDO: MONDO:0018608 - MeSH: Pure Autonomic Failure (D054970) - ICD-10: G90.3 (multi-system degeneration of the autonomic nervous system); ICD-11: autonomic nervous system disorder range - Orphanet: ORPHA:95429 (Pure autonomic failure) - OMIM: Not recorded as a Mendelian entry (sporadic disease; no causal gene registered)

Synonyms / alternative names. Bradbury–Eggleston syndrome; PAF; pure dysautonomia; pure idiopathic dysautonomia; idiopathic orthostatic hypotension.

Information source. Information is derived from aggregated disease-level resources (OMIM/Orphanet/MeSH, clinical cohort studies, autopsy series, and natural-history registries such as the Natural History Study of the Synucleinopathies and the Queen Square cohort), not single-patient EHR extraction.

2. Etiology

Primary cause. PAF is a sporadic neurodegenerative α-synucleinopathy. The proximal molecular cause is misfolding and aggregation of α-synuclein (SNCA) into β-sheet-rich fibrils forming intraneuronal Lewy bodies in peripheral autonomic neurons. No environmental trigger or infectious agent is established as causal.

Genetic risk factors. PAF occurs sporadically with no established Mendelian inheritance (PMID: 24095130: "PAF occurs sporadically"). However, rare SNCA lesions can produce a PAF-like noradrenergic/cardiac denervation phenotype, directly implicating α-synuclein dosage and structure (see Section 4). As a member of the α-synucleinopathy family, PAF likely shares susceptibility architecture (e.g., SNCA common variants, GBA variants) with PD/DLB, though PAF-specific GWAS data are lacking.

Environmental risk factors. Older age is the dominant demographic risk factor (mean onset ~63 years). A modest male predominance is observed (~64% male in large cohorts). No specific toxin, occupational exposure, or lifestyle factor has been causally linked.

Protective factors. None established genetically or environmentally for PAF specifically.

Gene–environment interactions. Not characterized for PAF. The disease is best modeled as a predominantly stochastic/age-related proteinopathy with rare monogenic (SNCA-dosage) phenocopies.

3. Phenotypes

The core phenotype is neurogenic orthostatic hypotension with multi-system autonomic failure. Autonomic failure manifests across genitourinary, bowel, and thermoregulatory domains (PMID: 31515103: "Autonomic failure may also manifest as genitourinary, bowel, and thermoregulatory dysfunction.").

Phenotype	Type	HPO term	Onset/Severity/Course	Frequency
Neurogenic orthostatic hypotension (dizziness, presyncope, syncope)	Clinical sign / symptom	HP:0004926 (Orthostatic hypotension); HP:0001278 (Syncope)	Adult/late-onset; moderate–severe; progressive	Universal (defining feature)
Supine hypertension	Clinical sign	HP:0012694	Co-occurs with nOH; variable	Common (>50% of nOH patients across dysautonomias)
Erectile/sexual dysfunction, urinary urgency/retention	Symptom	HP:0000012 (Abnormality of the urinary system); HP:0000144	Often early; progressive	Common
Constipation / bowel dysmotility	Symptom	HP:0002019	Progressive	Common
Anhidrosis / hypohidrosis (thermoregulatory/sudomotor failure)	Clinical sign	HP:0000966 / HP:0000821	Progressive	Common
REM sleep behavior disorder (dream enactment)	Behavioral/sleep	HP:0002494	Often prodromal	Frequent; prodromal synucleinopathy marker

Quality-of-life impact. nOH substantially impairs daily functioning, increasing risk of falls, syncope, and functional disability; orthostatic symptoms limit upright activity. The combination of OH + RBD marks a "malignant" phenotype associated with cognitive impairment, postural instability, and reduced survival (PMID: 31142660: "The combination of OH and RBD was associated with cognitive impairment and more rapid progression of postural instability").

4. Genetic / Molecular Information

Causal gene. There is no Mendelian causal gene for sporadic PAF. The causal protein is α-synuclein (SNCA, HGNC:11138; OMIM gene 163890; chromosome 4q22.1), which is the aggregating species in all PAF neuropathology.

Rare SNCA lesions producing a PAF-like phenotype (PMID: 14736756; PMID: 31178336):

Variant	Type	Functional consequence	Phenotype
SNCA whole-gene triplication (Iowa kindred)	Copy-number / structural	Gain of function via overexpression of normal α-synuclein	Lewy body parkinsonism with cardiac sympathetic denervation and orthostatic hypotension
SNCA E46K	Missense	Aggregation-prone; aggressive Lewy body disease	Can present as PAF with severe cutaneous p-synuclein and small-fiber denervation

"cardiac sympathetic denervation cosegregates with parkinsonism" … "where disease is caused by overexpression of normal alpha-synuclein" — PMID: 14736756

"All E46K-SNCA carriers had moderate to severe p-synuclein deposits and small fiber neurodegeneration" — PMID: 31178336

These establish SNCA gene dosage/structure as mechanistically sufficient to produce the cardiac noradrenergic denervation characteristic of PAF, even though sporadic PAF carries no recurrent germline mutation.

Variant classification. The triplication and E46K are pathogenic for Lewy body disease; no recurrent pathogenic variant exists for sporadic PAF. Allele frequencies of these lesions are effectively absent in gnomAD (private/family-specific).

Somatic vs germline. The SNCA lesions above are germline. Sporadic PAF is not driven by an identified somatic variant.

Modifier genes / epigenetics / chromosomal abnormalities. Not characterized specifically for PAF beyond the SNCA-dosage effect (a copy-number/structural mechanism). The SNCA triplication is itself a large-scale genomic (copy-number) abnormality.

5. Environmental Information

Environmental factors / toxins: None established as causal for PAF.
Lifestyle factors: None causally linked. Dietary salt/fluid status strongly modulates symptom severity (volume depletion worsens nOH) but is not etiologic.
Infectious agents: Not applicable — PAF is a degenerative proteinopathy, not an infectious or post-infectious disorder.

6. Mechanism / Pathophysiology

Ordered causal chain

α-synuclein (SNCA) misfolds and aggregates into β-sheet-rich, seeding-competent fibrils in peripheral autonomic neurons (gain of toxic function) — leads to →
Intraneuronal Lewy-body / Lewy-neurite inclusions form in sympathetic ganglia, intermediolateral columns of the spinal cord, and distal autonomic axons of heart and bladder — results in →
Noradrenergic neuron dysfunction: tyrosine-hydroxylase (TH) depletion, impaired vesicular catecholamine storage, and postganglionic denervation — leads to →
Deficient norepinephrine release at sympathetic vascular terminals (very low supine plasma NE, no orthostatic rise) — results in →
Failure of baroreflex-mediated vasoconstriction on standing — leads to →
Neurogenic orthostatic hypotension and multi-system autonomic failure (urogenital, GI, sudomotor), the clinical manifestation.
Branch (in ~30% over ~6 yr): α-synuclein pathology spreads to the CNS (locus coeruleus, substantia nigra) — leads to phenoconversion to:
PD / DLB — if sympathetic intraneuronal Lewy-type synucleinopathy with low NE, OR
MSA — if preserved noradrenergic status (normal supine NE, intact pupils, cardiovagal responses).

Steps 1–2 (prion-like seeding/spread) are partly inferred from CSF seed-amplification assays and animal models rather than fully demonstrated in situ in living humans.

Supporting detail by category

Protein dysfunction: α-synuclein misfolding/aggregation (loss of normal synaptic function + toxic gain of function). CSF αSyn-PMCA is positive in ~94% of PAF, confirming seeding-competent misfolded α-synuclein (PMID: 33881777). In PAF/PD the aggregates are neuronal cytoplasmic inclusions (Lewy bodies), in contrast to the glial cytoplasmic inclusions of MSA (PMID: 24095130: "they take the form of neuronal cytoplasmic inclusions called Lewy bodies in PAF and PD").
Biochemical abnormality: Profound tyrosine-hydroxylase deficiency (the rate-limiting catecholamine-synthesis enzyme, tyrosine→L-DOPA) with relatively preserved norepinephrine transporter (NET) in sympathetic nerves — "normal abundance of the NE transporter (NET) protein, together with very low levels of tyrosine hydroxylase (TH)" (PMID: 29162745). This suggests synthetic dysfunction may precede/exceed outright structural denervation.
Dual lesion (imaging): Cardiac sympathetic PET shows that "PAF entails moderately decreased cardiac sympathetic innervation and a substantial vesicular storage defect in residual nerves" (PMID: 32945121) — i.e., both denervation and a vesicular catecholamine storage defect.
Cellular processes: Neurodegeneration of noradrenergic neurons; baroreflex failure.
Molecular pathways / metabolic changes: Catecholamine biosynthesis pathway disrupted at the TH step (tyrosine → L-DOPA → dopamine → norepinephrine).

Suggested GO terms: GO:0042423 (catecholamine biosynthetic process), GO:0042136 (neurotransmitter biosynthetic process), GO:0007268 (chemical synaptic transmission), GO:0003018 (vascular process in circulatory system). GO cellular component: GO:0097413 (Lewy body); synaptic vesicle (GO:0008021). CL terms: CL:0000540 (neuron), CL:0011103 (sympathetic noradrenergic neuron / postganglionic sympathetic neuron).

7. Anatomical Structures Affected

Organ / system level. - Primary: Peripheral autonomic nervous system — sympathetic ganglia, postganglionic sympathetic nerves. Body systems: autonomic (sympathetic) nervous system; cardiovascular (blood-pressure regulation); genitourinary; gastrointestinal; integumentary (sudomotor). - Secondary (with phenoconversion): central nervous system (locus coeruleus, substantia nigra).

Autopsy-defined pathology (PMID: 9255396): cell loss in intermediolateral columns (spinal cord) and sympathetic ganglia; Lewy bodies in substantia nigra, locus coeruleus, substantia innominata, and sympathetic ganglia; and in distal autonomic axons — epicardial fat (cardiac), periadrenal adipose nerve fascicles, and nerves in the muscularis of the urinary bladder. "Sites of autonomic nerve involvement correlated with clinical symptomatology."

"histopathologically by cell loss in intermediolateral columns and sympathetic ganglia" — PMID: 9255396

"Lewy bodies in this disease may be seen in distal axons at a great length from their primary cell bodies" — PMID: 9255396

Tissue / cell level. Nervous tissue; postganglionic sympathetic noradrenergic neurons (CL:0011103). Subcellular: neuronal cytoplasm (Lewy-body inclusions; GO:0097413 Lewy body); synaptic vesicle catecholamine storage compartment (vesicular storage defect).

Localization (UBERON): UBERON:0001806 (sympathetic ganglion / paravertebral ganglion), UBERON:0002260 (intermediolateral nucleus — spinal cord lateral horn), UBERON:0000948 (heart), UBERON:0001255 (urinary bladder), UBERON:0001872 (locus coeruleus), UBERON:0002038 (substantia nigra). Lateralization: bilateral/systemic.

8. Temporal Development

Onset: Adult/late-onset; mean age ~63 years (63.1 yr in meta-analysis). Pattern: insidious, chronic.
Progression: Slowly progressive over years to decades. Disease course is chronic and progressive; nOH is often a relatively late and severe sign of autonomic degeneration. In some patients the "pure" peripheral phase is stable for many years (Queen Square median follow-up ~10 yr).
Critical transition / phenoconversion: ~30% convert to a central synucleinopathy over a mean of ~6.4 years (meta-analysis); independent cohorts report ~33% over ~10–13 years. This defines a critical window for prognostication and potential future neuroprotective intervention.
Duration: Chronic, lifelong.

9. Inheritance and Population

Epidemiology. PAF is rare (Orphanet ORPHA:95429). Precise population prevalence/incidence estimates are not well established; it is the least common of the primary chronic autonomic failure syndromes. Cohort demographics: mean onset ~63 years, male predominance ~64% (meta-analytic cohort, PMID: 42081229).

Inheritance. Sporadic / non-Mendelian (multifactorial, age-related). No inheritance pattern, penetrance, anticipation, founder effect, consanguinity role, or carrier frequency applies to sporadic PAF. The rare SNCA triplication kindred shows autosomal-dominant transmission of a Lewy body phenotype that includes PAF-like cardiac denervation, but this is a phenocopy, not sporadic PAF.

Population demographics. No specific ethnic/geographic predilection established. Sex ratio modestly male-skewed; age distribution concentrated in older adults.

10. Diagnostics

Autonomic function testing is the diagnostic cornerstone: demonstration of neurogenic OH (sustained BP fall on standing/head-up tilt with inadequate heart-rate compensation and blunted NE response).

Biomarkers and tests:

Test	Finding in PAF	Performance	PMID
Supine plasma norepinephrine	Low (often <100–200 pg/mL), no orthostatic rise	Differentiates peripheral (PAF/PD) vs central (MSA) lesion	24095130, 40696849
Cutaneous p-synuclein (distal-leg skin biopsy)	Present in 22/22 (100%) PAF	Total p-syn score >3: 100% specificity, 82% sensitivity vs MSA	39608812
CSF αSyn-PMCA (seed amplification)	Positive in ~94% of PAF	Confirms α-synucleinopathy; MSA-type kinetics + NfL predict MSA conversion	33881777
¹²³I-MIBG cardiac scintigraphy	Reduced/absent uptake (PAF/PD); intact in MSA	"most sensitive test for early detection of autonomic dysfunction"	38216420
CSF/plasma NfL + αSyn oligomers	Elevated NfL predicts conversion	Prognostic	33881777
NM-MRI / FDOPA-PET	Reduced LC/SN contrast in high-conversion-risk PAF	Early CNS involvement biomarker	39825743

"Total p-syn score >3 distinguished PAF from MSA with 100% specificity and 82% sensitivity." — PMID: 39608812

"αSyn-PMCA is almost invariably positive in the CSF of patients with PAF establishing this condition as α-synucleinopathy." — PMID: 33881777

"MIBG myocardial scintigraphy is the most sensitive test for early detection of autonomic dysfunction." — PMID: 38216420

Genetic testing. Not routinely indicated for sporadic PAF. SNCA copy-number/sequence testing is relevant only where a strong family history of Lewy body disease suggests an SNCA-dosage phenocopy.

Differential diagnosis. MSA (preserved supine NE, intact pupils/cardiovagal responses, glial inclusions), PD/DLB with autonomic failure, dopamine-β-hydroxylase deficiency, diabetic/amyloid autonomic neuropathy, and non-neurogenic OH (volume depletion, drugs). The supine plasma NE level is a key discriminator — a normal supine NE in a PAF-like presentation is a red flag for later MSA conversion (PMID: 35790426; PMID: 40696849).

Screening. No population screening for PAF. Research-grade risk stratification of RBD patients and PAF patients identifies individuals at high prodromal risk for synucleinopathy conversion.

11. Outcome / Prognosis

PAF itself is relatively benign in its "pure" peripheral phase compared with MSA, but it carries a substantial risk of phenoconversion to a more disabling central synucleinopathy.

Phenoconversion (PMID: 42081229): In a meta-analysis of 9 studies / 900 PAF patients, 270/900 (30%) phenoconverted over mean 6.4 years — 12% to MSA, 11% to DLB, 7% to PD (pooled incidence ~5.6/100 person-years). The Queen Square cohort (n=281, median 10-yr follow-up) reported 33% conversion (PMID: 40397689).

"270 of 900 individuals with PAF (30%) experienced phenoconversion to a central α-synucleinopathy (12% to MSA, 11% to DLB, 7% to PD)" — PMID: 42081229

"Of these, 33% (91) converted to a more widespread synucleinopathy" — PMID: 40397689

Prognostic factors (PMID: 38366572; PMID: 40696849): - Faster phenoconversion associated with urinary dysfunction (HR 5.9), sexual dysfunction (HR 3.6), subtle motor signs (HR 2.7), dysphagia (HR 2.5), speech changes (HR 2.4). - Noradrenergic status bifurcates trajectory: low supine NE + Lewy bodies → PD/DLB; preserved/normal NE, normal pupils, intact cardiovagal response → MSA. Younger age + higher supine NE favor MSA. - OH + RBD "malignant" phenotype → cognitive decline, postural instability, reduced survival (PMID: 31142660).

"Faster phenoconversion from study enrolment to any diagnosis was associated with urinary and sexual dysfunction" — PMID: 38366572

Morbidity. Falls, syncope, injury, and functional disability from nOH; supine hypertension risks target-organ damage. Mortality is driven largely by the central synucleinopathy following conversion (MSA conveys the worst prognosis).

12. Treatment

Treatment is symptomatic — there is no disease-modifying therapy. Drug selection is pathophysiology-guided: because PAF has peripheral noradrenergic degeneration and low sympathetic reserve, patients respond better to norepinephrine "replacers" (midodrine, droxidopa) than to NE "enhancers" (pyridostigmine, atomoxetine), which require spared postganglionic fibers (as in MSA) (PMID: 32979782; PMID: 31996627; PMID: 33705537).

"those with peripheral noradrenergic degeneration (pure autonomic failure, Parkinson's disease) and low plasma norepinephrine, tend to respond better to 'norepinephrine replacers' (midodrine and droxidopa)" — PMID: 32979782

"Patients with peripheral sympathetic denervation respond better to norepinephrine agonists/precursors such as droxidopa" — PMID: 31996627

Non-pharmacologic (first-line): increased fluid and dietary salt, compression stockings/abdominal binders, physical counter-maneuvers, head-up sleeping, portioned meals, bolus water drinking.

Pharmacologic:

Drug	Class / mechanism	Evidence	NCIT
Midodrine	α1-adrenergic agonist (direct pressor)	Approved for OH; first-line pressor	NCIT:C61721
Droxidopa (L-threo-DOPS)	Norepinephrine prodrug	FDA-approved for nOH; 3 RCTs (see below)	NCIT:C66878
Fludrocortisone	Mineralocorticoid (volume expander)	Adjunct; use with caution	NCIT:C29082
Pyridostigmine	Acetylcholinesterase inhibitor (NE enhancer)	Better in MSA/mild disease; less effective in PAF	NCIT:C47629
Ampreloxetine	Selective norepinephrine reuptake inhibitor	Phase 2 positive (emerging)	—
Desmopressin	Vasopressin analog (nocturnal polyuria)	Caution (hyponatremia)	NCIT:C61763

Droxidopa RCT evidence (PMID: 28494751; PMID: 27538531): Pooled analysis (n=460) showed droxidopa significantly reduced OHQ composite (−2.68±2.20 vs −1.82±2.34; P<0.001) and dizziness/lightheadedness, improved activities of daily living, and raised upright systolic BP (11.5±20.5 vs 4.8±21.0 mmHg; P<0.001), with low supine-hypertension rates (≤7.9% vs ≤4.6% placebo). NNT for OHSA item-1 improvement was <10.

"Droxidopa improved virtually all nOH symptom scores compared with placebo, significantly reducing OHQ composite score (−2.68 ± 2.20 vs −1.82 ± 2.34 units; P < 0.001)" — PMID: 28494751

"The NNT for droxidopa for improvement in OHSA Item 1 was <10" — PMID: 27538531

Durability caveat: Benefit is largely short-term; durability beyond weeks 1–2 was inconsistent across endpoints (PMID: 25487613; PMID: 25350981, the latter a randomized-withdrawal study that failed its primary endpoint though secondary/composite outcomes favored droxidopa).

Ampreloxetine (NRI) raised seated SBP (+29.9 mmHg vs placebo; P=0.0112) and improved symptoms in a phase 2 nOH trial (PMID: 34657222).

"Seated blood pressure increased 15.7 mmHg 4 h after ampreloxetine and decreased 14.2 mmHg after placebo" — PMID: 34657222

Key therapeutic trade-off: nOH and neurogenic supine hypertension are hemodynamically opposed — "Because nOH and nSH are hemodynamically opposed, therapies to treat one condition may exacerbate the other" (PMID: 33687577) — requiring individualized balancing (e.g., short-acting nocturnal antihypertensives, avoiding late-day pressors).

13. Prevention

Primary prevention: None available (no modifiable cause).
Secondary prevention: Early recognition of nOH and identification of high-conversion-risk patients (biomarker/clinical stratification) for enrollment in neuroprotective trials and close monitoring.
Tertiary prevention: Fall prevention, management of supine hypertension to limit target-organ damage, patient education on high-risk situations (heat, large meals, posture, dehydration).
Genetic counseling: Generally not applicable (sporadic); relevant only for rare SNCA-dosage kindreds.
Immunization / public-health / environmental interventions: Not applicable.

14. Other Species / Natural Disease

Taxonomy: Homo sapiens (NCBI:txid9606) is the species with the natural disease. No recognized spontaneous PAF-equivalent in companion animals is documented in OMIA.
Orthologous gene: Snca in mouse (NCBI Gene ID 20617); SNCA orthologs are conserved across vertebrates.
Comparative biology: α-synuclein aggregation and autonomic/cardiac sympathetic denervation mechanisms are evolutionarily conserved and modeled experimentally (see Section 15).
Transmission: Not applicable (non-infectious, non-zoonotic). Note the experimental "prion-like" seeding behavior of α-synuclein is a laboratory phenomenon, not natural transmission.

15. Model Organisms

Dedicated PAF mouse model (PMID: 32071315): injection of α-synuclein preformed fibrils into autonomic ganglia of human A53T α-synuclein transgenic (TgM83) mice produces α-synuclein pathology confined to the autonomic nervous system with autonomic dysfunction and NO motor features — recapitulating the "pure" peripheral phenotype.

"in the pure autonomic failure (PAF), α-synuclein (α-Syn) pathology is confined within the autonomic nervous system with no motor features, but mouse models recapitulating PAF without motor dysfunction are lacking" — PMID: 32071315

Broader rodent synucleinopathy models (PMID: 23933655): genetic and toxin-induced models reproduce cardiovascular autonomic dysfunction and sympathetic denervation that often precede motor signs:

"cardiovascular autonomic impairments including orthostatic hypotension and sympathetic denervation may precede the development of the cardinal motor symptoms" — PMID: 23933655

Human genetic "model": the SNCA-triplication kindred confirms gene-dosage causality for cardiac denervation + parkinsonism (PMID: 14736756).

Model types: mammalian (mouse — A53T TgM83, MGI resources); induced (fibril-injection, toxin). Genetic models: transgenic human α-synuclein (A53T). Recapitulation: autonomic-restricted pathology without motor involvement (good model for the "pure" peripheral phase). Limitations: phenoconversion to human-like MSA/DLB/PD subtypes and the TH-selective biochemical lesion are incompletely modeled.

Mechanistic Model / Interpretation

    SNCA (α-synuclein) misfolding & aggregation (toxic gain of function)
                   │  [CSF αSyn-PMCA + in ~94%]
                   ▼
     Lewy-body inclusions in peripheral autonomic neurons
     (sympathetic ganglia, IML columns, cardiac & bladder axons)  [autopsy: 9255396]
                   │
                   ▼
     Noradrenergic neuron dysfunction:
     ↓Tyrosine hydroxylase  +  vesicular storage defect  +  denervation
     (NET relatively preserved)              [29162745, 32945121]
                   │
                   ▼
     ↓↓ Norepinephrine release (low supine plasma NE, no orthostatic rise)
                   │
                   ▼
     Baroreflex vasoconstriction failure on standing
                   │
                   ▼
     NEUROGENIC ORTHOSTATIC HYPOTENSION  +  urogenital/GI/sudomotor failure
                   │
                   ▼  (~30% over ~6 yr; CNS spread to LC/SN)
    ┌──────────────────────┴──────────────────────┐
    ▼                                              ▼
   Low NE + Lewy type                           Preserved NE, normal pupils,
   → PD / DLB                                    intact cardiovagal → MSA
   [34669076, 40696849]                          [35790426, 40696849]

The model is internally consistent and well-supported through step 6 (clinical manifestation). The upstream seeding/spreading steps (1–2) and the CNS-spread branch (step 7) are supported by seed-amplification assays, imaging, and animal models but remain partly inferred rather than directly demonstrated in situ in living humans. Branch assignment is supported by PMID: 34669076: "the form of PAF that involves sympathetic intraneuronal synucleinopathy and noradrenergic deficiency can phenoconvert to PD or DLB-but not to MSA."

Evidence Base

PMID	Role in report	Key contribution
31515103	Supports F001, F008	Defines peripheral α-synuclein pathology; multi-system phenotype
24095130	Supports F001, F005, F006	Peripheral autonomic dysfunction, NE deficiency, sporadic occurrence, neuronal vs glial inclusions
9255396	Supports F005	Autopsy distribution of Lewy bodies / IML & ganglion cell loss / distal axons
29162745	Supports F009	TH-deficient, NET-preserved biochemical lesion
32945121	Supports F001, F010	Dual lesion: denervation + vesicular storage defect (PET)
33881777	Supports F003, F010	CSF αSyn-PMCA positivity; NfL + oligomers predict conversion
39608812	Supports F003	Cutaneous p-synuclein diagnostic performance
38216420	Supports F003	MIBG scintigraphy
42081229	Supports F002	Meta-analytic phenoconversion rates (30%)
38366572	Supports F002	Clinical predictors of phenoconversion
40397689	Supports F002	Queen Square natural history (33% conversion)
40696849	Supports F002, prognosis	Multimodal autonomic biomarkers predict conversion; MSA vs LBD
34669076	Supports F010 branch	PD/DLB vs MSA conversion pathways
14736756	Supports F006, F007	SNCA triplication → cardiac denervation + parkinsonism (gene dosage)
31178336	Supports F006	E46K-SNCA skin p-synuclein + small-fiber loss
32071315	Supports F007	Dedicated PAF mouse model
23933655	Supports F007	Rodent autonomic denervation precedes motor signs
31142660	Supports F008	OH+RBD malignant phenotype
32979782, 31996627, 33705537	Supports F004	Pathophysiology-guided drug selection
33687577	Supports F004	nOH/supine-hypertension trade-off
28494751, 27538531	Supports F011	Droxidopa pooled efficacy; NNT<10
25487613, 25350981	Challenges durability	Short-term benefit; inconsistent long-term/withdrawal endpoints
34657222	Supports F011	Ampreloxetine phase 2
39825743	Diagnostics/prognosis	NM-MRI + FDOPA-PET early CNS involvement
35790426, 42444112	Diagnostics	Normal supine NE flags MSA conversion; prodromal MSA criteria validation

Limitations and Knowledge Gaps

No PAF-specific genetics/GWAS. Susceptibility architecture is inferred from the broader α-synucleinopathy family; no PAF-specific common-variant or modifier-gene data exist.
Prevalence/incidence are poorly quantified. PAF is rare and often reclassified upon phenoconversion, confounding epidemiologic estimates.
Upstream mechanism partly inferred. Prion-like seeding and spread (steps 1–2, 7) rely on seed-amplification assays and animal models, not direct in vivo human demonstration.
Treatment durability uncertain. Droxidopa's long-term efficacy is inconsistent; one randomized-withdrawal trial failed its primary endpoint (PMID: 25350981). Most PAF-specific treatment data derive from mixed nOH cohorts rather than PAF-only trials.
No disease-modifying therapy. Nothing yet alters phenoconversion risk or α-synuclein accumulation.
Conversion prediction imperfect. Biomarkers improve but do not perfectly predict which patients convert or to which subtype.

Proposed Follow-up Experiments / Actions

Prospective biomarker-stratified cohort combining supine plasma NE, pupillometry, cardiovagal responses, CSF αSyn-PMCA kinetics, NfL, and NM-MRI/FDOPA-PET to build a validated conversion-risk calculator (building on PMID: 40696849, 39825743).
Neuroprotective trials in high-risk PAF — target the prodromal window using α-synuclein–directed agents (immunotherapy, aggregation inhibitors) with phenoconversion as the endpoint.
PAF-only pragmatic treatment trials of droxidopa vs midodrine vs ampreloxetine with durability (≥6-month) and supine-hypertension co-endpoints.
Mechanistic work on the TH-selective lesion (PMID: 29162745) — determine whether restoring catecholamine synthesis (e.g., optimized L-DOPS dosing, TH cofactor support) rescues function before structural denervation is complete.
Refine the TgM83 ganglionic-fibril model (PMID: 32071315) to model phenoconversion branches and test anti-spreading therapeutics.
Harmonize diagnostic criteria to incorporate skin p-synuclein, seed amplification, and MIBG, and prospectively validate against autopsy (extending PMID: 42444112).

Report compiled from 11 confirmed findings and 37 reviewed papers. Evidence source types span human clinical (cohorts, RCTs, autopsy), model organism (transgenic/fibril mouse, rodent), in vitro/ex vivo (skin biopsy, CSF seed amplification), and imaging. Ontology suggestions: MONDO:0018608; HGNC:11138 (SNCA); HP:0004926, HP:0012694, HP:0000012, HP:0002019, HP:0000966, HP:0002494; GO:0042423, GO:0007268, GO:0097413; CL:0011103; UBERON:0001806, UBERON:0002260, UBERON:0000948, UBERON:0001255, UBERON:0001872, UBERON:0002038; CHEBI:18357 (noradrenaline), CHEBI:28918 (L-DOPA); NCIT:C66878 (droxidopa), NCIT:C61721 (midodrine).

Artifacts

Reference Validation

Checked with linkml-reference-validator 0.4.0.

Outcome	Count
References checked	30
Resolved	30
Unresolved (possible confabulation)	0
Unverifiable	0
Quoted claims checked	22
Quoted claims found in source	22
Quoted claims not found in source	0
References weighed for topical relevance	30
On topic	24
Off topic	0

All extracted references resolved successfully.

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Outcome	Count
Terms checked	33
Resolved	30
Unresolved (possible confabulation)	0
Obsolete	1
Unverifiable	2
Terms whose name was checked	20
Terms named correctly	6
Terms named as a different term	9
Terms whose name is worth a second look	5

Terms the report names something else

These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:

HP:0012694 (2 mentions) - the report calls it "Clinical sign"; HP calls it Enlarged thalamic volume
HP:0002019 (2 mentions) - the report calls it "Symptom"; HP calls it Constipation
UBERON:0002260 (2 mentions) - the report calls it "intermediolateral nucleus — spinal cord lateral horn"; UBERON calls it ventral root of spinal cord
NCIT:C61721 (2 mentions) - the report calls it "Approved for OH; first-line pressor", "midodrine"; NCIT calls it Diethylpropion
NCIT:C66878 (2 mentions) - the report calls it "FDA-approved for nOH; 3 RCTs (see below)", "droxidopa"; NCIT calls it Lapatinib Ditosylate
NCIT:C29082 (1 mention) - the report calls it "Adjunct; use with caution"; NCIT calls it Guaifenesin/Codeine
NCIT:C47629 (1 mention) - the report calls it "Better in MSA/mild disease; less effective in PAF"; NCIT calls it Nalbuphine Hydrochloride
NCIT:C61763 (1 mention) - the report calls it "Caution (hyponatremia)"; NCIT calls it Ferrous Fumarate
CHEBI:28918 (1 mention) - the report calls it "L-DOPA"; CHEBI calls it (R)-adrenaline

Obsolete terms

These terms are real but deprecated. Citing one is not a fabrication; it does mean the report is naming something the ontology has retired:

GO:0042136 (obsolete neurotransmitter biosynthetic process) (1 mention)

Terms whose name is worth a second look

The report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:

HP:0002494 (2 mentions) - the report calls it "Behavioral/sleep"; HP calls it Abnormal rapid eye movement sleep, and lists "Abnormal REM sleep" among its other names
CL:0011103 (3 mentions) - the report calls it "sympathetic noradrenergic neuron / postganglionic sympathetic neuron", "postganglionic sympathetic noradrenergic neurons"; CL calls it sympathetic neuron
UBERON:0001806 (2 mentions) - the report calls it "sympathetic ganglion / paravertebral ganglion"; UBERON calls it sympathetic ganglion
UBERON:0001872 (2 mentions) - the report calls it "locus coeruleus"; UBERON calls it parietal lobe, and lists "lobus parietalis" among its other names
CHEBI:18357 (1 mention) - the report calls it "noradrenaline"; CHEBI calls it (R)-noradrenaline, and lists "(-)-noradrenaline" among its other names

Terms named inconsistently

The report gives these identifiers more than one name of its own:

CL:0011103 - called "sympathetic noradrenergic neuron / postganglionic sympathetic neuron", "postganglionic sympathetic noradrenergic neurons"
NCIT:C61721 - called "Approved for OH; first-line pressor", "midodrine"
NCIT:C66878 - called "FDA-approved for nOH; 3 RCTs (see below)", "droxidopa"

Prefixes with no resolver

Terms carrying these prefixes were not checked either way, because no configured ontology covers them. An unrecognised prefix may name an ontology this run could not reach as easily as one that does not exist, so nothing here is evidence of fabrication: ORPHA.

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Phenotypes

Medical Actions

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Differential Diagnoses

Clinical Trials

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Pure Autonomic Failure (PAF): Research Report

1. Disease information

Overview

Synonyms

Nature of the data

A conceptual caveat

2. Etiology

3. Phenotypes

4. Genetic and molecular information

5. Environmental information

6. Mechanism and pathophysiology

Ordered causal chain

Checklist mapping

7. Anatomical structures affected

8. Temporal development

9. Inheritance and population

10. Diagnostics

11. Outcome and prognosis

12. Treatment

13. Prevention

14. Other species and natural disease

15. Model organisms

Notes for knowledge-base curation

Reference Validation

Term Validation

Terms the report names something else

Terms whose name is worth a second look

Prefixes with no resolver

Pure Autonomic Failure (MONDO:0018608) — Comprehensive Disease Characteristics Report

Summary

1. Disease Information

2. Etiology

3. Phenotypes

4. Genetic / Molecular Information

5. Environmental Information

6. Mechanism / Pathophysiology

Ordered causal chain

Supporting detail by category

7. Anatomical Structures Affected

8. Temporal Development

9. Inheritance and Population

10. Diagnostics

11. Outcome / Prognosis

12. Treatment

13. Prevention

14. Other Species / Natural Disease

15. Model Organisms

Mechanistic Model / Interpretation

Evidence Base

Limitations and Knowledge Gaps

Proposed Follow-up Experiments / Actions

Artifacts

Reference Validation

Term Validation

Terms the report names something else

Obsolete terms

Terms whose name is worth a second look

Terms named inconsistently