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

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).

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

1. 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.
2. 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."
3. Branch: the non-Lewy form, a preganglionic lesion only, carries a risk of premotor MSA (PMID:34669076).
4. 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).
5. 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.
6. 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."
7. Cerebral and muscle hypoperfusion follow, producing syncope, dizziness, visual disturbance, and coat-hanger pain (PMID:10552235).
8. Parallel branches from denervation:
9. 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).
10. 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.
11. Loss of sympathetic drive to erythropoiesis, giving low erythropoietin and anemia (PMID:8017744; the authors' hypothesis is that "the sympathetic nervous system stimulates erythropoiesis").
12. Sudomotor, bladder, bowel, and sexual dysfunction from involvement of the cholinergic sympathetic and parasympathetic pathways.
13. 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):

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.

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).

• 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

1. 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).
2. Do not add genetic: causal genes. SNCA belongs on pathophysiology nodes (aggregation) as the disease protein.
3. 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.
4. Conformance target: check just list-modules for an α-synuclein aggregation or autonomic module before adding one.
5. 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.
6. 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.

All extracted references resolved successfully.

Term Validation

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

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.