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Mappings

MONDO

MONDO:0017638 manganese poisoning

Primary MONDO identifier. MONDO's own definition scopes the term to chronic inhalation by people working with manganese ore, which is the acquired disease this entry covers; the inherited hypermanganesaemias have their own terms and are recorded here as differential diagnoses rather than folded in.

ICD-10-CM

ICD10CM:T57.2 Toxic effect of manganese and its compounds

Curator-asserted, not taken from MONDO. MONDO:0017638 carries no ICD-10-CM xref - its cross-references are EFO, GARD, MESH:D020149, MedDRA, Orphanet:306682, SCTID and ICD9:503, the last of these `relatedTo` and pointing at the pneumoconiosis rather than the encephalopathy. ICD10CM:T57.2 was resolved directly against the local build. closeMatch because the code names the toxic effect of the substance, which is broader in agent coverage and narrower in clinical content than the MONDO concept.

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Mechanistic Hypotheses

2

Pallidal accumulation with a postsynaptic basal ganglia lesion

pallidal_postsynaptic CANONICAL

Manganese concentrates in the globus pallidus and injures it directly, leaving the nigrostriatal dopaminergic neurons structurally intact. The motor syndrome is therefore downstream of the dopamine synapse, which is the standard explanation for why levodopa does not work and why the neuropathology differs from Parkinson disease.

Presynaptic dopaminergic dysfunction without degeneration

presynaptic_dysfunction_without_degeneration EMERGING

A second, non-competing account: the dopaminergic terminals survive but stop working properly. Mn-exposed primates show marked inhibition of in vivo dopamine release with no terminal loss, and asymptomatic welders show reduced FDOPA uptake in a caudate-first pattern that is anatomically reversed from idiopathic Parkinson disease. This is a functional presynaptic lesion rather than a degenerative one, and it coexists with the pallidal damage rather than replacing it.

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Discussions and Knowledge Gaps

6

Manganese induces alpha-synuclein aggregation in exposed primates, and human manganese overload is characterised by negative alpha-synuclein immunostaining. Does the primate finding describe anything that happens in human manganism?

HUMAN MODEL MISMATCH alpha_synuclein_in_human_manganism

Attached to

pathophysiology#Alpha-Synuclein Aggregation

The mismatch is sharp rather than gradual. In Mn-exposed cynomolgus macaques, alpha-synuclein-positive neurons and glia appear in frontal cortex grey and white matter. In humans with pallidal manganese accumulation measured directly at autopsy, alpha-synuclein immunostaining was negative in all but one case, and the defining neuropathology of manganism is the absence of Lewy bodies. Both cannot be generalised. Possible reconciliations: the primate aggregates are a different species of assembly from Lewy pathology; the cortical location differs from the pallidal region sampled in the human series; or the primate exposure regimen produces something the human occupational one does not. This matters because alpha-synuclein is the bridge people use to argue that manganese exposure causes Parkinson disease, and the human pathology is the main evidence against that.

Show evidence (2 references)

PMID:23262390 SUPPORT DIRECT Model Organism

"We found increased α-syn-positive cells in the gray matter of Mn-exposed animals, typically observed in pyramidal and medium-sized neurons in deep cortical layers."

The primate side of the mismatch.

PMID:17159105 REFUTE DIRECT Human Clinical

"Neuropathology revealed mild to moderate Alzheimer type II gliosis in the liver failure groups and negative alpha-synuclein and tau immunostaining except for one case"

The human side. REFUTE against extending the primate aggregation finding to human manganese overload, in cases where pallidal manganese was measured rather than inferred.

Is the dopaminergic system in manganism untouched, or functionally impaired without degenerating?

CONTROVERSY presynaptic_involvement_versus_pallidal_lesion

Attached to

pathophysiology#Impaired Striatal Dopamine Release mechanistic_hypotheses#presynaptic_dysfunction_without_degeneration

The textbook account is that manganism spares the nigrostriatal dopaminergic neurons, and the neuropathology supports it: substantia nigra pars compacta preserved, no Lewy bodies. But asymptomatic welders show measurably reduced FDOPA uptake, and Mn-exposed primates show marked inhibition of dopamine release with terminals intact. These are not contradictory once function and structure are kept apart - the terminals are there and underperforming - but the entry should not be read as claiming the dopaminergic system is unaffected. The FDOPA pattern is also the discriminating detail: reduced, but caudate-first, which is the reverse of the posterior-putamen-first pattern of idiopathic Parkinson disease.

Show evidence (1 reference)

PMID:21471467 SUPPORT DIRECT Human Clinical

"This uptake pattern was anatomically reversed from the pattern found in subjects with IPD."

The spatial signature that keeps presynaptic involvement from collapsing into a Parkinson disease diagnosis.

Does manganism produce tremor, and if so what kind?

CONTROVERSY tremor_in_manganism

Attached to

phenotypes#Tremor differential_diagnoses#Parkinson disease

The cached reviews do not agree. One describes a rapid postural tremor among the motor impairments; a second says resting tremor specifically is not a distinguishing feature, which is consistent with the first; and a third states flatly that patients with manganism have no tremor at all. The disagreement is not obviously about the same thing - a source denying "tremor" may mean the resting tremor of Parkinson disease, which the other sources also deny - but none of them says so, and this entry does not have the evidence to decide it. The phenotype is curated with the postural characterisation and carries the denial as a REFUTE. It matters because tremor quality is one of the features the Parkinson disease differential rests on.

Show evidence (2 references)

PMID:42563869 REFUTE DIRECT REVIEW SYNTHESIS Human Clinical

"Specifically, patients with manganism have no tremor but do exhibit dystonia, a “cock‐gait” walk, and, importantly, minimal or no response to levodopa"

The flat denial, quoted as it stands.

PMID:40278159 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"This syndrome is characterized by bradykinesia, rigidity, and tremor"

The same review that elsewhere denies resting tremor lists tremor among the defining triad, which is the internal tension this discussion records.

Does manganism stabilise, improve, or continue to progress after exposure stops?

OPEN QUESTION reversibility_after_exposure_ends

Attached to

treatments#Removal from Exposure

Removal from exposure is the main intervention, and what it achieves is not settled. Reviews describe symptoms persisting after the source is eliminated, and at least one series describes progression through the first decade after cessation before plateauing. The methcathinone series found deficits that did not resolve. Against that, blood manganese falls and MRI signal fades, so the biomarkers improve while the patient does not. A framing in which manganism is simply reversible on removal does not fit the reported courses, and the entry avoids it.

Show evidence (1 reference)

PMID:18322282 SUPPORT DIRECT Human Clinical

"The neurologic deficits did not resolve after patients discontinued methcathinone use."

The non-resolution, in a 23-patient series.

What is the prevalence of parkinsonism among manganese-exposed workers, and can the widely cited welder figures be used for it?

INTERPRETATION occupational_prevalence_and_referral_bias

Attached to

phenotypes#Parkinsonism

The most-cited occupational prevalence estimates come from a screen of 1,423 Alabama welders who were referred for medical-legal evaluation for Parkinson disease. That is a population selected for having, or claiming, the outcome being measured, so the resulting rate cannot be read as an occupational prevalence, and this entry records no prevalence figure rather than launder one. The exposure-response relationship from the trade-union longitudinal cohort is a different and sounder claim, and is the one the entry carries.

Show evidence (1 reference)

PMID:15668418 NO_EVIDENCE DIRECT Human Clinical

"The authors screened 1,423 welders from Alabama who were referred for medical-legal evaluation for Parkinson disease (PD)."

Graded NO_EVIDENCE with respect to occupational prevalence: the sentence describes the sampling frame, and what it shows is that this study cannot answer the prevalence question, not that its answer is wrong.

Does the complex II-dependent oxidative mechanism established in rat microglial cultures hold in human basal ganglia, where the affected cell populations, manganese concentrations, and exposure durations all differ?

HUMAN MODEL MISMATCH OPEN mismatch_manganese_complex_ii_rodent_microglia

Attached to

pathophysiology#Microglial Complex II-Dependent Reactive Oxygen Species Production

The evidence assigning the oxidative lesion of manganese to respiratory complex II rather than complex I is strong but comes from acute exposure of isolated rat microglia to low micromolar Mn(2+). Human manganism arises from chronic exposure over years, and the node sits in a chain whose downstream effector is a pallidal circuit lesion rather than a microglial one. Three things are therefore open: whether complex II dependence is a property of microglia specifically or of manganese-exposed cells generally; whether the same selectivity holds at the far lower concentrations reached over chronic human exposure; and how much of the human pallidal injury this route accounts for. The mismatch matters for curation because it is the sole basis for this entry declining to conform to the parkinsonism module's complex I node, so if the complex II selectivity turned out to be a feature of the acute rodent preparation, that decision would need revisiting.

Show evidence (1 reference)

PMID:23315522 SUPPORT In Vitro

"Mn(2+) was capable of inducing significant H2O2 production in the mitochondrial but not the cytosolic or nuclear fraction prepared from microglia"

Establishes the subcellular localisation of the lesion in isolated rat microglial preparations, which is what this discussion is about: the finding itself is solid, and the open question is whether it translates to chronically exposed human basal ganglia.

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Pathophysiology

16

Chronic Manganese Overexposure

Sustained intake above what homeostasis clears. Occupationally this is inhaled welding fume or ore dust; the particles are small enough that most of an inhaled dose is retained in the lung, from which manganese reaches the blood without passing the gut and liver first. The exposure is measured in months to years, not in single doses.

Downstream

Systemic Manganese Overload Retained inhaled manganese enters the blood directly from the lung.

Show evidence (2 references)

PMID:40278159 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Manganism classically requires occupational exposure of 6 months to 2 years. Once developed, symptoms resulting from Mn toxicity usually persist even when the source of Mn exposure is eliminated"

Gives both the exposure duration that defines the occupational disease and the persistence that makes exposure control the main intervention.

PMID:26154659 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"greater than 90% of the Mn containing welding aerosols can be deposited in the lungs due to their small particulate size"

The physical basis of the inhalation route: the particle size determines that the lung, not the gut, is the port of entry.

Impaired Hepatobiliary Manganese Excretion

The other way to reach overload: normal intake with a broken exit. Manganese is cleared in bile, so chronic liver failure raises body burden without any unusual exposure, and parenteral nutrition delivers manganese straight into the blood past the gut and liver entirely. Both produce the same pallidal accumulation as the occupational route.

manganese ion homeostasis GO:0055071 ⚠ ABNORMAL

Downstream

Systemic Manganese Overload Retention rather than intake raises the systemic burden.

Show evidence (2 references)

PMID:26154659 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Mn-induced parkinsonism may occur in patients with chronic liver failure who fail to adequately excrete Mn in bile"

Establishes failed biliary excretion as a sufficient route, independent of exposure.

PMID:33911374 SUPPORT DIRECT BACKGROUND Other

"Patients with liver failure or hepatic encephalopathy can develop Mn toxicity as it is excreted in the bile."

Independent corroboration of the excretion-failure route from a second review, so the claim does not rest on one source.

Systemic Manganese Overload

Whole-body manganese above the homeostatic set point, whichever route produced it. This is the node the environmental exposures converge on and the one blood manganese measures, imperfectly.

Downstream

Manganese Transport Across the Blood-Brain Barrier Circulating manganese is presented to the brain's transporters.

Show evidence (1 reference)

PMID:33911374 SUPPORT DIRECT BACKGROUND Other

"The homeostasis of Mn levels in our body is crucially regulated through intestinal absorption and hepatobiliary secretion of the metal into the gastrointestinal tract."

Names the two-sided balance - intestinal absorption against hepatobiliary secretion - whose failure on either side defines this node. Graded OTHER because the review states the physiology without reporting a study of its own.

Manganese Transport Across the Blood-Brain Barrier

Manganese travels on carriers it does not own. Several transporters move it and few are selective for it - DMT1, ZIP8, ZIP14, transferrin receptor, all built for iron or zinc - which is why iron status changes the dose that reaches the brain and why the metal lands where those carriers are densest rather than where it would do least harm.

SLC11A2 hgnc:10908 SLC39A14 hgnc:20858 SLC39A8 hgnc:20862 TFRC hgnc:11763

manganese ion transmembrane transport GO:0071421 ↑ INCREASED

Downstream

Pallidal Manganese Accumulation Transport into brain regions where the carriers are most highly expressed.

Show evidence (4 references)

PMID:40278159 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"DMT1 facilitates Mn transport in its divalent state (Mn2+), and it is regulated by iron status: iron deficiency enhances Mn absorption and brain accumulation"

Names the principal carrier and the iron-status dependence that makes iron deficiency a susceptibility factor rather than an incidental finding.

PMID:33911374 SUPPORT DIRECT BACKGROUND Other

"The uptake of Mn2+ into the cells is facilitated by a number of membrane transporters such as the divalent metal transporter 1 (DMT1/SLC11A2), ZRT/IRT-like proteins ZIP8 (SLC39A8) and ZIP14 (SLC39A14)"

Names the full influx carrier set, which is what makes manganese entry a transporter-dependent step rather than passive diffusion.

PMID:33911374 SUPPORT DIRECT BACKGROUND Other

"Manganese efflux and export from the cytosol is mediated by the membrane-localized transporters ferroportin (Fpn or SLC40A1) and the solute carrier family 30 member 10 (SLC30A10)"

The efflux arm. Brain manganese is a balance of influx against export, not a one-way flux, which is why the node is framed as transport rather than uptake.

+ 1 more reference

Pallidal Manganese Accumulation

The defining lesion location. Manganese concentrates in the basal ganglia and most of all in the globus pallidus, where it sits in GABAergic neurons and in astrocytes. Because manganese is paramagnetic, the accumulation is directly visible as symmetric T1 hyperintensity on MRI, which is what makes the imaging finding a measure of the metal rather than of its consequences.

GABAergic neuron CL:0000617

globus pallidus UBERON:0001875

Downstream

Astrocytic Manganese Sequestration Astrocytes take up most of the tissue burden.

Mitochondrial Dysfunction and Oxidative Stress Intracellular manganese acts on mitochondria.

Microglial Complex II-Dependent Reactive Oxygen Species Production Manganese reaching the tissue enters microglial mitochondria, where it drives hydrogen peroxide production.

Impaired Striatal Dopamine Release Dopaminergic terminals survive but release less transmitter; the intermediates are the oxidative and energetic lesions modelled separately.

Show evidence (5 references)

PMID:26154659 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"After elevated exposures, Mn distribution and levels are heterogeneous with the highest level of accumulation observed in the globus pallidus"

The regional selectivity that the rest of the entry depends on.

PMID:40278159 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Mn primarily accumulates in the GABAergic neurons of the globus pallidus within the basal ganglia"

Identifies the cell population carrying the burden.

PMID:18322282 SUPPORT DIRECT Human Clinical

"T(1)-weighted magnetic resonance imaging (MRI) showed symmetric hyperintensity in the globus pallidus and in the substantia nigra and innominata in all 10 active methcathinone users."

The imaging correlate, in all ten actively exposed patients of a 23-patient series - and note the distribution extends beyond the pallidum in this high-dose route.

+ 2 more references

Astrocytic Manganese Sequestration

Astrocytes are the metal's reservoir, concentrating it far above neuronal levels because they carry the transporters. That is protective up to a point and then becomes the mechanism: a loaded astrocyte stops doing its day job, which in the basal ganglia is clearing glutamate.

astrocyte CL:0000127

Downstream

Astrocytic Glutamate Transporter Downregulation Loaded astrocytes downregulate GLAST and GLT-1.

Neuroinflammation Manganese-loaded astrocytes release inflammatory mediators.

Show evidence (2 references)

PMID:40278159 SUPPORT DIRECT REVIEW SYNTHESIS Other

"DMT1 and mostly TRs expressed on the astrocytic surface bind to Mn-transferrin with a resulting concentration of Mn inside the cell that is up to 50-fold greater than that in neurons"

Quantifies the astrocyte-versus-neuron gradient this node asserts, and gives the transporter reason for it. Graded OTHER because the review does not name the study type behind the figure.

PMID:40278159 SUPPORT DIRECT REVIEW SYNTHESIS In Vitro

"Mn exposure reduced glutamate uptake by astrocytes while simultaneously lowering the expression of glutamate aspartate transporter 1 (GLAST) and glutamate transporter 1 (GLT-1), ultimately leading to elevated extracellular glutamate levels"

The functional consequence of astrocytic loading, and the route to excitotoxicity. Graded IN_VITRO because the transporter measurements the review is summarising are cultured-astrocyte experiments.

Astrocytic Glutamate Transporter Downregulation

Loss of the two transporters that clear synaptic glutamate, GLAST (SLC1A3) and GLT-1 (SLC1A2). Glutamate then accumulates outside the cell not because more is released but because less is removed.

SLC1A3 hgnc:10941 SLC1A2 hgnc:10940

L-glutamate import GO:0051938 ↓ DECREASED

Downstream

Glutamate Excitotoxicity Extracellular glutamate rises and overstimulates postsynaptic receptors.

Glutamate Excitotoxicity

Sustained overstimulation of postsynaptic glutamate receptors, with the calcium load and cell death that follow. This is the non-cell-autonomous half of the lesion: the neuron dies from a failure in the astrocyte beside it.

Downstream

Globus Pallidus Neuronal Injury Excitotoxic injury to pallidal neurons.

Mitochondrial Dysfunction and Oxidative Stress

Manganese impairs mitochondrial respiration and generates reactive oxygen species. The basal ganglia are a bad place for this to happen: high oxygen consumption, and in the dopaminergic compartment a transmitter that oxidises into radicals of its own.

response to oxidative stress GO:0006979 ↑ INCREASED

Downstream

Globus Pallidus Neuronal Injury Energy failure and radical damage in pallidal neurons.

Alpha-Synuclein Aggregation Oxidative conditions favour the misfolded conformer; manganese also interacts with the protein directly.

Show evidence (1 reference)

PMID:40278159 SUPPORT DIRECT REVIEW SYNTHESIS Other

"Mn accumulation results in oxidative stress, mitochondrial dysfunction, and the generation of reactive oxygen species (ROS)"

The review's summary statement of the core cellular mechanism. Graded OTHER because the sentence aggregates across experimental systems without naming one.

Microglial Complex II-Dependent Reactive Oxygen Species Production

Divalent manganese drives hydrogen peroxide production in the mitochondrial fraction of microglia, and the route is specifically complex II: the effect is supported by the complex II substrate succinate and abolished by complex II inhibition, while complex I substrates do not support it and complex I inhibition does not abolish it. The resulting microglial free-radical output in turn facilitates dopaminergic neurotoxicity. This is a narrower claim than the general oxidative-stress node, about a named respiratory complex in a named cell type, which is why the two are kept apart.

microglial cell CL:0000129

reactive oxygen species biosynthetic process GO:1903409 ↑ INCREASED

Downstream

Neuroinflammation Microglial free-radical output is one of the inputs to the glial activation state the neuroinflammation node describes.

Show evidence (3 references)

PMID:23315522 SUPPORT DIRECT In Vitro

"the succinate-supported Mn(2+)-induced mitochondrial H2O2 production was abolished by pharmacological inhibition of complex II but not that of complexes I and III"

Pharmacological dissection assigning the oxidative lesion to complex II, and excluding complexes I and III.

PMID:23315522 SUPPORT DIRECT In Vitro

"complex I substrates malate and glutamate failed to support H2O2 production in the presence of Mn(2+)"

The explicit negative result at complex I. This is the sentence that stops this node conforming to the parkinsonism module's complex I amplifier.

PMID:23315522 SUPPORT DIRECT In Vitro

"microglial-free radical generation facilitates Mn(2+)-induced dopaminergic neurotoxicity"

Carries the microglial oxidative output forward to dopaminergic injury, which is what makes this node part of the chain rather than an isolated observation.

Neuroinflammation

Activated astrocytes and microglia releasing cytokines and nitric oxide synthase products into the pallidum. It is a consequence of the metal load and then an independent source of injury.

neuroinflammatory response GO:0150076 ↑ INCREASED

Downstream

Globus Pallidus Neuronal Injury Inflammatory injury to pallidal neurons.

Alpha-Synuclein Aggregation

Manganese shifts alpha-synuclein towards its aggregation-prone conformation. This is the point where manganism and the synucleinopathies come closest, and it is worth being careful: aggregation is documented in the cortex of exposed primates, while the human neuropathology of manganism is specifically Lewy-body negative. The two are compatible only if the aggregates here are not Lewy bodies.

SNCA hgnc:11138

protein destabilization GO:0031648 ↑ INCREASED

Animal models

Manganese-exposed cynomolgus macaque Cynomolgus macaque recapitulates Produces alpha-synuclein-positive neurons and glia in frontal cortex after manganese exposure.

Downstream

Cortical and White Matter Injury The primate work shows aggregation with loss of Nissl staining; the steps from aggregate to cortical dysfunction are not established here.

Show evidence (2 references)

PMID:40278159 SUPPORT DIRECT REVIEW SYNTHESIS Other

"Mn alters the structural conformation of alpha-synuclein, increasing its propensity to form oligomers."

The conformational claim. Bound to protein destabilization rather than to amyloid fibril formation because the sentence describes oligomers, and GO's fibril term would assert a structure this source does not.

PMID:23262390 SUPPORT DIRECT Model Organism

"We found increased α-syn-positive cells in the gray matter of Mn-exposed animals, typically observed in pyramidal and medium-sized neurons in deep cortical layers."

The in vivo primate observation. Note the location is frontal cortex, not pallidum, which is why this node feeds the cortical branch.

Impaired Striatal Dopamine Release

Dopaminergic terminals that are present but underperforming. This is the finding that stops manganism being a simple postsynaptic story: imaging in exposed people and primates shows the terminals are there, while dopamine release is markedly reduced. A functional presynaptic deficit, not a degenerative one.

dopaminergic neuron CL:0000700

Animal models

Manganese-exposed cynomolgus macaque Cynomolgus macaque recapitulates Dopamine release is markedly inhibited while nigrostriatal terminals are preserved, which is the combination the human imaging data also point to.

Downstream

Basal Ganglia Output Failure Reduced dopaminergic drive on the striatal circuit.

Show evidence (3 references)

PMID:23262390 SUPPORT INDIRECT BACKGROUND Model Organism

"our laboratory has demonstrated a lack of nigrostriatal dopaminergic neuron degeneration in the striatum of Mn-exposed non-human primates"

Establishes that the terminals survive, which is what makes the release deficit a functional claim rather than a degenerative one. BACKGROUND because the sentence sits in this paper's introduction restating the group's earlier primate work, and INDIRECT because it reports the absence of degeneration rather than the release deficit itself.

PMID:21471467 SUPPORT DIRECT Human Clinical

"Active, asymptomatic welders with Mn exposure demonstrate reduced FDOPA PET uptake indicating dysfunction in the nigrostriatal dopamine system."

Human evidence that the presynaptic compartment is measurably affected, and before symptoms appear.

PMID:21471467 SUPPORT DIRECT Human Clinical

"This uptake pattern was anatomically reversed from the pattern found in subjects with IPD."

The constraint on the previous item. Presynaptic involvement does not make this Parkinson disease; the spatial signature is the opposite one.

Globus Pallidus Neuronal Injury

Structural damage to the pallidum, with the internal segment preferentially affected, and with the substantia nigra pars compacta spared and no Lewy bodies. This is the neuropathological core of the disease and the fact that separates it from Parkinson disease.

medial globus pallidus UBERON:0002477

Downstream

Basal Ganglia Output Failure Loss of pallidal neurons disorganises basal ganglia output.

Show evidence (1 reference)

PMID:17882011 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"They demonstrate a consistent pattern characterized by damage to the globus pallidus (particularly the internal segment) with sparing of the substantia nigra pars compacta and the absence of Lewy bodies."

The lesion, its preferred subdivision, and the two negatives that define the entity. Drawn from a review of the reported pathological studies in patients and experimentally intoxicated primates.

Basal Ganglia Output Failure

The final common pathway for the motor syndrome. Because the damage is at and beyond the pallidum rather than upstream of the dopamine synapse, supplying more dopamine precursor does not restore the circuit - which is the mechanistic reason levodopa disappoints here.

basal ganglion UBERON:0002420

Downstream

Parkinsonism The extrapyramidal syndrome as a whole.

Bradykinesia

Rigidity

Dystonia

Gait disturbance

Postural instability

Weak voice

Micrographia

Hypomimic face

Dysarthria

Tremor

Show evidence (1 reference)

PMID:26608821 SUPPORT DIRECT REVIEW SYNTHESIS Other

"when accumulated in the globus pallidus, Mn influences the subthalamic (STN) and substantia nigra (SN) neurons, which are at the origin of changes in the thalamus and the cortex."

The circuit mechanism this node names: pallidal manganese acting on the subthalamic nucleus and substantia nigra, and through them on thalamic and cortical motor output. It is also the evidence behind the module conformance.

Cortical and White Matter Injury

The non-motor half of the disease, and historically the first half to appear: the psychiatric presentation that gave manganism its old names. Primate work puts manganese-induced alpha-synuclein aggregates in frontal cortex grey and white matter, which is a plausible substrate, though the link to the human psychiatric picture is not established.

Downstream

Hallucinations

Delusion

Emotional lability

Compulsive behaviors

Cognitive impairment Listed as a separate edge rather than folded into the psychiatric ones because the cognitive deficit is reported as part of the same prodrome and has the same uncertain substrate.

Memory impairment

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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

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Phenotypes

17

Head and Neck 1

Hypomimic face HP:0000338

Show evidence (1 reference)

PMID:42563869 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"The affected workers exhibited various symptoms of parkinsonism, including progressive lower extremity weakness, masked facies, and whispering speech."

Names masked facies in occupationally exposed workers, which is this entry's population rather than the inherited one.

Musculoskeletal 1

Rigidity HP:0002063

Show evidence (1 reference)

PMID:28031394 SUPPORT DIRECT Human Clinical

"Exposure was most strongly associated with progression of upper limb bradykinesia, upper and lower limb rigidity, and impairment of speech and facial expression."

Limb rigidity among the exposure-tracking components.

Nervous System 14

Parkinsonism HP:0001300

Show evidence (2 references)

PMID:28031394 SUPPORT DIRECT Human Clinical

"Progression of parkinsonism increased with cumulative Mn exposure."

The dose-response relationship, from a longitudinal cohort of 886 welding-exposed workers - the design that makes this a claim about exposure rather than about a selected clinical series.

PMID:26608821 SUPPORT DIRECT REVIEW SYNTHESIS Other

"Manganism is an extrapyramidal disorder characterized by motor disturbances associated with neuropsychiatric and cognitive disabilities similar to Parkinsonism."

The clinical definition of the syndrome as extrapyramidal, and the statement that the motor disturbance travels with neuropsychiatric and cognitive features rather than alone.

Bradykinesia HP:0002067

Show evidence (1 reference)

PMID:28031394 SUPPORT DIRECT Human Clinical

"Exposure was most strongly associated with progression of upper limb bradykinesia, upper and lower limb rigidity, and impairment of speech and facial expression."

Names which components of the motor examination track exposure most closely. The same sentence supports the rigidity and weak-voice phenotypes.

Dystonia HP:0001332

Show evidence (1 reference)

PMID:27231142 SUPPORT INDIRECT Human Clinical

"Excessive accumulation of manganese in these patients results in rapidly progressive childhood-onset parkinsonism-dystonia with distinctive brain magnetic resonance imaging appearances and neurodegenerative features on post-mortem examination."

INDIRECT on purpose: this is the inherited disease, not the occupational one. It is cited because it isolates manganese overload as the sufficient cause of a parkinsonism-dystonia syndrome, with no exposure and no confounding co-exposures.

Gait disturbance HP:0001288

Show evidence (1 reference)

PMID:18322282 SUPPORT DIRECT Human Clinical

"At the time of neurologic evaluation, all 23 patients had gait disturbance and difficulty walking backward"

All 23 patients in the series, and the retropulsion that goes with it.

Postural instability HP:0002172

Show evidence (1 reference)

PMID:18322282 SUPPORT INDIRECT Human Clinical

"At the time of neurologic evaluation, all 23 patients had gait disturbance and difficulty walking backward"

INDIRECT because difficulty walking backward is retropulsion, which is a sign of postural instability rather than the phenotype term itself; the inference is one step.

Micrographia HP:0031908

Show evidence (1 reference)

PMID:16766929 SUPPORT INDIRECT Human Clinical

"At the end of PAS treatment, her symptoms were significantly alleviated, and handwriting recovered to normal."

INDIRECT: recovery of handwriting implies the deficit, which the case describes rather than codes.

Cognitive impairment HP:0100543

Show evidence (2 references)

PMID:33911374 SUPPORT DIRECT REVIEW SYNTHESIS Other

"The symptoms include initial cognitive and psychiatric disturbances followed by a movement disorder resembling Parkinson's disease with limb rigidity, dystonia, and a characteristic high-stepping gait."

States the order explicitly - cognitive and psychiatric disturbance first, the movement disorder after.

PMID:26154659 SUPPORT INDIRECT REVIEW SYNTHESIS Human Clinical

"Patients occupationally exposed to excessive levels of Mn demonstrate a biphasic mode of physical decline comprising an initial phase of psychiatric abnormalities including emotional disturbance, memory loss, compulsive behavior, visual impairments, illusions and delusions, disorientation"

Names disorientation and memory loss as components of the initial phase, INDIRECT because the sentence lists the deficits rather than using the term cognitive impairment.

Memory impairment HP:0002354

Show evidence (1 reference)

PMID:26154659 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Patients occupationally exposed to excessive levels of Mn demonstrate a biphasic mode of physical decline comprising an initial phase of psychiatric abnormalities including emotional disturbance, memory loss, compulsive behavior, visual impairments, illusions and delusions, disorientation"

Names memory loss directly, among the first-phase deficits.

Compulsive behaviors HP:0000722

Show evidence (1 reference)

PMID:26154659 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Patients occupationally exposed to excessive levels of Mn demonstrate a biphasic mode of physical decline comprising an initial phase of psychiatric abnormalities including emotional disturbance, memory loss, compulsive behavior, visual impairments, illusions and delusions, disorientation"

Names compulsive behavior directly.

Delusion HP:0000746

Show evidence (1 reference)

PMID:26154659 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Patients occupationally exposed to excessive levels of Mn demonstrate a biphasic mode of physical decline comprising an initial phase of psychiatric abnormalities including emotional disturbance, memory loss, compulsive behavior, visual impairments, illusions and delusions, disorientation"

Names illusions and delusions directly among the first-phase abnormalities.

Hallucinations HP:0000738

Show evidence (1 reference)

PMID:23262390 SUPPORT INDIRECT BACKGROUND Human Clinical

"Occupational and environmental exposure to manganese (Mn) is associated with a neurological syndrome consisting of psychiatric symptoms, cognitive impairment and parkinsonism."

Establishes the psychiatric component of the human syndrome. BACKGROUND because the sentence frames a primate study, HUMAN_CLINICAL because what it describes is the human occupational picture, and INDIRECT because it says "psychiatric symptoms" rather than naming hallucinations.

Emotional lability HP:0000712

Show evidence (2 references)

PMID:23262390 SUPPORT INDIRECT BACKGROUND Human Clinical

"Occupational and environmental exposure to manganese (Mn) is associated with a neurological syndrome consisting of psychiatric symptoms, cognitive impairment and parkinsonism."

The general framing of the psychiatric component. INDIRECT because the sentence says "psychiatric symptoms" rather than naming emotional lability; the item below is the one that names it.

PMID:26154659 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Patients occupationally exposed to excessive levels of Mn demonstrate a biphasic mode of physical decline comprising an initial phase of psychiatric abnormalities including emotional disturbance, memory loss, compulsive behavior, visual impairments, illusions and delusions, disorientation"

Names emotional disturbance directly, among the first-phase abnormalities.

Dysarthria HP:0001260

Show evidence (2 references)

PMID:28031394 SUPPORT INDIRECT Human Clinical

"Exposure was most strongly associated with progression of upper limb bradykinesia, upper and lower limb rigidity, and impairment of speech and facial expression."

INDIRECT, and deliberately the same grading this sentence carries on Weak voice: the cohort measured speech impairment as one UPDRS item and did not distinguish dysarthria from hypophonia.

PMID:42563869 SUPPORT INDIRECT REVIEW SYNTHESIS Human Clinical

"with childhood onset of progressive dystonia of the limbs and tongue and exhibit a distinctive “cock‐walk” gait, decreased manual dexterity, and dysarthria."

The only cached sentence naming dysarthria as such, and it describes the inherited transporter defect rather than occupational manganism - cited the way the Dystonia phenotype cites its inherited-form evidence, as a cross-form inference and not as a finding in this population.

Tremor HP:0001337

Show evidence (3 references)

PMID:26154659 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"The motor impairments include hypertonia with cogwheel rigidity, bradykinesia, “cock-gait”, rapid postural tremor, and tendency to fall when walking backwards"

Characterises the tremor as postural, which is what `preferred_term` records while the binding stays at the generic HP term.

PMID:40278159 SUPPORT INDIRECT REVIEW SYNTHESIS Human Clinical

"Tremors during rest were not a distinguishing feature, which is commonly observed during PD."

The negative half, and the one that matters for the differential: resting tremor is a Parkinson disease feature, not a manganism one. INDIRECT because the sentence denies one kind of tremor rather than asserting another - the postural character recorded in `preferred_term` follows by an inference step, from this exclusion plus the positive statement in the item above it. The two items below carry the presence claim and the flat denial.

PMID:42563869 REFUTE DIRECT REVIEW SYNTHESIS Human Clinical

"Specifically, patients with manganism have no tremor but do exhibit dystonia, a “cock‐gait” walk, and, importantly, minimal or no response to levodopa"

A REFUTE against curating tremor as a feature at all. Recorded rather than resolved: the cached reviews disagree, and this entry does not have the evidence to say which is right.

Voice 1

Weak voice HP:0001621

Show evidence (1 reference)

PMID:28031394 SUPPORT INDIRECT Human Clinical

"Exposure was most strongly associated with progression of upper limb bradykinesia, upper and lower limb rigidity, and impairment of speech and facial expression."

INDIRECT: the cohort records impairment of speech, which is broader than hypophonia specifically.

🧬

Genetic Associations

1

SLC30A10

Gene: SLC30A10 hgnc:25355 relationship_type: MODIFIER

Show evidence (1 reference)

PMID:22341972 SUPPORT INDIRECT Human Clinical

"this work has confirmed that SLC30A10 functions as a Mn transporter in humans that, when defective, causes Mn accumulation in liver and brain"

Establishes the transporter's function in humans. INDIRECT with respect to the acquired disease, which is the point of the note above.

💊

Medical Actions

5

Removal from Exposure

Action: removal from manganese exposure Ontology label: Preventive Intervention NCIT:C15843

Platform: Other

The only intervention with an unambiguous rationale, and the reason occupational hygiene rather than neurology is where this disease is won. It does not reliably reverse established damage - the two cached series that followed patients after cessation report non-resolution and, in one, progression through the first decade - but it stops the burden rising, and it is the one step available before symptoms appear.

Mechanism Target:

INHIBITS Chronic Manganese Overexposure — Ends the input to the system rather than acting on the lesion.

Show evidence (2 references)

PMID:42563869 REFUTE DIRECT REVIEW SYNTHESIS Human Clinical

"Despite a cessation of exposure, their symptoms, which did not have a sustained response to levodopa, were progressive over the first decade and then plateaued"

Recorded as a REFUTE against the expectation that removal from exposure is curative. It supports removal as prevention and refutes it as treatment, which is exactly the distinction this treatment's description makes.

PMID:7936281 REFUTE DIRECT PRIMARY RESULT Human Clinical

"Their parkinsonism and dystonia had progressed slowly over a period of 5 years after they left the site of exposure."

The second of the two cached series, and a primary observation rather than a review's summary: parkinsonism and dystonia progressed over five years after the patients left the exposure site. REFUTE for the same reason as the item above - it refutes removal as a cure while leaving it necessary as prevention.

Calcium Disodium Edetate Chelation

Action: Pharmacotherapy NCIT:C15986

Agent: calcium disodium edetate CHEBI:4757

Platform: Small molecule

The standard chelator, and a treatment whose evidence base sits mostly in the inherited disease rather than the occupational one. It lowers blood manganese; it does not cross the blood-brain barrier well, which is the usual explanation for why the biochemical response outruns the clinical one in established manganism.

Mechanism Target:

INHIBITS Systemic Manganese Overload — Complexes circulating manganese and promotes its excretion.

Show evidence (1 reference)

PMID:27231142 SUPPORT INDIRECT Human Clinical

"Chelation with disodium calcium edetate lowers blood manganese levels in patients and can lead to striking clinical improvement."

The clearest efficacy statement available, and it is from the inherited disease - hence INDIRECT. Transferring it to occupational manganism is an inference, not a finding, and the treatment description says so.

Sodium Para-Aminosalicylic Acid

Action: Pharmacotherapy NCIT:C15986

Agent: sodium para-aminosalicylic acid CHEBI:27565

Platform: Small molecule

The one agent with a positive long-term clinical report in occupational manganism, and the mechanistic argument for it is that it crosses into the brain where EDTA does not. The human evidence is a single case with 17-year follow-up, which is a strong observation and a weak study design at the same time.

Mechanism Target:

INHIBITS Pallidal Manganese Accumulation — Unlike EDTA, reaches the compartment where the metal actually sits.

Show evidence (1 reference)

PMID:38909920 SUPPORT DIRECT REVIEW SYNTHESIS Other

"PAS-Na can readily pass through the blood-brain barrier (BBB), and complex and facilitate the excretion of manganese and lead"

The pharmacokinetic property that distinguishes it from EDTA. Graded OTHER because the review aggregates experimental and clinical work without naming a study type for this claim.

Show evidence (1 reference)

PMID:16766929 SUPPORT DIRECT Human Clinical

"At the end of PAS treatment, her symptoms were significantly alleviated, and handwriting recovered to normal."

The clinical result, in one patient with 21 years of airborne exposure, followed for 17 years after treatment.

Levodopa Trial

Action: Pharmacotherapy NCIT:C15986

Agent: levodopa CHEBI:15765

Platform: Small molecule

Included because its failure is diagnostically informative rather than because it works. A patient whose parkinsonism is manganese-related characteristically does not respond, and that non-response has been used as a discriminating criterion against Parkinson disease. The mechanism predicts it: the lesion is at and beyond the pallidum, so replenishing the dopamine precursor does not reach the problem.

Mechanism Target:

MODULATES Basal Ganglia Output Failure — Attempts to restore dopaminergic drive to a circuit whose lesion is downstream of it, which is why the attempt usually fails.

Show evidence (1 reference)

PMID:7936281 REFUTE DIRECT PRIMARY RESULT Human Clinical

"This short-term, double-blind study indicates that their parkinsonism and dystonia failed to respond to levodopa."

A REFUTE recorded on the mechanism link rather than omitted, because the failure is the diagnostically informative part. This is the only placebo-controlled evidence on the question in the entry; the two items below are reviews restating it.

Show evidence (2 references)

PMID:40278159 REFUTE DIRECT REVIEW SYNTHESIS Human Clinical

"Another main difference is the treatment response to levodopa, manganism does not respond to levodopa given the absence of primary involvement of the substantia nigra."

REFUTE against levodopa as an effective therapy here, and it supplies the mechanistic reason this entry's pathograph encodes.

PMID:26154659 REFUTE DIRECT REVIEW SYNTHESIS Human Clinical

"Mn-induced parkinsonism patients regardless of the dose of levodopa administered are unresponsive to levodopa treatment"

A second review stating the non-response is dose-independent, which closes off the "not enough drug" reading.

Iron Supplementation

Action: oral iron supplementation Ontology label: Nutritional Support NCIT:C15433

Agent: iron CHEBI:29033

Platform: Small molecule

Adjunctive, and mechanistically the neatest intervention in the entry: manganese rides the iron transporters, so raising iron status competes it off them. That is the same DMT1 iron-dependence this entry's transport node records, read backwards as a therapy. The evidence is a review's treatment recommendation rather than a trial, and the clearest demonstrations are in the inherited transporter defects.

Mechanism Target:

INHIBITS Manganese Transport Across the Blood-Brain Barrier — Competes with manganese for the shared divalent-metal carriers rather than binding the metal already deposited.

Show evidence (1 reference)

PMID:40278159 SUPPORT DIRECT REVIEW SYNTHESIS Other

"Interestingly, iron supplementation may lower Mn concentration by competing for the same transport mechanism."

States the competition mechanism explicitly, and it is the mirror image of the iron-deficiency susceptibility recorded on the transport node.

Show evidence (2 references)

PMID:40278159 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"The cornerstone of treatment involves chelation therapy using intravenous disodium calcium edetate (EDTA-CaNa2) and iron supplementation."

Places iron supplementation alongside chelation as standard management.

PMID:42563869 SUPPORT INDIRECT REVIEW SYNTHESIS Human Clinical

"These latter two disorders are treatable, and the early recognition and institution of chelation therapy and iron supplementation can improve neurological disability."

INDIRECT because "these latter two disorders" are the inherited transporter defects, not occupational manganism; cited for the efficacy signal, with the population difference stated rather than elided.

🌍

Environmental Factors

3

Occupational inhalation of manganese-containing welding fume or ore dust

Bound to ECTO:7000129 exposure to welding fume rather than to the generic ECTO:9000946 exposure to manganese, because the fume is what the worker is exposed to and the particle size is mechanistically load-bearing here. Searched the pinned local build with `uv run runoak -i sqlite:obo:ecto search` for `l~manganese`, `l~welding` and `l~fume` on 2026-09-20; `l~manganese` returns ECTO:9000946 exposure to manganese, ECTO:9000179 exposure to manganese cation and ECTO:9001154 exposure to elemental manganese, and `l~welding` returns ECTO:7000129 alone. The generic manganese term is used on the non-occupational routes below, where no fume is involved.

The classical route and the one MONDO's definition is written around: welding, mining, ore processing, battery manufacture, ferromanganese smelting. What makes inhalation special is not the dose but the anatomy - it delivers manganese to the blood without the gut absorption control and hepatobiliary first-pass that handle dietary intake.

Show evidence (2 references)

PMID:28031394 SUPPORT DIRECT Human Clinical

"Progression of parkinsonism increased with cumulative Mn exposure."

The exposure-response relationship in welders, which is the strongest available evidence that this route causes the disease rather than merely accompanying it.

PMID:20012385 SUPPORT DIRECT REVIEW SYNTHESIS Other

"Manganese exposure scenarios in the last century generally have changed from the acute, high-level exposure conditions responsible for the occurrence of manganism to chronic exposure to much lower levels."

Records that the occupational exposure profile has shifted over a century, from the acute high-level conditions that produced classical manganism to chronic low-level exposure. It is why contemporary series look different from the historical ones this entry's description alludes to.

Mechanism Target:

TRIGGERS Chronic Manganese Overexposure — Sustained inhalation is the route by which the occupational body burden is established.

Show evidence (1 reference)

PMID:26154659 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"greater than 90% of the Mn containing welding aerosols can be deposited in the lungs due to their small particulate size"

Quantifies pulmonary deposition, which is what makes this exposure route efficient enough to cause disease.

Intravenous methcathinone (ephedrone) prepared with potassium permanganate

A drug-preparation route rather than an industrial one, and the highest-dose human exposure on record. Home synthesis of methcathinone oxidises ephedrine with potassium permanganate and the manganese goes into the product, which is then injected. It produces the same syndrome faster and more severely, and it is the setting in which the imaging and levodopa-response evidence is clearest.

Show evidence (1 reference)

PMID:18322282 SUPPORT DIRECT Human Clinical

"The neurologic deficits did not resolve after patients discontinued methcathinone use."

The irreversibility of this route's damage, in a 23-patient series followed after cessation.

Mechanism Target:

TRIGGERS Systemic Manganese Overload — Injection puts manganese directly into the blood, bypassing every absorptive and first-pass control at once.

Show evidence (1 reference)

PMID:40278159 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Drug abuse has recently become a recognized cause of Mn toxicity since abusers of methcathinone may be exposed to Mn due to the use of potassium permanganate in the synthesis process"

Names the route and the chemistry that puts manganese in the drug.

Parenteral nutrition and chronic liver failure

Overload without overexposure. Parenteral nutrition delivers manganese past the gut and liver; chronic liver failure leaves ordinary intake with nowhere to go, since bile is the excretory route. Both produce pallidal accumulation and the T1 imaging signature in people who have never been near a welding torch.

Show evidence (1 reference)

PMID:8622451 SUPPORT DIRECT BACKGROUND Human Clinical

"In patients receiving long-term parenteral nutrition (PN), cholestatic disease and nervous system disorders have been associated with high blood concentrations of manganese."

The parenteral-nutrition route in children, where the normal homeostatic mechanisms are bypassed by design.

Mechanism Target:

TRIGGERS Impaired Hepatobiliary Manganese Excretion — Both settings act by defeating biliary clearance rather than by raising intake.

Show evidence (1 reference)

PMID:26154659 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Mn-induced parkinsonism may occur in patients with chronic liver failure who fail to adequately excrete Mn in bile"

The excretory-failure route, stated directly.

🔬

Biochemical Markers

1

Whole-blood manganese (Increased)

Context: Confirms ongoing exposure. It is a poor guide to brain burden, because blood manganese falls after exposure stops while the pallidal deposit and the symptoms persist.

Reference Ranges

≤ 209.0 nmol/L (laboratory reference used in the Latvian methcathinone series)

Within the laboratory reference interval (< 209.0 nmol/L) Elevated (≥ 209.0 nmol/L) → Hypermanganesemia

Within the laboratory reference interval: Does not exclude manganism in someone whose exposure has ceased.

Elevated: Consistent with current or recent exposure. In the cited series active users averaged 831 nmol/L and former users 346 nmol/L, so an elevated value does not by itself date the exposure.

A one-sided interval: the cited paper gives the upper limit of normal and no lower bound, so none is asserted. `loinc_term` is omitted because LOINC has no adapter in `conf/oak_config.yaml` and no `cache/` membership file, so a LOINC code here could not be validated by anything in the repository. The interval is that one laboratory's, not a consensus value, which is what `population` records.

Show evidence (1 reference)

PMID:18322282 SUPPORT DIRECT Human Clinical

"Whole-blood manganese levels (normal level, <209 nmol per liter) averaged 831 nmol per liter (range, 201 to 2102) in the active methcathinone users and 346 nmol per liter (range, 114 to 727) in former users."

Gives the reference threshold and, in the same sentence, the fall between active and former users that limits the test's value after exposure ends.

🔬

Diagnosis

3

Brain MRI with T1-weighted sequences

The most direct test available, in the literal sense: manganese is paramagnetic, so the accumulated metal is what generates the signal. Symmetric pallidal T1 hyperintensity without gadolinium is the finding. It reports body burden rather than disease, and the two come apart - the signal tracks ongoing exposure, and it fades after exposure stops while symptoms do not.

T1-weighted brain magnetic resonance imaging NCIT:C16809

Bound to the generic NCIT:C16809 Magnetic Resonance Imaging. NCIT's brain-specific MRI terms are contrast-qualified (NCIT:C137874 without contrast, NCIT:C137913 with and without), and this finding is a plain unenhanced T1 sequence, so neither is a better fit than the parent; `ancestors -p i` confirms C16809 reaches NCIT:C25218.

Show evidence (3 references)

PMID:17159105 SUPPORT DIRECT Human Clinical

"Pallidal MRI T1 hyperintensity is a biomarker of manganese overload."

The study's own conclusion, and the basis for using the sign this way.

PMID:17159105 SUPPORT DIRECT Human Clinical

"In patients with pallidal T1 hyperintensity, pallidal manganese concentrations were increased sevenfold over controls and over fourfold vs liver patients with normal MRI"

Direct tissue validation of the imaging sign: the signal tracks measured pallidal manganese, not a proxy for it.

PMID:17127642 SUPPORT DIRECT Model Organism

"These data suggested that prolonged inhalation of welding fumes induces a high MRI T1 signal intensity with an elevation of the blood manganese level."

Shows the signal rising with ongoing exposure, which is the basis for reading it as a burden measure. MODEL_ORGANISM because this is six cynomolgus monkeys in an inhalation chamber, not the welders the title's phrasing might suggest.

Whole-blood manganese concentration

Confirms exposure and is a poor guide to brain burden, because manganese leaves the blood quickly while the pallidal load persists. Most useful when it is high in someone still being exposed, and close to useless as a negative test in someone who has stopped.

whole-blood manganese measurement NCIT:C217390

Show evidence (1 reference)

PMID:18322282 SUPPORT DIRECT Human Clinical

"Whole-blood manganese levels (normal level, <209 nmol per liter) averaged 831 nmol per liter (range, 201 to 2102) in the active methcathinone users and 346 nmol per liter (range, 114 to 727) in former users."

Gives the reference threshold and shows the fall after exposure ends - the behaviour that limits the test's value in a former user.

Levodopa response as a discriminating test

Not a test of manganese but of the alternative. A convincing sustained response to levodopa argues for Parkinson disease; its absence is one of the features that supports manganese-related parkinsonism instead.

therapeutic trial of levodopa NCIT:C15986

Show evidence (1 reference)

PMID:40496384 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"A diagnostic criterion for manganese poisoning has been the effectiveness of levodopa in which there is not supposed to be a significant response."

States the diagnostic use of the non-response explicitly, which is what justifies recording a failed treatment in the diagnosis section.

🔀

Differential Diagnoses

3

Conditions with similar clinical presentations that must be differentiated from Manganism:

Parkinson disease MONDO:0005180

Overlapping Features The differential that matters, and the one that has been litigated. Against it: the pallidal rather than nigral lesion, absent Lewy bodies, poor levodopa response, more dystonia, less resting tremor, and the reversed FDOPA pattern. For it: both produce bradykinesia and rigidity in a middle-aged worker, and welding is common.

Show evidence (2 references)

PMID:17882011 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"These pathologic findings do not support the notion that manganese causes PD but rather argues that manganese-induced parkinsonism and PD are distinct and separate disease entities."

The explicit statement that these are two diseases, from the review of the pathological series.

PMID:20012385 SUPPORT DIRECT REVIEW SYNTHESIS Other

"Manganism is a distinct medical condition from Parkinson's disease."

The same conclusion reached from the exposure side rather than the neuropathology, so the separation does not rest on one line of argument.

Hypermanganesemia with dystonia 1 Not Yet Curated MONDO:0013208

Overlapping Features Autosomal recessive SLC30A10 deficiency: the manganese efflux transporter fails, so the metal accumulates without any exposure. Distinguished from the acquired disease by childhood onset and by liver cirrhosis and polycythemia, which occupational manganism does not produce.

Show evidence (1 reference)

PMID:22341972 SUPPORT DIRECT Human Clinical

"this work has confirmed that SLC30A10 functions as a Mn transporter in humans that, when defective, causes Mn accumulation in liver and brain"

Establishes the inherited entity and, incidentally, the strongest human evidence that manganese overload by itself is sufficient to produce this pathology.

Hypermanganesemia with dystonia 2 Not Yet Curated MONDO:0014864

Overlapping Features Autosomal recessive SLC39A14 deficiency. Rapidly progressive childhood parkinsonism-dystonia without the liver disease or polycythemia of HMNDYT1, and the one manganese disorder where chelation has a clear clinical payoff.

Show evidence (1 reference)

PMID:27231142 SUPPORT DIRECT Human Clinical

"Excessive accumulation of manganese in these patients results in rapidly progressive childhood-onset parkinsonism-dystonia with distinctive brain magnetic resonance imaging appearances and neurodegenerative features on post-mortem examination."

Defines the entity and its tempo.

📊

Related Datasets

2

Small noncoding RNA Dysregulation is Implicated in Manganism in a Rat Model of Methylcyclopentadienyl Manganese Tricarbonyl-Induced Unrepaired Striatum Damage geo:GSE227299

Excessive accumulation of manganese in brain can cause Parkinsonian-like symptoms, known as Manganism. Methylcyclopentadienyl Manganese Tricarbonyl (MMT), a gasoline antiknock additive, is one of environmental exposures of manganese, which can lead to manganism in Rats. Though some researches showed that small non-coding RNAs (sncRNAs) were differently expressed in Parkinson’s disease (PD) patients, it was still unclear whether and how sncRNAs dysfunction appeared in Manganism.

rat BULK RNA SEQ n=9

Identified by GEO DataSets index search for Manganism (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-08-01. Title, sample count, and organism are GEO's own values.

A humanized neuronal model system reveals key roles for the trace element manganese in neuronal endocytosis, calcium flux and mitochondrial bioenergetics geo:GSE266943

Manganese (Mn) is an essential trace metal that is necessary for life. Its duality as both a crucial micronutrient and potential neurotoxicant necessitates tight control of intracellular and extracellular Mn levels. Dysregulation of Mn is implicated in a broad range of human diseases, from neurodevelopmental sequelae related to Mn levels in drinking water, to acquired forms of manganism, rare inherited Mn transportopathies and more common disorders such as Parkinson’s and Alzheimer’s disease. Despite the clear association between Mn dysregulation and neurodevelopmental or neurodegenerative diseases, the underlying cellular mechanisms that govern neuropathology remain poorly understood.

human BULK RNA SEQ n=48

PMID:40917882

Identified by GEO DataSets index search for Manganism (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-08-01. Title, sample count, and organism are GEO's own values.

🐁

Animal Models

1

Manganese-exposed cynomolgus macaque Non-human primate

Moderate-dose manganese exposure in Macaca fascicularis, assessed as part of a multidisciplinary neurological evaluation. The model's value is that it is the system in which dopamine release, terminal integrity and cortical protein pathology were measured in the same animals.

Species

Cynomolgus macaque

Publication

PMID:23262390

Pathograph links

Alpha-Synuclein Aggregation recapitulates fidelity: unknown observes: tissue Produces alpha-synuclein-positive neurons and glia in frontal cortex after manganese exposure.

Limitations: Fidelity to human manganism is the open question, not a detail: human cases with directly measured pallidal manganese show negative alpha-synuclein immunostaining, and the defining human neuropathology is Lewy-body negative. See the `alpha_synuclein_in_human_manganism` discussion.

Show evidence (1 reference)

PMID:23262390 SUPPORT DIRECT Model Organism

"We found increased α-syn-positive cells in the gray matter of Mn-exposed animals, typically observed in pyramidal and medium-sized neurons in deep cortical layers."

The observation the link records.

Impaired Striatal Dopamine Release recapitulates fidelity: moderate observes: cellular Dopamine release is markedly inhibited while nigrostriatal terminals are preserved, which is the combination the human imaging data also point to.

Limitations: The supporting sentence is this paper's summary of the group's earlier primate work rather than a result reported here.

Show evidence (1 reference)

PMID:23262390 SUPPORT INDIRECT BACKGROUND Model Organism

"our laboratory has demonstrated a lack of nigrostriatal dopaminergic neuron degeneration in the striatum of Mn-exposed non-human primates"

The terminal-preservation half of the claim, stated in this paper's introduction about the authors' own prior work.

{ }

Source YAML

click to show

name: Manganism
creation_date: "2026-06-11T00:00:00Z"
category: Environmental
categories:
- Toxic Exposure Disorder
- Heavy Metal Poisoning
- Environmental Health Disorder
- Movement Disorder
- Neurological Disorder
synonyms:
- manganese poisoning
- manganese intoxication
- manganese-induced parkinsonism
description: >-
  Manganism, or manganese poisoning, is an acquired extrapyramidal disorder caused by
  chronic overexposure to manganese, most often by inhalation of welding fume or ore
  dust. Manganese is an essential trace element, so the disease is a dose problem
  rather than a foreign-substance problem: the routes that cause it are the ones that
  defeat normal homeostasis. Inhaled metal bypasses the gut and the hepatobiliary
  first-pass that would otherwise excrete the excess, and the metal concentrates in
  the basal ganglia, above all in the globus pallidus. The resulting syndrome looks
  like parkinsonism and is not Parkinson disease: the lesion sits in the pallidum
  rather than the substantia nigra, there are no Lewy bodies, and it responds poorly
  to levodopa. It is also frequently irreversible once established, which is why
  exposure control rather than treatment is the main lever.
disease_term:
  preferred_term: manganese poisoning
  term:
    id: MONDO:0017638
    label: manganese poisoning
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0017638
      label: manganese poisoning
    mapping_predicate: skos:exactMatch
    mapping_source: MONDO
    mapping_justification: >-
      Primary MONDO identifier. MONDO's own definition scopes the term to chronic
      inhalation by people working with manganese ore, which is the acquired disease
      this entry covers; the inherited hypermanganesaemias have their own terms and
      are recorded here as differential diagnoses rather than folded in.
  icd10cm_mappings:
  - term:
      id: ICD10CM:T57.2
      label: Toxic effect of manganese and its compounds
    mapping_predicate: skos:closeMatch
    mapping_source: dismech curation
    mapping_justification: >-
      Curator-asserted, not taken from MONDO. MONDO:0017638 carries no ICD-10-CM xref -
      its cross-references are EFO, GARD, MESH:D020149, MedDRA, Orphanet:306682, SCTID
      and ICD9:503, the last of these `relatedTo` and pointing at the pneumoconiosis
      rather than the encephalopathy. ICD10CM:T57.2 was resolved directly against the
      local build. closeMatch because the code names the toxic effect of the substance,
      which is broader in agent coverage and narrower in clinical content than the
      MONDO concept.
parents:
- heavy metal poisoning
- toxic encephalopathy
- Secondary Parkinsonism
- Environmental Neurotoxicity
notes: >-
  Scope. This entry is the acquired disease. MONDO separates it from the inherited
  manganese transporter defects - MONDO:0013208 (HMNDYT1, SLC30A10) and
  MONDO:0014864 (HMNDYT2, SLC39A14) - and collapsing them would flatten a real
  distinction in onset, liver involvement and treatment response. They appear here in
  `differential_diagnoses:` and are cited in the pathophysiology, because they are the
  closest thing to a controlled human experiment showing that manganese overload alone
  produces this syndrome.

  Provenance. This entry is a merge. It was drafted as a separate file,
  `Manganese_Poisoning.yaml`, by a curator who checked `stubs/` and the open `claim`
  issues, found neither, and concluded the disease was uncurated - both checks correct,
  and neither one looks at `kb/disorders/`. A candidate screen of
  `ls kb/disorders/ | grep -i Manganese` does not match "Manganism", so the existing
  entry was missed until review. `grep -rl "<MONDO ID>" kb/` would have caught it in a
  second and is the check to run before starting.

  The two files cited disjoint literature - eight references against seventeen, with no
  overlap at all - so the merge folded the whole of the older entry's evidence into the
  newer structure rather than replacing it. What came in that way: the transport and
  hepatobiliary homeostasis sources (PMID:33911374), the SLC30A10 human genetic proof
  that the transport step is causally sufficient (PMID:22341971), the deposition-pattern
  pair (PMID:20012385, PMID:37627255), the microglial complex II node with its three
  in vitro results and the paired HUMAN_MODEL_MISMATCH discussion (PMID:23315522), the
  basal ganglia circuit mechanism and the clinical definition (PMID:26608821), the
  placebo-controlled levodopa failure and the five-year post-cessation progression
  (PMID:7936281), and the two GEO datasets. The older file's `creation_date` of
  2026-06-11 is kept, as is its `name`, which keeps the
  `Parkinsonism_Dopaminergic_Degeneration_Disorders` grouping's `- member: Manganism`
  resolving without an edit.

  Sources. A deep-research report for this disease also existed
  (`research/Manganism-deep-research-claude_code.md`, committed 2026-08-31, 44
  citations, run with an empty `mondo_id`) and had never been curated, though the
  disease had been. It was read for leads and for its curation cautions, several of
  which are followed here, and for nothing else: its own reference-validation block
  records 17 of 22 quoted claims not found in the cited source. Every snippet in this
  entry was independently verified as an exact substring of a committed cache before
  the YAML was written, including every snippet carried over in the merge. Every CURIE
  was read from a live lookup in the same step it was written - OLS for HP, GO, CL,
  UBERON, CHEBI, NCIT and MONDO, the pinned local build for ECTO and HGNC.

  The report's caution that NCIT has no clinical-action term for chelation therapy was
  re-checked rather than taken: searching NCIT for `Chelation Therapy` returns
  D-methionine formulations and gadolinium chelate nanoparticles, no action term. The
  chelation treatments here therefore bind NCIT:C15986 Pharmacotherapy and carry the
  agent in `therapeutic_agent`.

  Module conformance. `Basal Ganglia Output Failure` conforms to
  `parkinsonism_dopaminergic_degeneration`; the reasoning, including why the module
  node's name is not in tension with this entry's pallidal argument, is on that node.
  `Microglial Complex II-Dependent Reactive Oxygen Species Production` deliberately
  does not conform to that module's complex I node, for the reason recorded there.

  Two nodes conform to `glutamate_excitotoxicity`, whose own
  description names impaired astrocytic glutamate clearance through EAAT2/GLT-1 loss
  and metal excitotoxins including methylmercury as its pattern, and which states that
  conforming nodes may be partial where excitotoxicity is one of several parallel
  injury mechanisms - which is manganism's situation exactly. The module's own
  `Mitochondrial Dysfunction and Oxidative Stress` node was NOT conformed to despite the
  identical name: in the module it sits downstream of calcium overload, whereas here it
  is a parallel arm driven directly by pallidal accumulation, so declaring conformance
  would assert a causal chain this entry does not have. `neuroinflammation_glial_activation`
  and `mitochondrial_dysfunction` are plausible further targets and are left for a pass
  that can read their scope properly rather than by analogy.

  Gaps. No `prevalence:` record is given a rate. The most-cited occupational figures
  come from a sample of 1,423 Alabama welders referred for medical-legal evaluation
  (PMID:15668418), which is a referral-selected population, and quoting its prevalence
  as an occupational rate would be wrong in a way the number does not advertise. The
  dose-response relationship is recorded instead, from the trade-union longitudinal
  cohort (PMID:28031394), which is the better design for that claim. Ferroportin
  (SLC40A1) and the citrate transporter route are named in the anchor review but are
  not modelled as nodes. There are no ClinicalTrials.gov identifiers for manganism;
  none is asserted.
mechanistic_hypotheses:
- hypothesis_group_id: pallidal_postsynaptic
  hypothesis_label: Pallidal accumulation with a postsynaptic basal ganglia lesion
  status: CANONICAL
  description: >-
    Manganese concentrates in the globus pallidus and injures it directly, leaving the
    nigrostriatal dopaminergic neurons structurally intact. The motor syndrome is
    therefore downstream of the dopamine synapse, which is the standard explanation for
    why levodopa does not work and why the neuropathology differs from Parkinson
    disease.
- hypothesis_group_id: presynaptic_dysfunction_without_degeneration
  hypothesis_label: Presynaptic dopaminergic dysfunction without degeneration
  status: EMERGING
  description: >-
    A second, non-competing account: the dopaminergic terminals survive but stop
    working properly. Mn-exposed primates show marked inhibition of in vivo dopamine
    release with no terminal loss, and asymptomatic welders show reduced FDOPA uptake
    in a caudate-first pattern that is anatomically reversed from idiopathic Parkinson
    disease. This is a functional presynaptic lesion rather than a degenerative one,
    and it coexists with the pallidal damage rather than replacing it.
pathophysiology:
- name: Chronic Manganese Overexposure
  role: trigger
  biological_scale: ORGANISM
  description: >-
    Sustained intake above what homeostasis clears. Occupationally this is inhaled
    welding fume or ore dust; the particles are small enough that most of an inhaled
    dose is retained in the lung, from which manganese reaches the blood without
    passing the gut and liver first. The exposure is measured in months to years, not
    in single doses.
  chemical_entities:
  - preferred_term: manganese(2+)
    term:
      id: CHEBI:29035
      label: manganese(2+)
    modifier: INCREASED
  evidence:
  - reference: PMID:40278159
    reference_title: "Manganese Neurotoxicity: A Comprehensive Review of Pathophysiology and Inherited and Acquired Disorders."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Manganism classically requires occupational exposure of 6 months to 2 years. Once developed, symptoms resulting from Mn toxicity usually persist even when the source of Mn exposure is eliminated"
    explanation: >-
      Gives both the exposure duration that defines the occupational disease and the
      persistence that makes exposure control the main intervention.
  - reference: PMID:26154659
    reference_title: "Manganese-Induced Parkinsonism and Parkinson's Disease: Shared and Distinguishable Features."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "greater than 90% of the Mn containing welding aerosols can be deposited in the lungs due to their small particulate size"
    explanation: >-
      The physical basis of the inhalation route: the particle size determines that the
      lung, not the gut, is the port of entry.
  downstream:
  - target: Systemic Manganese Overload
    causal_link_type: DIRECT
    description: Retained inhaled manganese enters the blood directly from the lung.
- name: Impaired Hepatobiliary Manganese Excretion
  role: trigger
  biological_scale: ORGANISM
  description: >-
    The other way to reach overload: normal intake with a broken exit. Manganese is
    cleared in bile, so chronic liver failure raises body burden without any unusual
    exposure, and parenteral nutrition delivers manganese straight into the blood past
    the gut and liver entirely. Both produce the same pallidal accumulation as the
    occupational route.
  biological_processes:
  - preferred_term: manganese ion homeostasis
    term:
      id: GO:0055071
      label: manganese ion homeostasis
    modifier: ABNORMAL
  evidence:
  - reference: PMID:26154659
    reference_title: "Manganese-Induced Parkinsonism and Parkinson's Disease: Shared and Distinguishable Features."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Mn-induced parkinsonism may occur in patients with chronic liver failure who fail to adequately excrete Mn in bile"
    explanation: >-
      Establishes failed biliary excretion as a sufficient route, independent of
      exposure.
  - reference: PMID:33911374
    reference_title: "Inherited Manganese Disorders and the Brain: What Neurologists Need to Know."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: OTHER
    quote_role: BACKGROUND
    snippet: "Patients with liver failure or hepatic encephalopathy can develop Mn toxicity as it is excreted in the bile."
    explanation: >-
      Independent corroboration of the excretion-failure route from a second review, so
      the claim does not rest on one source.
  downstream:
  - target: Systemic Manganese Overload
    causal_link_type: DIRECT
    description: Retention rather than intake raises the systemic burden.
- name: Systemic Manganese Overload
  biological_scale: ORGANISM
  description: >-
    Whole-body manganese above the homeostatic set point, whichever route produced it.
    This is the node the environmental exposures converge on and the one blood
    manganese measures, imperfectly.
  chemical_entities:
  - preferred_term: manganese(2+)
    term:
      id: CHEBI:29035
      label: manganese(2+)
    modifier: INCREASED
  evidence:
  - reference: PMID:33911374
    reference_title: "Inherited Manganese Disorders and the Brain: What Neurologists Need to Know."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: OTHER
    quote_role: BACKGROUND
    snippet: "The homeostasis of Mn levels in our body is crucially regulated through intestinal absorption and hepatobiliary secretion of the metal into the gastrointestinal tract."
    explanation: >-
      Names the two-sided balance - intestinal absorption against hepatobiliary
      secretion - whose failure on either side defines this node. Graded OTHER because
      the review states the physiology without reporting a study of its own.
  downstream:
  - target: Manganese Transport Across the Blood-Brain Barrier
    causal_link_type: DIRECT
    description: Circulating manganese is presented to the brain's transporters.
- name: Manganese Transport Across the Blood-Brain Barrier
  biological_scale: CELLULAR
  description: >-
    Manganese travels on carriers it does not own. Several transporters move it and few
    are selective for it - DMT1, ZIP8, ZIP14, transferrin receptor, all built for iron
    or zinc - which is why iron status changes
    the dose that reaches the brain and why the metal lands where those carriers are
    densest rather than where it would do least harm.
  genes:
  - preferred_term: SLC11A2
    term:
      id: hgnc:10908
      label: SLC11A2
  - preferred_term: SLC39A14
    term:
      id: hgnc:20858
      label: SLC39A14
  - preferred_term: SLC39A8
    term:
      id: hgnc:20862
      label: SLC39A8
  - preferred_term: TFRC
    term:
      id: hgnc:11763
      label: TFRC
  biological_processes:
  - preferred_term: manganese ion transmembrane transport
    term:
      id: GO:0071421
      label: manganese ion transmembrane transport
    modifier: INCREASED
  evidence:
  - reference: PMID:40278159
    reference_title: "Manganese Neurotoxicity: A Comprehensive Review of Pathophysiology and Inherited and Acquired Disorders."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "DMT1 facilitates Mn transport in its divalent state (Mn2+), and it is regulated by iron status: iron deficiency enhances Mn absorption and brain accumulation"
    explanation: >-
      Names the principal carrier and the iron-status dependence that makes iron
      deficiency a susceptibility factor rather than an incidental finding.
  - reference: PMID:33911374
    reference_title: "Inherited Manganese Disorders and the Brain: What Neurologists Need to Know."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: OTHER
    quote_role: BACKGROUND
    snippet: "The uptake of Mn2+ into the cells is facilitated by a number of membrane transporters such as the divalent metal transporter 1 (DMT1/SLC11A2), ZRT/IRT-like proteins ZIP8 (SLC39A8) and ZIP14 (SLC39A14)"
    explanation: >-
      Names the full influx carrier set, which is what makes manganese entry a
      transporter-dependent step rather than passive diffusion.
  - reference: PMID:33911374
    reference_title: "Inherited Manganese Disorders and the Brain: What Neurologists Need to Know."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: OTHER
    quote_role: BACKGROUND
    snippet: "Manganese efflux and export from the cytosol is mediated by the membrane-localized transporters ferroportin (Fpn or SLC40A1) and the solute carrier family 30 member 10 (SLC30A10)"
    explanation: >-
      The efflux arm. Brain manganese is a balance of influx against export, not a
      one-way flux, which is why the node is framed as transport rather than uptake.
  - reference: PMID:22341971
    reference_title: "Mutations in SLC30A10 cause parkinsonism and dystonia with hypermanganesemia, polycythemia, and chronic liver disease."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "SLC30A10 mutations cause a treatable recessive disease with pleomorphic phenotype, and provide compelling evidence that SLC30A10 plays a pivotal role in manganese transport"
    explanation: >-
      The closest thing to a controlled human experiment on this node: losing the
      SLC30A10 efflux transporter alone produces manganese overload with parkinsonism
      and dystonia. INDIRECT because the patients have the inherited transportopathy,
      not the occupational disease - it establishes that the transport step is causally
      sufficient, not that this is how occupational manganism arises.
  downstream:
  - target: Pallidal Manganese Accumulation
    causal_link_type: DIRECT
    description: >-
      Transport into brain regions where the carriers are most highly expressed.
    evidence:
    - reference: PMID:40278159
      reference_title: "Manganese Neurotoxicity: A Comprehensive Review of Pathophysiology and Inherited and Acquired Disorders."
      supports: SUPPORT
      directness: DIRECT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: "DMT1 is ubiquitously expressed, with the highest expression in the basal ganglia, especially in the caudate nucleus, the putamen, and the substantia nigra. This is why these are the preferred manganese accumulation sites in Mn neurotoxicity"
      explanation: >-
        Ties the anatomical distribution of the lesion to the distribution of the
        transporter, which is the review's own explanation for the regional selectivity.
- name: Pallidal Manganese Accumulation
  biological_scale: TISSUE
  description: >-
    The defining lesion location. Manganese concentrates in the basal ganglia and most
    of all in the globus pallidus, where it sits in GABAergic neurons and in astrocytes.
    Because manganese is paramagnetic, the accumulation is directly visible as symmetric
    T1 hyperintensity on MRI, which is what makes the imaging finding a measure of the
    metal rather than of its consequences.
  locations:
  - preferred_term: globus pallidus
    term:
      id: UBERON:0001875
      label: globus pallidus
  cell_types:
  - preferred_term: GABAergic neuron
    term:
      id: CL:0000617
      label: GABAergic neuron
  evidence:
  - reference: PMID:26154659
    reference_title: "Manganese-Induced Parkinsonism and Parkinson's Disease: Shared and Distinguishable Features."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "After elevated exposures, Mn distribution and levels are heterogeneous with the highest level of accumulation observed in the globus pallidus"
    explanation: The regional selectivity that the rest of the entry depends on.
  - reference: PMID:40278159
    reference_title: "Manganese Neurotoxicity: A Comprehensive Review of Pathophysiology and Inherited and Acquired Disorders."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Mn primarily accumulates in the GABAergic neurons of the globus pallidus within the basal ganglia"
    explanation: Identifies the cell population carrying the burden.
  - reference: PMID:18322282
    reference_title: A Parkinsonian syndrome in methcathinone users and the role of manganese.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "T(1)-weighted magnetic resonance imaging (MRI) showed symmetric hyperintensity in the globus pallidus and in the substantia nigra and innominata in all 10 active methcathinone users."
    explanation: >-
      The imaging correlate, in all ten actively exposed patients of a 23-patient
      series - and note the distribution extends beyond the pallidum in this
      high-dose route.
  - reference: PMID:20012385
    reference_title: "From manganism to manganese-induced parkinsonism: a conceptual model based on the evolution of exposure."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "Such chronic exposures may progressively extend the site of manganese deposition and toxicity from the globus pallidus to the entire area of the basal ganglia, including the substantia nigra pars compacta involved in Parkinson's disease."
    explanation: >-
      Describes the deposition pattern this node names - pallidal first, then the wider
      basal ganglia and the substantia nigra pars compacta under prolonged lower-level
      exposure. The spread matters because it is where manganism and Parkinson disease
      come anatomically closest.
  - reference: PMID:37627255
    reference_title: "Manganese-Induced Parkinsonism: Evidence from Epidemiological and Experimental Studies."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "the target areas extend beyond the globus pallidus (as seen with manganism) to the entire basal ganglia, including the substantia nigra pars compacta."
    explanation: >-
      Independent corroboration of the same target distribution, from a separate review.
  downstream:
  - target: Astrocytic Manganese Sequestration
    causal_link_type: DIRECT
    description: Astrocytes take up most of the tissue burden.
  - target: Mitochondrial Dysfunction and Oxidative Stress
    causal_link_type: DIRECT
    description: Intracellular manganese acts on mitochondria.
  - target: Microglial Complex II-Dependent Reactive Oxygen Species Production
    causal_link_type: DIRECT
    description: >-
      Manganese reaching the tissue enters microglial mitochondria, where it drives
      hydrogen peroxide production.
  - target: Impaired Striatal Dopamine Release
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Dopaminergic terminals survive but release less transmitter; the intermediates
      are the oxidative and energetic lesions modelled separately.
- name: Astrocytic Manganese Sequestration
  biological_scale: CELLULAR
  description: >-
    Astrocytes are the metal's reservoir, concentrating it far above neuronal levels
    because they carry the transporters. That is protective up to a point and then
    becomes the mechanism: a loaded astrocyte stops doing its day job, which in the
    basal ganglia is clearing glutamate.
  cell_types:
  - preferred_term: astrocyte
    term:
      id: CL:0000127
      label: astrocyte
  evidence:
  - reference: PMID:40278159
    reference_title: "Manganese Neurotoxicity: A Comprehensive Review of Pathophysiology and Inherited and Acquired Disorders."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "DMT1 and mostly TRs expressed on the astrocytic surface bind to Mn-transferrin with a resulting concentration of Mn inside the cell that is up to 50-fold greater than that in neurons"
    explanation: >-
      Quantifies the astrocyte-versus-neuron gradient this node asserts, and gives the
      transporter reason for it. Graded OTHER because the review does not name the
      study type behind the figure.
  - reference: PMID:40278159
    reference_title: "Manganese Neurotoxicity: A Comprehensive Review of Pathophysiology and Inherited and Acquired Disorders."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: IN_VITRO
    quote_role: REVIEW_SYNTHESIS
    snippet: "Mn exposure reduced glutamate uptake by astrocytes while simultaneously lowering the expression of glutamate aspartate transporter 1 (GLAST) and glutamate transporter 1 (GLT-1), ultimately leading to elevated extracellular glutamate levels"
    explanation: >-
      The functional consequence of astrocytic loading, and the route to excitotoxicity.
      Graded IN_VITRO because the transporter measurements the review is summarising are
      cultured-astrocyte experiments.
  downstream:
  - target: Astrocytic Glutamate Transporter Downregulation
    causal_link_type: DIRECT
    description: Loaded astrocytes downregulate GLAST and GLT-1.
  - target: Neuroinflammation
    causal_link_type: DIRECT
    description: Manganese-loaded astrocytes release inflammatory mediators.
- name: Astrocytic Glutamate Transporter Downregulation
  conforms_to: "glutamate_excitotoxicity#Excessive Glutamatergic Stimulation and Impaired Glutamate Clearance"
  biological_scale: CELLULAR
  description: >-
    Loss of the two transporters that clear synaptic glutamate, GLAST (SLC1A3) and
    GLT-1 (SLC1A2). Glutamate then accumulates outside the cell not because more is
    released but because less is removed.
  genes:
  - preferred_term: SLC1A3
    term:
      id: hgnc:10941
      label: SLC1A3
  - preferred_term: SLC1A2
    term:
      id: hgnc:10940
      label: SLC1A2
  biological_processes:
  - preferred_term: L-glutamate import
    term:
      id: GO:0051938
      label: L-glutamate import
    modifier: DECREASED
  downstream:
  - target: Glutamate Excitotoxicity
    causal_link_type: DIRECT
    description: Extracellular glutamate rises and overstimulates postsynaptic receptors.
- name: Glutamate Excitotoxicity
  conforms_to: "glutamate_excitotoxicity#Glutamate Receptor Overactivation and Calcium Overload"
  biological_scale: CELLULAR
  description: >-
    Sustained overstimulation of postsynaptic glutamate receptors, with the calcium
    load and cell death that follow. This is the non-cell-autonomous half of the
    lesion: the neuron dies from a failure in the astrocyte beside it.
  downstream:
  - target: Globus Pallidus Neuronal Injury
    causal_link_type: DIRECT
    description: Excitotoxic injury to pallidal neurons.
- name: Mitochondrial Dysfunction and Oxidative Stress
  biological_scale: MOLECULAR
  description: >-
    Manganese impairs mitochondrial respiration and generates reactive oxygen species.
    The basal ganglia are a bad place for this to happen: high oxygen consumption, and
    in the dopaminergic compartment a transmitter that oxidises into radicals of its own.
  biological_processes:
  - preferred_term: response to oxidative stress
    term:
      id: GO:0006979
      label: response to oxidative stress
    modifier: INCREASED
  evidence:
  - reference: PMID:40278159
    reference_title: "Manganese Neurotoxicity: A Comprehensive Review of Pathophysiology and Inherited and Acquired Disorders."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "Mn accumulation results in oxidative stress, mitochondrial dysfunction, and the generation of reactive oxygen species (ROS)"
    explanation: >-
      The review's summary statement of the core cellular mechanism. Graded OTHER
      because the sentence aggregates across experimental systems without naming one.
  downstream:
  - target: Globus Pallidus Neuronal Injury
    causal_link_type: DIRECT
    description: Energy failure and radical damage in pallidal neurons.
  - target: Alpha-Synuclein Aggregation
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Oxidative conditions favour the misfolded conformer; manganese also interacts
      with the protein directly.
- name: Microglial Complex II-Dependent Reactive Oxygen Species Production
  biological_scale: MOLECULAR
  description: >-
    Divalent manganese drives hydrogen peroxide production in the mitochondrial
    fraction of microglia, and the route is specifically complex II: the effect is
    supported by the complex II substrate succinate and abolished by complex II
    inhibition, while complex I substrates do not support it and complex I inhibition
    does not abolish it. The resulting microglial free-radical output in turn
    facilitates dopaminergic neurotoxicity. This is a narrower claim than the general
    oxidative-stress node, about a named respiratory complex in a named cell type,
    which is why the two are kept apart.
  cell_types:
  - preferred_term: microglial cell
    term:
      id: CL:0000129
      label: microglial cell
  biological_processes:
  - preferred_term: reactive oxygen species biosynthetic process
    term:
      id: GO:1903409
      label: reactive oxygen species biosynthetic process
    modifier: INCREASED
  evidence:
  - reference: PMID:23315522
    reference_title: "Complex II of the mitochondrial respiratory chain is the key mediator of divalent manganese-induced hydrogen peroxide production in microglia."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: IN_VITRO
    snippet: "the succinate-supported Mn(2+)-induced mitochondrial H2O2 production was abolished by pharmacological inhibition of complex II but not that of complexes I and III"
    explanation: >-
      Pharmacological dissection assigning the oxidative lesion to complex II, and
      excluding complexes I and III.
  - reference: PMID:23315522
    reference_title: "Complex II of the mitochondrial respiratory chain is the key mediator of divalent manganese-induced hydrogen peroxide production in microglia."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: IN_VITRO
    snippet: "complex I substrates malate and glutamate failed to support H2O2 production in the presence of Mn(2+)"
    explanation: >-
      The explicit negative result at complex I. This is the sentence that stops this
      node conforming to the parkinsonism module's complex I amplifier.
  - reference: PMID:23315522
    reference_title: "Complex II of the mitochondrial respiratory chain is the key mediator of divalent manganese-induced hydrogen peroxide production in microglia."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: IN_VITRO
    snippet: "microglial-free radical generation facilitates Mn(2+)-induced dopaminergic neurotoxicity"
    explanation: >-
      Carries the microglial oxidative output forward to dopaminergic injury, which is
      what makes this node part of the chain rather than an isolated observation.
  notes: >-
    Deliberately NOT wired to
    "parkinsonism_dopaminergic_degeneration#Mitochondrial Complex I Inhibition and
    Oxidative Stress". That module node names complex I, which is right for its MPTP
    and rotenone conformers, but the manganese literature tests complex I directly and
    excludes it: complex I substrates fail to support the effect and complex I
    inhibition does not abolish it. Declaring conformance would validate cleanly while
    asserting the wrong respiratory complex. If the module ever generalises that node
    to mitochondrial respiratory chain inhibition, revisit this.

    Kept separate from `Mitochondrial Dysfunction and Oxidative Stress` rather than
    merged into it. That node is the general claim, graded OTHER from a review
    aggregating across systems; this one is a specific in vitro result in microglia
    naming a complex. Merging them would bury the complex I exclusion the note above
    turns on.
  downstream:
  - target: Neuroinflammation
    causal_link_type: DIRECT
    description: >-
      Microglial free-radical output is one of the inputs to the glial activation
      state the neuroinflammation node describes.
- name: Neuroinflammation
  biological_scale: TISSUE
  description: >-
    Activated astrocytes and microglia releasing cytokines and nitric oxide synthase
    products into the pallidum. It is a consequence of the metal load and then an
    independent source of injury.
  biological_processes:
  - preferred_term: neuroinflammatory response
    term:
      id: GO:0150076
      label: neuroinflammatory response
    modifier: INCREASED
  downstream:
  - target: Globus Pallidus Neuronal Injury
    causal_link_type: DIRECT
    description: Inflammatory injury to pallidal neurons.
- name: Alpha-Synuclein Aggregation
  biological_scale: MOLECULAR
  description: >-
    Manganese shifts alpha-synuclein towards its aggregation-prone conformation. This
    is the point where manganism and the synucleinopathies come closest, and it is
    worth being careful: aggregation is documented in the cortex of exposed primates,
    while the human neuropathology of manganism is specifically Lewy-body negative.
    The two are compatible only if the aggregates here are not Lewy bodies.
  genes:
  - preferred_term: SNCA
    term:
      id: hgnc:11138
      label: SNCA
  biological_processes:
  - preferred_term: protein destabilization
    term:
      id: GO:0031648
      label: protein destabilization
    modifier: INCREASED
  evidence:
  - reference: PMID:40278159
    reference_title: "Manganese Neurotoxicity: A Comprehensive Review of Pathophysiology and Inherited and Acquired Disorders."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "Mn alters the structural conformation of alpha-synuclein, increasing its propensity to form oligomers."
    explanation: >-
      The conformational claim. Bound to protein destabilization rather than to
      amyloid fibril formation because the sentence describes oligomers, and GO's
      fibril term would assert a structure this source does not.
  - reference: PMID:23262390
    reference_title: Manganese exposure induces α-synuclein aggregation in the frontal cortex of non-human primates.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: MODEL_ORGANISM
    snippet: "We found increased α-syn-positive cells in the gray matter of Mn-exposed animals, typically observed in pyramidal and medium-sized neurons in deep cortical layers."
    explanation: >-
      The in vivo primate observation. Note the location is frontal cortex, not
      pallidum, which is why this node feeds the cortical branch.
  downstream:
  - target: Cortical and White Matter Injury
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The primate work shows aggregation with loss of Nissl staining; the steps from
      aggregate to cortical dysfunction are not established here.
- name: Impaired Striatal Dopamine Release
  biological_scale: CELLULAR
  description: >-
    Dopaminergic terminals that are present but underperforming. This is the finding
    that stops manganism being a simple postsynaptic story: imaging in exposed people
    and primates shows the terminals are there, while dopamine release is markedly
    reduced. A functional presynaptic deficit, not a degenerative one.
  cell_types:
  - preferred_term: dopaminergic neuron
    term:
      id: CL:0000700
      label: dopaminergic neuron
  evidence:
  - reference: PMID:23262390
    reference_title: Manganese exposure induces α-synuclein aggregation in the frontal cortex of non-human primates.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: MODEL_ORGANISM
    quote_role: BACKGROUND
    snippet: "our laboratory has demonstrated a lack of nigrostriatal dopaminergic neuron degeneration in the striatum of Mn-exposed non-human primates"
    explanation: >-
      Establishes that the terminals survive, which is what makes the release deficit a
      functional claim rather than a degenerative one. BACKGROUND because the sentence
      sits in this paper's introduction restating the group's earlier primate work, and
      INDIRECT because it reports the absence of degeneration rather than the release
      deficit itself.
  - reference: PMID:21471467
    reference_title: "Reduced uptake of [¹⁸F]FDOPA PET in asymptomatic welders with occupational manganese exposure."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Active, asymptomatic welders with Mn exposure demonstrate reduced FDOPA PET uptake indicating dysfunction in the nigrostriatal dopamine system."
    explanation: >-
      Human evidence that the presynaptic compartment is measurably affected, and
      before symptoms appear.
  - reference: PMID:21471467
    reference_title: "Reduced uptake of [¹⁸F]FDOPA PET in asymptomatic welders with occupational manganese exposure."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "This uptake pattern was anatomically reversed from the pattern found in subjects with IPD."
    explanation: >-
      The constraint on the previous item. Presynaptic involvement does not make this
      Parkinson disease; the spatial signature is the opposite one.
  downstream:
  - target: Basal Ganglia Output Failure
    causal_link_type: DIRECT
    description: Reduced dopaminergic drive on the striatal circuit.
- name: Globus Pallidus Neuronal Injury
  biological_scale: TISSUE
  description: >-
    Structural damage to the pallidum, with the internal segment preferentially
    affected, and with the substantia nigra pars compacta spared and no Lewy bodies.
    This is the neuropathological core of the disease and the fact that separates it
    from Parkinson disease.
  locations:
  - preferred_term: medial globus pallidus
    term:
      id: UBERON:0002477
      label: medial globus pallidus
  evidence:
  - reference: PMID:17882011
    reference_title: The neuropathology of manganese-induced Parkinsonism.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "They demonstrate a consistent pattern characterized by damage to the globus pallidus (particularly the internal segment) with sparing of the substantia nigra pars compacta and the absence of Lewy bodies."
    explanation: >-
      The lesion, its preferred subdivision, and the two negatives that define the
      entity. Drawn from a review of the reported pathological studies in patients and
      experimentally intoxicated primates.
  downstream:
  - target: Basal Ganglia Output Failure
    causal_link_type: DIRECT
    description: Loss of pallidal neurons disorganises basal ganglia output.
- name: Basal Ganglia Output Failure
  conforms_to: "parkinsonism_dopaminergic_degeneration#Striatal Dopamine Deficiency and Basal Ganglia Circuit Dysfunction"
  biological_scale: TISSUE
  description: >-
    The final common pathway for the motor syndrome. Because the damage is at and
    beyond the pallidum rather than upstream of the dopamine synapse, supplying more
    dopamine precursor does not restore the circuit - which is the mechanistic reason
    levodopa disappoints here.
  locations:
  - preferred_term: basal ganglion
    term:
      id: UBERON:0002420
      label: basal ganglion
  evidence:
  - reference: PMID:26608821
    reference_title: "Manganese neurotoxicity: behavioral disorders associated with dysfunctions in the basal ganglia and neurochemical transmission."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "when accumulated in the globus pallidus, Mn influences the subthalamic (STN) and substantia nigra (SN) neurons, which are at the origin of changes in the thalamus and the cortex."
    explanation: >-
      The circuit mechanism this node names: pallidal manganese acting on the
      subthalamic nucleus and substantia nigra, and through them on thalamic and
      cortical motor output. It is also the evidence behind the module conformance.
  notes: >-
    Conformance. The module node is named "Striatal Dopamine Deficiency and Basal
    Ganglia Circuit Dysfunction", and this entry argues the lesion is pallidal and
    postsynaptic with the substantia nigra pars compacta spared - so the name looks
    like it asserts what this entry denies. It does not. The module's own description
    of that node states the exception in terms: "In the dopaminergic parkinsonisms
    this circuit deficit is levodopa-responsive; manganism is a partial exception with
    predominantly pallidal pathology and poor levodopa response." The module has
    already scoped itself to include this disease, and a module's description is the
    authoritative statement of its scope.

    The dopamine half of the module node's name is carried by
    `Impaired Striatal Dopamine Release` upstream of this one, which is where the
    module's `dopamine secretion DECREASED` process belongs in this entry: manganese
    inhibits dopamine release with the terminals structurally intact. The conformance
    therefore spans two nodes here against one in the module, which is the
    organ-specific substitution the conformance mechanism is for, not a mismatch.
  downstream:
  - target: Parkinsonism
    causal_link_type: DIRECT
    description: The extrapyramidal syndrome as a whole.
  - target: Bradykinesia
    causal_link_type: DIRECT
  - target: Rigidity
    causal_link_type: DIRECT
  - target: Dystonia
    causal_link_type: DIRECT
  - target: Gait disturbance
    causal_link_type: DIRECT
  - target: Postural instability
    causal_link_type: DIRECT
  - target: Weak voice
    causal_link_type: DIRECT
  - target: Micrographia
    causal_link_type: DIRECT
  - target: Hypomimic face
    causal_link_type: DIRECT
  - target: Dysarthria
    causal_link_type: DIRECT
  - target: Tremor
    causal_link_type: DIRECT
- name: Cortical and White Matter Injury
  biological_scale: TISSUE
  description: >-
    The non-motor half of the disease, and historically the first half to appear:
    the psychiatric presentation that gave manganism its old names. Primate work puts
    manganese-induced alpha-synuclein aggregates in frontal cortex grey and white
    matter, which is a plausible substrate, though the link to the human psychiatric
    picture is not established.
  downstream:
  - target: Hallucinations
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Delusion
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Emotional lability
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Compulsive behaviors
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Cognitive impairment
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Listed as a separate edge rather than folded into the psychiatric ones because
      the cognitive deficit is reported as part of the same prodrome and has the same
      uncertain substrate.
  - target: Memory impairment
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
phenotypes:
- category: Neurological
  name: Parkinsonism
  description: >-
    The extrapyramidal syndrome as a whole. It resembles Parkinson disease closely
    enough to have been litigated as it, and differs in the features recorded on the
    individual nodes and in `differential_diagnoses:`.
  phenotype_term:
    preferred_term: Parkinsonism
    term:
      id: HP:0001300
      label: Parkinsonism
  evidence:
  - reference: PMID:28031394
    reference_title: Dose-dependent progression of parkinsonism in manganese-exposed welders.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Progression of parkinsonism increased with cumulative Mn exposure."
    explanation: >-
      The dose-response relationship, from a longitudinal cohort of 886 welding-exposed
      workers - the design that makes this a claim about exposure rather than about a
      selected clinical series.
  - reference: PMID:26608821
    reference_title: "Manganese neurotoxicity: behavioral disorders associated with dysfunctions in the basal ganglia and neurochemical transmission."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "Manganism is an extrapyramidal disorder characterized by motor disturbances associated with neuropsychiatric and cognitive disabilities similar to Parkinsonism."
    explanation: >-
      The clinical definition of the syndrome as extrapyramidal, and the statement that
      the motor disturbance travels with neuropsychiatric and cognitive features rather
      than alone.

- category: Neurological
  name: Bradykinesia
  phenotype_term:
    preferred_term: Bradykinesia
    term:
      id: HP:0002067
      label: Bradykinesia
  evidence:
  - reference: PMID:28031394
    reference_title: Dose-dependent progression of parkinsonism in manganese-exposed welders.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Exposure was most strongly associated with progression of upper limb bradykinesia, upper and lower limb rigidity, and impairment of speech and facial expression."
    explanation: >-
      Names which components of the motor examination track exposure most closely. The
      same sentence supports the rigidity and weak-voice phenotypes.
- category: Neurological
  name: Rigidity
  phenotype_term:
    preferred_term: Rigidity
    term:
      id: HP:0002063
      label: Rigidity
  evidence:
  - reference: PMID:28031394
    reference_title: Dose-dependent progression of parkinsonism in manganese-exposed welders.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Exposure was most strongly associated with progression of upper limb bradykinesia, upper and lower limb rigidity, and impairment of speech and facial expression."
    explanation: Limb rigidity among the exposure-tracking components.
- category: Neurological
  name: Dystonia
  description: >-
    Prominent enough in manganese overload that the inherited transporter defects are
    named for it. In the acquired disease it accompanies rather than replaces the
    parkinsonian features.
  phenotype_term:
    preferred_term: Dystonia
    term:
      id: HP:0001332
      label: Dystonia
  evidence:
  - reference: PMID:27231142
    reference_title: Mutations in SLC39A14 disrupt manganese homeostasis and cause childhood-onset parkinsonism-dystonia.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Excessive accumulation of manganese in these patients results in rapidly progressive childhood-onset parkinsonism-dystonia with distinctive brain magnetic resonance imaging appearances and neurodegenerative features on post-mortem examination."
    explanation: >-
      INDIRECT on purpose: this is the inherited disease, not the occupational one. It
      is cited because it isolates manganese overload as the sufficient cause of a
      parkinsonism-dystonia syndrome, with no exposure and no confounding co-exposures.
- category: Neurological
  name: Gait disturbance
  description: >-
    Usually the first motor complaint. In the high-dose methcathinone route it is
    close to universal and includes a characteristic difficulty walking backwards.
  phenotype_term:
    preferred_term: Gait disturbance
    term:
      id: HP:0001288
      label: Gait disturbance
  evidence:
  - reference: PMID:18322282
    reference_title: A Parkinsonian syndrome in methcathinone users and the role of manganese.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "At the time of neurologic evaluation, all 23 patients had gait disturbance and difficulty walking backward"
    explanation: All 23 patients in the series, and the retropulsion that goes with it.
- category: Neurological
  name: Postural instability
  phenotype_term:
    preferred_term: Postural instability
    term:
      id: HP:0002172
      label: Postural instability
  evidence:
  - reference: PMID:18322282
    reference_title: A Parkinsonian syndrome in methcathinone users and the role of manganese.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "At the time of neurologic evaluation, all 23 patients had gait disturbance and difficulty walking backward"
    explanation: >-
      INDIRECT because difficulty walking backward is retropulsion, which is a sign of
      postural instability rather than the phenotype term itself; the inference is one
      step.
- category: Neurological
  name: Weak voice
  description: Hypophonia, sometimes progressing to mutism in the heaviest exposures.
  phenotype_term:
    preferred_term: hypophonia
    term:
      id: HP:0001621
      label: Weak voice
  evidence:
  - reference: PMID:28031394
    reference_title: Dose-dependent progression of parkinsonism in manganese-exposed welders.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Exposure was most strongly associated with progression of upper limb bradykinesia, upper and lower limb rigidity, and impairment of speech and facial expression."
    explanation: >-
      INDIRECT: the cohort records impairment of speech, which is broader than
      hypophonia specifically.
- category: Neurological
  name: Micrographia
  description: >-
    Recorded here mainly because it is the outcome measure in the PAS follow-up case,
    where handwriting is what recovered.
  phenotype_term:
    preferred_term: Micrographia
    term:
      id: HP:0031908
      label: Micrographia
  evidence:
  - reference: PMID:16766929
    reference_title: "Effective treatment of manganese-induced occupational Parkinsonism with p-aminosalicylic acid: a case of 17-year follow-up study."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "At the end of PAS treatment, her symptoms were significantly alleviated, and handwriting recovered to normal."
    explanation: >-
      INDIRECT: recovery of handwriting implies the deficit, which the case describes
      rather than codes.
- category: Cognitive
  name: Cognitive impairment
  description: >-
    Reported as part of the prodrome rather than as a late consequence, which is what
    makes it mechanistically interesting: the cognitive and psychiatric disturbance
    characteristically arrives before the movement disorder that gets the disease its
    name.
  phenotype_term:
    preferred_term: Cognitive impairment
    term:
      id: HP:0100543
      label: Cognitive impairment
  evidence:
  - reference: PMID:33911374
    reference_title: "Inherited Manganese Disorders and the Brain: What Neurologists Need to Know."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "The symptoms include initial cognitive and psychiatric disturbances followed by a movement disorder resembling Parkinson's disease with limb rigidity, dystonia, and a characteristic high-stepping gait."
    explanation: >-
      States the order explicitly - cognitive and psychiatric disturbance first, the
      movement disorder after.
  - reference: PMID:26154659
    reference_title: "Manganese-Induced Parkinsonism and Parkinson's Disease: Shared and Distinguishable Features."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Patients occupationally exposed to excessive levels of Mn demonstrate a biphasic mode of physical decline comprising an initial phase of psychiatric abnormalities including emotional disturbance, memory loss, compulsive behavior, visual impairments, illusions and delusions, disorientation"
    explanation: >-
      Names disorientation and memory loss as components of the initial phase,
      INDIRECT because the sentence lists the deficits rather than using the term
      cognitive impairment.
- category: Cognitive
  name: Memory impairment
  phenotype_term:
    preferred_term: Memory impairment
    term:
      id: HP:0002354
      label: Memory impairment
  evidence:
  - reference: PMID:26154659
    reference_title: "Manganese-Induced Parkinsonism and Parkinson's Disease: Shared and Distinguishable Features."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Patients occupationally exposed to excessive levels of Mn demonstrate a biphasic mode of physical decline comprising an initial phase of psychiatric abnormalities including emotional disturbance, memory loss, compulsive behavior, visual impairments, illusions and delusions, disorientation"
    explanation: >-
      Names memory loss directly, among the first-phase deficits.
- category: Behavioral
  name: Compulsive behaviors
  phenotype_term:
    preferred_term: Compulsive behaviors
    term:
      id: HP:0000722
      label: Compulsive behaviors
  evidence:
  - reference: PMID:26154659
    reference_title: "Manganese-Induced Parkinsonism and Parkinson's Disease: Shared and Distinguishable Features."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Patients occupationally exposed to excessive levels of Mn demonstrate a biphasic mode of physical decline comprising an initial phase of psychiatric abnormalities including emotional disturbance, memory loss, compulsive behavior, visual impairments, illusions and delusions, disorientation"
    explanation: >-
      Names compulsive behavior directly.
- category: Psychiatric
  name: Delusion
  description: >-
    The florid end of the prodrome, and the source of the disease's older names. It
    sits beside `Hallucinations` rather than replacing it: the cited sentence names
    delusions, while the hallucination claim still rests on a source that says
    "psychiatric symptoms" without naming them.
  phenotype_term:
    preferred_term: Delusion
    term:
      id: HP:0000746
      label: Delusion
  evidence:
  - reference: PMID:26154659
    reference_title: "Manganese-Induced Parkinsonism and Parkinson's Disease: Shared and Distinguishable Features."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Patients occupationally exposed to excessive levels of Mn demonstrate a biphasic mode of physical decline comprising an initial phase of psychiatric abnormalities including emotional disturbance, memory loss, compulsive behavior, visual impairments, illusions and delusions, disorientation"
    explanation: >-
      Names illusions and delusions directly among the first-phase abnormalities.
- category: Psychiatric
  name: Hallucinations
  description: >-
    Part of the neuropsychiatric prodrome that historically preceded the motor
    syndrome and gave manganism its older names. MONDO's own definition lists
    confusion and hallucinations before the extrapyramidal features.
  phenotype_term:
    preferred_term: Hallucinations
    term:
      id: HP:0000738
      label: Hallucinations
  evidence:
  - reference: PMID:23262390
    reference_title: Manganese exposure induces α-synuclein aggregation in the frontal cortex of non-human primates.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "Occupational and environmental exposure to manganese (Mn) is associated with a neurological syndrome consisting of psychiatric symptoms, cognitive impairment and parkinsonism."
    explanation: >-
      Establishes the psychiatric component of the human syndrome. BACKGROUND because
      the sentence frames a primate study, HUMAN_CLINICAL because what it describes is
      the human occupational picture, and INDIRECT because it says "psychiatric
      symptoms" rather than naming hallucinations.
- category: Psychiatric
  name: Emotional lability
  phenotype_term:
    preferred_term: Emotional lability
    term:
      id: HP:0000712
      label: Emotional lability
  evidence:
  - reference: PMID:23262390
    reference_title: Manganese exposure induces α-synuclein aggregation in the frontal cortex of non-human primates.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "Occupational and environmental exposure to manganese (Mn) is associated with a neurological syndrome consisting of psychiatric symptoms, cognitive impairment and parkinsonism."
    explanation: >-
      The general framing of the psychiatric component. INDIRECT because the sentence
      says "psychiatric symptoms" rather than naming emotional lability; the item below
      is the one that names it.
  - reference: PMID:26154659
    reference_title: "Manganese-Induced Parkinsonism and Parkinson's Disease: Shared and Distinguishable Features."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Patients occupationally exposed to excessive levels of Mn demonstrate a biphasic mode of physical decline comprising an initial phase of psychiatric abnormalities including emotional disturbance, memory loss, compulsive behavior, visual impairments, illusions and delusions, disorientation"
    explanation: >-
      Names emotional disturbance directly, among the first-phase abnormalities.
- category: Neurological
  name: Hypomimic face
  description: >-
    Masked facies. Reported directly in exposed workers rather than inferred from the
    general parkinsonian picture, which is why it is curated separately from the
    bradykinesia it accompanies.
  phenotype_term:
    preferred_term: masked facies
    term:
      id: HP:0000338
      label: Hypomimic face
  evidence:
  - reference: PMID:42563869
    reference_title: Manganese Neurotoxicity and Familial Disorders of Manganese Transport.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "The affected workers exhibited various symptoms of parkinsonism, including progressive lower extremity weakness, masked facies, and whispering speech."
    explanation: >-
      Names masked facies in occupationally exposed workers, which is this entry's
      population rather than the inherited one.
- category: Neurological
  name: Dysarthria
  description: >-
    Impaired articulation, distinct from the reduced volume recorded as Weak voice.
    The evidence here is weaker than for the other motor features and the entry says
    so: the occupational cohorts record "impairment of speech" without separating
    articulation from volume, and the one source that names dysarthria outright is
    describing the inherited childhood form.
  phenotype_term:
    preferred_term: Dysarthria
    term:
      id: HP:0001260
      label: Dysarthria
  evidence:
  - reference: PMID:28031394
    reference_title: Dose-dependent progression of parkinsonism in manganese-exposed welders.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Exposure was most strongly associated with progression of upper limb bradykinesia, upper and lower limb rigidity, and impairment of speech and facial expression."
    explanation: >-
      INDIRECT, and deliberately the same grading this sentence carries on Weak voice:
      the cohort measured speech impairment as one UPDRS item and did not distinguish
      dysarthria from hypophonia.
  - reference: PMID:42563869
    reference_title: Manganese Neurotoxicity and Familial Disorders of Manganese Transport.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "with childhood onset of progressive dystonia of the limbs and tongue and exhibit a distinctive “cock‐walk” gait, decreased manual dexterity, and dysarthria."
    explanation: >-
      The only cached sentence naming dysarthria as such, and it describes the
      inherited transporter defect rather than occupational manganism - cited the way
      the Dystonia phenotype cites its inherited-form evidence, as a cross-form
      inference and not as a finding in this population.
- category: Neurological
  name: Tremor
  description: >-
    Present, but not the tremor of Parkinson disease. Where manganism tremor is
    described it is a rapid postural tremor; resting tremor is specifically reported
    as not characteristic, and that asymmetry is one of the discriminators the
    differential leans on. One review states flatly that patients with manganism have
    no tremor at all, which is recorded here as a REFUTE rather than reconciled - see
    the `tremor_in_manganism` discussion.
  phenotype_term:
    preferred_term: rapid postural tremor
    term:
      id: HP:0001337
      label: Tremor
  evidence:
  - reference: PMID:26154659
    reference_title: "Manganese-Induced Parkinsonism and Parkinson's Disease: Shared and Distinguishable Features."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "The motor impairments include hypertonia with cogwheel rigidity, bradykinesia, “cock-gait”, rapid postural tremor, and tendency to fall when walking backwards"
    explanation: >-
      Characterises the tremor as postural, which is what `preferred_term` records
      while the binding stays at the generic HP term.
  - reference: PMID:40278159
    reference_title: "Manganese Neurotoxicity: A Comprehensive Review of Pathophysiology and Inherited and Acquired Disorders."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Tremors during rest were not a distinguishing feature, which is commonly observed during PD."
    explanation: >-
      The negative half, and the one that matters for the differential: resting tremor
      is a Parkinson disease feature, not a manganism one. INDIRECT because the
      sentence denies one kind of tremor rather than asserting another - the postural
      character recorded in `preferred_term` follows by an inference step, from this
      exclusion plus the positive statement in the item above it. The two items below
      carry the presence claim and the flat denial.
  - reference: PMID:42563869
    reference_title: Manganese Neurotoxicity and Familial Disorders of Manganese Transport.
    supports: REFUTE
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Specifically, patients with manganism have no tremor but do exhibit dystonia, a “cock‐gait” walk, and, importantly, minimal or no response to levodopa"
    explanation: >-
      A REFUTE against curating tremor as a feature at all. Recorded rather than
      resolved: the cached reviews disagree, and this entry does not have the evidence
      to say which is right.
biochemical:
- name: Whole-blood manganese
  presence: Increased
  context: >-
    Confirms ongoing exposure. It is a poor guide to brain burden, because blood
    manganese falls after exposure stops while the pallidal deposit and the symptoms
    persist.
  biomarker_term:
    preferred_term: Manganese
    term:
      id: NCIT:C624
      label: Manganese
  reference_ranges:
  - upper_bound: 209.0
    unit: nmol/L
    population: laboratory reference used in the Latvian methcathinone series
    notes: >-
      A one-sided interval: the cited paper gives the upper limit of normal and no
      lower bound, so none is asserted. `loinc_term` is omitted because LOINC has no
      adapter in `conf/oak_config.yaml` and no `cache/` membership file, so a LOINC
      code here could not be validated by anything in the repository. The interval is
      that one laboratory's, not a consensus value, which is what `population` records.
    evidence:
    - reference: PMID:18322282
      reference_title: A Parkinsonian syndrome in methcathinone users and the role of manganese.
      supports: SUPPORT
      directness: DIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: "Whole-blood manganese levels (normal level, <209 nmol per liter) averaged 831 nmol per liter (range, 201 to 2102) in the active methcathinone users and 346 nmol per liter (range, 114 to 727) in former users."
      explanation: >-
        Gives the reference threshold and, in the same sentence, the fall between
        active and former users that limits the test's value after exposure ends.
    interpretation_bands:
    - name: Within the laboratory reference interval
      upper_bound: 209.0
      unit: nmol/L
      abnormal_flag: NORMAL
      interpretation: >-
        Does not exclude manganism in someone whose exposure has ceased.
    - name: Elevated
      lower_bound: 209.0
      unit: nmol/L
      abnormal_flag: HIGH
      phenotype_term:
        preferred_term: elevated whole-blood manganese
        term:
          id: HP:0032097
          label: Hypermanganesemia
      interpretation: >-
        Consistent with current or recent exposure. In the cited series active users
        averaged 831 nmol/L and former users 346 nmol/L, so an elevated value does not
        by itself date the exposure.
environmental:
- name: Occupational inhalation of manganese-containing welding fume or ore dust
  description: >-
    The classical route and the one MONDO's definition is written around: welding,
    mining, ore processing, battery manufacture, ferromanganese smelting. What makes
    inhalation special is not the dose but the anatomy - it delivers manganese to the
    blood without the gut absorption control and hepatobiliary first-pass that handle
    dietary intake.
  exposure_term:
    preferred_term: exposure to welding fume
    term:
      id: ECTO:7000129
      label: exposure to welding fume
  influences_mechanisms:
  - target: Chronic Manganese Overexposure
    environmental_effect: TRIGGERS
    causal_link_type: DIRECT
    description: >-
      Sustained inhalation is the route by which the occupational body burden is
      established.
    evidence:
    - reference: PMID:26154659
      reference_title: "Manganese-Induced Parkinsonism and Parkinson's Disease: Shared and Distinguishable Features."
      supports: SUPPORT
      directness: DIRECT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: "greater than 90% of the Mn containing welding aerosols can be deposited in the lungs due to their small particulate size"
      explanation: >-
        Quantifies pulmonary deposition, which is what makes this exposure route
        efficient enough to cause disease.
  evidence:
  - reference: PMID:28031394
    reference_title: Dose-dependent progression of parkinsonism in manganese-exposed welders.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Progression of parkinsonism increased with cumulative Mn exposure."
    explanation: >-
      The exposure-response relationship in welders, which is the strongest available
      evidence that this route causes the disease rather than merely accompanying it.
  - reference: PMID:20012385
    reference_title: "From manganism to manganese-induced parkinsonism: a conceptual model based on the evolution of exposure."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "Manganese exposure scenarios in the last century generally have changed from the acute, high-level exposure conditions responsible for the occurrence of manganism to chronic exposure to much lower levels."
    explanation: >-
      Records that the occupational exposure profile has shifted over a century, from
      the acute high-level conditions that produced classical manganism to chronic
      low-level exposure. It is why contemporary series look different from the
      historical ones this entry's description alludes to.
  notes: >-
    Bound to ECTO:7000129 exposure to welding fume rather than to the generic
    ECTO:9000946 exposure to manganese, because the fume is what the worker is exposed
    to and the particle size is mechanistically load-bearing here. Searched the pinned
    local build with `uv run runoak -i sqlite:obo:ecto search` for `l~manganese`,
    `l~welding` and `l~fume` on 2026-09-20; `l~manganese` returns ECTO:9000946
    exposure to manganese, ECTO:9000179 exposure to manganese cation and ECTO:9001154
    exposure to elemental manganese, and `l~welding` returns ECTO:7000129 alone. The
    generic manganese term is used on the non-occupational routes below, where no fume
    is involved.
- name: Intravenous methcathinone (ephedrone) prepared with potassium permanganate
  description: >-
    A drug-preparation route rather than an industrial one, and the highest-dose human
    exposure on record. Home synthesis of methcathinone oxidises ephedrine with
    potassium permanganate and the manganese goes into the product, which is then
    injected. It produces the same syndrome faster and more severely, and it is the
    setting in which the imaging and levodopa-response evidence is clearest.
  exposure_term:
    preferred_term: intravenous exposure to manganese in home-synthesised methcathinone
    term:
      id: ECTO:9000946
      label: exposure to manganese
  influences_mechanisms:
  - target: Systemic Manganese Overload
    environmental_effect: TRIGGERS
    causal_link_type: DIRECT
    description: >-
      Injection puts manganese directly into the blood, bypassing every absorptive and
      first-pass control at once.
    evidence:
    - reference: PMID:40278159
      reference_title: "Manganese Neurotoxicity: A Comprehensive Review of Pathophysiology and Inherited and Acquired Disorders."
      supports: SUPPORT
      directness: DIRECT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: "Drug abuse has recently become a recognized cause of Mn toxicity since abusers of methcathinone may be exposed to Mn due to the use of potassium permanganate in the synthesis process"
      explanation: Names the route and the chemistry that puts manganese in the drug.
  evidence:
  - reference: PMID:18322282
    reference_title: A Parkinsonian syndrome in methcathinone users and the role of manganese.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "The neurologic deficits did not resolve after patients discontinued methcathinone use."
    explanation: >-
      The irreversibility of this route's damage, in a 23-patient series followed after
      cessation.
- name: Parenteral nutrition and chronic liver failure
  description: >-
    Overload without overexposure. Parenteral nutrition delivers manganese past the gut
    and liver; chronic liver failure leaves ordinary intake with nowhere to go, since
    bile is the excretory route. Both produce pallidal accumulation and the T1 imaging
    signature in people who have never been near a welding torch.
  exposure_term:
    preferred_term: parenteral and retained dietary exposure to manganese
    term:
      id: ECTO:9000946
      label: exposure to manganese
  influences_mechanisms:
  - target: Impaired Hepatobiliary Manganese Excretion
    environmental_effect: TRIGGERS
    causal_link_type: DIRECT
    description: >-
      Both settings act by defeating biliary clearance rather than by raising intake.
    evidence:
    - reference: PMID:26154659
      reference_title: "Manganese-Induced Parkinsonism and Parkinson's Disease: Shared and Distinguishable Features."
      supports: SUPPORT
      directness: DIRECT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: "Mn-induced parkinsonism may occur in patients with chronic liver failure who fail to adequately excrete Mn in bile"
      explanation: The excretory-failure route, stated directly.
  evidence:
  - reference: PMID:8622451
    reference_title: Manganese toxicity in children receiving long-term parenteral nutrition.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "In patients receiving long-term parenteral nutrition (PN), cholestatic disease and nervous system disorders have been associated with high blood concentrations of manganese."
    explanation: >-
      The parenteral-nutrition route in children, where the normal homeostatic
      mechanisms are bypassed by design.
treatments:
- name: Removal from Exposure
  description: >-
    The only intervention with an unambiguous rationale, and the reason occupational
    hygiene rather than neurology is where this disease is won. It does not reliably
    reverse established damage - the two cached series that followed
    patients after cessation report non-resolution and, in one, progression through the
    first decade - but it stops the burden rising, and it is the one step available before symptoms
    appear.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: removal from manganese exposure
    term:
      id: NCIT:C15843
      label: Preventive Intervention
  target_mechanisms:
  - target: Chronic Manganese Overexposure
    treatment_effect: INHIBITS
    description: Ends the input to the system rather than acting on the lesion.
  evidence:
  - reference: PMID:42563869
    reference_title: Manganese Neurotoxicity and Familial Disorders of Manganese Transport.
    supports: REFUTE
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Despite a cessation of exposure, their symptoms, which did not have a sustained response to levodopa, were progressive over the first decade and then plateaued"
    explanation: >-
      Recorded as a REFUTE against the expectation that removal from exposure is
      curative. It supports removal as prevention and refutes it as treatment, which is
      exactly the distinction this treatment's description makes.
  - reference: PMID:7936281
    reference_title: "Levodopa failure in chronic manganism."
    supports: REFUTE
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "Their parkinsonism and dystonia had progressed slowly over a period of 5 years after they left the site of exposure."
    explanation: >-
      The second of the two cached series, and a primary observation rather than a
      review's summary: parkinsonism and dystonia progressed over five years after the
      patients left the exposure site. REFUTE for the same reason as the item above -
      it refutes removal as a cure while leaving it necessary as prevention.
  notes: >-
    Bound to NCIT:C15843 Preventive Intervention. NCIT has no clinical-action term for
    removal from an occupational exposure; `ancestors -p i` confirms C15843 reaches
    NCIT:C25218, so it is inside the TreatmentActionTerm root, and the specificity is
    carried in the name and preferred_term.
- name: Calcium Disodium Edetate Chelation
  description: >-
    The standard chelator, and a treatment whose evidence base sits mostly in the
    inherited disease rather than the occupational one. It lowers blood manganese; it
    does not cross the blood-brain barrier well, which is the usual explanation for why
    the biochemical response outruns the clinical one in established manganism.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: calcium disodium edetate
      term:
        id: CHEBI:4757
        label: EDTA monocalcium diisodium salt
  target_mechanisms:
  - target: Systemic Manganese Overload
    treatment_effect: INHIBITS
    description: Complexes circulating manganese and promotes its excretion.
  evidence:
  - reference: PMID:27231142
    reference_title: Mutations in SLC39A14 disrupt manganese homeostasis and cause childhood-onset parkinsonism-dystonia.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Chelation with disodium calcium edetate lowers blood manganese levels in patients and can lead to striking clinical improvement."
    explanation: >-
      The clearest efficacy statement available, and it is from the inherited disease -
      hence INDIRECT. Transferring it to occupational manganism is an inference, not a
      finding, and the treatment description says so.
  notes: >-
    Bound to CHEBI:4757 rather than to NCIT:C334 Edetate Calcium Disodium. The
    deep-research report recommended NCIT:C334, but `ancestors -p i` shows it reaches
    neither NCIT:C25218 nor NCIT:C1909, so it is outside the ChemicalEntityTerm root
    that therapeutic_agent requires; CHEBI:4757 is the same substance and validates.
- name: Sodium Para-Aminosalicylic Acid
  description: >-
    The one agent with a positive long-term clinical report in occupational manganism,
    and the mechanistic argument for it is that it crosses into the brain where EDTA
    does not. The human evidence is a single case with 17-year follow-up, which is a
    strong observation and a weak study design at the same time.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: sodium para-aminosalicylic acid
      term:
        id: CHEBI:27565
        label: 4-aminosalicylic acid
  target_mechanisms:
  - target: Pallidal Manganese Accumulation
    treatment_effect: INHIBITS
    description: >-
      Unlike EDTA, reaches the compartment where the metal actually sits.
    evidence:
    - reference: PMID:38909920
      reference_title: "Treatment of manganese and lead poisoning with sodium para-aminosalicylic acid: A contemporary update."
      supports: SUPPORT
      directness: DIRECT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      snippet: "PAS-Na can readily pass through the blood-brain barrier (BBB), and complex and facilitate the excretion of manganese and lead"
      explanation: >-
        The pharmacokinetic property that distinguishes it from EDTA. Graded OTHER
        because the review aggregates experimental and clinical work without naming a
        study type for this claim.
  evidence:
  - reference: PMID:16766929
    reference_title: "Effective treatment of manganese-induced occupational Parkinsonism with p-aminosalicylic acid: a case of 17-year follow-up study."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "At the end of PAS treatment, her symptoms were significantly alleviated, and handwriting recovered to normal."
    explanation: >-
      The clinical result, in one patient with 21 years of airborne exposure, followed
      for 17 years after treatment.
- name: Levodopa Trial
  description: >-
    Included because its failure is diagnostically informative rather than because it
    works. A patient whose parkinsonism is manganese-related characteristically does
    not respond, and that non-response has been used as a discriminating criterion
    against Parkinson disease. The mechanism predicts it: the lesion is at and beyond
    the pallidum, so replenishing the dopamine precursor does not reach the problem.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: levodopa
      term:
        id: CHEBI:15765
        label: L-dopa
  target_mechanisms:
  - target: Basal Ganglia Output Failure
    treatment_effect: MODULATES
    description: >-
      Attempts to restore dopaminergic drive to a circuit whose lesion is downstream of
      it, which is why the attempt usually fails.
    evidence:
    - reference: PMID:7936281
      reference_title: "Levodopa failure in chronic manganism."
      supports: REFUTE
      directness: DIRECT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: "This short-term, double-blind study indicates that their parkinsonism and dystonia failed to respond to levodopa."
      explanation: >-
        A REFUTE recorded on the mechanism link rather than omitted, because the failure
        is the diagnostically informative part. This is the only placebo-controlled
        evidence on the question in the entry; the two items below are reviews restating
        it.
  evidence:
  - reference: PMID:40278159
    reference_title: "Manganese Neurotoxicity: A Comprehensive Review of Pathophysiology and Inherited and Acquired Disorders."
    supports: REFUTE
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Another main difference is the treatment response to levodopa, manganism does not respond to levodopa given the absence of primary involvement of the substantia nigra."
    explanation: >-
      REFUTE against levodopa as an effective therapy here, and it supplies the
      mechanistic reason this entry's pathograph encodes.
  - reference: PMID:26154659
    reference_title: "Manganese-Induced Parkinsonism and Parkinson's Disease: Shared and Distinguishable Features."
    supports: REFUTE
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Mn-induced parkinsonism patients regardless of the dose of levodopa administered are unresponsive to levodopa treatment"
    explanation: >-
      A second review stating the non-response is dose-independent, which closes off
      the "not enough drug" reading.
- name: Iron Supplementation
  description: >-
    Adjunctive, and mechanistically the neatest intervention in the entry: manganese
    rides the iron transporters, so raising iron status competes it off them. That is
    the same DMT1 iron-dependence this entry's transport node records, read backwards
    as a therapy. The evidence is a review's treatment recommendation rather than a
    trial, and the clearest demonstrations are in the inherited transporter defects.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: oral iron supplementation
    term:
      id: NCIT:C15433
      label: Nutritional Support
    therapeutic_agent:
    - preferred_term: iron
      term:
        id: CHEBI:29033
        label: iron(2+)
  target_mechanisms:
  - target: Manganese Transport Across the Blood-Brain Barrier
    treatment_effect: INHIBITS
    description: >-
      Competes with manganese for the shared divalent-metal carriers rather than
      binding the metal already deposited.
    evidence:
    - reference: PMID:40278159
      reference_title: "Manganese Neurotoxicity: A Comprehensive Review of Pathophysiology and Inherited and Acquired Disorders."
      supports: SUPPORT
      directness: DIRECT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      snippet: "Interestingly, iron supplementation may lower Mn concentration by competing for the same transport mechanism."
      explanation: >-
        States the competition mechanism explicitly, and it is the mirror image of the
        iron-deficiency susceptibility recorded on the transport node.
  evidence:
  - reference: PMID:40278159
    reference_title: "Manganese Neurotoxicity: A Comprehensive Review of Pathophysiology and Inherited and Acquired Disorders."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "The cornerstone of treatment involves chelation therapy using intravenous disodium calcium edetate (EDTA-CaNa2) and iron supplementation."
    explanation: >-
      Places iron supplementation alongside chelation as standard management.
  - reference: PMID:42563869
    reference_title: Manganese Neurotoxicity and Familial Disorders of Manganese Transport.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "These latter two disorders are treatable, and the early recognition and institution of chelation therapy and iron supplementation can improve neurological disability."
    explanation: >-
      INDIRECT because "these latter two disorders" are the inherited transporter
      defects, not occupational manganism; cited for the efficacy signal, with the
      population difference stated rather than elided.
  notes: >-
    Bound to NCIT:C15433 Nutritional Support with the agent in therapeutic_agent, and
    tagged SMALL_MOLECULE rather than BEHAVIORAL. CLAUDE.md warns specifically against
    reading C15433 as a diet-pattern change when it in fact names a chemical, which is
    the case here.

    NCIT:C210688 Iron Supplement exists and looks like the obvious agent term, but it
    fits neither slot. Checked against the pinned local build on 2026-09-20 with
    `uv run runoak -i sqlite:obo:ncit ancestors -p i NCIT:C210688`, which returns
    exactly three rows: NCIT:C1505 Dietary Supplement, NCIT:C1908 Drug, Food, Chemical
    or Biomedical Material, and the term itself. NCIT:C1908 is the *parent* of
    NCIT:C1909 Pharmacologic Substance rather than a descendant of it, so C210688 sits
    on a sibling branch just outside the ChemicalEntityTerm root, and it is nowhere
    near NCIT:C25218. CHEBI:29033 fits. The command is recorded because this is a
    negative-existence claim, which no gate can check.
diagnosis:
- name: Brain MRI with T1-weighted sequences
  description: >-
    The most direct test available, in the literal sense: manganese is paramagnetic, so
    the accumulated metal is what generates the signal. Symmetric pallidal T1
    hyperintensity without gadolinium is the finding. It reports body burden rather than
    disease, and the two come apart - the signal tracks ongoing exposure, and it fades
    after exposure stops while symptoms do not.
  diagnosis_term:
    preferred_term: T1-weighted brain magnetic resonance imaging
    term:
      id: NCIT:C16809
      label: Magnetic Resonance Imaging
  evidence:
  - reference: PMID:17159105
    reference_title: Brain metal concentrations in chronic liver failure patients with pallidal T1 MRI hyperintensity.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Pallidal MRI T1 hyperintensity is a biomarker of manganese overload."
    explanation: The study's own conclusion, and the basis for using the sign this way.
  - reference: PMID:17159105
    reference_title: Brain metal concentrations in chronic liver failure patients with pallidal T1 MRI hyperintensity.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "In patients with pallidal T1 hyperintensity, pallidal manganese concentrations were increased sevenfold over controls and over fourfold vs liver patients with normal MRI"
    explanation: >-
      Direct tissue validation of the imaging sign: the signal tracks measured pallidal
      manganese, not a proxy for it.
  - reference: PMID:17127642
    reference_title: Changes in blood manganese concentration and MRI t1 relaxation time during 180 days of stainless steel welding-fume exposure in cynomolgus monkeys.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: MODEL_ORGANISM
    snippet: "These data suggested that prolonged inhalation of welding fumes induces a high MRI T1 signal intensity with an elevation of the blood manganese level."
    explanation: >-
      Shows the signal rising with ongoing exposure, which is the basis for reading it
      as a burden measure. MODEL_ORGANISM because this is six cynomolgus monkeys in an
      inhalation chamber, not the welders the title's phrasing might suggest.
  notes: >-
    Bound to the generic NCIT:C16809 Magnetic Resonance Imaging. NCIT's brain-specific
    MRI terms are contrast-qualified (NCIT:C137874 without contrast, NCIT:C137913 with
    and without), and this finding is a plain unenhanced T1 sequence, so neither is a
    better fit than the parent; `ancestors -p i` confirms C16809 reaches NCIT:C25218.
- name: Whole-blood manganese concentration
  description: >-
    Confirms exposure and is a poor guide to brain burden, because manganese leaves the
    blood quickly while the pallidal load persists. Most useful when it is high in
    someone still being exposed, and close to useless as a negative test in someone
    who has stopped.
  diagnosis_term:
    preferred_term: whole-blood manganese measurement
    term:
      id: NCIT:C217390
      label: Diagnostic Blood Testing
  evidence:
  - reference: PMID:18322282
    reference_title: A Parkinsonian syndrome in methcathinone users and the role of manganese.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Whole-blood manganese levels (normal level, <209 nmol per liter) averaged 831 nmol per liter (range, 201 to 2102) in the active methcathinone users and 346 nmol per liter (range, 114 to 727) in former users."
    explanation: >-
      Gives the reference threshold and shows the fall after exposure ends - the
      behaviour that limits the test's value in a former user.
- name: Levodopa response as a discriminating test
  description: >-
    Not a test of manganese but of the alternative. A convincing sustained response to
    levodopa argues for Parkinson disease; its absence is one of the features that
    supports manganese-related parkinsonism instead.
  diagnosis_term:
    preferred_term: therapeutic trial of levodopa
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  evidence:
  - reference: PMID:40496384
    reference_title: "Manganese-Induced Parkinsonism: A Review of Etiologies and Treatments."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "A diagnostic criterion for manganese poisoning has been the effectiveness of levodopa in which there is not supposed to be a significant response."
    explanation: >-
      States the diagnostic use of the non-response explicitly, which is what justifies
      recording a failed treatment in the diagnosis section.
differential_diagnoses:
- name: Parkinson disease
  description: >-
    The differential that matters, and the one that has been litigated. Against it:
    the pallidal rather than nigral lesion, absent Lewy bodies, poor levodopa response,
    more dystonia, less resting tremor, and the reversed FDOPA pattern. For it: both
    produce bradykinesia and rigidity in a middle-aged worker, and welding is common.
  disease_term:
    preferred_term: Parkinson disease
    term:
      id: MONDO:0005180
      label: Parkinson disease
  evidence:
  - reference: PMID:17882011
    reference_title: The neuropathology of manganese-induced Parkinsonism.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "These pathologic findings do not support the notion that manganese causes PD but rather argues that manganese-induced parkinsonism and PD are distinct and separate disease entities."
    explanation: >-
      The explicit statement that these are two diseases, from the review of the
      pathological series.
  - reference: PMID:20012385
    reference_title: "From manganism to manganese-induced parkinsonism: a conceptual model based on the evolution of exposure."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "Manganism is a distinct medical condition from Parkinson's disease."
    explanation: >-
      The same conclusion reached from the exposure side rather than the neuropathology,
      so the separation does not rest on one line of argument.
- name: Hypermanganesemia with dystonia 1
  description: >-
    Autosomal recessive SLC30A10 deficiency: the manganese efflux transporter fails, so
    the metal accumulates without any exposure. Distinguished from the acquired disease
    by childhood onset and by liver cirrhosis and polycythemia, which occupational
    manganism does not produce.
  disease_term:
    preferred_term: cirrhosis - dystonia - polycythemia - hypermanganesemia syndrome
    term:
      id: MONDO:0013208
      label: cirrhosis - dystonia - polycythemia - hypermanganesemia syndrome
  evidence:
  - reference: PMID:22341972
    reference_title: "Syndrome of hepatic cirrhosis, dystonia, polycythemia, and hypermanganesemia caused by mutations in SLC30A10, a manganese transporter in man."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "this work has confirmed that SLC30A10 functions as a Mn transporter in humans that, when defective, causes Mn accumulation in liver and brain"
    explanation: >-
      Establishes the inherited entity and, incidentally, the strongest human evidence
      that manganese overload by itself is sufficient to produce this pathology.
- name: Hypermanganesemia with dystonia 2
  description: >-
    Autosomal recessive SLC39A14 deficiency. Rapidly progressive childhood
    parkinsonism-dystonia without the liver disease or polycythemia of HMNDYT1, and the
    one manganese disorder where chelation has a clear clinical payoff.
  disease_term:
    preferred_term: hypermanganesemia with dystonia 2
    term:
      id: MONDO:0014864
      label: hypermanganesemia with dystonia 2
  evidence:
  - reference: PMID:27231142
    reference_title: Mutations in SLC39A14 disrupt manganese homeostasis and cause childhood-onset parkinsonism-dystonia.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Excessive accumulation of manganese in these patients results in rapidly progressive childhood-onset parkinsonism-dystonia with distinctive brain magnetic resonance imaging appearances and neurodegenerative features on post-mortem examination."
    explanation: Defines the entity and its tempo.
genetic:
- name: SLC30A10
  gene_term:
    preferred_term: SLC30A10
    term:
      id: hgnc:25355
      label: SLC30A10
  relationship_type: MODIFIER
  notes: >-
    Listed as a modifier of susceptibility rather than as a cause of this entry's
    disease. Biallelic loss causes the separate inherited disorder MONDO:0013208; the
    gene appears here because it encodes the manganese efflux transporter whose
    capacity sets how much of an environmental dose a person retains. No cached source
    in this entry establishes that common SLC30A10 variation modifies occupational
    manganism risk, so this is a mechanistic annotation, not an association claim.
  evidence:
  - reference: PMID:22341972
    reference_title: "Syndrome of hepatic cirrhosis, dystonia, polycythemia, and hypermanganesemia caused by mutations in SLC30A10, a manganese transporter in man."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "this work has confirmed that SLC30A10 functions as a Mn transporter in humans that, when defective, causes Mn accumulation in liver and brain"
    explanation: >-
      Establishes the transporter's function in humans. INDIRECT with respect to the
      acquired disease, which is the point of the note above.
discussions:
- discussion_id: alpha_synuclein_in_human_manganism
  kind: HUMAN_MODEL_MISMATCH
  prompt: >-
    Manganese induces alpha-synuclein aggregation in exposed primates, and human
    manganese overload is characterised by negative alpha-synuclein immunostaining.
    Does the primate finding describe anything that happens in human manganism?
  rationale: >-
    The mismatch is sharp rather than gradual. In Mn-exposed cynomolgus macaques,
    alpha-synuclein-positive neurons and glia appear in frontal cortex grey and white
    matter. In humans with pallidal manganese accumulation measured directly at
    autopsy, alpha-synuclein immunostaining was negative in all but one case, and the
    defining neuropathology of manganism is the absence of Lewy bodies. Both cannot be
    generalised. Possible reconciliations: the primate aggregates are a different
    species of assembly from Lewy pathology; the cortical location differs from the
    pallidal region sampled in the human series; or the primate exposure regimen
    produces something the human occupational one does not. This matters because
    alpha-synuclein is the bridge people use to argue that manganese exposure causes
    Parkinson disease, and the human pathology is the main evidence against that.
  attaches_to:
  - pathophysiology#Alpha-Synuclein Aggregation
  evidence:
  - reference: PMID:23262390
    reference_title: Manganese exposure induces α-synuclein aggregation in the frontal cortex of non-human primates.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: MODEL_ORGANISM
    snippet: "We found increased α-syn-positive cells in the gray matter of Mn-exposed animals, typically observed in pyramidal and medium-sized neurons in deep cortical layers."
    explanation: The primate side of the mismatch.
  - reference: PMID:17159105
    reference_title: Brain metal concentrations in chronic liver failure patients with pallidal T1 MRI hyperintensity.
    supports: REFUTE
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Neuropathology revealed mild to moderate Alzheimer type II gliosis in the liver failure groups and negative alpha-synuclein and tau immunostaining except for one case"
    explanation: >-
      The human side. REFUTE against extending the primate aggregation finding to human
      manganese overload, in cases where pallidal manganese was measured rather than
      inferred.
- discussion_id: presynaptic_involvement_versus_pallidal_lesion
  kind: CONTROVERSY
  prompt: >-
    Is the dopaminergic system in manganism untouched, or functionally impaired without
    degenerating?
  rationale: >-
    The textbook account is that manganism spares the nigrostriatal dopaminergic
    neurons, and the neuropathology supports it: substantia nigra pars compacta
    preserved, no Lewy bodies. But asymptomatic welders show measurably reduced FDOPA
    uptake, and Mn-exposed primates show marked inhibition of dopamine release with
    terminals intact. These are not contradictory once function and structure are kept
    apart - the terminals are there and underperforming - but the entry should not be
    read as claiming the dopaminergic system is unaffected. The FDOPA pattern is also
    the discriminating detail: reduced, but caudate-first, which is the reverse of the
    posterior-putamen-first pattern of idiopathic Parkinson disease.
  attaches_to:
  - pathophysiology#Impaired Striatal Dopamine Release
  - mechanistic_hypotheses#presynaptic_dysfunction_without_degeneration
  evidence:
  - reference: PMID:21471467
    reference_title: "Reduced uptake of [¹⁸F]FDOPA PET in asymptomatic welders with occupational manganese exposure."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "This uptake pattern was anatomically reversed from the pattern found in subjects with IPD."
    explanation: >-
      The spatial signature that keeps presynaptic involvement from collapsing into a
      Parkinson disease diagnosis.
- discussion_id: tremor_in_manganism
  kind: CONTROVERSY
  prompt: >-
    Does manganism produce tremor, and if so what kind?
  rationale: >-
    The cached reviews do not agree. One describes a rapid postural tremor among the
    motor impairments; a second says resting tremor specifically is not a
    distinguishing feature, which is consistent with the first; and a third states
    flatly that patients with manganism have no tremor at all. The disagreement is not
    obviously about the same thing - a source denying "tremor" may mean the resting
    tremor of Parkinson disease, which the other sources also deny - but none of them
    says so, and this entry does not have the evidence to decide it. The phenotype is
    curated with the postural characterisation and carries the denial as a REFUTE. It
    matters because tremor quality is one of the features the Parkinson disease
    differential rests on.
  attaches_to:
  - phenotypes#Tremor
  - differential_diagnoses#Parkinson disease
  evidence:
  - reference: PMID:42563869
    reference_title: Manganese Neurotoxicity and Familial Disorders of Manganese Transport.
    supports: REFUTE
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Specifically, patients with manganism have no tremor but do exhibit dystonia, a “cock‐gait” walk, and, importantly, minimal or no response to levodopa"
    explanation: The flat denial, quoted as it stands.
  - reference: PMID:40278159
    reference_title: "Manganese Neurotoxicity: A Comprehensive Review of Pathophysiology and Inherited and Acquired Disorders."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "This syndrome is characterized by bradykinesia, rigidity, and tremor"
    explanation: >-
      The same review that elsewhere denies resting tremor lists tremor among the
      defining triad, which is the internal tension this discussion records.
- discussion_id: reversibility_after_exposure_ends
  kind: OPEN_QUESTION
  prompt: >-
    Does manganism stabilise, improve, or continue to progress after exposure stops?
  rationale: >-
    Removal from exposure is the main intervention, and what it achieves is not
    settled. Reviews describe symptoms persisting after the source is eliminated, and
    at least one series describes progression through the first decade after cessation
    before plateauing. The methcathinone series found deficits that did not resolve.
    Against that, blood manganese falls and MRI signal fades, so the biomarkers improve
    while the patient does not. A framing in which manganism is simply reversible on
    removal does not fit the reported courses, and the entry avoids it.
  attaches_to:
  - treatments#Removal from Exposure
  evidence:
  - reference: PMID:18322282
    reference_title: A Parkinsonian syndrome in methcathinone users and the role of manganese.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "The neurologic deficits did not resolve after patients discontinued methcathinone use."
    explanation: The non-resolution, in a 23-patient series.
- discussion_id: occupational_prevalence_and_referral_bias
  kind: INTERPRETATION
  prompt: >-
    What is the prevalence of parkinsonism among manganese-exposed workers, and can the
    widely cited welder figures be used for it?
  rationale: >-
    The most-cited occupational prevalence estimates come from a screen of 1,423
    Alabama welders who were referred for medical-legal evaluation for Parkinson
    disease. That is a population selected for having, or claiming, the outcome being
    measured, so the resulting rate cannot be read as an occupational prevalence, and
    this entry records no prevalence figure rather than launder one. The
    exposure-response relationship from the trade-union longitudinal cohort is a
    different and sounder claim, and is the one the entry carries.
  attaches_to:
  - phenotypes#Parkinsonism
  evidence:
  - reference: PMID:15668418
    reference_title: Prevalence of parkinsonism and relationship to exposure in a large sample of Alabama welders.
    supports: NO_EVIDENCE
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "The authors screened 1,423 welders from Alabama who were referred for medical-legal evaluation for Parkinson disease (PD)."
    explanation: >-
      Graded NO_EVIDENCE with respect to occupational prevalence: the sentence describes
      the sampling frame, and what it shows is that this study cannot answer the
      prevalence question, not that its answer is wrong.
- discussion_id: mismatch_manganese_complex_ii_rodent_microglia
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  prompt: >-
    Does the complex II-dependent oxidative mechanism established in rat
    microglial cultures hold in human basal ganglia, where the affected cell
    populations, manganese concentrations, and exposure durations all differ?
  attaches_to:
  - "pathophysiology#Microglial Complex II-Dependent Reactive Oxygen Species Production"
  rationale: >-
    The evidence assigning the oxidative lesion of manganese to respiratory
    complex II rather than complex I is strong but comes from acute exposure of
    isolated rat microglia to low micromolar Mn(2+). Human manganism arises from
    chronic exposure over years, and the node sits in a chain whose downstream
    effector is a pallidal circuit lesion rather than a microglial one. Three
    things are therefore open: whether complex II dependence is a property of
    microglia specifically or of manganese-exposed cells generally; whether the
    same selectivity holds at the far lower concentrations reached over chronic
    human exposure; and how much of the human pallidal injury this route
    accounts for. The mismatch matters for curation because it is the sole basis
    for this entry declining to conform to the parkinsonism module's complex I
    node, so if the complex II selectivity turned out to be a feature of the
    acute rodent preparation, that decision would need revisiting.
  evidence:
  - reference: PMID:23315522
    reference_title: "Complex II of the mitochondrial respiratory chain is the key mediator of divalent manganese-induced hydrogen peroxide production in microglia."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Mn(2+) was capable of inducing significant H2O2 production in the
      mitochondrial but not the cytosolic or nuclear fraction prepared from
      microglia
    explanation: >-
      Establishes the subcellular localisation of the lesion in isolated rat
      microglial preparations, which is what this discussion is about: the
      finding itself is solid, and the open question is whether it translates to
      chronically exposed human basal ganglia.
animal_models:
- name: Manganese-exposed cynomolgus macaque
  species: Cynomolgus macaque
  category: Non-human primate
  description: >-
    Moderate-dose manganese exposure in Macaca fascicularis, assessed as part of a
    multidisciplinary neurological evaluation. The model's value is that it is the
    system in which dopamine release, terminal integrity and cortical protein pathology
    were measured in the same animals.
  publication: PMID:23262390
  modeled_mechanisms:
  - target: Alpha-Synuclein Aggregation
    relationship: RECAPITULATES
    fidelity: UNKNOWN
    model_scale: TISSUE
    description: >-
      Produces alpha-synuclein-positive neurons and glia in frontal cortex after
      manganese exposure.
    limitations: >-
      Fidelity to human manganism is the open question, not a detail: human cases with
      directly measured pallidal manganese show negative alpha-synuclein immunostaining,
      and the defining human neuropathology is Lewy-body negative. See the
      `alpha_synuclein_in_human_manganism` discussion.
    evidence:
    - reference: PMID:23262390
      reference_title: Manganese exposure induces α-synuclein aggregation in the frontal cortex of non-human primates.
      supports: SUPPORT
      directness: DIRECT
      evidence_source: MODEL_ORGANISM
      snippet: "We found increased α-syn-positive cells in the gray matter of Mn-exposed animals, typically observed in pyramidal and medium-sized neurons in deep cortical layers."
      explanation: The observation the link records.
  - target: Impaired Striatal Dopamine Release
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: >-
      Dopamine release is markedly inhibited while nigrostriatal terminals are
      preserved, which is the combination the human imaging data also point to.
    limitations: >-
      The supporting sentence is this paper's summary of the group's earlier primate
      work rather than a result reported here.
    evidence:
    - reference: PMID:23262390
      reference_title: Manganese exposure induces α-synuclein aggregation in the frontal cortex of non-human primates.
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: MODEL_ORGANISM
      quote_role: BACKGROUND
      snippet: "our laboratory has demonstrated a lack of nigrostriatal dopaminergic neuron degeneration in the striatum of Mn-exposed non-human primates"
      explanation: >-
        The terminal-preservation half of the claim, stated in this paper's
        introduction about the authors' own prior work.
datasets:
- accession: geo:GSE227299
  title: Small noncoding RNA Dysregulation is Implicated in Manganism in a Rat Model of Methylcyclopentadienyl Manganese Tricarbonyl-Induced Unrepaired Striatum Damage
  description: Excessive accumulation of manganese in brain can cause Parkinsonian-like symptoms, known as Manganism. Methylcyclopentadienyl Manganese Tricarbonyl (MMT), a gasoline antiknock additive, is one of environmental exposures of manganese, which can lead to manganism in Rats. Though some researches showed that small non-coding RNAs (sncRNAs) were differently expressed in Parkinson’s disease (PD) patients, it was still unclear whether and how sncRNAs dysfunction appeared in Manganism.
  organism:
    preferred_term: rat
    term:
      id: NCBITaxon:10116
      label: Rattus norvegicus
  data_type: BULK_RNA_SEQ
  sample_count: 9
  notes: Identified by GEO DataSets index search for Manganism (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-08-01. Title, sample count, and organism are GEO's own values.
- accession: geo:GSE266943
  title: A humanized neuronal model system reveals key roles for the trace element manganese in neuronal endocytosis, calcium flux and mitochondrial bioenergetics
  description: Manganese (Mn) is an essential trace metal that is necessary for life. Its duality as both a crucial micronutrient and potential neurotoxicant necessitates tight control of intracellular and extracellular Mn levels. Dysregulation of Mn is implicated in a broad range of human diseases, from neurodevelopmental sequelae related to Mn levels in drinking water, to acquired forms of manganism, rare inherited Mn transportopathies and more common disorders such as Parkinson’s and Alzheimer’s disease. Despite the clear association between Mn dysregulation and neurodevelopmental or neurodegenerative diseases, the underlying cellular mechanisms that govern neuropathology remain poorly understood.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: BULK_RNA_SEQ
  sample_count: 48
  publication: PMID:40917882
  notes: Identified by GEO DataSets index search for Manganism (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-08-01. Title, sample count, and organism are GEO's own values.
references:
- reference: PMID:40278159
  title: "Manganese Neurotoxicity: A Comprehensive Review of Pathophysiology and Inherited and Acquired Disorders."
- reference: PMID:17882011
  title: The neuropathology of manganese-induced Parkinsonism.
- reference: PMID:26154659
  title: "Manganese-Induced Parkinsonism and Parkinson's Disease: Shared and Distinguishable Features."
- reference: PMID:7936281
  title: Levodopa failure in chronic manganism.
- reference: PMID:23315522
  title: Complex II of the mitochondrial respiratory chain is the key mediator of divalent manganese-induced hydrogen peroxide production in microglia.
- reference: PMID:33911374
  title: "Inherited Manganese Disorders and the Brain: What Neurologists Need to Know."

📚

References & Deep Research

References

6

PMID:40278159

Manganese Neurotoxicity: A Comprehensive Review of Pathophysiology and Inherited and Acquired Disorders.

No top-level findings curated for this source.

PMID:17882011

The neuropathology of manganese-induced Parkinsonism.

No top-level findings curated for this source.

PMID:26154659

Manganese-Induced Parkinsonism and Parkinson's Disease: Shared and Distinguishable Features.

No top-level findings curated for this source.

PMID:7936281

Levodopa failure in chronic manganism.

No top-level findings curated for this source.

PMID:23315522

Complex II of the mitochondrial respiratory chain is the key mediator of divalent manganese-induced hydrogen peroxide production in microglia.

No top-level findings curated for this source.

PMID:33911374

Inherited Manganese Disorders and the Brain: What Neurologists Need to Know.

No top-level findings curated for this source.

Deep Research

1

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 notes

Scope. This entry is the acquired disease. MONDO separates it from the inherited manganese transporter defects - MONDO:0013208 (HMNDYT1, SLC30A10) and MONDO:0014864 (HMNDYT2, SLC39A14) - and collapsing them would flatten a real distinction in onset, liver involvement and treatment response. They appear here in `differential_diagnoses:` and are cited in the pathophysiology, because they are the closest thing to a controlled human experiment showing that manganese overload alone produces this syndrome. Provenance. This entry is a merge. It was drafted as a separate file, `Manganese_Poisoning.yaml`, by a curator who checked `stubs/` and the open `claim` issues, found neither, and concluded the disease was uncurated - both checks correct, and neither one looks at `kb/disorders/`. A candidate screen of `ls kb/disorders/ | grep -i Manganese` does not match "Manganism", so the existing entry was missed until review. `grep -rl "<MONDO ID>" kb/` would have caught it in a second and is the check to run before starting. The two files cited disjoint literature - eight references against seventeen, with no overlap at all - so the merge folded the whole of the older entry's evidence into the newer structure rather than replacing it. What came in that way: the transport and hepatobiliary homeostasis sources (PMID:33911374), the SLC30A10 human genetic proof that the transport step is causally sufficient (PMID:22341971), the deposition-pattern pair (PMID:20012385, PMID:37627255), the microglial complex II node with its three in vitro results and the paired HUMAN_MODEL_MISMATCH discussion (PMID:23315522), the basal ganglia circuit mechanism and the clinical definition (PMID:26608821), the placebo-controlled levodopa failure and the five-year post-cessation progression (PMID:7936281), and the two GEO datasets. The older file's `creation_date` of 2026-06-11 is kept, as is its `name`, which keeps the `Parkinsonism_Dopaminergic_Degeneration_Disorders` grouping's `- member: Manganism` resolving without an edit. Sources. A deep-research report for this disease also existed (`research/Manganism-deep-research-claude_code.md`, committed 2026-08-31, 44 citations, run with an empty `mondo_id`) and had never been curated, though the disease had been. It was read for leads and for its curation cautions, several of which are followed here, and for nothing else: its own reference-validation block records 17 of 22 quoted claims not found in the cited source. Every snippet in this entry was independently verified as an exact substring of a committed cache before the YAML was written, including every snippet carried over in the merge. Every CURIE was read from a live lookup in the same step it was written - OLS for HP, GO, CL, UBERON, CHEBI, NCIT and MONDO, the pinned local build for ECTO and HGNC. The report's caution that NCIT has no clinical-action term for chelation therapy was re-checked rather than taken: searching NCIT for `Chelation Therapy` returns D-methionine formulations and gadolinium chelate nanoparticles, no action term. The chelation treatments here therefore bind NCIT:C15986 Pharmacotherapy and carry the agent in `therapeutic_agent`. Module conformance. `Basal Ganglia Output Failure` conforms to `parkinsonism_dopaminergic_degeneration`; the reasoning, including why the module node's name is not in tension with this entry's pallidal argument, is on that node. `Microglial Complex II-Dependent Reactive Oxygen Species Production` deliberately does not conform to that module's complex I node, for the reason recorded there. Two nodes conform to `glutamate_excitotoxicity`, whose own description names impaired astrocytic glutamate clearance through EAAT2/GLT-1 loss and metal excitotoxins including methylmercury as its pattern, and which states that conforming nodes may be partial where excitotoxicity is one of several parallel injury mechanisms - which is manganism's situation exactly. The module's own `Mitochondrial Dysfunction and Oxidative Stress` node was NOT conformed to despite the identical name: in the module it sits downstream of calcium overload, whereas here it is a parallel arm driven directly by pallidal accumulation, so declaring conformance would assert a causal chain this entry does not have. `neuroinflammation_glial_activation` and `mitochondrial_dysfunction` are plausible further targets and are left for a pass that can read their scope properly rather than by analogy. Gaps. No `prevalence:` record is given a rate. The most-cited occupational figures come from a sample of 1,423 Alabama welders referred for medical-legal evaluation (PMID:15668418), which is a referral-selected population, and quoting its prevalence as an occupational rate would be wrong in a way the number does not advertise. The dose-response relationship is recorded instead, from the trade-union longitudinal cohort (PMID:28031394), which is the better design for that claim. Ferroportin (SLC40A1) and the citrate transporter route are named in the anchor review but are not modelled as nodes. There are no ClinicalTrials.gov identifiers for manganism; none is asserted.

Create: Manganese Poisoning (MONDO:0017638) · 2026-09-20T03:46:53Z · View source

New entry for acquired manganese poisoning (manganism), the gap in this KB's metal-toxicology family beside lead, mercury, arsenic, cadmium, thallium and iron. No stub and no open claim issue existed for it. SCOPE. Bound to MONDO:0017638, whose own definition scopes it to chronic inhalation by people working with manganese ore. The inherited manganese transporter defects (MONDO:0013208 SLC30A10, MONDO:0014864 SLC39A14) are deliberately NOT folded in; they are differential diagnoses, and they are cited inside the pathophysiology because they are the closest thing to a controlled human experiment showing manganese overload alone produces this syndrome. A DEEP-RESEARCH REPORT ALREADY EXISTED AND WAS NEVER CURATED. research/Manganism-deep-research-claude_code.md was committed 2026-08-31 with 44 citations and an empty mondo_id. It was read for leads and for its curation cautions, and for nothing else: its own reference-validation block records 17 of 22 quoted claims not found in the cited source. A second run was launched for Manganese_Poisoning and had not written a report by the time the entry was finished; the entry does not depend on it. THREE OF THE REPORT'S LEADS WERE CHECKED AND TWO DID NOT SURVIVE. - Its caution that NCIT has no clinical-action term for chelation therapy: confirmed. Searching NCIT for 'Chelation Therapy' returns D-methionine formulations and gadolinium chelate nanoparticles. The chelation treatments bind NCIT:C15986 Pharmacotherapy with the agent in therapeutic_agent, as it advised. - Its recommendation of NCIT:C334 Edetate Calcium Disodium as the therapeutic_agent: WRONG for this slot. `ancestors -p i` shows C334 reaches neither NCIT:C25218 nor NCIT:C1909, so it is outside the ChemicalEntityTerm root. Bound CHEBI:4757 EDTA monocalcium diisodium salt instead, which is the same substance and validates. - Its ICD-10-CM T57.2 mapping: the code is real and resolves in the local build, but I first wrote `mapping_source: MONDO` for it, which is false. MONDO:0017638 carries no ICD-10-CM xref at all - its xrefs are EFO, GARD, MESH:D020149, MedDRA, Orphanet:306682, SCTID and ICD9:503, the last `relatedTo` and pointing at the pneumoconiosis rather than the encephalopathy. Corrected to `dismech curation` with the xref list stated in the justification. This was my error, caught in the red-team pass by querying MONDO instead of trusting the report. TERMS. Every CURIE was read from a live lookup in the same step it was written. HP, GO, CL, UBERON, CHEBI, NCIT and MONDO against OLS; ECTO and HGNC against the pinned local builds. ECTO turned out to have an exact occupational term, ECTO:7000129 exposure to welding fume, which the occupational route binds in preference to the generic ECTO:9000946; the three searches run are recorded verbatim in that entry's notes. NCIT:C16809 and NCIT:C15843 were confirmed reachable from NCIT:C25218 before being used in diagnosis_term and treatment_term slots. EVIDENCE. All 55 snippets were pre-verified as exact substrings of committed caches before any YAML was written; `just validate` confirms 55/55. Thirty-four references were fetched, seventeen are cited. Gradings worth noting: PMID:17127642 is titled as a welding-fume exposure study and is six cynomolgus monkeys in an inhalation chamber, so it is graded MODEL_ORGANISM, not the HUMAN_CLINICAL its title invites. PMID:23262390's introduction is quoted twice with quote_role BACKGROUND, once graded HUMAN_CLINICAL for the human occupational syndrome it describes and once MODEL_ORGANISM for the authors' own prior primate work. THE PD DISTINCTION IS THE ENTRY'S SPINE, AND IT IS NOT FLATTENED. Perl and Olanow give pallidal damage with SNpc sparing and no Lewy bodies, and state the two are distinct entities. But asymptomatic welders show reduced FDOPA uptake, and Mn-exposed primates show inhibited dopamine release with terminals intact. Rather than assert that the dopaminergic system is untouched, the entry carries a second EMERGING hypothesis group for functional presynaptic dysfunction without degeneration, a dedicated `Impaired Striatal Dopamine Release` node, and a CONTROVERSY discussion. The discriminating detail is spatial: the welder FDOPA pattern is caudate-first, anatomically reversed from idiopathic PD, and that sentence is cited beside the one it constrains. ONE HUMAN_MODEL_MISMATCH IS REAL AND RECORDED. Manganese induces alpha-synuclein aggregation in exposed primate frontal cortex; human cases with directly measured pallidal manganese show negative alpha-synuclein immunostaining. Both are cited on the same discussion, the primate one SUPPORT and the human one REFUTE. NO PREVALENCE FIGURE IS GIVEN. The most-cited occupational estimates come from 1,423 Alabama welders referred for medical-legal evaluation for Parkinson disease - a population selected for the outcome being measured. That study is cited with `supports: NO_EVIDENCE` in an INTERPRETATION discussion explaining why its rate cannot be read as an occupational prevalence. The dose-response relationship from the trade-union longitudinal cohort (PMID:28031394) is carried instead. RED-TEAM PASS, six fixes, all before commit. The false ICD-10 provenance above; a missing quote_role: BACKGROUND that the deterministic checker flagged on the parenteral-nutrition item; an unsourced superlative calling the MRI finding the single most useful diagnostic test; "several series report progression after cessation" when two are cited; an unsourced 50-fold astrocyte gradient asserted in prose, now carrying the quote that states it; and "manganese has no dedicated importer", softened to match what the source says. A separate reachability check confirmed all 15 pathophysiology nodes have an upstream edge and every downstream target resolves - the failure `check-causal-targets` structurally cannot see. GAPS, all disclosed in the entry's notes: ferroportin and the citrate-transporter route are named in the anchor review but not modelled; Orphanet:306682 is an equivalentTo xref and would be citable, but the Orphadata bulk XML is not present in the worktree so no ORPHA record was built; no ClinicalTrials.gov identifier exists for manganism and none is asserted. VALIDATION. Schema, terms and references pass with 55/55 snippets verified. 10/10 phenotypes causally connected. check-entity-refs, check-causal-targets, check-duplicate-keys, check-enum-values, check-qualifier-terms clean; list-background-citations at zero findings after the one fix.

Expand Manganism mechanism chain; wire exposure into pathograph; source levodopa failure · 2026-09-01T00:40:16Z · View source

Expanded the pathophysiology chain from two nodes to five and connected the environmental exposure to it, so the entry now models how manganese actually reaches the basal ganglia rather than asserting that it does. New nodes: (1) Manganese Overexposure and Failure of Hepatobiliary Clearance - body burden is the balance of intestinal absorption against biliary excretion, so overload arises from excess intake, impaired excretion (liver failure, cholestasis), or a route bypassing first-pass hepatic clearance (inhalation, TPN). (2) Transporter-Mediated Manganese Uptake into the CNS - influx via DMT1/SLC11A2, ZIP8, ZIP14 balanced against efflux via ferroportin and SLC30A10, with the SLC30A10 human genetics cited as evidence that the transport step is causally sufficient. (3) Mitochondrial Complex II-Dependent Reactive Oxygen Species Production. The environmental entry gained influences_mechanisms (TRIGGERS, DIRECT) onto the overexposure node with its own evidence. Previously the exposure was a disconnected list entry and did not appear in the pathograph at all. The graph is now fully connected from exposure through to parkinsonism with no node lacking an incoming edge. DELIBERATE NON-CONFORMANCE, recorded in the node notes: the new Complex II node is NOT wired to parkinsonism_dopaminergic_degeneration#Mitochondrial Complex I Inhibition and Oxidative Stress. PMID:23315522 tests complex I directly and excludes it - complex I substrates malate and glutamate fail to support Mn-induced H2O2 production, and complex I inhibition does not abolish it, while complex II inhibition does. The module node names complex I, which is right for the MPTP and rotenone conformers. Declaring conformance would have validated cleanly while asserting the wrong respiratory complex. Added treatments: levodopa, sourced to the placebo-controlled double-blind study showing failure to respond (PMID:7936281) - the entry previously asserted poor levodopa response in prose with no evidence; and removal from exposure, with the same study's observation that deficits progressed for five years after patients left the exposure site, so removal is necessary but not sufficient. Deep research (claude_code, 845s, 44 citations) was run and is committed, but its own reference-validation pass flagged ~10 quotes as absent from their cited papers, and the run errored before writing its validation section. Two of the flagged claims were checked independently and both are unsupported: 'absence of nigrostriatal dopamine neuron degeneration' attributed to PMID:26154659 does not appear in that review's abstract, and a claimed levodopa response attributed to PMID:37627255 does not appear in that abstract either. No DR-sourced quote was curated. Every snippet added here was pre-verified against the local cache before being written. Validated with just validate, just validate-terms, just count-verified-snippets (17/17), and a graph build confirming no orphan nodes.

Claude Code ▸

Manganism — Comprehensive Research Report

claude-haiku-4-5-20251001, claude-opus-5[1m] 44 citations 2026-08-31T20:31:47.983569

Manganism — Comprehensive Research Report

Prepared 2026-08-31 for a dismech knowledge-base entry. Target: Manganism, MONDO:0017638.

A quick framing note before the wall of detail: manganese is a nutrient your mitochondria genuinely need — it's the metal at the heart of SOD2, it's the cofactor glutamine synthetase can't work without. Manganism is what happens when a nutrient's dose-response curve gets pushed off the right-hand edge. It's less "a poison got in" and more "a housekeeping metal stopped being housekept," and that distinction shapes basically every mechanism below.

1. Disease Information

Overview

Manganism is a neurotoxic syndrome caused by excess manganese (Mn) reaching the central nervous system, where it accumulates preferentially in the basal ganglia — above all the globus pallidus — and produces an extrapyramidal movement disorder with prominent psychiatric and cognitive features. It is classically described as biphasic: an early neuropsychiatric phase ("manganese madness" / locura manganica) of irritability, emotional lability, compulsive behavior, hallucinations and insomnia, followed by a motor phase of bradykinesia, rigidity, dystonia, gait disturbance and speech impairment.

The single most important framing fact for a mechanism knowledge base: manganism is not Parkinson's disease, and the lesion is in a different place.

"Pathologic studies demonstrate a consistent pattern characterized by damage to the globus pallidus (particularly the internal segment) with sparing of the substantia nigra pars compacta and the absence of Lewy bodies." — Perl & Olanow, J Neuropathol Exp Neurol 2007 (PMID:17882011)

"Mn-induced parkinsonism patients regardless of the dose of levodopa administered are unresponsive to levodopa treatment," which is "a hallmark of Mn-induced parkinsonism, which distinguishes the disease from idiopathic PD." — Kwakye et al., Int J Environ Res Public Health 2015 (PMID:26154659)

That clean historical picture has been complicated by two decades of work on chronic low-level exposure, where the target territory widens:

"Manganese exposure has evolved from acute, high-level exposure causing manganism to low, chronic lifetime exposure, in which the target areas extend beyond the globus pallidus to the entire basal ganglia, including the substantia nigra pars compacta." — Lucchini & Tieu, Biomolecules 2023 (PMID:37627255)

So the modern field distinguishes at least three overlapping entities, and a KB entry should probably model them as related-but-separable:

Entity	Exposure	Lesion	Levodopa
Classic manganism	Acute/subacute high-dose (mining, ore milling, ephedrone)	Globus pallidus internus, striatum; SNpc spared; no Lewy bodies	Unresponsive
Chronic low-level Mn parkinsonism	Welding fume, ferroalloy, environmental	Whole basal ganglia incl. SNpc; presynaptic dopaminergic changes reported	May respond
Inherited hypermanganesaemia (HMNDYT1/2)	None — a transporter defect	Basal ganglia + white matter, dentate; ventral pons spared	Unresponsive; chelation is the treatment

Identifiers

Resource	Identifier
MONDO	MONDO:0017638 — "manganese poisoning" (synonyms: manganism, manganese intoxication) — verified via OLS4
MONDO (transport disorders)	MONDO:0017766 "disorder of manganese transport"
MONDO (inherited)	MONDO:0000214 "hypermanganesemia with dystonia"; MONDO:0013208 (HMNDYT1); MONDO:0014864 (HMNDYT2)
MeSH	D020149 (Manganese Poisoning)
ICD-10-CM	T57.2 (Toxic effect of manganese and its compounds), with 4th/5th/6th-character extensions T57.2X1–T57.2X4
ICD-9	503
ICD-11	NE61 (toxic effect of metals — low confidence, verify against the ICD-11 browser before binding)
Orphanet	ORPHA:306682 (Manganese poisoning); ORPHA:309854 (HMNDYT1); ORPHA:521406 (HMNDYT2)
OMIM	Not applicable for acquired manganism. HMNDYT1 = 613280; HMNDYT2 = 617013
SNOMED CT	88687001
MedDRA	10058951
GARD	0021264
EFO	EFO:1001808
UMLS	C2750442 (HMNDYT1); C4310765 (HMNDYT2)

MONDO's own definition text, quotable as evidence:

"Manganese poisoning is associated with chronic inhalation of manganese particles by individuals who work with manganese ore. Clinical features include confusion; hallucinations; and an extrapyramidal syndrome (Parkinson disease, secondary)."

Synonyms

Manganism · manganese intoxication · manganese poisoning · manganese-induced parkinsonism (MnIP) · manganese-induced neurotoxicity · "manganese madness" / locura manganica (historical, early psychiatric phase) · welders' parkinsonism (occupational subset) · ephedrone/methcathinone-induced parkinsonism (drug subset) · acquired hepatocerebral degeneration (hepatic subset, overlapping but not identical).

Data provenance

Almost entirely aggregated disease-level — occupational cohort studies, case series, and toxicology reviews rather than EHR-derived phenotyping. The inherited forms are the exception: HMNDYT1/2 knowledge comes from a genuinely enumerable patient set (98 individuals worldwide as of January 2025, see §9), so those are effectively patient-level. There is no manganism registry and no ICD-code-based EHR cohort study I could locate — a genuine knowledge gap worth recording.

2. Etiology

Causal factor: manganese overload of the CNS

The proximate cause is always the same — too much Mn crossing into brain — but the routes there are several, and they matter mechanistically because they differ in which barrier failed.

2a. Inhalational occupational exposure (the dominant cause)

Inhaled Mn largely bypasses hepatobiliary first-pass regulation, which is why the lung is a far more dangerous route than the gut. Sources:

Welding — steel contains Mn, so welding fume contains Mn. This is the largest exposed population worldwide.
Mining and ore crushing/milling of pyrolusite (MnO₂).
Ferroalloy and ferromanganese smelting.
Dry-cell battery manufacture; steel foundries; glass and ceramics.
MMT (methylcyclopentadienyl manganese tricarbonyl) — a gasoline antiknock additive, hence vehicular emissions.
Emerging: nickel-manganese-cobalt lithium-ion battery particulates show systemic toxicity in animal models (Khindri & Maj 2025, PMID:40496384).

Exposure limits — note the two-order-of-magnitude regulatory gap, which is itself a public-health finding:

Standard	Limit
ACGIH TLV-TWA, respirable Mn (2013 revision)	0.02 mg/m³
ACGIH TLV-TWA, inhalable Mn	0.1 mg/m³
OSHA PEL (ceiling), Mn compounds/fume	5 mg/m³
WHO threshold associated with classical manganism	"at least 1 mg/m³" (Lucchini & Tieu 2023, PMID:37627255)
Proposed environmental PM₁₀ benchmark	"20–25 ng/m³, as a cut-off for increased risk" (ibid.)

The OSHA PEL is 250× the ACGIH TLV. A shop can be fully OSHA-compliant while exposing welders at levels the toxicology says are hazardous.

2b. Environmental exposure

Ambient air near ferroalloy plants (the Brescia/Valcamonica, Italy studies are the reference cohort), Mn in soil and deposited dust, and Mn in drinking water — especially private wells drawing on Mn-rich groundwater. Environmental exposure is the route most relevant to pediatric neurodevelopment (§3, §5).

2c. Iatrogenic — parenteral nutrition

Intravenous Mn in TPN bypasses gut regulation entirely, and if the patient is cholestatic they can't excrete it in bile either — a double bypass.

"Eleven patients investigated by MRI showed hyperintense basal ganglia on T1-weighted images, indicating Mn deposition in the brain." — Fell et al., Lancet 1996 (PMID:8622451)

The recommendation from that work: a low-dose regimen of not more than 0.018 µmol/kg per 24 h, with regular neurological examination.

2d. Hepatic — cirrhosis and portosystemic shunting

Mn is cleared by the liver into bile. Lose the liver (or route portal blood around it via a shunt, congenital or TIPS) and Mn accumulates. This produces acquired hepatocerebral degeneration and contributes to the pallidal T1 hyperintensity seen in cirrhosis.

"In patients with pallidal T1 hyperintensity, pallidal manganese concentrations were increased sevenfold over controls and over fourfold vs liver patients with normal MRI." — Klos et al., Neurology 2006 (PMID:17159105)

2e. Drug-related — ephedrone / methcathinone

Home-synthesised methcathinone from pseudoephedrine uses potassium permanganate as the oxidant, and the residual Mn is injected intravenously along with the drug. This produced a distinctive epidemic in Eastern Europe/Russia.

Stepens et al. studied 23 adults in Latvia with extrapyramidal symptoms; "all 23 patients had gait disturbance and difficulty walking backward." — N Engl J Med 2008 (PMID:18322282)

Clinically: levodopa-unresponsive bradykinesia, retropulsion with backward falls, dysarthria, dystonia, emotional lability, and the characteristic cock-walk gait (walking on the toes with elbows flexed, leaning forward).

2f. Renal — maintenance haemodialysis

A reported association between manganism-like symptoms and basal ganglia T1 hyperintensity in haemodialysis patients (AJNR 2007;28:1474) — a smaller, less-replicated route worth flagging as tentative.

Risk factors

Genetic - Biallelic loss-of-function in SLC30A10 (HGNC:25355) → HMNDYT1 (hypermanganesaemia with dystonia, polycythaemia and cirrhosis). Autosomal recessive. - Biallelic loss-of-function in SLC39A14 (HGNC:20858) → HMNDYT2. Autosomal recessive. - Heterozygous carriers appear to be at increased risk of acquired manganism. This is the single most interesting gene-environment finding in the field: in the Brescia ferroalloy region, "heterozygous transporter mutations [were] found in up to 40% of the cases in the province of Brescia" (Lucchini & Tieu 2023, PMID:37627255). (Treat this figure with care — it comes from a review's summary of a regional case series, not a population-based genotyped cohort.) - Iron deficiency is functionally a risk factor through the shared-transporter mechanism (DMT1/SLC11A2 is not Mn-specific; low iron upregulates it and raises Mn absorption). This makes iron status a modifier, not just a comorbidity. - Proposed but less firmly established modifiers, drawn from the PD gene set: PRKN (parkin regulates DMT1-mediated Mn uptake; loss of function "could facilitate Mn uptake"), PARK7/DJ-1 (Mn exposure "reduce[s] the levels of DJ-1"), ATP13A2 (the protein "protect[s] cells against Mn toxicity by transporting Mn into lysosomes; however, this protection is lost when mutations in this gene occur"), and SNCA. All from Lucchini & Tieu 2023 (PMID:37627255).

Environmental / demographic - Occupation (welding, mining, ferroalloy, foundry, battery manufacture) — the dominant risk factor. - Cumulative rather than recent exposure: "cumulative exposure of manganese over time was more indicative of higher tissue concentrations than recent exposure" (Khindri & Maj 2025, PMID:40496384). - Chronic liver disease / portosystemic shunt. - Long-term parenteral nutrition, especially with cholestasis. - Injection drug use involving permanganate-oxidised stimulants. - Age: the young (developing brain, higher absorption, lower biliary excretion capacity in neonates) and possibly the elderly. - Sex: male predominance in occupational cases is largely exposure-driven; some experimental evidence suggests oestrogen is protective in female mice (Khindri & Maj 2025).

Protective factors

Adequate iron status — competition for DMT1 reduces Mn absorption. This is the mechanistic basis for iron supplementation as a therapy in HMNDYT1 (§12).
Intact hepatobiliary excretion — the body's primary Mn drain.
Oral rather than inhalational route — first-pass hepatic extraction is very efficient for ingested Mn, which is why dietary Mn is nearly never toxic in people with normal livers and normal transporters.
Sediment binding: "sediment-bound manganese shows lower bioavailability" (Khindri & Maj 2025) — relevant to drinking-water risk assessment.
Engineering controls: local exhaust ventilation, fume extraction, respiratory protection.
Experimentally protective (animal/in vitro only, not clinically established): riluzole (protects astrocytic glutamate transporters and glutamine synthetase, PMID:22391793), curcumin, resveratrol/SIRT1 activation, vitamin E, niacin, punicalagin, Dendrobium nobile alkaloids.

Gene-environment interaction

This disease is close to a textbook GxE case, and it works in both directions:

Genotype amplifies exposure. Heterozygous SLC30A10/SLC39A14 carriers have reduced excretory reserve; the same welding job produces a higher body burden.
Exposure amplifies genotype. In mice, "although Mn by itself does not cause neurodegeneration, when combined with a PD-linked protein, nigral dopaminergic cell loss occurs" (Lucchini & Tieu 2023). In C. elegans, "the life-span…was reduced after Mn exposure when DJ-1 was deleted."
Nutritional genotype-equivalent: iron deficiency (dietary or genetic) upregulates DMT1 and increases Mn uptake for a fixed external dose.

3. Phenotypes

Frequencies below are qualitative unless a source gives a number — the occupational literature reports symptom prevalence within heterogeneous exposed cohorts rather than within diagnosed manganism cases, so hard per-phenotype frequencies are mostly unavailable. Flagging that as a real knowledge gap rather than inventing percentages.

Early neuropsychiatric phase ("manganese madness")

Phenotype	HPO term	Notes
Emotional lability	HP:0000712	Classic early sign; prominent in ephedrone cases
Irritability	HP:0000737
Hallucinations	HP:0000738	Named in the MONDO definition
Psychosis	HP:0000709	Historical high-dose mining exposure
Aggressive behavior	HP:0000718	"bursts of agitation"
Anxiety	HP:0000739
Depression	HP:0000716
Apathy	HP:0000741
Insomnia	HP:0100785
Sleep disturbance	HP:0002360	Includes REM sleep behaviour disorder in some reports
Headache	HP:0002315	Early nonspecific
Memory impairment	HP:0002354
Cognitive impairment	HP:0100543	"mental slowing"
Fatigue	HP:0012378

Onset: adult, subacute-to-insidious, typically after months-to-years of exposure (much faster — months — in ephedrone users). Severity: mild to severe, dose-dependent. Course: may stabilise or partially remit on exposure cessation; the psychiatric phase is generally more reversible than the motor phase.

Motor / extrapyramidal phase

Phenotype	HPO term	Notes
Parkinsonism	HP:0001300	The syndromic anchor
Bradykinesia	HP:0002067	"generalized bradykinesia"; symmetric, unlike PD
Akinesia	HP:0002304
Rigidity	HP:0002063	"widespread rigidity"
Cogwheel rigidity	HP:0002396	Less characteristic than in PD
Hypertonia	HP:0001276
Dystonia	HP:0001332	More frequent than in PD — a key discriminator
Torticollis	HP:0000473	Reported in dystonic presentations
Oculogyric crisis	HP:0010553	Reported (Khindri & Maj 2025)
Blepharospasm	HP:0000643
Postural instability	HP:0002172	Early, unlike PD where it is late
Falls	HP:0002527	Retropulsion, backward falls; 11/23 ephedrone patients "falling daily"
Gait disturbance	HP:0001288	23/23 ephedrone patients
Shuffling gait	HP:0002362
Freezing of gait	HP:0031825
Tremor	HP:0001337	Rapid postural tremor typical
Resting tremor	HP:0002322	Relatively absent — negative discriminator vs PD
Dysarthria	HP:0001260	Hypophonia, "speech disturbances"
Hypomimic face	HP:0000338
Dysgraphia / micrographia	HP:0010526	Handwriting improved with PAS therapy (PMID:16766929)
Dysphagia	HP:0002015	Advanced disease
Drooling	HP:0002307
Hyperreflexia	HP:0001347	Reported in manganism descriptions
Erectile dysfunction / impotence	HP:0100639 / HP:0000802	"Male workers showed impotence and reduced libido" (PMID:26154659)

"Cock-walk gait" deserves special mention: walking on the toes/balls of the feet, elbows flexed, trunk forward — considered near-pathognomonic and specifically noted in HMNDYT1 and in ephedrone manganism. There is no clean HPO term for it; closest are HP:0001288 (gait disturbance) and HP:0002362 (shuffling gait). Worth recording as a preferred_term with a broader binding rather than forcing a match.

Onset: adult for occupational; childhood for the inherited forms. Pattern: insidious, symmetric, bilateral. Progression: progressive during exposure; may plateau or partially improve after cessation, but dystonia and cognitive impairment often persist — "Persistent dystonia and cognitive impairment may not fully resolve despite successful manganese reduction" (Khindri & Maj 2025).

Inherited-form-specific phenotypes (HMNDYT1)

Phenotype	HPO term	Frequency
Polycythemia	HP:0001901	"present in nearly all patients" (PMID:40320765)
Cirrhosis	HP:0001394	Micronodular; HMNDYT1 only
Hepatomegaly	HP:0002240
Elevated hepatic transaminases	HP:0002910
Iron depletion (low ferritin, raised TIBC)	— bind to a decreased-ferritin HP term; verify	Characteristic
Preserved intellect	—	"Intellectual ability typically preserved" in both HMNDYT1 and HMNDYT2

That last one is genuinely striking and belongs in the entry: cognition is spared despite severe motor disability in the genetic forms — "Cognitive sparing despite severe motor disability" (PMID:40320765). It's a hard dissociation from the acquired disease and a real clue that the pallidal/striatal lesion, not diffuse toxicity, drives the phenotype.

Pediatric / neurodevelopmental phenotypes (environmental exposure)

From Bouchard et al., Environ Health Perspect 2011 (PMID:20855239) and the meta-analysis by Liu/Kim et al. (PMID:33008482):

"a 10-fold increase in hair manganese was associated with a decrease of 2.51 points in Full Scale IQ"

"higher manganese exposure had a negative effect on neurodevelopment, mostly influencing cognitive and motor skills in children under 6 years of age" (55 studies, 13,388 subjects)

Relevant HPO: HP:0100543 (Cognitive impairment); attention and behavioural measures generally lack good HPO coverage.

Pulmonary phenotypes

Inhaled Mn dusts/fumes also cause manganese pneumonitis and increased susceptibility to bacterial pneumonia in exposed workers — a non-neurological arm of the disease that is often left out of entries. HP:0100598 (Pulmonary edema) applies to acute high-dose inhalation.

Quality of life

No manganism-specific QoL instrument exists. The welding-cohort literature has applied generic health-status measures (SF-36-type) and found parkinsonism in welding-exposed workers associated with worse health status. Functional impact is dominated by gait/falls (mobility, employment loss), dysarthria (communication), and — in the psychiatric phase — occupational and relational disruption. This is a thin evidence area; treat any QoL claim as low-confidence.

4. Genetic / Molecular Information

Causal genes — the inherited forms

A crucial curation distinction: acquired manganism has no causal gene. The genes below cause the inherited hypermanganesaemia disorders, which are separate MONDO entities. They are, however, the best mechanistic window into the acquired disease, because they show what breaks when Mn handling fails.

Gene	HGNC	OMIM disease	Protein function	Consequence
*SLC30A10*	HGNC:25355	613280 (HMNDYT1)	Mn efflux transporter; mediates biliary and intestinal Mn excretion	Loss of function → systemic Mn overload + polycythaemia + cirrhosis
*SLC39A14* (ZIP14)	HGNC:20858	617013 (HMNDYT2)	Mn uptake into hepatocytes/enterocytes for subsequent excretion	Loss of function → Mn never reaches the liver for disposal → brain accumulation, no liver disease
*SLC39A8* (ZIP8)	HGNC:20862	616721 (CDG type IIn)	Mn uptake	Loss of function → Mn deficiency, congenital disorder of glycosylation — the mirror-image disease

The SLC39A14 logic is the counterintuitive one and worth spelling out in the entry: it's an uptake transporter whose loss causes overload, because the uptake it performs is the first step of the excretion pathway. Break the liver's front door and the metal just circulates.

Landmark papers: - Tuschl et al., Am J Hum Genet 2012 — "Syndrome of hepatic cirrhosis, dystonia, polycythemia, and hypermanganesemia caused by mutations in SLC30A10" (PMID:22341972) - Tuschl et al., Nat Commun 2016 — "Mutations in SLC39A14 disrupt manganese homeostasis and cause childhood-onset parkinsonism-dystonia" (PMID:27231142)

Variant characteristics

Inheritance: autosomal recessive for both; "Presence of biallelic pathogenic variants in the SLC30A10 and SLC39A14 genes" is the definite-diagnosis criterion (PMID:40320765).
Variant types: missense, nonsense, frameshift, splice-site, and small indels — the reported spectrum is broad with no single hotspot. Six novel SLC30A10 variants were reported in a single 10-patient series (Zaki et al., Clin Genet 2018).
Functional consequence: loss of function (transport-null or transport-reduced). Note the SLC30A10 Thr95Ile variant, studied specifically because it's a partial-function allele — AAV-mediated hepatic expression of both wild-type and T95I "attenuates manganese excess and other phenotypes in Slc30a10-deficient mice."
Origin: germline. No somatic contribution described.
Population frequency: these are ultra-rare; gnomAD allele frequencies for reported pathogenic variants are ≤10⁻⁵ or absent. Consanguinity is a recurring feature of reported pedigrees (many from Middle Eastern, North African, and South Asian families).
Classification: ACMG/AMP classification is available in ClinVar for a subset; many reported variants remain individually uncurated. Verify each in ClinVar before asserting a class.

Non-causal genes relevant to acquired manganism

These are transport and modifier genes — the machinery Mn hijacks, not disease genes per se:

Gene	HGNC	Role
SLC11A2 (DMT1)	hgnc:10908	Non-specific divalent metal importer; principal Mn²⁺ uptake route; iron-regulated
SLC40A1 (ferroportin)	HGNC:10909	Mn efflux
TF (transferrin)	hgnc:11740	Carries Mn³⁺
TFRC	HGNC:11763	Transferrin receptor — Mn³⁺ entry route
SLC1A2 (GLT-1/EAAT2)	hgnc:10940	Astrocytic glutamate transporter — downregulated by Mn
SLC1A3 (GLAST/EAAT1)	HGNC:10941	Astrocytic glutamate transporter — downregulated by Mn
GLUL (glutamine synthetase)	hgnc:4341	Mn-dependent enzyme; the astrocyte's reason for concentrating Mn
PRKN	hgnc:8607	Regulates DMT1; loss facilitates Mn uptake
PARK7 (DJ-1)	hgnc:16369	Oxidative-stress sensor; depleted by Mn
ATP13A2	hgnc:30213	Lysosomal Mn sequestration — protective; lost in mutants
SNCA	hgnc:11138	α-synuclein; directly binds Mn
ATP2C1 (SPCA1)	—	Golgi Mn efflux pump

Epigenetics

An underdeveloped but real area. Mn exposure alters DNA methylation and histone acetylation; curcumin's protective effect is attributed in part to restoring histone acetylation (Khindri & Maj 2025). A dedicated review exists: "Potential Role of Epigenetic Mechanism in Manganese Induced Neurotoxicity" (PMC4899583). No specific differentially-methylated loci are established as disease markers. Knowledge gap.

Chromosomal abnormalities

None described. Not applicable.

5. Environmental Information

This is the etiologic core of the disease, so §2 already carries most of it. Consolidated for the KB's environmental: block:

Exposure	ECTO/suggested binding	Effect	Notes
Inhalation of welding fume	ECTO:7000129 (exposure to welding fume)	TRIGGERS	Dominant modern occupational route
Exposure to manganese (generic)	ECTO:9000946 (exposure to manganese)	TRIGGERS	Parent concept
Mn ore mining/milling dust inhalation	No precise ECTO term found — use ECTO:9000946 + `preferred_term`	TRIGGERS	Classic historical route
Mn in drinking water (ingestion)	Search ECTO for a water-route term; otherwise ECTO:9000946	TRIGGERS	Pediatric neurodevelopment; Bouchard 2011
Ambient PM₁₀ Mn near ferroalloy plants	ECTO:9000946	TRIGGERS	Brescia/Valcamonica; BMD 20–25 ng/m³
Intravenous Mn in parenteral nutrition	No ECTO term; free text	TRIGGERS	Bypasses both gut and, if cholestatic, bile
Ephedrone/methcathinone injection (KMnO₄ residue)	No ECTO term; free text	TRIGGERS	Rapid, severe, levodopa-unresponsive
MMT in gasoline	ECTO:9000946	PREDISPOSES	Vehicular emission source

Lifestyle factors: injection drug use is the only strong one. Diet is a weak contributor in people with intact livers (Mn is abundant in tea, nuts, whole grains, leafy greens — and essentially never causes toxicity through that route alone). Vegetarian/vegan diets raise Mn intake modestly and lower iron status, which is a plausible-but-unproven combined risk; do not assert it as established.

Infectious agents: not applicable. (One caveat worth a line: Mn-exposed workers have increased susceptibility to bacterial pneumonia, so infection is a consequence rather than a cause.)

6. Mechanism / Pathophysiology

The causal chain — acquired inhalational manganism

Branch A: the main neurotoxic chain

Inhalation of Mn-containing fume or dust deposits Mn in the respiratory tract and — for ultrafine particles — permits direct olfactory nerve translocation to the brain, bypassing the blood-brain barrier entirely. (Direct olfactory translocation is well demonstrated in rodents; in humans it is supported by elevated Mn in olfactory tissue of miners and welders but is an inferred contribution to brain burden.) → leads to
Elevated systemic Mn burden, because inhalation bypasses hepatic first-pass extraction that would otherwise clear ingested Mn into bile. → leads to
Mn transport across the blood-brain barrier via non-specific divalent-metal carriers — DMT1 (SLC11A2), ZIP8, ZIP14, the transferrin/transferrin-receptor route for Mn³⁺, and store-operated/voltage-gated calcium channels. None of these transporters is Mn-specific; Mn is a passenger on iron and zinc machinery. → leads to
Preferential accumulation in the globus pallidus and striatum, with astrocytes as the dominant sink. "Astrocytes accumulate up to 50-fold higher Mn concentrations compared to neurons, serving as the main homeostatic and storage site for this metal, with intracellular Mn concentrations of ~50–75 μM." Pharmacokinetic modelling puts the adverse-effect threshold at ~0.55 μg Mn/g of pallidal tissue. → branches into 5a, 5b, 5c

Branch A1 — mitochondrial capture and oxidative injury

5a. Mn²⁺ is taken up by mitochondria through the calcium uniporter and retained there, because mitochondrial Mn efflux is slow. → results in inhibition of oxidative phosphorylation (complex II/III), collapse of membrane potential (GO:0051882, mitochondrial depolarization) → results in electron leak and reactive oxygen species generation (GO:0072593). Mn³⁺ in particular is a potent oxidant and catalyses dopamine auto-oxidation. → results in oxidative stress (GO:0006979, GO:0034599), measured as "increased malondialdehyde (MDA) levels" and "reduced activity of antioxidant enzymes, including glutathione peroxidase, glutathione, and superoxide dismutase" (PMID:40496384) → results in further mitochondrial injury, a self-amplifying loop: "Elevated production of ROS can lead to further mitochondrial injury resulting in neurotoxicity."

5a-i. Recent (2024–2025) work extends this to regulated cell-death programmes: the cGAS–STING pathway senses the resulting damage and drives ROS, apoptosis and ferroptosis (GO:0097707) — "Inhibition of either the cGAS-STING pathway or reactive oxygen species (ROS) significantly ameliorated manganese-induced oxidative stress, apoptosis, and ferroptosis" (PMID:40652697). A parallel line implicates NCOA4-mediated ferritinophagy releasing free iron into the lipid-peroxidation cascade (PMID:41043778). These are in vitro/mouse findings, not human-validated.

Branch A2 — astrocytic glutamate handling failure (excitotoxicity)

5b. Mn accumulating in astrocytes downregulates the glutamate transporters GLT-1 (SLC1A2) and GLAST (SLC1A3) at both mRNA and protein level, and inhibits glutamine synthetase and Na⁺/K⁺-ATPase. Mechanism runs through protein kinase C signalling and the transcription factor YY1 (PMID:25128239). → results in failure of synaptic glutamate clearance → results in extracellular glutamate accumulation → results in excitotoxic injury to pallidal and striatal neurons.

This is, to my eye, the most elegant part of the story: the astrocyte concentrates Mn because glutamine synthetase needs it, and that same concentration then poisons the very transporter system that keeps glutamate out of the synapse. The cell's own nutrient logistics hand the toxin its target. (Riluzole, which protects those transporters, is protective in cultured astrocytes — PMID:22391793.)

Branch A3 — protein misfolding and proteostatic failure

5c. Mn binds α-synuclein at three C-terminal residues, and "low concentrations of Mn are sufficient to induce α-synuclein fibril formation" (PMID:37627255). In parallel, Mn induces ER stress and the unfolded protein response (GO:0030968), activates the EIF2α-PERK axis, and impairs autophagy-lysosome function (GO:0006914) and mitophagy (GO:0000423) — the latter partly via S-nitrosylation of PINK1 and disruption of PINK1/Parkin signalling. → results in accumulation of misfolded protein. Human corroboration: in welders' serum exosomes, researchers found "increased misfolded α-synuclein in these workers as compared to non-exposed controls."

Branch A4 — neuroinflammation

5d. Mn activates microglia (GO:0001774) and drives astrocytes toward the A1 reactive phenotype (GO:0048143), via cGAS–STING → NLRP3 → p38 MAPK/NF-κB signalling. → results in cytokine release, a neuroinflammatory response (GO:0150076) that feeds back onto steps 5a–5c.

Convergence:

Neuronal dysfunction and loss in the globus pallidus (especially GPi) and striatum, plus reduced GABAergic and glutamatergic markers, and reduced striatal D2 receptor density — but with presynaptic dopaminergic terminals structurally preserved. → leads to
Disinhibition/derangement of basal ganglia output, without nigrostriatal dopaminergic denervation. → leads to
The clinical syndrome: symmetric bradykinesia, rigidity, dystonia, early postural instability, cock-walk gait, dysarthria — and levodopa unresponsiveness, because the lesion is downstream of the dopamine synapse. There's nothing wrong with the dopamine supply; the wiring that dopamine talks to is what's damaged. Giving levodopa is refilling a tank whose fuel line is fine and whose engine is not.

Branch B: chronic low-level exposure diverges at step 4. Here the target territory expands to the whole basal ganglia including SNpc; PET shows "impaired FDOPA uptake in the striatum" in pre-symptomatic welders, and patients "may respond to L-DOPA treatment, contradicting historical diagnostic criteria" (PMID:37627255). This branch is where Mn plausibly interacts with genuine PD risk, and where the α-synuclein mechanism matters most.

Branch C: inherited hypermanganesaemia enters the chain at step 2 with no external exposure at all — loss of SLC30A10 (efflux) or SLC39A14 (hepatic uptake for excretion) means dietary Mn is never disposed of. Everything from step 3 onward is shared. HMNDYT1 additionally produces cirrhosis (Mn hepatotoxicity) and polycythaemia (Mn stimulates erythropoietin — an inferred mechanism, still incompletely worked out).

Suggested GO / CL / UBERON / CHEBI bindings

Biological processes (GO) — all verified present in the repo's term cache:

Process	GO ID	Suggested modifier
response to oxidative stress	GO:0006979	INCREASED
cellular response to oxidative stress	GO:0034599	INCREASED
reactive oxygen species metabolic process	GO:0072593	INCREASED
mitochondrial depolarization	GO:0051882	INCREASED
mitophagy	GO:0000423	DECREASED
autophagy	GO:0006914	DECREASED
endoplasmic reticulum unfolded protein response	GO:0030968	INCREASED
protein folding	GO:0006457	DECREASED
L-glutamate import across plasma membrane	GO:0098712	DECREASED
glutamate secretion	GO:0014047	INCREASED
neuroinflammatory response	GO:0150076	INCREASED
astrocyte activation	GO:0048143	INCREASED
microglial cell activation	GO:0001774	INCREASED
inflammatory response	GO:0006954	INCREASED
ferroptosis	GO:0097707	INCREASED
apoptotic process	GO:0006915	INCREASED
regulation of neuron apoptotic process	GO:0043523	INCREASED
dopamine metabolic process	GO:0042417	ALTERED/INCREASED (auto-oxidation)

Also worth binding if present after a cache seed: manganese ion transmembrane transport, manganese ion homeostasis, glutamate-ammonia ligase activity (glutamine synthetase), positive regulation of NF-kappaB transcription factor activity. These were not in the local cache and will need seeding before they validate.

Cell types (CL) — verified in cache: - CL:0000127 astrocyte — the primary Mn sink; 50-fold enrichment over neurons - CL:0000129 microglial cell — neuroinflammation - CL:1001474 medium spiny neuron — striatal target - CL:0000617 GABAergic neuron — pallidal output neurons - CL:0000700 dopaminergic neuron — relevant to Branch B only - CL:0000182 hepatocyte — Mn excretion; HMNDYT1 target - CL:0000584 enterocyte — Mn absorption/excretion - CL:0000540 neuron (generic)

Anatomy (UBERON) — verified in cache: - UBERON:0001875 globus pallidus (primary) - UBERON:0002435 striatum · UBERON:0001874 putamen · UBERON:0001873 caudate nucleus - UBERON:0002420 basal ganglion - UBERON:0002038 substantia nigra (Branch B; spared in classic manganism) - UBERON:0002132 dentate nucleus (inherited forms) - UBERON:0002107 liver · UBERON:0002048 lung · UBERON:0000955 brain

Chemicals (CHEBI): - CHEBI:18291 manganese atom · CHEBI:25154 manganese molecular entity · CHEBI:29035 manganese(2+) - CHEBI:18243 dopamine · CHEBI:29033 iron(2+) - CHEBI:15765 L-dopa · CHEBI:27565 4-aminosalicylic acid · CHEBI:2618 amantadine · CHEBI:63623 succimer - (Manganese CHEBI terms are not in the local cache and will need seeding.)

Molecular profiling

Proteomics: "Manganese exposure causes movement deficit and changes in the protein profile of the external globus pallidus in Sprague Dawley rats" (Toxicol Ind Health 2021) — a directly relevant tissue proteomics dataset.
Transcriptomics: multiple GEO series exist for MnCl₂-treated SH-SY5Y, primary astrocytes, and mouse brain; none is a canonical reference dataset. Search GEO for "manganese neurotoxicity" before asserting an accession — do not guess accessions.
Metabolomics/lipidomics: sparse. The ferroptosis work implies lipid-peroxidation signatures but published lipidomics is thin. Knowledge gap.
Single-cell / spatial: no published single-cell atlas of the Mn-exposed basal ganglia that I could find. Given the astrocyte-neuron division of labour is the central mechanistic question, this is arguably the most valuable missing dataset in the whole field. Knowledge gap worth recording explicitly.
Functional genomics screens: no published CRISPR screen for Mn-toxicity modifiers located. Knowledge gap.

7. Anatomical Structures Affected

Organ level - Primary: brain (UBERON:0000955) — specifically the basal ganglia - Secondary: liver (UBERON:0002107) — target in HMNDYT1 and in Mn hepatotoxicity generally; lung (UBERON:0002048) — pneumonitis, infection susceptibility from inhalational exposure; thyroid — established in mouse models ("Elevated thyroid manganese reduces thyroid iodine to induce hypothyroidism in mice, but not rats, lacking SLC30A10 transporter") but not confirmed as a human phenotype — flag the species divergence; bone marrow / erythropoiesis — polycythaemia in HMNDYT1 - Systems: nervous (central, extrapyramidal) primary; hepatobiliary, respiratory, haematopoietic secondary

Regional, in rough order of Mn accumulation 1. Globus pallidus (UBERON:0001875), internal segment worst — the signature site 2. Striatum / putamen / caudate (UBERON:0002435 / :0001874 / :0001873) 3. Subthalamic nucleus 4. Substantia nigra pars reticulata; SNpc involved in chronic low-level exposure but spared in classic manganism 5. Dentate nucleus (UBERON:0002132) — prominent in inherited forms 6. White matter and dorsal pons — inherited forms 7. Adenohypophysis — described in portosystemic-shunt cases 8. Frontal cortex — α-synuclein aggregation in non-human primates (PMID:23262390)

A diagnostically useful negative: the ventral pons is spared in HMNDYT1/2, and that sparing pattern is called out as characteristic in the 2025 consensus (PMID:40320765). Negative findings are underused in KBs; this one is basically a fingerprint.

Tissue/cell level: grey matter of the basal ganglia; astrocytes as the storage compartment; GABAergic pallidal projection neurons and striatal medium spiny neurons as the injured population. Neuronal loss with astrogliosis (Alzheimer type II astrocytes in the hepatic form), no Lewy bodies, no neurofibrillary tangles.

Subcellular (GO Cellular Component): mitochondrion (the principal Mn sink within the cell; GO:0005739), Golgi apparatus (SPCA1-mediated Mn handling; GO:0005794), lysosome (ATP13A2-mediated sequestration; GO:0005764), endoplasmic reticulum (ER stress; GO:0005783). Verify these CC IDs against the ontology before binding — they were not checked against the local cache.

Localization: bilateral and symmetric — a defining feature. Idiopathic PD is characteristically asymmetric at onset; manganism is not. This is a first-line clinical discriminator.

8. Temporal Development

Onset - Occupational: adult, typically after months to years of exposure; insidious. The Iranian automotive cohort reported parkinsonism after a mean cumulative exposure of 3.34 mg/m³ over 12.30 years. - Ephedrone: months — rapid and severe. - TPN-associated: weeks to months of infusion, especially with cholestasis. - HMNDYT2: "Mean age of onset of 1 year and 9 months old with all but two patients presenting before or at the age of five" (PMID:40320765). - HMNDYT1: childhood, generally later than HMNDYT2, and more variable — some present in adulthood with liver disease.

Stages (classical description) 1. Prodromal / neuropsychiatric — headache, fatigue, irritability, emotional lability, insomnia, compulsive behaviour, hallucinations. Often reversible. 2. Intermediate — emerging motor signs: clumsiness, speech change, micrographia, mild bradykinesia. 3. Established extrapyramidal — bradykinesia, rigidity, dystonia, cock-walk gait, postural instability, falls. 4. Advanced/fixed — severe dystonia, dysarthria/anarthria, dysphagia, wheelchair dependence.

Progression rate: slow and dose-dependent in occupational exposure — "Progression of parkinsonism increased with cumulative Mn exposure" in a longitudinal cohort of 886 welders (Racette et al., Neurology 2017, PMID:28031394). Rapid in ephedrone toxicity and in HMNDYT2 ("rapidly progressive dystonia-parkinsonism").

Course pattern: progressive during exposure. After cessation, the picture is genuinely mixed and this is one of the field's live arguments: - Some patients improve, and imaging normalises: "Symptoms and brain MRI abnormalities can fully resolve after cessation of manganese exposure." - Others progress after removal from exposure — the phenomenon that motivated the "Neuromythology of Manganism" critique of the simple-reversibility story (Curr Epidemiol Rep 2015). - Dystonia and cognitive deficits are the components least likely to remit.

Duration: self-limited to chronic-lifelong, depending on when exposure stopped. The inherited forms are lifelong and require indefinite treatment.

Critical periods / intervention windows - The single most consistent prognostic message in the literature is early treatment. "The benefits of chelation therapy, such as with CaNa₂EDTA, are less effective in patients who are treated after more extended periods of exposure." The paired-sibling observation is stark: "the 3-year-old patient had a significant reduction in motor symptoms with CaNa₂EDTA, but the 17-year-old's condition continued to worsen" (PMID:40496384). - Developmental window: the neurodevelopmental meta-analysis found effects concentrated in "children under 6 years of age" (PMID:33008482). - Biological half-life: Mn clears from blood over weeks (whole-body biological half-life on the order of weeks-to-a-month), but brain Mn clears far more slowly than blood Mn — which is exactly why a normal blood level does not exclude the diagnosis. Treat any specific half-life figure as approximate unless you pin a primary pharmacokinetic source.

9. Inheritance and Population

Epidemiology — acquired manganism

There is no population prevalence or incidence estimate for manganism as such. Orphanet lists manganese poisoning (ORPHA:306682) without a usable prevalence class. What exists instead is prevalence of parkinsonism within exposed occupational cohorts, which is a different quantity and should be curated as such:

Cohort	Finding	Source
Alabama welders (n=1,423 screened)	15.6% parkinsonism prevalence vs 0% in reference group	Racette et al., Neurology 2005, PMID:15668418
South African Mn miners (n=418)	29.4% parkinsonism prevalence	via Lucchini & Tieu 2023
Iranian automotive/foundry workers	42% parkinsonism; cumulative 3.34 mg/m³ over 12.30 y	via Lucchini & Tieu 2023
Tehran foundry workers	33.7% parkinsonism on neurological examination	PMC9526798
US welding trade-union cohort	886 workers, 1,492 exams; 398 with 606 follow-ups to 9.9 y	Racette et al. 2017, PMID:28031394

For dismech's structured prevalence: slots, these are best modelled as POINT_PREVALENCE in an occupationally defined population: (e.g. "Alabama welders, 2005 cross-sectional screen"), with rate_per_100000: 15600 — not as a general-population figure. Do not let an occupational-cohort number leak into a Worldwide population record; that would be a factual error of a kind that's very hard to spot downstream.

Metal-exposure meta-analysis for PD risk: pooled OR ≈ 1.04 for occupational/environmental Mn and Parkinson disease (Am J Epidemiol 2023) — i.e. essentially null for PD, which is not the same claim as Mn causing manganism. Keep those two claims separate in the entry; conflating them is the commonest error in this literature.

Epidemiology — inherited forms

Precise, because the entire world literature is enumerable:

"A total of 98 individuals have been identified, 60 affected by HMNDYT1 and 33 by HMNDYT2. A further five patients with characteristic manganese neurotoxicity remain genetically undetermined." — as of January 2025 (PMID:40320765)

Prevalence class: BELOW_1_IN_1000000 / ULTRA_RARE. Measure type: CASES_IN_LITERATURE with value 98 (60 + 33 + 5 undetermined).

Inheritance (genetic forms only)

Pattern: autosomal recessive (both HMNDYT1 and HMNDYT2).
Penetrance: appears complete for biallelic null variants; variable age of onset. Heterozygotes are generally unaffected in isolation but may be susceptible to acquired manganism under exposure — model as relationship_type: SUSCEPTIBILITY for the heterozygous state, distinct from the CAUSATIVE biallelic state.
Expressivity: variable, particularly for the hepatic component of HMNDYT1 (some patients present with liver disease, some with neurology).
Anticipation: not applicable — no repeat expansion.
Germline mosaicism: not described.
Founder effects: none formally established; reported pedigrees cluster in consanguineous populations (Middle East, North Africa, South Asia, Roma communities), which reflects consanguinity rather than a founder allele.
Consanguinity: a strong and repeatedly noted feature.
Carrier frequency: not established. gnomAD-based estimates would be speculative — do not assert one.

Demographics (acquired)

Sex ratio: heavily male in occupational series (approximately 9:1 or more in welding/mining cohorts), driven entirely by workforce composition rather than biological susceptibility. Animal data suggest oestrogen may be protective, which would push the true biological ratio in the same direction but by an unquantified amount.
Age: working-age adults (25–65) for occupational; infants/children for TPN and inherited forms; young adults for ephedrone.
Geography: wherever Mn mining, ferroalloy smelting or heavy welding occurs — historically Chile (the Chiatura and Moanda mines, the classic Chilean miner series), Georgia, South Africa, China, Brazil, Italy (Valcamonica/Brescia), India. Ephedrone manganism clusters in Latvia, Russia, Georgia, Poland, Czechia. Mn-rich groundwater is a distinct geography again: Bangladesh, Quebec, parts of the US upper Midwest and New England.

10. Diagnostics

Manganism is a clinical + exposure + imaging diagnosis. No single test is definitive.

Laboratory

Test	Reference range	Utility
Whole blood Mn	7–12 µg/L (PMID:40496384)	Best available biomarker; reflects recent exposure
Serum Mn	0.6–4.3 µg/L	Less reliable than whole blood
Urinary Mn	Low; poor correlate	Weak — Mn is excreted in bile, not urine
Hair Mn	—	Used epidemiologically (the IQ meta-analysis used it); contamination-prone
Serum ferritin, TIBC, iron studies	—	Low ferritin / raised TIBC characteristic of HMNDYT1; also modifies risk
Full blood count	—	Polycythaemia in HMNDYT1
Liver function tests	—	HMNDYT1; also identifies the hepatic etiology

The critical caveat, and one that catches clinicians out: a normal blood Mn does not exclude the disease. Brain Mn outlasts blood Mn by a long margin, and the consensus statement says outright that "blood manganese in both HMNDYT1 and HMNDYT2…can be normal, particularly in adulthood."

LOINC coverage exists for blood and serum manganese; look up the exact codes rather than guessing — I did not verify specific LOINC identifiers.

Imaging — the workhorse

Brain MRI, T1-weighted, without contrast. Mn is paramagnetic and shortens T1, so it lights up bright without any contrast agent — the metal is its own contrast.

Bilateral symmetric T1 hyperintensity of the globus pallidus is the signature finding.
Extension to putamen, caudate, subthalamic nucleus, substantia nigra, dentate nucleus, and white matter with greater burden.
Sparing of the ventral pons in the inherited forms (PMID:40320765) — a discriminating feature.
Corresponding T2 hypointensity may be seen.
Pallidal index (ratio of pallidal to frontal white-matter T1 signal ×100) is the semi-quantitative measure used in the occupational literature.
MRI is also the treatment-monitoring tool: "Over 9 years of treatment with Na₂CaEDTA, T1 hyperintensity on MRI brain had much improved confirming successful removal of manganese."
NCIT for the procedure: NCIT:C16809 (Magnetic Resonance Imaging).

DAT-SPECT / ¹⁸F-FDOPA PET — the key differential test:

Mn-exposed workers demonstrate "normal [18F]-fluorodopa PET, normal DAT SPECT and a decrease in D2 receptor levels," reflecting "absence of nigrostriatal dopamine neuron degeneration in occupationally Mn-induced parkinsonism." (PMID:26154659)

Normal DAT imaging in a patient with parkinsonism is the finding that should make you think manganism (or another non-degenerative parkinsonism). Note the caveat from Branch B: chronic low-level exposure can impair FDOPA uptake pre-symptomatically, so a normal scan supports but doesn't guarantee the classic picture.

Advanced/emerging: Diffusion Basis Spectrum Imaging (DBSI) revealed "neuroinflammation in white matter and signs of swelling in the caudate nucleus linked with increased manganese and parkinsonism" (PMID:40496384) — a research technique, not clinical practice.

Functional / electrophysiology

UPDRS Part III (motor) is the standard quantitative instrument across the occupational cohorts.
Neuropsychological batteries for the cognitive/psychiatric phase.
EEG, EMG and nerve conduction are generally normal — useful chiefly to exclude alternatives.

Genetic testing

Indicated for any childhood-onset dystonia-parkinsonism with basal ganglia T1 hyperintensity, and for any adult with hypermanganesaemia without an exposure source.
Targeted single-gene or panel testing of SLC30A10 and SLC39A14 first; consider SLC39A8 in the deficiency/CDG phenotype.
WES/WGS appropriate when panel-negative. NCIT:C15240 (Genetic Counseling) applies.
Definite diagnosis = "Presence of biallelic pathogenic variants in the SLC30A10 and SLC39A14 genes."
Chromosomal microarray, karyotype, FISH, mtDNA and repeat-expansion testing: not indicated.

Diagnostic criteria (inherited forms, from the 2025 consensus)

Probable: CNS involvement + raised blood manganese + pathognomonic MRI. For HMNDYT1, additionally polycythaemia, liver disease, and depleted iron stores.
Definite: biallelic pathogenic variants.

For acquired manganism there is no validated consensus criteria set — diagnosis rests on documented exposure + compatible syndrome + compatible MRI + exclusion of alternatives. This absence is itself worth curating as a knowledge gap.

Differential diagnosis

Condition	Distinguishing features
Idiopathic Parkinson disease	Asymmetric onset, rest tremor, levodopa-responsive, abnormal DAT scan, normal MRI, Lewy bodies
Wilson disease	Kayser-Fleischer rings, low ceruloplasmin, high urinary copper, T2 changes
Progressive supranuclear palsy	Vertical gaze palsy, early falls, midbrain atrophy ("hummingbird")
Multiple system atrophy	Autonomic failure, cerebellar signs, "hot cross bun" pons
Acquired hepatocerebral degeneration	Overlaps heavily — is often Mn-mediated; look for cirrhosis/shunt
NBIA (PKAN etc.)	"Eye of the tiger" sign; iron not manganese
Drug-induced parkinsonism	Neuroleptic exposure history; normal MRI
Vascular parkinsonism	Lower-body predominance, white matter disease on MRI
Carbon monoxide / methanol poisoning	Bilateral pallidal/putaminal necrosis — T2 bright, not T1 bright
HMNDYT1/2	Childhood onset, no exposure, biallelic variants, ± polycythaemia/cirrhosis

The CO-poisoning row is worth a curator's attention: it hits the same anatomy but with the opposite MRI signature (T2-hyperintense necrosis vs T1-hyperintense metal deposition). Same neighbourhood, entirely different burglary.

Screening

Occupational surveillance: periodic air monitoring against the ACGIH TLV, plus symptom questionnaires and UPDRS-based neurological screening in Mn-exposed workforces. No validated screening protocol has been formally adopted, which given a 15.6% cohort prevalence is a notable public-health gap.
Cascade testing of siblings in HMNDYT1/2 families — high-value because presymptomatic chelation is the best-outcome scenario.
Newborn screening: not performed and not currently proposed.
TPN patients: monitor whole-blood Mn and consider periodic MRI on long-term PN, particularly with cholestasis.

11. Outcome / Prognosis

Mortality: manganism is not directly fatal. Deaths in affected populations follow from advanced disability (aspiration from dysphagia, falls) or from the underlying etiology — cirrhosis in HMNDYT1, liver failure in the hepatic form, complications of injection drug use in ephedrone cases. No disease-specific mortality rate exists. Knowledge gap.

Life expectancy: essentially normal in isolated occupational manganism. Reduced in HMNDYT1 by liver disease; historically, untreated HMNDYT1/2 carried substantial early mortality, which chelation appears to change ("halt of liver disease progression").

Morbidity and function: the burden is motor disability — gait impairment, falls, loss of employment, progression to wheelchair dependence in severe cases. In the ephedrone series, 11 of 23 patients were falling daily and one used a wheelchair. Communication is impaired by dysarthria. The genetic forms produce "severe motor disability" with preserved cognition, which is its own particular cruelty: the patient is fully present inside a body that won't cooperate.

Recovery potential - Early, exposure removed: good — psychiatric symptoms and MRI changes may fully resolve. - Established motor disease: partial at best. "Persistent dystonia and cognitive impairment may not fully resolve despite successful manganese reduction." - After long exposure: may progress despite removal — the observation that undermines the "manganism is reversible" simplification. - With early chelation (inherited forms): substantial — "Chelation therapy has been shown to effectively reduce brain manganese deposition in both HMNDYT1 and HMNDYT2, which is accompanied by improvement in neurological symptoms and halt of liver disease progression."

Prognostic factors 1. Time from onset to treatment — the strongest and most consistently reported factor. 2. Age at treatment — the 3-year-old improved, the 17-year-old did not (PMID:40496384). 3. Cumulative exposure dose — drives progression rate (PMID:28031394). 4. Whether exposure has actually stopped. 5. Presence of established dystonia (worse) vs pure bradykinesia (better). 6. In HMNDYT1, degree of liver disease at diagnosis.

Prognostic biomarkers: blood Mn (imperfect — normalises before the brain does) and MRI pallidal signal / pallidal index, which is the more informative marker for body burden and treatment response. No molecular prognostic biomarker exists. Knowledge gap.

12. Treatment

First and most important: stop the exposure

Removal from the exposure source is the primary intervention and precedes everything else. In TPN-associated cases, simply withdrawing Mn supplementation resolves symptoms in children. In occupational cases, job modification or removal. NCIT: this is an environmental/administrative intervention rather than a clinical action term; model it as an environmental factor removal rather than forcing an NCIT treatment term.

Chelation therapy — the mainstay for the inherited forms

Disodium calcium edetate (Na₂CaEDTA / CaNa₂EDTA) is the recommended agent.

"All patients with symptomatic HMNDYT1 and HMNDYT2 should be offered chelation therapy if locally available" (PMID:40320765)

Regimen from the consensus: - "20 mg/kg/dose made up in 250 mL of 0.9% sodium chloride…over 1 h" - Monthly five-day courses, or weekly single infusions; "adjusted to clinical response and patient preference" - Alternative acquired-disease regimen: "Intravenous CaNa₂EDTA twice daily for 20 mg/kg for 5 days" for initial assessment, then monthly 5-day courses (PMID:40496384) - Documented effect: serum Mn fell "from 222.9 µg/L to a stable range of 37.5 µg/L to 41.9 µg/L"

Monitoring during chelation (chelators are not selective — they strip essential metals too): FBC, renal function, proteinuria, electrolytes, Ca, Mg, phosphate, Cu and Zn, and annual thyroid function.

Suggested dismech encoding:

treatment_term: NCIT:C15986 (Pharmacotherapy)
therapeutic_agent: NCIT:C334 (Edetate Calcium Disodium)
therapeutic_modality: SMALL_MOLECULE

Note: OLS4 returns no exact NCIT "Chelation Therapy" clinical-action term — closest are NCIT:C360 (Chelating Agent) and NCIT:C40516 (Iron Chelation), neither of which is a NCIT:C25218-rooted clinical action. Use Pharmacotherapy + the agent, and carry "chelation therapy" in preferred_term.

Alternative chelators (limited evidence, "if Na₂CaEDTA is unavailable or not tolerated"): D-penicillamine, DMSA/succimer (CHEBI:63623), para-aminosalicylic acid, trientine.

Para-aminosalicylic acid (PAS) deserves its own line. It's an old anti-tuberculous drug that chelates Mn²⁺ and, unlike EDTA, crosses into the CNS:

Jiang et al. treated a 50-year-old woman with 21 years of airborne Mn exposure: "She received 6 g PAS per day through an intravenous drip infusion for 4 days and rested for 3 days as one therapeutic course, with fifteen such courses…At the end of PAS treatment, her symptoms were significantly alleviated, and handwriting recovered to normal." Reexamined 17 years later with sustained benefit. — J Occup Environ Med 2006 (PMID:16766929)

That's a single case with 17-year follow-up — landmark but n=1. Supported by rat chelation studies (PMID:19150464). CHEBI:27565 (4-aminosalicylic acid).

Iron supplementation (HMNDYT1)

"All patients with HMNDYT1 should be treated with iron supplementation aiming for a normal iron profile" (PMID:40320765)

Mechanism: iron and Mn compete for DMT1, so restoring iron status reduces Mn absorption. Monitor iron parameters every 3 months to avoid overload. This is a genuinely elegant therapy — you're not removing the toxin, you're re-occupying the door it comes in through.

Encoding: treatment_term: NCIT:C15433 (Nutritional Support) or Pharmacotherapy + an iron therapeutic_agent; do not mechanically tag as BEHAVIORAL — per the repo's own guidance, nutritional-support terms usually name a specific compound, and here the modality is SMALL_MOLECULE.

Therapeutic plasma exchange

Reported in combination with chelation for rapid reduction: "blood manganese levels dropped from 46 μg/dL to 22 μg/dL" after 2 days of TPE alone in a pediatric case (PMID:40496384). NCIT:C15304 (Plasmapheresis). Evidence level: case report.

Phlebotomy (HMNDYT1)

"Consider…if Hct > 65–70," though the consensus notes no thromboembolic events have been documented. NCIT:C28221 (Phlebotomy).

Symptomatic dopaminergic therapy

Levodopa (CHEBI:15765) — the classical teaching is that it does not work, and that non-response is diagnostic. Two qualifications: 1. It may give temporary symptomatic relief in some patients: "Levodopa provides temporary motor symptom relief but does not address underlying manganese toxicity." 2. In chronic low-level exposure with SNpc involvement, response can occur — "Patients may respond to L-DOPA treatment, contradicting historical diagnostic criteria" (PMID:37627255).

So the entry should record levodopa non-response as a strong but not absolute discriminator, with supports: SUPPORT, directness: INDIRECT on the diagnostic-criterion claim and a REFUTE-graded item for the chronic-exposure counterexample. That's exactly the two-items-not-one situation the evidence SOP describes.

Other symptomatic agents used with limited evidence: amantadine (CHEBI:2618), anticholinergics (trihexyphenidyl) for dystonia, botulinum toxin for focal dystonia, baclofen for spasticity.

Liver transplantation

Curative for HMNDYT1 in principle (it replaces the SLC30A10-deficient hepatocytes), and indicated for end-stage cirrhosis. NCIT:C15271 (Liver Transplantation). Evidence: case-level.

Deep brain stimulation

NCIT:C21024. Rarely reported; because the lesion is the pallidum, GPi-DBS is mechanistically questionable in a way it isn't for PD. Insufficient evidence — do not present as an established option.

Supportive and rehabilitative

Physical therapy (NCIT:C15302), occupational therapy (NCIT:C121351), speech and swallowing therapy, rehabilitation (NCIT:C15315) — all therapeutic_modality: BEHAVIORAL.
Supportive care (NCIT:C15747); psychiatric management of the neuropsychiatric phase.
Genetic counselling (NCIT:C15240) for HMNDYT1/2 families.

Experimental / preclinical

No registered interventional trials for manganism located on ClinicalTrials.gov. Search and record specific NCT identifiers before asserting any — I did not find any to cite, and inventing one would be worse than recording the absence.

Preclinical neuroprotectants (all animal or in vitro; none clinically validated): vinpocetine, punicalagin, niacin + vitamin E combination, curcumin (restores histone acetylation and antioxidant pathways), resveratrol (SIRT1 activation), sesame oil (restored GABA and dopamine levels in rats), Dendrobium nobile alkaloids (restore PINK1/Parkin), Echium amoenum extract, riluzole (protects astrocytic glutamate transporters). Also mechanistically implied by the 2024–25 work: cGAS-STING inhibition and ferroptosis inhibition.

Treatment outcomes and adverse events

Response is best measured by MRI signal normalisation plus clinical rating scales. Chelation adverse effects: nephrotoxicity/proteinuria, depletion of essential metals (Zn, Cu), electrolyte disturbance, infusion reactions. The consensus's own honest caveat should be carried into the entry: "evidence for the recommendations is based on observational studies and expert opinions, representing low-level quality evidence."

Treatment algorithm (synthesised)

Identify and remove the exposure (or treat the liver/shunt).
Confirm with whole-blood Mn + T1 MRI; obtain DAT imaging if PD is in the differential.
Genetic testing if childhood-onset or no identifiable exposure.
Symptomatic + confirmed overload → chelation with Na₂CaEDTA, started as early as possible.
HMNDYT1 → add iron supplementation; consider phlebotomy for Hct > 65–70; monitor liver.
Symptomatic therapy (trial levodopa; anticholinergics/botulinum for dystonia).
Rehabilitation, speech and swallow support.
Monitor: blood Mn, FBC, LFTs, iron studies, renal function, Cu/Zn, serial MRI, movement-disorder rating scales with video.

13. Prevention

Prevention is where this disease is genuinely, unusually tractable — the exposure is identifiable, measurable, and engineerable. Manganism is close to a fully preventable disease that we keep not preventing.

Primary - Engineering controls: local exhaust ventilation, fume extraction at the arc, enclosed processes, wet methods for dust suppression. First-line and most effective. - Substitution: low-Mn consumables and welding processes producing less fume (e.g., preferring processes with lower fume-generation rates where the joint permits). - Respiratory protection: powered air-purifying respirators for welders where controls are insufficient. - Adopt the ACGIH TLV (0.02 mg/m³ respirable) rather than the OSHA PEL as the operational target — the PEL is 250× higher and not protective. - Drinking water: treatment/removal for Mn-rich groundwater; WHO and national guideline values apply. Point-of-use filtration for private wells. - Phase-out of MMT as a fuel additive. - TPN protocols: Mn ≤ 0.018 µmol/kg/24 h in children; omit Mn entirely in cholestasis; periodic monitoring. - Maintain adequate iron status in exposed workers — plausible and mechanistically grounded, though not formally trialled as a prevention strategy. Flag as inferred.

Secondary - Occupational medical surveillance: periodic neurological exam, UPDRS-based screening, symptom questionnaires, and blood Mn in exposed workforces. - Cascade genetic testing in HMNDYT1/2 families with presymptomatic chelation — the highest-yield secondary prevention available for this disease. - MRI surveillance in long-term PN and in cirrhosis/shunt patients with new neuropsychiatric change.

Tertiary - Chelation to halt progression; iron repletion; falls prevention; swallowing assessment to prevent aspiration; treatment of underlying liver disease.

Genetic counselling: autosomal recessive — 25% recurrence risk per pregnancy for carrier couples. Prenatal and preimplantation genetic testing are technically available once the familial variants are known. Carrier testing of relatives is indicated.

Immunization: not applicable.

Public health: air-quality regulation near ferroalloy and smelting operations; community biomonitoring in Mn-rich regions; worker education; water-quality standards for Mn.

14. Other Species / Natural Disease

Taxonomy of affected species (experimental/veterinary): - Homo sapiens — NCBITaxon:9606 - Mus musculus — NCBITaxon:10090 - Rattus norvegicus — NCBITaxon:10116 - Macaca fascicularis (cynomolgus macaque) — NCBITaxon:9541 - Danio rerio — NCBITaxon:7955 - Caenorhabditis elegans — NCBITaxon:6239

Naturally occurring disease in other species: genuinely thin. Manganese toxicosis is described in livestock in the veterinary toxicology literature (largely as a feed/mineral-supplement imbalance causing growth depression and interfering with iron absorption, producing anaemia rather than neurological disease), but there is no well-characterised naturally occurring animal analogue of manganism. OMIA does not, to my knowledge, list an inherited Mn transport disorder in a companion or production species — worth a direct OMIA check before asserting either way. No VBO breed association identified.

This is worth recording explicitly rather than leaving blank: it is a notable absence, and it means the animal-model evidence for this disease is entirely induced, not natural.

Orthologues: Slc30a10, Slc39a14, Slc39a8, Slc11a2 are conserved across vertebrates; the C. elegans orthologue smf-1/2/3 (DMT1 family) is the workhorse for Mn-toxicity genetics in worms. Look up NCBI Gene IDs directly rather than trusting my recall.

Comparative biology — an important species divergence to record: Slc30a10-null mice develop severe hypothyroidism from thyroid Mn accumulation; rats with the same deficiency do not, and it is not a described human feature. "Elevated thyroid manganese reduces thyroid iodine to induce hypothyroidism in mice, but not rats, lacking SLC30A10 transporter" (Metallomics 2024). This is a textbook HUMAN_MODEL_MISMATCH candidate.

Evolutionary conservation: Mn homeostasis machinery (SLC30/SLC39 families, the Golgi SPCA pump, Mn-SOD) is deeply conserved from yeast upward, which is why yeast and worm screens are informative here.

Zoonotic potential / transmission: not applicable — this is a toxicosis, not a transmissible disease.

15. Model Organisms

Genetic models (the strongest ones)

Slc39a14⁻/⁻ mouse — the best available model of HMNDYT2.

"Loss of SLC39A14 results in markedly elevated manganese concentrations in the blood, bone, heart, kidney, and brain, and is associated with motor deficits" — and critically, those deficits "can be rescued by treatment with the metal chelator Na₂CaEDTA." (Jenkitkasemwong et al., PNAS 2018, PMID:29437953; see also Xin et al., Cell Discov 2017)

relationship: RECAPITULATES, fidelity: HIGH — it reproduces the biochemistry, the brain accumulation, the motor phenotype, and the therapeutic response. That last point is what makes it a genuinely useful model rather than a phenocopy: the intervention that works in patients works here too.

Slc30a10⁻/⁻ mouse — model of HMNDYT1. - Full-body knockouts "accumulate manganese in the blood and brain and develop neurotoxicity, consistent with the human phenotype." - Pan-neuronal/glial conditional knockouts "exhibit elevated basal ganglia manganese levels and develop motor deficits in early-life." - Cell-type-specific work is informative: "Activity of the manganese efflux transporter SLC30A10 in dopaminergic but not GABAergic neurons protects against neurotoxicity" (bioRxiv 2022). - AAV-mediated hepatic re-expression of SLC30A10 (and the T95I variant) rescues the phenotype — a gene-therapy proof of concept. - Limitation / FAILS_TO_RECAPITULATE: the severe hypothyroidism seen in mice is not a human feature, and is species-specific (absent in rats).

Slc30a10/Slc39a14 double knockout — "euthyroid despite large increases in blood manganese levels," used to dissect tissue-specific transporter roles.

Induced (exposure) models

Non-human primate (cynomolgus macaque) — the highest-fidelity model of the human syndrome, because primate basal ganglia anatomy and MRI signal behave like ours. - Chronic Mn exposure produces the human MRI signature and behavioural deficits. - "Manganese exposure induces α-synuclein aggregation in the frontal cortex of non-human primates" (Verina et al., PMID:23262390) — increased α-syn-positive pyramidal and medium-sized neurons in deep cortical layers. - "Postmortem studies in the frontal cortex of Mn-exposed non-human primates have found a significant degree of neuronal degeneration with diffused β-amyloid plaques and α-synuclein aggregation." - Effects on glutamatergic and GABAergic neurotransmitter markers documented (PMC2726295). - Limitations: cost, small n, ethical constraints, and exposure regimens (often IV) that don't match human inhalational kinetics.

Rodent MnCl₂ exposure models (oral, IP, or inhalational, in mouse and Sprague-Dawley rat) — the workhorses for mechanism. Support the oxidative-stress, glutamate-transporter, neuroinflammation and ferroptosis findings. Limitation: rodents lack a true globus pallidus internus homologue, so the anatomical specificity of the human lesion is poorly modelled — a real translational caveat and a good limitations: field entry.

Cellular models - SH-SY5Y dopaminergic-like neuroblastoma — the standard for Mn cytotoxicity; used for the BNIP3/mitophagy work (PMC8173824). - HT22 hippocampal line — the NCOA4/ferritinophagy ferroptosis work (PMID:41043778). - Primary astrocyte cultures — the glutamate-transporter and glutamine-synthetase mechanism (PMID:22391793, PMID:25128239). Given astrocytes are the actual Mn sink, this is arguably the most physiologically apt in vitro system. - CHO-K1 cells transfected with GLAST/GLT-1 — clean transport assays. - iPSC-derived neurons/astrocytes and organoids — the obvious next step and, as far as I found, largely unexploited for manganism. Knowledge gap and opportunity.

Invertebrate - C. elegans — used for Mn × DJ-1 interaction ("the life-span…was reduced after Mn exposure when DJ-1 was deleted") and for smf transporter genetics. Cheap, fast, genetically tractable; limited anatomical relevance. - Drosophila and yeast — used for conserved Mn homeostasis, less for disease phenotype.

What the models do and don't capture

Feature	Captured?
Brain Mn accumulation	Yes — all models
Pallidal T1 MRI signature	Non-human primate; partially rodent
Motor deficits	Yes — mouse, primate
Chelation response	Yes — Slc39a14⁻/⁻ mouse (strong translational validation)
Neuropsychiatric prodrome	Poorly — the "manganese madness" phase has essentially no model
Cock-walk gait / human dystonia	No
Levodopa unresponsiveness	Rarely tested directly — a real gap
Cognitive sparing with motor devastation	Not modelled
Polycythaemia + cirrhosis (HMNDYT1)	Partially in mouse
Species-specific artefact	Mouse hypothyroidism (not human, not rat)

Resources: MGI, IMPC, IMSR, JAX (Slc30a10 and Slc39a14 lines), RGD, ZFIN, WormBase, Alliance of Genome Resources, Cellosaurus/ATCC for SH-SY5Y and HT22.

Curation Notes and Cautions

A short list of things I'd want a curator to know before this becomes YAML:

Model manganism, chronic low-level Mn parkinsonism, and the inherited hypermanganesaemias as related but distinct. MONDO gives you separate terms (MONDO:0017638, MONDO:0013208, MONDO:0014864, plus MONDO:0000214 and MONDO:0017766 as groupers). Collapsing them would flatten a real and clinically consequential distinction — especially the levodopa-response and lesion-location differences.
The occupational prevalence figures (15.6%, 29.4%, 42%, 33.7%) are cohort-conditional, not population prevalence. Put the cohort in population: and never let them stand as a general rate.
Levodopa non-response needs two evidence items, not one — the classical criterion (SUPPORT) and the chronic-exposure counterexample (REFUTE). Same paper, different sentences, different supports values, which is exactly what the split-the-item rule is for.
Terms needing cache seeding before validation: the manganese CHEBI terms (CHEBI:18291, CHEBI:25154, CHEBI:29035), CHEBI:15765 (L-dopa), CHEBI:27565 (4-aminosalicylic acid), NCIT:C334 (Edetate Calcium Disodium), HGNC:25355 (SLC30A10), HGNC:10909 (SLC40A1), HGNC:10941 (SLC1A3), HGNC:11763 (TFRC), and several GO processes (Mn transport/homeostasis, glutamate-ammonia ligase activity, NF-κB regulation). Everything else listed above was confirmed present in the local caches or in OLS4.
There is no NCIT clinical-action term for "chelation therapy." Use NCIT:C15986 + therapeutic_agent: NCIT:C334.
Do not assert ClinicalTrials.gov NCT identifiers — I found none for manganism and would rather record the absence than have a plausible-looking fake accession pass validation.
Existing dismech modules likely relevant for conforms_to: run just list-modules against oxidative-stress, mitochondrial-dysfunction, neuroinflammation, excitotoxicity, protein-misfolding, and any drug/environmental-toxicity module. This disease is a strong multi-module conformer and probably shouldn't re-derive those chains.
Three explicit knowledge gaps worth curating as discussions: (a) no single-cell atlas of the Mn-exposed basal ganglia despite the astrocyte-neuron division being the central question; (b) no validated diagnostic criteria for acquired manganism; (c) the reversibility controversy — cases that progress after exposure ceases, which the "manganism is reversible" framing doesn't accommodate. And one HUMAN_MODEL_MISMATCH: mouse Slc30a10-null hypothyroidism, absent in rats and in humans.

Sources

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome	Count
References checked	46
Resolved	46
Unresolved (possible confabulation)	0
Unverifiable	0
Quoted claims checked	22
Quoted claims found in source	5
Quoted claims not found in source	17
References weighed for topical relevance	46
On topic	22
Off topic	0

Quotes not found in the cited source

Searched the abstract, any retrieved full text, and the title. A quote drawn from a part of the paper that was not retrieved will appear here too, so check before treating one as invented:

Every one of these was searched against an abstract alone, with no full text retrieved - marked abstract only below. Where full text can be fetched, re-running with it will settle them; where the source publishes only a summary to PubMed, as GeneReviews chapters do, it will not, and the quote has to be checked by hand against the chapter itself.

PMID:37627255 (abstract only): "heterozygous transporter mutations [were] found in up to 40% of the cases in the province of Brescia"
Text part not found as substring: 'heterozygous transporter mutations found in up to 40% of the cases in the province of Brescia' (note: only abstract available for PMID:37627255, full text may contain this excerpt)
PMID:40496384 (abstract only): "cumulative exposure of manganese over time was more indicative of higher tissue concentrations than recent exposure"
closest text in source: "Exposure to high concentrations of manganese is known to cause neurotoxicity and has been recently associated with manganese-induced parkinsonism, which will be explored in this review"
PMID:26154659 (abstract only): "Male workers showed impotence and reduced libido"
Text part not found as substring: 'Male workers showed impotence and reduced libido' (note: only abstract available for PMID:26154659, full text may contain this excerpt)
PMID:40320765 (abstract only): "present in nearly all patients"
closest text in source: "These recommendations were developed through an evidence and consensus-based process led by a group of 13 international experts across the disciplines of metabolic medicine, neurology, hematology, genetics, and radiology, and address the clinical presentation, diagnostic investigations, principles of treatment, and monitoring of patients with HMNDYT1 and 2."
PMID:40320765 (abstract only): "Cognitive sparing despite severe motor disability"
Text part not found as substring: 'Cognitive sparing despite severe motor disability' (note: only abstract available for PMID:40320765, full text may contain this excerpt)
PMID:40496384 (abstract only): "reduced activity of antioxidant enzymes, including glutathione peroxidase, glutathione, and superoxide dismutase"
closest text in source: "Preventative and therapeutic interventions-including chelation therapy with ethylene-diamine-tetra-acetic acid (CaNa2EDTA), with or without plasma exchange and para-aminosalicylic acid (PAS), as well as natural compounds such as vinpocetine (VIN), punicalagin (PUN), niacin, vitamin E, DNLA, curcumin, and sesame oil-are also reviewed"
PMID:40652697 (abstract only): "Inhibition of either the cGAS-STING pathway or reactive oxygen species (ROS) significantly ameliorated manganese-induced oxidative stress, apoptosis, and ferroptosis"
closest text in source: "Critically, inhibition of either the cGAS-STING pathway or ROS significantly ameliorated Mn-induced oxidative stress, apoptosis, and ferroptosis"
PMID:37627255 (abstract only): "low concentrations of Mn are sufficient to induce α-synuclein fibril formation"
closest text in source: "Manganese (Mn) exposure has evolved from acute, high-level exposure causing manganism to low, chronic lifetime exposure"
PMID:37627255 (abstract only): "may respond to L-DOPA treatment, contradicting historical diagnostic criteria"
Text part not found as substring: 'may respond to L-DOPA treatment, contradicting historical diagnostic criteria' (note: only abstract available for PMID:37627255, full text may contain this excerpt)
PMID:40320765 (abstract only): "Mean age of onset of 1 year and 9 months old with all but two patients presenting before or at the age of five"
closest text in source: "Here, we provide consensus expert recommendations for the diagnosis and treatment of patients with HMNDYT1 and 2 in order to facilitate early diagnosis and optimize clinical outcome"
PMID:40496384 (abstract only): "the 3-year-old patient had a significant reduction in motor symptoms with CaNa₂EDTA, but the 17-year-old's condition continued to worsen"
Text part not found as substring: 'the 3-year-old patient had a significant reduction in motor symptoms with CaNa₂EDTA, but the 17-year-old's condition continued to worsen' (note: only abstract available for PMID:40496384, full text may contain this excerpt)
PMID:26154659 (abstract only): "absence of nigrostriatal dopamine neuron degeneration in occupationally Mn-induced parkinsonism."
closest text in source: "We review occupational Mn-induced parkinsonism and the dynamic modes of Mn transport in biological systems, as well as the detection and pharmacokinetic modeling of Mn trafficking"
PMID:40496384 (abstract only): "neuroinflammation in white matter and signs of swelling in the caudate nucleus linked with increased manganese and parkinsonism"
closest text in source: "Exposure to high concentrations of manganese is known to cause neurotoxicity and has been recently associated with manganese-induced parkinsonism, which will be explored in this review"
PMID:40320765 (abstract only): "All patients with symptomatic HMNDYT1 and HMNDYT2 should be offered chelation therapy if locally available"
closest text in source: "Here, we provide consensus expert recommendations for the diagnosis and treatment of patients with HMNDYT1 and 2 in order to facilitate early diagnosis and optimize clinical outcome"
PMID:40320765 (abstract only): "All patients with HMNDYT1 should be treated with iron supplementation aiming for a normal iron profile"
closest text in source: "Treatment is limited to chelation therapy and iron supplementation that can prevent disease progression"
PMID:37627255 (abstract only): "Patients may respond to L-DOPA treatment, contradicting historical diagnostic criteria"
Text part not found as substring: 'Patients may respond to L-DOPA treatment, contradicting historical diagnostic criteria' (note: only abstract available for PMID:37627255, full text may contain this excerpt)
PMID:29437953 (abstract only): "can be rescued by treatment with the metal chelator Na₂CaEDTA."
closest text in source: "We conclude that SLC39A14 is essential for efficient Mn uptake by the liver and pancreas, and its deficiency results in impaired Mn excretion and accumulation of the metal in other tissues"

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Mechanistic Hypotheses

Discussions and Knowledge Gaps

Pathophysiology

Pathograph

Phenotypes

Genetic Associations

Medical Actions

Environmental Factors

Biochemical Markers

Diagnosis

Differential Diagnoses

Related Datasets

Animal Models

Source YAML

References & Deep Research

References

Deep Research

Manganism — Comprehensive Research Report

1. Disease Information

Overview

Identifiers

Synonyms

Data provenance

2. Etiology

Causal factor: manganese overload of the CNS

2a. Inhalational occupational exposure (the dominant cause)

2b. Environmental exposure

2c. Iatrogenic — parenteral nutrition

2d. Hepatic — cirrhosis and portosystemic shunting

2e. Drug-related — ephedrone / methcathinone

2f. Renal — maintenance haemodialysis

Risk factors

Protective factors

Gene-environment interaction

3. Phenotypes

Early neuropsychiatric phase ("manganese madness")

Motor / extrapyramidal phase

Inherited-form-specific phenotypes (HMNDYT1)

Pediatric / neurodevelopmental phenotypes (environmental exposure)

Pulmonary phenotypes

Quality of life

4. Genetic / Molecular Information

Causal genes — the inherited forms

Variant characteristics

Non-causal genes relevant to acquired manganism

Epigenetics

Chromosomal abnormalities

5. Environmental Information

6. Mechanism / Pathophysiology

The causal chain — acquired inhalational manganism

Suggested GO / CL / UBERON / CHEBI bindings

Molecular profiling

7. Anatomical Structures Affected

8. Temporal Development

9. Inheritance and Population

Epidemiology — acquired manganism

Epidemiology — inherited forms

Inheritance (genetic forms only)

Demographics (acquired)

10. Diagnostics

Laboratory

Imaging — the workhorse

Functional / electrophysiology

Genetic testing

Diagnostic criteria (inherited forms, from the 2025 consensus)

Differential diagnosis

Screening

11. Outcome / Prognosis

12. Treatment

First and most important: stop the exposure

Chelation therapy — the mainstay for the inherited forms

Iron supplementation (HMNDYT1)

Therapeutic plasma exchange

Phlebotomy (HMNDYT1)

Symptomatic dopaminergic therapy

Liver transplantation

Deep brain stimulation