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Inheritance

2

Autosomal dominant HP:0000006

The majority pattern. A heterozygous variant in the 3-prime RING-encoding exons whose premature termination codon escapes nonsense-mediated decay yields a truncated protein that acts dominant-negatively, so one allele is enough. Penetrance is incomplete and expressivity wide: asymptomatic carriers occur in several pedigrees and may be identifiable only by lower-limb muscle MRI.

Autosomal dominant inheritance

Show evidence (2 references)

PMID:33414056 SUPPORT Human Clinical

"The majority follows dominant inheritance, whereas recessive inheritance has been described for one variant."

Establishes dominant inheritance as the usual pattern and recessive as the exception, which is why this block is listed first.

PMID:33568173 SUPPORT Human Clinical

"Asymptomatic individuals were identified in several pedigrees exemplifying the strong phenotypic variability of these patients requiring serial clinical evaluation to establish correct diagnosis"

Documents incomplete penetrance and its practical consequence for diagnosis, which is what makes the dominant pattern hard to recognise in a small family.

Autosomal recessive HP:0000007

The minority pattern, established in the large consanguineous eastern Canadian kindred in which LRSAM1 was first identified. A homozygous splice-acceptor variant causes aberrant splicing, an obligatory frameshift and premature truncation, and no detectable protein - so heterozygotes, retaining one working allele, are unaffected.

Autosomal recessive inheritance

Show evidence (2 references)

PMID:20865121 SUPPORT Human Clinical

"We studied a large family from a rural eastern Canadian community, with multiple individuals suffering from a condition clinically most similar to autosomal recessive axonal CMT, or AR-CMT2."

The founding recessive kindred and its clinical classification.

PMID:33568173 SUPPORT Human Clinical

"The recessive CMT mutations lead to complete loss of LRSAM1, contrary to the heterozygous dominant variants."

States the molecular difference between the two inheritance patterns, which is the reason they are two blocks and not two diseases.

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Mechanistic Hypotheses

2

Loss of LRSAM1 Ubiquitin Ligase Activity

lrsam1_ubiquitylation_failure CANONICAL

Both the recessive and the dominant allele classes end at the same place: LRSAM1 cannot transfer ubiquitin to its substrates, because either no protein is made or a truncated RING-domain protein poisons the residual activity. Loss of ubiquitylation impairs TSG101-dependent endosomal sorting and neuronal proteostasis, lowering the threshold at which the longest peripheral axons degenerate. CANONICAL because the human genetics, the in vitro ubiquitylation assays on three separate disease alleles, and the sensitised mouse axon all converge on it.

Pathograph links

LRSAM1 RING-Domain Variants -> Nonsense-Mediated Decay and Complete Loss of LRSAM1 Protein The recessive route: the mutant transcript is degraded and no protein is made.

LRSAM1 RING-Domain Variants -> Dominant-Negative Truncated RING-Domain Protein The dominant route: the premature termination codon escapes nonsense-mediated decay and a truncated protein is made.

Nonsense-Mediated Decay and Complete Loss of LRSAM1 Protein -> Failure of E2-E3 Interaction and Loss of Ubiquitylation Activity No ligase present to transfer ubiquitin.

Dominant-Negative Truncated RING-Domain Protein -> Failure of E2-E3 Interaction and Loss of Ubiquitylation Activity Truncated or altered RING domain poisons residual ligase activity.

Failure of E2-E3 Interaction and Loss of Ubiquitylation Activity -> Impaired TSG101-Dependent Endosomal Sorting Loss of ubiquitylation of the one well-validated substrate.

Impaired TSG101-Dependent Endosomal Sorting -> Increased Vulnerability of Long Peripheral Axons Perturbed neuronal proteostasis and membrane traffic, inferred rather than demonstrated in neurons.

Increased Vulnerability of Long Peripheral Axons -> Distal Muscle Weakness Degeneration of the longest motor axons.

Increased Vulnerability of Long Peripheral Axons -> Distal Sensory Impairment Degeneration of the longest sensory axons.

Increased Vulnerability of Long Peripheral Axons -> Distal Amyotrophy Muscle wasting following denervation.

Increased Vulnerability of Long Peripheral Axons -> Reduced Tendon Reflexes Loss of the afferent and efferent limbs of the reflex arc distally.

Increased Vulnerability of Long Peripheral Axons -> Pes Cavus Foot deformity from chronic imbalance between intrinsic and extrinsic foot muscles.

Increased Vulnerability of Long Peripheral Axons -> Neuropathic Pain Sensory axon involvement, unusually prominent in this CMT subtype.

Increased Vulnerability of Long Peripheral Axons -> Foot Drop Loss of the longest motor axons supplying the ankle dorsiflexors.

Central Nervous System Extension to Late-Onset Parkinsonism

lrsam1_cns_parkinsonism_extension EMERGING

The same ligase defect may, decades later, affect substantia nigra neurons, producing parkinsonism on top of the neuropathy. The evidence is one kindred in which three of five affected members developed Parkinson disease between 50 and 65, plus scattered later cases. Nothing connects LRSAM1 to nigral biology mechanistically, and the authors themselves frame the association as speculation. EMERGING, and deliberately kept out of the canonical group so that the peripheral mechanism does not inherit its uncertainty.

Pathograph links

Failure of E2-E3 Interaction and Loss of Ubiquitylation Activity -> Nigral Neuron Degeneration Proposed central extension of the same ligase defect, decades later. The edge is drawn so the parkinsonism branch is part of the graph rather than a disconnected component; its uncertainty is carried by the hypothesis group, which is EMERGING, and no mechanism linking this ligase to nigral neurons has been established.

Nigral Neuron Degeneration -> Parkinsonism Clinical expression of nigral involvement.

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Discussions and Knowledge Gaps

3

Which LRSAM1 ubiquitylation substrates matter in peripheral axons, and how does losing their ubiquitylation cause axonal degeneration?

KNOWLEDGE GAP lrsam1_substrate_gap

Attached to

pathophysiology#Impaired TSG101-Dependent Endosomal Sorting

This is the weakest step in an otherwise well-measured chain. TSG101 is the only validated substrate, and the reviewers of this gene say so explicitly and call it a limit on understanding the protein's cellular role. Two results make the endosomal reading harder rather than easier: LRSAM1 sits in a post-Golgi perinuclear compartment with little overlap with endosome-to-lysosome trafficking machinery, and the p.Cys694Tyr allele leaves TSG101 protein levels unchanged in patient cells. Until axon-relevant substrates are mapped, the link between the biochemical lesion, which is well established, and the clinical phenotype, which is well described, is an inference across a gap.

Proposed experiments

Ubiquitylation proteomics in LRSAM1-deficient human neurons

lrsam1_neuronal_ubiquitylome

Compare the ubiquitylome of iPSC-derived motor and sensory neurons carrying dominant-negative and loss-of-function LRSAM1 alleles against isogenic controls, to identify substrates whose ubiquitylation depends on LRSAM1 in the cell type the disease affects.

Would support

pathophysiology#Impaired TSG101-Dependent Endosomal Sorting

Supporting outcome

TSG101 ubiquitylation is reduced in mutant neurons, together with other substrates in endosomal sorting, supporting the pathway as curated.

Refuting outcome

TSG101 ubiquitylation is unchanged while other, non-endosomal substrates lose ubiquitylation, which would move this node off the ESCRT pathway entirely.

Why does complete loss of Lrsam1 leave a mouse with almost no neuropathy while loss or dominant-negative disruption of LRSAM1 causes a progressive neuropathy in people?

HUMAN MODEL MISMATCH lrsam1_mouse_severity_mismatch

Attached to

animal_models#Lrsam1 mutant mouse pathophysiology#Increased Vulnerability of Long Peripheral Axons

The mismatch is large and it is not a detail: the mouse is the only animal model of this disease and its spontaneous phenotype is very mild in both homozygotes and heterozygotes. Two explanations are available and neither has been tested. The first is scale, since a mouse sciatic axon is short and a mouse lifespan is brief, and this is a length-dependent, late-onset degeneration. The second is mechanism, since the mouse models loss of function while most human disease is dominant-negative, so the model may simply not be modelling the human lesion. Which of the two it is determines whether the acrylamide-sensitisation result can be read as disease-relevant or only as a general vulnerability assay.

Proposed experiments

Knock-in mouse carrying a human dominant-negative LRSAM1 allele

lrsam1_dominant_negative_knockin_mouse

Introduce a human RING-domain frameshift such as p.Leu708Argfs*28 into the mouse germline and compare its spontaneous neuropathy with the existing Lrsam1 loss-of-function mutant, ageing both cohorts.

Would support

pathophysiology#Dominant-Negative Truncated RING-Domain Protein

Supporting outcome

The knock-in develops a spontaneous progressive neuropathy that the loss-of-function mutant does not, which would show the mild mouse phenotype reflects the wrong mechanism rather than the wrong species.

Refuting outcome

The knock-in is as mild as the existing mutant, which would point to axon length and lifespan as the reason and would mean no mouse can model this disease's course.

Is late-onset parkinsonism part of the LRSAM1 phenotype, and if so what connects a peripheral-axon ligase defect to substantia nigra neurons?

KNOWLEDGE GAP lrsam1_parkinsonism_association

Attached to

pathophysiology#Nigral Neuron Degeneration mechanistic_hypotheses#lrsam1_cns_parkinsonism_extension

The observation is striking - three of five affected members of one kindred, at ages 50 to 65 - and the authors are careful to call it speculation. Two things are unresolved. Whether the association is real needs systematic ascertainment across LRSAM1 cohorts rather than retrospective notice in the family where it was first seen, since Parkinson disease is common enough at those ages that a single pedigree cannot settle it. And if it is real, no mechanism exists: nothing links this ligase to nigral biology, although the broader ubiquitin-proteostasis theme it shares with neurodegeneration makes the idea plausible rather than arbitrary. This matters clinically because it determines whether LRSAM1 carriers should be watched for parkinsonian features at all.

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Pathophysiology

7

LRSAM1 RING-Domain Variants

LRSAM1 encodes a universally expressed RING-type E3 ubiquitin ligase with an LRR-coiled-coil-SAM-PDZ-binding-RING architecture, in which the LRR domain selects substrates and the RING domain catalyses ubiquitin transfer. Pathogenic variants cluster tightly in the 3-prime exons encoding the C-terminal RING domain: a homozygous splice-acceptor variant in the founding recessive kindred, the dominant frameshift p.Leu708Argfs*28, and the missense alleles p.Pro707Leu and p.Cys694Tyr. Reported series add further alleles, most of them novel and most of them dominant. The clustering is not incidental. Because these variants sit near the end of the transcript, whether the premature termination codon they introduce is recognised by nonsense-mediated decay is genuinely uncertain in individual cases, which is what makes variant interpretation here difficult and what determines the inheritance pattern.

Loss of LRSAM1 Ubiquitin Ligase Activity

LRSAM1 hgnc:25135

Genetic context variant_origin: GERMLINE

Germline LRSAM1 variants concentrated in the 3-prime RING-encoding exons, heterozygous in the dominant families and homozygous in the recessive kindred.

Downstream

Nonsense-Mediated Decay and Complete Loss of LRSAM1 Protein The recessive route: the mutant transcript is degraded and no protein is made.

Dominant-Negative Truncated RING-Domain Protein The dominant route: the premature termination codon escapes nonsense-mediated decay and a truncated protein is made.

Show evidence (3 references)

PMID:33414056 SUPPORT Human Clinical

"Due to variable inheritance patterns and clustering of pathogenic variants in 3´-prime exons, interpretation of genetic variants in LRSAM1 is challenging."

The positional clustering, and its practical consequence for variant interpretation.

PMID:22012984 SUPPORT Human Clinical

"This frameshift mutation (p.Leu708Argfx28) is located in the C-terminal RING finger motif of the encoded protein."

Localises the founding dominant allele to the RING domain, which is the observation the whole domain-clustering story is built on.

PMID:33568173 SUPPORT Other

"These tightly cluster in the C-terminal RING domain highlighting its importance in governing the CMT disease."

Independent statement of the clustering from a review of the whole reported allelic series.

Nonsense-Mediated Decay and Complete Loss of LRSAM1 Protein

The recessive route. In the founding kindred a single base change converts an intronic acceptor splice site from AG to AA; the affected exon is mis-spliced, an obligatory frameshift truncates the protein, and western blotting of immortalised patient cells shows no detectable LRSAM1 at all. A carrier keeps one functioning allele and is unaffected, which is what makes this route recessive.

Loss of LRSAM1 Ubiquitin Ligase Activity

LRSAM1 hgnc:25135 ↓ DECREASED

Genetic context variant_origin: GERMLINE zygosity: HOMOZYGOUS functional_impact_category: LOSS_OF_FUNCTION

Homozygous intronic splice-acceptor variant causing aberrant splicing and truncation, with no detectable protein product.

Downstream

Failure of E2-E3 Interaction and Loss of Ubiquitylation Activity No ligase present to transfer ubiquitin.

Show evidence (2 references)

PMID:20865121 SUPPORT Human Clinical

"Direct analysis of RNA from patient blood demonstrated aberrant splicing of the affected exon, causing an obligatory frameshift and premature truncation of the protein."

Transcript-level demonstration that the splice variant does what it is predicted to do, in patient material rather than in a construct.

PMID:20865121 SUPPORT Human Clinical

"Western blotting of immortalized cells from a homozygous patient showed complete absence of detectable protein, consistent with the splice site defect."

Protein-level confirmation that this route is a true null, which is what distinguishes it from the dominant-negative route.

Dominant-Negative Truncated RING-Domain Protein

The dominant route, and the majority of reported disease. A premature termination codon in the 3-prime exons escapes nonsense-mediated decay, so a truncated RING-domain protein is made rather than degraded. That protein interferes with the ligase function of the normal allele's product, which is why a single altered copy is sufficient to cause disease. The same dominant-negative reading applies to the RING missense alleles, which make a full-length protein carrying an altered RING domain.

Loss of LRSAM1 Ubiquitin Ligase Activity

LRSAM1 hgnc:25135

Genetic context variant_origin: GERMLINE zygosity: HETEROZYGOUS functional_impact_category: DOMINANT_NEGATIVE

Heterozygous frameshift or missense variants in the C-terminal RING domain, producing a protein that escapes nonsense-mediated decay.

Downstream

Failure of E2-E3 Interaction and Loss of Ubiquitylation Activity Truncated or altered RING domain poisons residual ligase activity.

Show evidence (2 references)

PMID:33414056 SUPPORT Human Clinical

"Our data emphasize the importance of the C-terminal RING domain, which exerts a dominant-negative effect on protein function, whenever affected by an altered or truncated protein."

The dominant-negative claim stated directly, and stated for both altered and truncated protein, which is why the missense alleles sit in this node too.

PMID:33414056 SUPPORT Human Clinical

"Variants at the 3`end may or may not escape from nonsense-mediated decay, thereby defining the pattern of inheritance."

The rule that separates this node from the recessive one: the same region produces either route depending on whether the transcript survives.

Failure of E2-E3 Interaction and Loss of Ubiquitylation Activity

Where the two allelic routes converge, and the best-measured step in the disease. Three separate disease alleles - the p.Leu708Argfs frameshift and the missense alleles p.Pro707Leu and p.Cys694Tyr - were assayed and all showed in vitro ubiquitylation activity largely abrogated. The reason is specific: they lose the E2-E3 interaction that ubiquitin transfer requires. The negative result in the same experiment is what makes this node precise. LRSAM1 dimerisation and its binding to TSG101 were not disrupted, so the lesion is in catalysis rather than in assembly or substrate recognition. A therapeutic strategy aimed at restoring substrate binding would therefore be aimed at a step that is not broken.

Central Nervous System Extension to Late-Onset Parkinsonism Loss of LRSAM1 Ubiquitin Ligase Activity

protein ubiquitination GO:0016567 ↓ DECREASED

ubiquitin protein ligase activity GO:0061630 ↓ DECREASED

Downstream

Impaired TSG101-Dependent Endosomal Sorting Loss of ubiquitylation of the one well-validated substrate.

Nigral Neuron Degeneration Proposed central extension of the same ligase defect, decades later. The edge is drawn so the parkinsonism branch is part of the graph rather than a disconnected component; its uncertainty is carried by the hypothesis group, which is EMERGING, and no mechanism linking this ligase to nigral neurons has been established.

Show evidence (3 references)

PMID:28335037 SUPPORT In Vitro

"We demonstrate that loss of the E2-E3 interaction that is an essential prerequisite for supporting ubiquitylation of target substrates, underlies this reduced ubiquitylation capacity."

Identifies the specific biochemical step that fails, rather than only reporting that activity is reduced.

PMID:28335037 SUPPORT In Vitro

"In contrast, LRSAM1 dimerization and interaction with the bona fide target TSG101 were not disrupted."

The negative control within the same experiment, which localises the defect to catalysis and rules out substrate recognition.

PMID:28335037 SUPPORT In Vitro

"our study provides further support for the role of LRSAM1 in CMT and identifies LRSAM1-mediated ubiquitylation as a common determinant of disease-associated LRSAM1 mutations."

States that this endpoint is common to the disease alleles tested, which is what licenses drawing both upstream routes into one node.

Impaired TSG101-Dependent Endosomal Sorting

Mechanism confidence: Hypothetical

The weakest link in the chain, and it is marked as such. TSG101, a component of the ESCRT-I complex, is the only well-validated LRSAM1 ubiquitylation target; LRSAM1 was originally characterised as Tal, a Tsg101-specific E3 ligase regulating receptor endocytosis and retrovirus budding. Loss of that ubiquitylation is expected to perturb endosomal sorting and multivesicular-body traffic, and several other CMT gene products act in the same pathway, which is the argument for its relevance here. But the inference is not demonstrated in neurons. Two observations complicate it. In transfected cells LRSAM1 localises to a perinuclear compartment just beyond the Golgi and shows little colocalisation with endosome-to-lysosome trafficking machinery, which the authors take as a reason to consider other cellular mechanisms. And in patient lymphoblasts carrying p.Cys694Tyr, TSG101 protein levels were unchanged. This node is therefore curated as an inferred step, not an established one.

Loss of LRSAM1 Ubiquitin Ligase Activity

endosome organization GO:0007032 ⚠ ABNORMAL

endosome GO:0005768

Downstream

Increased Vulnerability of Long Peripheral Axons Perturbed neuronal proteostasis and membrane traffic, inferred rather than demonstrated in neurons.

Show evidence (4 references)

PMID:15256501 SUPPORT In Vitro

"We report a novel protein, Tal (Tsg101-associated ligase), whose RING finger is necessary for multiple monoubiquitylation of Tsg101."

Establishes the substrate relationship and that the RING finger is what carries it out. This is the paper that makes TSG101 the substrate the disease chain runs through, and LRSAM1 was named Tal in it.

PMID:33568173 SUPPORT Other

"Strikingly, TSG101 remains the only known ubiquitination target hampering our mechanistic understanding of the role of LRSAM1 in the cell."

States that the substrate list is a list of one, which is the reason this node is confident about the substrate and not about the pathway.

PMID:23519028 NO_EVIDENCE In Vitro

"In transfected cells, LRSAM1 primarily localizes in a perinuclear compartment immediately beyond the Golgi and shows little colocalization with components of the endosome to lysosome trafficking pathway, suggesting that other cellular mechanisms also merit consideration."

A localisation result that does not support the endosomal reading of this node. Graded NO_EVIDENCE rather than REFUTE because it bears on where the protein sits, not on whether TSG101 ubiquitylation matters, and the authors present it as a reason to look elsewhere rather than as a refutation.

+ 1 more reference

Increased Vulnerability of Long Peripheral Axons

The node that carries the length-dependence, and the one the mouse model speaks to most directly. Lrsam1 is abundantly expressed in peripheral motor and sensory neurons. Mutant mice, homozygous or heterozygous, have largely normal neuromuscular performance and only a very mild age-related neuropathy - so loss of the ligase is not sufficient to degenerate a mouse axon on its own. It does, however, lower the threshold: mutant mice are more sensitive than controls to acrylamide, a neurotoxin that causes axon degeneration, which the authors read as showing the axons are compromised. A transcriptomic observation points the same way from the human side. Patient cells carrying p.Cys694Tyr upregulate TNFRSF21, a key regulator of axonal degeneration, alongside the E3 ligase NEDD4L.

Loss of LRSAM1 Ubiquitin Ligase Activity

motor neuron CL:0000100 sensory neuron CL:0000101

peripheral nervous system UBERON:0000010

Animal models

Lrsam1 mutant mouse Mouse partially recapitulates Mutant mice show only a very mild age-related neuropathy on their own but degenerate readily on acrylamide challenge, which is the evidence that losing the ligase lowers the axonal threshold.

Downstream

Distal Muscle Weakness Degeneration of the longest motor axons.

Distal Sensory Impairment Degeneration of the longest sensory axons.

Distal Amyotrophy Muscle wasting following denervation.

Reduced Tendon Reflexes Loss of the afferent and efferent limbs of the reflex arc distally.

Pes Cavus Foot deformity from chronic imbalance between intrinsic and extrinsic foot muscles.

Neuropathic Pain Sensory axon involvement, unusually prominent in this CMT subtype.

Foot Drop Loss of the longest motor axons supplying the ankle dorsiflexors.

Show evidence (3 references)

PMID:23519028 SUPPORT Model Organism

"Lrsam1 mutant mice are more sensitive to challenge with acrylamide, a neurotoxic agent that causes axon degeneration, indicating that the axons in the mutant mice are indeed compromised"

The sensitisation result, which is the primary evidence that losing LRSAM1 makes axons vulnerable rather than sick.

PMID:23519028 SUPPORT Model Organism

"Mouse Lrsam1 is abundantly expressed in the motor and sensory neurons of the peripheral nervous system."

Expression evidence placing the gene in the cells this node is about.

PMID:27686364 SUPPORT In Vitro

"a significant upregulation of another E3 ubiquitin-protein ligase, NEDD4L, and of TNFRSF21, a key regulator of axonal degeneration"

A human transcriptional change implicating an axon-degeneration regulator, which is independent support for this node from patient material.

Nigral Neuron Degeneration

Mechanism confidence: Hypothetical

An emerging and unexplained branch. Within one generation of the original dominant Dutch kindred, three of five affected members developed Parkinson disease between the ages of 50 and 65, many years after their neuropathy began. The authors propose that the parkinsonism is part of the LRSAM1 phenotype rather than coincidence, and say plainly that how the mutant protein affects substantia nigra neurons is unclear. Nothing connects the ligase to nigral biology, and the observation rests on one family plus scattered later cases, so this node exists to hold the association rather than to explain it.

Central Nervous System Extension to Late-Onset Parkinsonism

Downstream

Parkinsonism Clinical expression of nigral involvement.

Show evidence (4 references)

PMID:26900582 SUPPORT Human Clinical

"Within one generation of the original Dutch family in which the dominant LRSAM1 mutation was identified, three of the five affected family members have developed Parkinson's disease between ages 50 and 65 years, many years after neuropathy onset."

The observation itself, with its numerator, denominator and timing, which is the entire human evidence base for this branch.

PMID:26900582 SUPPORT Human Clinical

"How the mutated Lrsam1 protein, which normally has E3 ubiquitin ligase activity and is expressed in the nervous system, impacts on substantia nigra neurons is unclear."

The authors' own statement that the mechanism is unknown, which is why this node is HYPOTHETICAL and sits in a separate hypothesis group.

PMID:40721190 SUPPORT Human Clinical

"To the best of our knowledge, this is the seventh clinical description linking an LRSAM1 pathogenic variant and parkinsonism."

Independent corroboration, and it changes how strong this association looks: seven descriptions rather than one kindred. This is the citation behind the phrase "scattered later cases" in this entry, which was previously asserted without one.

+ 1 more reference

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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

9

Limbs 2

Foot Drop Foot dorsiflexor weakness HP:0009027

Sequelae: Gait Disturbance

Show evidence (1 reference)

PMID:40636623 SUPPORT INDIRECT Other

"individuals often develop foot drop and foot deformities such as pes cavus and equinus, leading to a significant decline in gait function"

Documents foot drop in Charcot-Marie-Tooth disease. Graded INDIRECT because the source addresses CMT as a whole rather than the LRSAM1 subtype.

Pes Cavus HP:0001761

Show evidence (1 reference)

PMID:40636623 SUPPORT INDIRECT Other

"individuals often develop foot drop and foot deformities such as pes cavus and equinus, leading to a significant decline in gait function"

Documents pes cavus as characteristic of CMT. Graded INDIRECT because the source describes Charcot-Marie-Tooth disease generally rather than the LRSAM1 subtype, and no cached CMT2P-specific source states it.

Musculoskeletal 2

Distal Muscle Weakness HP:0002460

Course: PROGRESSIVE

Show evidence (2 references)

PMID:33568173 SUPPORT Human Clinical

"dominant CMT2P is usually characterized by relatively mild, slowly progressive axonal neuropathy, mainly involving lower limbs, with age of onset between the second and fifth decades of life"

Severity, tempo, distribution and onset window in one statement.

PMID:33414056 SUPPORT Human Clinical

"Clinical and electrophysiological data confirm a late-onset axonal neuropathy with a predominance of sensorimotor impairment."

Independent confirmation in the largest series, with electrophysiology establishing that the process is axonal rather than demyelinating.

Distal Amyotrophy HP:0003693

Show evidence (1 reference)

PMID:27686364 SUPPORT Human Clinical

"Magnetic resonance imaging (MRI) of lower-limb musculature systematically showed fatty atrophy in clinical and subclinical mutation carriers."

Documents the muscle change and, importantly, that it is present in carriers who are clinically unaffected - which is the imaging basis for the incomplete-penetrance claim elsewhere in this entry.

Nervous System 4

Distal Sensory Impairment HP:0002936

Show evidence (1 reference)

PMID:33414056 SUPPORT Human Clinical

"Clinical and electrophysiological data confirm a late-onset axonal neuropathy with a predominance of sensorimotor impairment."

Documents sensory involvement as part of the confirmed sensorimotor phenotype.

Gait Disturbance Unsteady gait HP:0002317

Show evidence (1 reference)

PMID:40636623 SUPPORT INDIRECT Other

"individuals often develop foot drop and foot deformities such as pes cavus and equinus, leading to a significant decline in gait function"

Documents decline in gait function as the consequence of the distal deficits. Graded INDIRECT for the same whole-CMT scope.

Reduced Tendon Reflexes HP:0001315

Show evidence (1 reference)

PMID:33414056 SUPPORT INDIRECT Human Clinical

"Clinical and electrophysiological data confirm a late-onset axonal neuropathy with a predominance of sensorimotor impairment."

Graded INDIRECT: the cached sources establish a sensorimotor axonal neuropathy, from which distal reflex loss follows, but none of them states reflex findings in CMT2P patients in so many words. The HPO binding is deliberately `Reduced tendon reflexes` rather than `Areflexia`, which is a stronger claim than the evidence supports.

Parkinsonism HP:0001300

Show evidence (2 references)

PMID:26900582 SUPPORT Human Clinical

"Within one generation of the original Dutch family in which the dominant LRSAM1 mutation was identified, three of the five affected family members have developed Parkinson's disease between ages 50 and 65 years, many years after neuropathy onset."

The full observation with numerator, denominator and age range.

PMID:26900582 SUPPORT Human Clinical

"We speculate that this late-onset parkinsonism is part of the LRSAM1 phenotype, thus associating a hitherto peripheral nerve disease with a central nervous system phenotype."

The authors' own framing of the claim as speculation, quoted so the strength of the association is on the record next to the observation.

Constitutional 1

Neuropathic Pain HP:0012531

Show evidence (1 reference)

PMID:33414056 SUPPORT Human Clinical

"In conclusion, CMT2P is a rare, but nevertheless relevant cause of adult-onset axonal and painful neuropathy."

Names painfulness as characteristic of the entity, which is what this phenotype asserts. The binding is HP:0012531 Pain with the specificity carried in preferred_term, because HP:6000040 Neuropathic pain is not a member of the PhenotypeTerm dynamic enum.

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Genetic Associations

1

LRSAM1

Gene: LRSAM1 hgnc:25135 relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (3 references)

PMID:20865121 SUPPORT Human Clinical

"A homozygous pathogenic variant was identified in the gene encoding leucine rich repeat and sterile alpha motif 1 (LRSAM1) by direct DNA sequencing of genes within the region in affected DNA samples."

The gene-disease assertion in the paper that first made it.

PMID:22012984 SUPPORT Human Clinical

"Our data strongly support the hypothesis that LRSAM1 mutations can cause both dominant and recessive forms of CMT."

Establishes that one gene accounts for both inheritance patterns, which is the basis for curating them as one disease.

PMID:23245322 SUPPORT In Vitro

"these functions require LRSAM1's leucine-rich repeat and RING domains, respectively"

The division of labour between the two domains, which is why a RING-domain variant removes catalysis without removing targeting.

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Medical Actions

5

Physical and Occupational Therapy

Action: physical therapy Ontology label: Physical Therapy NCIT:C15302

Platform: Behavioral / lifestyle

Rehabilitation aimed at gait, balance and preservation of function. There is no disease-modifying therapy for CMT2P, and the whole of management is symptomatic.

Show evidence (1 reference)

PMID:40636623 SUPPORT INDIRECT Other

"Management focuses on symptomatic interventions, including orthotic support, surgical procedures, and physical therapy."

Establishes physical therapy as standard management. Graded INDIRECT because the source addresses Charcot-Marie-Tooth disease as a whole rather than the LRSAM1 subtype; no CMT2P-specific management study exists.

Ankle-Foot Orthoses

Action: orthotic supportive care Ontology label: Supportive Care NCIT:C15747

Platform: Device

Orthotic support for foot drop and gait stability, the mainstay of functional management in a distal-predominant neuropathy.

Show evidence (1 reference)

PMID:40636623 SUPPORT INDIRECT Other

"Management focuses on symptomatic interventions, including orthotic support, surgical procedures, and physical therapy."

Establishes orthotic support as standard management, with the same whole-disease rather than subtype-specific scope.

Foot Deformity Surgery

Action: surgical procedure Ontology label: Surgical Procedure NCIT:C15329

Platform: Surgery

Surgical correction of pes cavus and related deformity when orthoses no longer maintain function.

Show evidence (1 reference)

PMID:40636623 SUPPORT INDIRECT Other

"Management focuses on symptomatic interventions, including orthotic support, surgical procedures, and physical therapy."

Establishes surgery as part of standard management, again at the level of Charcot-Marie-Tooth disease as a whole.

Neuropathic Pain Management

Action: Pharmacotherapy NCIT:C15986

Agent: gabapentin CHEBI:42797 carbamazepine CHEBI:3387 amitriptyline CHEBI:2666

Platform: Small molecule

The gap between what this entry says distinguishes CMT2P and what it offered clinically. Pain is prominent enough here that the largest series calls the disorder a cause of painful neuropathy specifically, and pain is treatable where the neuropathy is not. A caution on the evidence, because the sources sit at three different scopes and none is CMT2P-specific. That pain needs treating in CMT2 is stated by the CMT2 GeneReviews chapter. That pain is a major and inadequately managed problem across CMT is established in a patient cohort. The specific agent classes - tricyclic antidepressants, carbamazepine, gabapentin - are named only in the GeneReviews chapter for MFN2-related CMT2, a sibling subtype, as generic symptomatic management rather than anything MFN2-specific. No trial of any of these agents in CMT2P exists, and none is likely to. The agents are curated because a queryable treatment with no named agent is not useful to a clinician, and every item is graded INDIRECT with its scope stated.

Show evidence (3 references)

PMID:20301462 SUPPORT INDIRECT Other

"symptomatic treatment of pain, depression, sleep apnea, restless legs syndrome"

The GeneReviews chapter for Charcot-Marie-Tooth neuropathy type 2, the group CMT2P belongs to, listing symptomatic treatment of pain in its management section. Correct in scope but it names no agents, which is why the two further items below are needed.

PMID:36793224 SUPPORT INDIRECT Human Clinical

"Chronic pain is a major problem for patients with Charcot-Marie-Tooth (CMT) disease."

Establishes that the problem this treatment addresses is real and common across CMT, from a patient cohort rather than expert opinion. Graded INDIRECT because the cohort is CMT-wide rather than CMT2P.

PMID:20301684 SUPPORT INDIRECT Other

"treatment of neuropathic pain with tricyclic antidepressants or drugs such as carbamazepine or gabapentin"

The only cached source naming agent classes for neuropathic pain in axonal CMT. Read the scope carefully before reusing it: this is the GeneReviews chapter for MFN2-related CMT2, a different subtype from CMT2P. It is cited because the recommendation it makes is generic symptomatic management of neuropathic pain in axonal CMT and carries nothing MFN2-specific, not because MFN2 disease is a proxy for this one. Graded INDIRECT for exactly that reason.

Genetic Counselling

Action: genetic counseling Ontology label: Genetic Counseling NCIT:C15240

Platform: Other

Counselling is unusually consequential here, because the mode of inheritance is a property of the variant rather than of the gene: recurrence risk depends on whether the family's premature termination codon escapes nonsense-mediated decay. Incomplete penetrance and asymptomatic carriers complicate family assessment further.

Show evidence (1 reference)

PMID:33414056 SUPPORT Human Clinical

"ACMG (American College of Medical Genetics and genomics) criteria should be carefully applied in variant interpretation, with special attention to premature termination codon-introducing variants and their location within the gene."

The interpretive care this disease requires, which is the substance of what counselling has to convey to a family.

🔬

Diagnosis

3

Nerve conduction studies and electromyography

Establishes that the neuropathy is axonal rather than demyelinating, which places the patient in CMT2 and narrows the gene panel. In CMT2P the electrophysiology confirms a late-onset axonal sensorimotor process.

Show evidence (1 reference)

PMID:33414056 SUPPORT Human Clinical

"Clinical and electrophysiological data confirm a late-onset axonal neuropathy with a predominance of sensorimotor impairment."

Establishes the electrophysiological phenotype the test is looking for.

Lower-limb muscle MRI

Detects fatty atrophy in carriers who are clinically unaffected. In a family with a known LRSAM1 variant this is what converts an ambiguous pedigree into a resolved one, and it is why the disease's penetrance cannot be assessed on clinical examination alone.

Show evidence (1 reference)

PMID:27686364 SUPPORT Human Clinical

"Magnetic resonance imaging (MRI) of lower-limb musculature systematically showed fatty atrophy in clinical and subclinical mutation carriers."

The finding and its extension to subclinical carriers, which is what makes the test diagnostically useful beyond confirming clinical disease.

LRSAM1 sequencing within a multigene neuropathy panel

Definitive diagnosis. The interpretive difficulty is specific and worth stating: because pathogenic variants cluster in the 3-prime exons, whether a premature termination codon escapes nonsense-mediated decay determines both pathogenicity assessment and the inheritance pattern to counsel on, and prediction is not always reliable.

Show evidence (1 reference)

PMID:33414056 SUPPORT Human Clinical

"Due to variable inheritance patterns and clustering of pathogenic variants in 3´-prime exons, interpretation of genetic variants in LRSAM1 is challenging."

States the interpretive problem that makes this more than a routine panel result.

📊

Prevalence

1

Worldwide, published cases

Cases In Literature Ultra Rare

No prevalence estimate specific to CMT2P exists. The largest published series is 14 patients from 12 families; two systematic Dutch cohorts screened for LRSAM1 (107 sequenced across the whole coding region, 468 across the RING-encoding exon alone) found the variants to be rare within CMT2 itself.

Show evidence (2 references)

PMID:33414056 SUPPORT Human Clinical

"Mutations of LRSAM1 were identified as a rare cause and define the subgroup of axonal neuropathy CMT2P. We identified additional 14 patients out of 12 families."

Establishes both the rarity of the cause and the size of the largest published series, which is the denominator this entry works from.

PMID:28335037 SUPPORT Human Clinical

"Based on our genetic analysis, the occurrence of pathogenic LRSAM1 mutations is estimated to be rare."

A rarity estimate grounded in unbiased sequencing of two cohorts rather than in how many families happened to be reported.

🐁

Animal Models

1

Lrsam1 mutant mouse

The only animal model of this disease. Its value is not that it reproduces the neuropathy - it barely does - but that it separates vulnerability from degeneration: the axons are compromised without being lost, and a neurotoxic challenge reveals it.

Species

Mouse

Genotype

Lrsam1 mutant, homozygous and heterozygous

Publication

PMID:23519028

Pathograph links

Increased Vulnerability of Long Peripheral Axons partially recapitulates fidelity: moderate Mutant mice show only a very mild age-related neuropathy on their own but degenerate readily on acrylamide challenge, which is the evidence that losing the ligase lowers the axonal threshold.

Limitations: The spontaneous phenotype is far milder than the human disease, so the model cannot report on the course or severity of CMT2P. It is a loss of function model and so cannot represent the dominant-negative mechanism that accounts for most human cases, and it does not show the parkinsonism reported in the dominant kindred.

Readouts

Axon degeneration after acrylamide challenge

Direction: INCREASED

Interpretation: Heightened sensitivity to a known axonal neurotoxin, read as evidence that the mutant axons are already compromised.

Show evidence (1 reference)

PMID:23519028 SUPPORT Model Organism

"Lrsam1 mutant mice are more sensitive to challenge with acrylamide, a neurotoxic agent that causes axon degeneration, indicating that the axons in the mutant mice are indeed compromised"

The measurement and the authors' reading of it.

Show evidence (1 reference)

PMID:23519028 SUPPORT Model Organism

"We have generated mouse mutations in Lrsam1 to create an animal model of this form of CMT (CMT2P)."

States that the model was built as a model of this disease specifically.

{ }

Source YAML

click to show

name: Charcot-Marie-Tooth Disease Axonal Type 2P
creation_date: "2026-09-02T00:00:00Z"
category: Mendelian
disease_term:
  preferred_term: Charcot-Marie-Tooth disease axonal type 2P
  term:
    id: MONDO:0013753
    label: Charcot-Marie-Tooth disease axonal type 2P
description: >
  Charcot-Marie-Tooth disease axonal type 2P (CMT2P, OMIM #614436) is a rare
  axonal hereditary motor and sensory neuropathy caused by variants in
  LRSAM1, which encodes a RING-type E3 ubiquitin ligase. Clinically it is an
  ordinary length-dependent CMT2 phenotype, distinguished mainly by being
  mild, late in onset - typically the second to fifth decade - slowly
  progressive, lower-limb predominant, and unusually often painful. Its
  expressivity is wide enough that asymptomatic carriers exist and are
  detectable only on lower-limb muscle MRI.

  What makes CMT2P mechanistically interesting is not the neuropathy but the
  genetics. Pathogenic variants cluster in the 3-prime exons that encode the
  C-terminal RING domain, and that clustering has a consequence: whether a
  premature termination codon there triggers nonsense-mediated decay or
  escapes it decides the mode of inheritance. A variant whose transcript is
  degraded leaves no protein, so disease requires two alleles and is
  recessive. A variant whose transcript survives produces a truncated
  RING-domain protein that acts dominant-negatively on the ligase, so one
  allele suffices. The gene is therefore a worked example of variant position
  determining inheritance mode, and this entry curates the two routes as
  separate upstream nodes converging on one functional endpoint.

  That endpoint is measured directly. Biochemically, disease RING variants
  abolish the E2-E3 interaction that ubiquitin transfer depends on, so
  ubiquitylation activity is largely abrogated - while, notably, LRSAM1
  dimerisation and binding to its target TSG101 are preserved. The lesion is
  in catalysis, not in substrate recognition.

  Downstream of that the chain is weaker, and the entry says so. TSG101, an
  ESCRT-I component, remains the only well-validated LRSAM1 ubiquitylation
  target, and how impaired endosomal sorting kills the longest peripheral
  axons has not been demonstrated. The strongest evidence that axons are
  compromised at all is indirect: Lrsam1-mutant mice have almost no
  spontaneous neuropathy but degenerate readily when challenged with the
  axonal neurotoxin acrylamide.

  A separate and still preliminary strand is a central nervous system
  extension. Three of five affected members of the original dominant Dutch
  kindred developed parkinsonism between 50 and 65, many years after their
  neuropathy began. This entry curates that as an emerging hypothesis with
  its own hypothesis group, not as an established feature.

synonyms:
- CMT2P
- Charcot-Marie-Tooth disease, axonal, type 2P
- LRSAM1-related Charcot-Marie-Tooth disease
- CMT2G
- Charcot-Marie-Tooth disease type 2G

parents:
- Charcot-Marie-Tooth disease type 2
- Hereditary motor and sensory neuropathy

notes: >
  CMT2G and CMT2P are the same disease. A large pedigree had been classified
  as a distinct entity, CMT2G, on linkage grounds; re-mapping and sequencing
  identified LRSAM1 p.Cys694Tyr in it, which collapsed CMT2G into CMT2P. Both
  designations are carried as synonyms here so a search on either finds this
  entry.

  Why this entry has two inheritance blocks rather than two entries. Dominant
  and recessive CMT2P are one disease with one gene and one functional
  endpoint, differing in whether the mutant transcript survives
  nonsense-mediated decay. Splitting them would duplicate the whole pathograph
  to record a difference that is properly a property of the allele, so the two
  routes are curated as separate pathophysiology nodes converging on the same
  ubiquitylation-failure node, with an `inheritance` block for each pattern.

  A hallucinated identifier caught in preflight, recorded so it is not
  repeated. The openscientist deep-research report used for this entry
  proposed MONDO:0013749 as the term for CMT2P. That CURIE resolves, so it
  does not look like a fabrication, but it is `ventricular septal defect 3`.
  The report's own term-validation section flagged it, and the correct term,
  MONDO:0013753, came from the curation stub. The report's reference
  validation was otherwise clean (20 of 20 identifiers resolved, no quote
  failures), which is exactly the situation the term check exists for: clean
  citations tell you nothing about whether the ontology bindings are right.
  Two of its suggested NCIT treatment terms were wrong in the same way -
  NCIT:C15224 offered for "pain management" is `Nutrition Research, Fats`, and
  NCIT:C15633 offered for "genetic counseling" is `Cancer Pain Management` -
  and neither was used.

  What this entry deliberately does not claim. No phenotype carries a
  `frequency`: the literature is a set of pedigrees and small series, the
  largest being 14 patients from 12 families, and the cohorts include
  asymptomatic carriers ascertained by family testing, so any percentage would
  describe who was sequenced rather than the disease. The step from impaired
  TSG101 ubiquitylation to axon degeneration is marked as inferred in the node
  that asserts it, and the parkinsonism association is kept out of the
  canonical hypothesis group.

references:
- reference: PMID:20301532
  title: "Charcot-Marie-Tooth Hereditary Neuropathy Overview."
  tags:
  - GeneReviews
- reference: PMID:20301462
  title: "Charcot-Marie-Tooth Neuropathy Type 2 - RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY."
  tags:
  - GeneReviews

prevalence:
- population: Worldwide, published cases
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    No prevalence estimate specific to CMT2P exists. The largest published
    series is 14 patients from 12 families; two systematic Dutch cohorts
    screened for LRSAM1 (107 sequenced across the whole coding region, 468
    across the RING-encoding exon alone) found the variants to be rare within
    CMT2 itself.
  evidence:
  - reference: PMID:33414056
    reference_title: "Location matters - Genotype-phenotype correlation in LRSAM1 mutations associated with rare Charcot-Marie-Tooth neuropathy CMT2P."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Mutations of LRSAM1 were identified as a rare cause and define the subgroup of axonal neuropathy CMT2P. We identified additional 14 patients out of 12 families."
    explanation: >-
      Establishes both the rarity of the cause and the size of the largest
      published series, which is the denominator this entry works from.
  - reference: PMID:28335037
    reference_title: "LRSAM1-mediated ubiquitylation is disrupted in axonal Charcot-Marie-Tooth disease 2P."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Based on our genetic analysis, the occurrence of pathogenic LRSAM1 mutations is estimated to be rare."
    explanation: >-
      A rarity estimate grounded in unbiased sequencing of two cohorts rather
      than in how many families happened to be reported.

inheritance:
- name: Autosomal dominant
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  description: >
    The majority pattern. A heterozygous variant in the 3-prime RING-encoding
    exons whose premature termination codon escapes nonsense-mediated decay
    yields a truncated protein that acts dominant-negatively, so one allele is
    enough. Penetrance is incomplete and expressivity wide: asymptomatic
    carriers occur in several pedigrees and may be identifiable only by
    lower-limb muscle MRI.
  evidence:
  - reference: PMID:33414056
    reference_title: "Location matters - Genotype-phenotype correlation in LRSAM1 mutations associated with rare Charcot-Marie-Tooth neuropathy CMT2P."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The majority follows dominant inheritance, whereas recessive inheritance has been described for one variant."
    explanation: >-
      Establishes dominant inheritance as the usual pattern and recessive as
      the exception, which is why this block is listed first.
  - reference: PMID:33568173
    reference_title: "LRSAM1 and the RING domain: Charcot-Marie-Tooth disease and beyond."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Asymptomatic individuals were identified in several pedigrees exemplifying the strong phenotypic variability of these patients requiring serial clinical evaluation to establish correct diagnosis"
    explanation: >-
      Documents incomplete penetrance and its practical consequence for
      diagnosis, which is what makes the dominant pattern hard to recognise in
      a small family.

- name: Autosomal recessive
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >
    The minority pattern, established in the large consanguineous eastern
    Canadian kindred in which LRSAM1 was first identified. A homozygous
    splice-acceptor variant causes aberrant splicing, an obligatory frameshift
    and premature truncation, and no detectable protein - so heterozygotes,
    retaining one working allele, are unaffected.
  evidence:
  - reference: PMID:20865121
    reference_title: "Mutation in the gene encoding ubiquitin ligase LRSAM1 in patients with Charcot-Marie-Tooth disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We studied a large family from a rural eastern Canadian community, with multiple individuals suffering from a condition clinically most similar to autosomal recessive axonal CMT, or AR-CMT2."
    explanation: >-
      The founding recessive kindred and its clinical classification.
  - reference: PMID:33568173
    reference_title: "LRSAM1 and the RING domain: Charcot-Marie-Tooth disease and beyond."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The recessive CMT mutations lead to complete loss of LRSAM1, contrary to the heterozygous dominant variants."
    explanation: >-
      States the molecular difference between the two inheritance patterns,
      which is the reason they are two blocks and not two diseases.

mechanistic_hypotheses:
- hypothesis_group_id: lrsam1_ubiquitylation_failure
  hypothesis_label: Loss of LRSAM1 Ubiquitin Ligase Activity
  status: CANONICAL
  description: >-
    Both the recessive and the dominant allele classes end at the same place:
    LRSAM1 cannot transfer ubiquitin to its substrates, because either no
    protein is made or a truncated RING-domain protein poisons the residual
    activity. Loss of ubiquitylation impairs TSG101-dependent endosomal
    sorting and neuronal proteostasis, lowering the threshold at which the
    longest peripheral axons degenerate. CANONICAL because the human genetics,
    the in vitro ubiquitylation assays on three separate disease alleles, and
    the sensitised mouse axon all converge on it.

- hypothesis_group_id: lrsam1_cns_parkinsonism_extension
  hypothesis_label: Central Nervous System Extension to Late-Onset Parkinsonism
  status: EMERGING
  description: >-
    The same ligase defect may, decades later, affect substantia nigra
    neurons, producing parkinsonism on top of the neuropathy. The evidence is
    one kindred in which three of five affected members developed Parkinson
    disease between 50 and 65, plus scattered later cases. Nothing connects
    LRSAM1 to nigral biology mechanistically, and the authors themselves frame
    the association as speculation. EMERGING, and deliberately kept out of the
    canonical group so that the peripheral mechanism does not inherit its
    uncertainty.

pathophysiology:
- name: LRSAM1 RING-Domain Variants
  biological_scale: MOLECULAR
  description: >
    LRSAM1 encodes a universally expressed RING-type E3 ubiquitin ligase with
    an LRR-coiled-coil-SAM-PDZ-binding-RING architecture, in which the LRR
    domain selects substrates and the RING domain catalyses ubiquitin
    transfer. Pathogenic variants cluster tightly in the 3-prime exons
    encoding the C-terminal RING domain: a homozygous splice-acceptor variant
    in the founding recessive kindred, the dominant frameshift
    p.Leu708Argfs*28, and the missense alleles p.Pro707Leu and p.Cys694Tyr.
    Reported series add further alleles, most of them novel and most of them
    dominant.

    The clustering is not incidental. Because these variants sit near the end
    of the transcript, whether the premature termination codon they introduce
    is recognised by nonsense-mediated decay is genuinely uncertain in
    individual cases, which is what makes variant interpretation here
    difficult and what determines the inheritance pattern.
  genes:
  - preferred_term: LRSAM1
    term:
      id: hgnc:25135
      label: LRSAM1
  genetic_context:
    description: >-
      Germline LRSAM1 variants concentrated in the 3-prime RING-encoding
      exons, heterozygous in the dominant families and homozygous in the
      recessive kindred.
    variant_origin: GERMLINE
  evidence:
  - reference: PMID:33414056
    reference_title: "Location matters - Genotype-phenotype correlation in LRSAM1 mutations associated with rare Charcot-Marie-Tooth neuropathy CMT2P."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Due to variable inheritance patterns and clustering of pathogenic variants in 3´-prime exons, interpretation of genetic variants in LRSAM1 is challenging."
    explanation: >-
      The positional clustering, and its practical consequence for variant
      interpretation.
  - reference: PMID:22012984
    reference_title: "A frameshift mutation in LRSAM1 is responsible for a dominant hereditary polyneuropathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This frameshift mutation (p.Leu708Argfx28) is located in the C-terminal RING finger motif of the encoded protein."
    explanation: >-
      Localises the founding dominant allele to the RING domain, which is the
      observation the whole domain-clustering story is built on.
  - reference: PMID:33568173
    reference_title: "LRSAM1 and the RING domain: Charcot-Marie-Tooth disease and beyond."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "These tightly cluster in the C-terminal RING domain highlighting its importance in governing the CMT disease."
    explanation: >-
      Independent statement of the clustering from a review of the whole
      reported allelic series.
  downstream:
  - target: Nonsense-Mediated Decay and Complete Loss of LRSAM1 Protein
    description: >-
      The recessive route: the mutant transcript is degraded and no protein is
      made.
    hypothesis_groups:
    - lrsam1_ubiquitylation_failure
  - target: Dominant-Negative Truncated RING-Domain Protein
    description: >-
      The dominant route: the premature termination codon escapes
      nonsense-mediated decay and a truncated protein is made.
    hypothesis_groups:
    - lrsam1_ubiquitylation_failure

- name: Nonsense-Mediated Decay and Complete Loss of LRSAM1 Protein
  biological_scale: MOLECULAR
  description: >
    The recessive route. In the founding kindred a single base change converts
    an intronic acceptor splice site from AG to AA; the affected exon is
    mis-spliced, an obligatory frameshift truncates the protein, and western
    blotting of immortalised patient cells shows no detectable LRSAM1 at all.
    A carrier keeps one functioning allele and is unaffected, which is what
    makes this route recessive.
  genes:
  - preferred_term: LRSAM1
    term:
      id: hgnc:25135
      label: LRSAM1
    modifier: DECREASED
  genetic_context:
    description: >-
      Homozygous intronic splice-acceptor variant causing aberrant splicing
      and truncation, with no detectable protein product.
    variant_origin: GERMLINE
    zygosity: HOMOZYGOUS
    functional_impact_category: LOSS_OF_FUNCTION
  evidence:
  - reference: PMID:20865121
    reference_title: "Mutation in the gene encoding ubiquitin ligase LRSAM1 in patients with Charcot-Marie-Tooth disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Direct analysis of RNA from patient blood demonstrated aberrant splicing of the affected exon, causing an obligatory frameshift and premature truncation of the protein."
    explanation: >-
      Transcript-level demonstration that the splice variant does what it is
      predicted to do, in patient material rather than in a construct.
  - reference: PMID:20865121
    reference_title: "Mutation in the gene encoding ubiquitin ligase LRSAM1 in patients with Charcot-Marie-Tooth disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Western blotting of immortalized cells from a homozygous patient showed complete absence of detectable protein, consistent with the splice site defect."
    explanation: >-
      Protein-level confirmation that this route is a true null, which is what
      distinguishes it from the dominant-negative route.
  downstream:
  - target: Failure of E2-E3 Interaction and Loss of Ubiquitylation Activity
    description: No ligase present to transfer ubiquitin.
    hypothesis_groups:
    - lrsam1_ubiquitylation_failure

- name: Dominant-Negative Truncated RING-Domain Protein
  biological_scale: MOLECULAR
  description: >
    The dominant route, and the majority of reported disease. A premature
    termination codon in the 3-prime exons escapes nonsense-mediated decay, so
    a truncated RING-domain protein is made rather than degraded. That protein
    interferes with the ligase function of the normal allele's product, which
    is why a single altered copy is sufficient to cause disease. The same
    dominant-negative reading applies to the RING missense alleles, which make
    a full-length protein carrying an altered RING domain.
  genes:
  - preferred_term: LRSAM1
    term:
      id: hgnc:25135
      label: LRSAM1
  genetic_context:
    description: >-
      Heterozygous frameshift or missense variants in the C-terminal RING
      domain, producing a protein that escapes nonsense-mediated decay.
    variant_origin: GERMLINE
    zygosity: HETEROZYGOUS
    functional_impact_category: DOMINANT_NEGATIVE
  evidence:
  - reference: PMID:33414056
    reference_title: "Location matters - Genotype-phenotype correlation in LRSAM1 mutations associated with rare Charcot-Marie-Tooth neuropathy CMT2P."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our data emphasize the importance of the C-terminal RING domain, which exerts a dominant-negative effect on protein function, whenever affected by an altered or truncated protein."
    explanation: >-
      The dominant-negative claim stated directly, and stated for both altered
      and truncated protein, which is why the missense alleles sit in this
      node too.
  - reference: PMID:33414056
    reference_title: "Location matters - Genotype-phenotype correlation in LRSAM1 mutations associated with rare Charcot-Marie-Tooth neuropathy CMT2P."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Variants at the 3`end may or may not escape from nonsense-mediated decay, thereby defining the pattern of inheritance."
    explanation: >-
      The rule that separates this node from the recessive one: the same
      region produces either route depending on whether the transcript
      survives.
  downstream:
  - target: Failure of E2-E3 Interaction and Loss of Ubiquitylation Activity
    description: >-
      Truncated or altered RING domain poisons residual ligase activity.
    hypothesis_groups:
    - lrsam1_ubiquitylation_failure

- name: Failure of E2-E3 Interaction and Loss of Ubiquitylation Activity
  biological_scale: MOLECULAR
  description: >
    Where the two allelic routes converge, and the best-measured step in the
    disease. Three separate disease alleles - the p.Leu708Argfs frameshift and
    the missense alleles p.Pro707Leu and p.Cys694Tyr - were assayed and all
    showed in vitro ubiquitylation activity largely abrogated. The reason is
    specific: they lose the E2-E3 interaction that ubiquitin transfer requires.

    The negative result in the same experiment is what makes this node
    precise. LRSAM1 dimerisation and its binding to TSG101 were not disrupted,
    so the lesion is in catalysis rather than in assembly or substrate
    recognition. A therapeutic strategy aimed at restoring substrate binding
    would therefore be aimed at a step that is not broken.
  molecular_functions:
  - preferred_term: ubiquitin protein ligase activity
    modifier: DECREASED
    term:
      id: GO:0061630
      label: ubiquitin protein ligase activity
  biological_processes:
  - preferred_term: protein ubiquitination
    modifier: DECREASED
    term:
      id: GO:0016567
      label: protein ubiquitination
  evidence:
  - reference: PMID:28335037
    reference_title: "LRSAM1-mediated ubiquitylation is disrupted in axonal Charcot-Marie-Tooth disease 2P."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "We demonstrate that loss of the E2-E3 interaction that is an essential prerequisite for supporting ubiquitylation of target substrates, underlies this reduced ubiquitylation capacity."
    explanation: >-
      Identifies the specific biochemical step that fails, rather than only
      reporting that activity is reduced.
  - reference: PMID:28335037
    reference_title: "LRSAM1-mediated ubiquitylation is disrupted in axonal Charcot-Marie-Tooth disease 2P."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "In contrast, LRSAM1 dimerization and interaction with the bona fide target TSG101 were not disrupted."
    explanation: >-
      The negative control within the same experiment, which localises the
      defect to catalysis and rules out substrate recognition.
  - reference: PMID:28335037
    reference_title: "LRSAM1-mediated ubiquitylation is disrupted in axonal Charcot-Marie-Tooth disease 2P."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "our study provides further support for the role of LRSAM1 in CMT and identifies LRSAM1-mediated ubiquitylation as a common determinant of disease-associated LRSAM1 mutations."
    explanation: >-
      States that this endpoint is common to the disease alleles tested, which
      is what licenses drawing both upstream routes into one node.
  downstream:
  - target: Impaired TSG101-Dependent Endosomal Sorting
    description: >-
      Loss of ubiquitylation of the one well-validated substrate.
    hypothesis_groups:
    - lrsam1_ubiquitylation_failure
  - target: Nigral Neuron Degeneration
    description: >-
      Proposed central extension of the same ligase defect, decades later. The
      edge is drawn so the parkinsonism branch is part of the graph rather than
      a disconnected component; its uncertainty is carried by the hypothesis
      group, which is EMERGING, and no mechanism linking this ligase to nigral
      neurons has been established.
    hypothesis_groups:
    - lrsam1_cns_parkinsonism_extension

- name: Impaired TSG101-Dependent Endosomal Sorting
  biological_scale: CELLULAR
  description: >
    The weakest link in the chain, and it is marked as such. TSG101, a
    component of the ESCRT-I complex, is the only well-validated LRSAM1
    ubiquitylation target; LRSAM1 was originally characterised as Tal, a
    Tsg101-specific E3 ligase regulating receptor endocytosis and retrovirus
    budding. Loss of that ubiquitylation is expected to perturb endosomal
    sorting and multivesicular-body traffic, and several other CMT gene
    products act in the same pathway, which is the argument for its relevance
    here.

    But the inference is not demonstrated in neurons. Two observations
    complicate it. In transfected cells LRSAM1 localises to a perinuclear
    compartment just beyond the Golgi and shows little colocalisation with
    endosome-to-lysosome trafficking machinery, which the authors take as a
    reason to consider other cellular mechanisms. And in patient lymphoblasts
    carrying p.Cys694Tyr, TSG101 protein levels were unchanged. This node is
    therefore curated as an inferred step, not an established one.
  cellular_components:
  - preferred_term: endosome
    term:
      id: GO:0005768
      label: endosome
  biological_processes:
  - preferred_term: endosome organization
    modifier: ABNORMAL
    term:
      id: GO:0007032
      label: endosome organization
  mechanism_confidence: HYPOTHETICAL
  evidence:
  - reference: PMID:15256501
    reference_title: "Tal, a Tsg101-specific E3 ubiquitin ligase, regulates receptor endocytosis and retrovirus budding."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "We report a novel protein, Tal (Tsg101-associated ligase), whose RING finger is necessary for multiple monoubiquitylation of Tsg101."
    explanation: >-
      Establishes the substrate relationship and that the RING finger is what
      carries it out. This is the paper that makes TSG101 the substrate the
      disease chain runs through, and LRSAM1 was named Tal in it.
  - reference: PMID:33568173
    reference_title: "LRSAM1 and the RING domain: Charcot-Marie-Tooth disease and beyond."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Strikingly, TSG101 remains the only known ubiquitination target hampering our mechanistic understanding of the role of LRSAM1 in the cell."
    explanation: >-
      States that the substrate list is a list of one, which is the reason
      this node is confident about the substrate and not about the pathway.
  - reference: PMID:23519028
    reference_title: "Loss of the E3 ubiquitin ligase LRSAM1 sensitizes peripheral axons to degeneration in a mouse model of Charcot-Marie-Tooth disease."
    supports: NO_EVIDENCE
    evidence_source: IN_VITRO
    snippet: "In transfected cells, LRSAM1 primarily localizes in a perinuclear compartment immediately beyond the Golgi and shows little colocalization with components of the endosome to lysosome trafficking pathway, suggesting that other cellular mechanisms also merit consideration."
    explanation: >-
      A localisation result that does not support the endosomal reading of
      this node. Graded NO_EVIDENCE rather than REFUTE because it bears on
      where the protein sits, not on whether TSG101 ubiquitylation matters,
      and the authors present it as a reason to look elsewhere rather than as
      a refutation.
  - reference: PMID:27686364
    reference_title: "Charcot-Marie-Tooth disease type 2G redefined by a novel mutation in LRSAM1."
    supports: NO_EVIDENCE
    evidence_source: IN_VITRO
    snippet: "we demonstrated in patients' lymphoblasts that the mutation does not influence overall protein levels of LRSAM1, nor of its ubiquitylation target TSG101"
    explanation: >-
      Patient-cell evidence that the disease allele does not change TSG101
      abundance. It does not settle whether TSG101 ubiquitylation state
      changes, so it is recorded as bearing on the node without contradicting
      it.
  downstream:
  - target: Increased Vulnerability of Long Peripheral Axons
    description: >-
      Perturbed neuronal proteostasis and membrane traffic, inferred rather
      than demonstrated in neurons.
    hypothesis_groups:
    - lrsam1_ubiquitylation_failure

- name: Increased Vulnerability of Long Peripheral Axons
  biological_scale: CELLULAR
  description: >
    The node that carries the length-dependence, and the one the mouse model
    speaks to most directly. Lrsam1 is abundantly expressed in peripheral
    motor and sensory neurons. Mutant mice, homozygous or heterozygous, have
    largely normal neuromuscular performance and only a very mild age-related
    neuropathy - so loss of the ligase is not sufficient to degenerate a mouse
    axon on its own. It does, however, lower the threshold: mutant mice are
    more sensitive than controls to acrylamide, a neurotoxin that causes axon
    degeneration, which the authors read as showing the axons are compromised.

    A transcriptomic observation points the same way from the human side.
    Patient cells carrying p.Cys694Tyr upregulate TNFRSF21, a key regulator of
    axonal degeneration, alongside the E3 ligase NEDD4L.
  cell_types:
  - preferred_term: motor neuron
    term:
      id: CL:0000100
      label: motor neuron
  - preferred_term: sensory neuron
    term:
      id: CL:0000101
      label: sensory neuron
  locations:
  - preferred_term: peripheral nervous system
    term:
      id: UBERON:0000010
      label: peripheral nervous system
  evidence:
  - reference: PMID:23519028
    reference_title: "Loss of the E3 ubiquitin ligase LRSAM1 sensitizes peripheral axons to degeneration in a mouse model of Charcot-Marie-Tooth disease."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Lrsam1 mutant mice are more sensitive to challenge with acrylamide, a neurotoxic agent that causes axon degeneration, indicating that the axons in the mutant mice are indeed compromised"
    explanation: >-
      The sensitisation result, which is the primary evidence that losing
      LRSAM1 makes axons vulnerable rather than sick.
  - reference: PMID:23519028
    reference_title: "Loss of the E3 ubiquitin ligase LRSAM1 sensitizes peripheral axons to degeneration in a mouse model of Charcot-Marie-Tooth disease."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Mouse Lrsam1 is abundantly expressed in the motor and sensory neurons of the peripheral nervous system."
    explanation: >-
      Expression evidence placing the gene in the cells this node is about.
  - reference: PMID:27686364
    reference_title: "Charcot-Marie-Tooth disease type 2G redefined by a novel mutation in LRSAM1."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "a significant upregulation of another E3 ubiquitin-protein ligase, NEDD4L, and of TNFRSF21, a key regulator of axonal degeneration"
    explanation: >-
      A human transcriptional change implicating an axon-degeneration
      regulator, which is independent support for this node from patient
      material.
  downstream:
  - target: Distal Muscle Weakness
    description: Degeneration of the longest motor axons.
    hypothesis_groups:
    - lrsam1_ubiquitylation_failure
  - target: Distal Sensory Impairment
    description: Degeneration of the longest sensory axons.
    hypothesis_groups:
    - lrsam1_ubiquitylation_failure
  - target: Distal Amyotrophy
    description: Muscle wasting following denervation.
    hypothesis_groups:
    - lrsam1_ubiquitylation_failure
  - target: Reduced Tendon Reflexes
    description: Loss of the afferent and efferent limbs of the reflex arc distally.
    hypothesis_groups:
    - lrsam1_ubiquitylation_failure
  - target: Pes Cavus
    description: >-
      Foot deformity from chronic imbalance between intrinsic and extrinsic
      foot muscles.
    hypothesis_groups:
    - lrsam1_ubiquitylation_failure
  - target: Neuropathic Pain
    description: >-
      Sensory axon involvement, unusually prominent in this CMT subtype.
    hypothesis_groups:
    - lrsam1_ubiquitylation_failure
  - target: Foot Drop
    description: >-
      Loss of the longest motor axons supplying the ankle dorsiflexors.
    hypothesis_groups:
    - lrsam1_ubiquitylation_failure

- name: Nigral Neuron Degeneration
  biological_scale: CELLULAR
  description: >
    An emerging and unexplained branch. Within one generation of the original
    dominant Dutch kindred, three of five affected members developed
    Parkinson disease between the ages of 50 and 65, many years after their
    neuropathy began. The authors propose that the parkinsonism is part of the
    LRSAM1 phenotype rather than coincidence, and say plainly that how the
    mutant protein affects substantia nigra neurons is unclear. Nothing
    connects the ligase to nigral biology, and the observation rests on one
    family plus scattered later cases, so this node exists to hold the
    association rather than to explain it.
  mechanism_confidence: HYPOTHETICAL
  evidence:
  - reference: PMID:26900582
    reference_title: "A LRSAM1 mutation links Charcot-Marie-Tooth type 2 to Parkinson's disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Within one generation of the original Dutch family in which the dominant LRSAM1 mutation was identified, three of the five affected family members have developed Parkinson's disease between ages 50 and 65 years, many years after neuropathy onset."
    explanation: >-
      The observation itself, with its numerator, denominator and timing,
      which is the entire human evidence base for this branch.
  - reference: PMID:26900582
    reference_title: "A LRSAM1 mutation links Charcot-Marie-Tooth type 2 to Parkinson's disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "How the mutated Lrsam1 protein, which normally has E3 ubiquitin ligase activity and is expressed in the nervous system, impacts on substantia nigra neurons is unclear."
    explanation: >-
      The authors' own statement that the mechanism is unknown, which is why
      this node is HYPOTHETICAL and sits in a separate hypothesis group.
  - reference: PMID:40721190
    reference_title: "Further delineation of LRSAM1-related Charcot-Marie-Tooth type 2P with parkinsonism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "To the best of our knowledge, this is the seventh clinical description linking an LRSAM1 pathogenic variant and parkinsonism."
    explanation: >-
      Independent corroboration, and it changes how strong this association
      looks: seven descriptions rather than one kindred. This is the citation
      behind the phrase "scattered later cases" in this entry, which was
      previously asserted without one.
  - reference: PMID:40721190
    reference_title: "Further delineation of LRSAM1-related Charcot-Marie-Tooth type 2P with parkinsonism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "123 I-FP-CIT single-photon emission computed tomography revealed bilateral alteration of the presynaptic dopaminergic pathway, especially regarding the putamen."
    explanation: >-
      Imaging evidence of presynaptic dopaminergic loss in an LRSAM1 patient.
      It matters because it moves the claim from a clinical impression of
      parkinsonism to a demonstrated nigrostriatal deficit, which is what this
      node asserts.
  downstream:
  - target: Parkinsonism
    description: Clinical expression of nigral involvement.
    hypothesis_groups:
    - lrsam1_cns_parkinsonism_extension

phenotypes:
- category: Neurologic
  name: Distal Muscle Weakness
  description: >
    Length-dependent, lower limbs before and more than upper limbs, mild to
    moderate, and slowly progressive. Onset is usually between the second and
    fifth decades, which is late for CMT and is one of the features that makes
    the diagnosis easy to miss.
  phenotype_term:
    preferred_term: Distal muscle weakness
    term:
      id: HP:0002460
      label: Distal muscle weakness
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:33568173
    reference_title: "LRSAM1 and the RING domain: Charcot-Marie-Tooth disease and beyond."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "dominant CMT2P is usually characterized by relatively mild, slowly progressive axonal neuropathy, mainly involving lower limbs, with age of onset between the second and fifth decades of life"
    explanation: >-
      Severity, tempo, distribution and onset window in one statement.
  - reference: PMID:33414056
    reference_title: "Location matters - Genotype-phenotype correlation in LRSAM1 mutations associated with rare Charcot-Marie-Tooth neuropathy CMT2P."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Clinical and electrophysiological data confirm a late-onset axonal neuropathy with a predominance of sensorimotor impairment."
    explanation: >-
      Independent confirmation in the largest series, with electrophysiology
      establishing that the process is axonal rather than demyelinating.

- category: Neurologic
  name: Distal Sensory Impairment
  description: >
    The sensory half of the sensorimotor picture, length-dependent and
    symmetric.
  phenotype_term:
    preferred_term: Distal sensory impairment
    term:
      id: HP:0002936
      label: Distal sensory impairment
  evidence:
  - reference: PMID:33414056
    reference_title: "Location matters - Genotype-phenotype correlation in LRSAM1 mutations associated with rare Charcot-Marie-Tooth neuropathy CMT2P."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Clinical and electrophysiological data confirm a late-onset axonal neuropathy with a predominance of sensorimotor impairment."
    explanation: >-
      Documents sensory involvement as part of the confirmed sensorimotor
      phenotype.

- category: Neurologic
  name: Neuropathic Pain
  description: >
    Pain is prominent enough in CMT2P that the largest series describes the
    disorder as a cause of painful neuropathy specifically. That is not
    typical of CMT2 as a group, and it is one of the few clinical pointers to
    this subtype.
  phenotype_term:
    preferred_term: neuropathic pain
    term:
      id: HP:0012531
      label: Pain
  evidence:
  - reference: PMID:33414056
    reference_title: "Location matters - Genotype-phenotype correlation in LRSAM1 mutations associated with rare Charcot-Marie-Tooth neuropathy CMT2P."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In conclusion, CMT2P is a rare, but nevertheless relevant cause of adult-onset axonal and painful neuropathy."
    explanation: >-
      Names painfulness as characteristic of the entity, which is what this
      phenotype asserts. The binding is HP:0012531 Pain with the specificity
      carried in preferred_term, because HP:6000040 Neuropathic pain is not a
      member of the PhenotypeTerm dynamic enum.

- category: Neurologic
  name: Foot Drop
  description: >
    Weakness of ankle dorsiflexion, the functional expression of distal motor
    axon loss and the deficit orthoses are prescribed for. Arguably subsumed by
    distal muscle weakness, but curated separately because it is what
    determines gait and what the management targets.
  phenotype_term:
    preferred_term: Foot dorsiflexor weakness
    term:
      id: HP:0009027
      label: Foot dorsiflexor weakness
  sequelae:
  - target: Gait Disturbance
    description: >-
      Loss of ankle dorsiflexion is the proximate cause of the gait
      abnormality and of the falls risk that follows it.
  evidence:
  - reference: PMID:40636623
    reference_title: "Clinical Characteristics of Gait Disturbance in Charcot-Marie-Tooth Disease and Future Directions in Physical Therapy."
    supports: SUPPORT
    evidence_source: OTHER
    directness: INDIRECT
    snippet: "individuals often develop foot drop and foot deformities such as pes cavus and equinus, leading to a significant decline in gait function"
    explanation: >-
      Documents foot drop in Charcot-Marie-Tooth disease. Graded INDIRECT
      because the source addresses CMT as a whole rather than the LRSAM1
      subtype.

- category: Neurologic
  name: Gait Disturbance
  description: >
    The dominant functional burden of the disease, and the endpoint most of the
    management addresses. Follows from foot drop and the foot deformity
    together, and carries the falls risk.
  phenotype_term:
    preferred_term: Unsteady gait
    term:
      id: HP:0002317
      label: Unsteady gait
  evidence:
  - reference: PMID:40636623
    reference_title: "Clinical Characteristics of Gait Disturbance in Charcot-Marie-Tooth Disease and Future Directions in Physical Therapy."
    supports: SUPPORT
    evidence_source: OTHER
    directness: INDIRECT
    snippet: "individuals often develop foot drop and foot deformities such as pes cavus and equinus, leading to a significant decline in gait function"
    explanation: >-
      Documents decline in gait function as the consequence of the distal
      deficits. Graded INDIRECT for the same whole-CMT scope.

- category: Musculoskeletal
  name: Pes Cavus
  description: >
    The classic CMT foot deformity, following chronic imbalance between
    intrinsic and extrinsic foot muscles.
  phenotype_term:
    preferred_term: Pes cavus
    term:
      id: HP:0001761
      label: Pes cavus
  evidence:
  - reference: PMID:40636623
    reference_title: "Clinical Characteristics of Gait Disturbance in Charcot-Marie-Tooth Disease and Future Directions in Physical Therapy."
    supports: SUPPORT
    evidence_source: OTHER
    directness: INDIRECT
    snippet: "individuals often develop foot drop and foot deformities such as pes cavus and equinus, leading to a significant decline in gait function"
    explanation: >-
      Documents pes cavus as characteristic of CMT. Graded INDIRECT because
      the source describes Charcot-Marie-Tooth disease generally rather than
      the LRSAM1 subtype, and no cached CMT2P-specific source states it.

- category: Neurologic
  name: Distal Amyotrophy
  description: >
    Wasting of the denervated distal muscles. Detectable as fatty atrophy on
    lower-limb muscle MRI before it is clinically apparent, which is how
    subclinical carriers in a known pedigree are found.
  phenotype_term:
    preferred_term: Distal amyotrophy
    term:
      id: HP:0003693
      label: Distal amyotrophy
  evidence:
  - reference: PMID:27686364
    reference_title: "Charcot-Marie-Tooth disease type 2G redefined by a novel mutation in LRSAM1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Magnetic resonance imaging (MRI) of lower-limb musculature systematically showed fatty atrophy in clinical and subclinical mutation carriers."
    explanation: >-
      Documents the muscle change and, importantly, that it is present in
      carriers who are clinically unaffected - which is the imaging basis for
      the incomplete-penetrance claim elsewhere in this entry.

- category: Neurologic
  name: Reduced Tendon Reflexes
  description: >
    Distal areflexia or hyporeflexia, expected from loss of both limbs of the
    reflex arc in a length-dependent sensorimotor axonopathy.
  phenotype_term:
    preferred_term: Reduced tendon reflexes
    term:
      id: HP:0001315
      label: Reduced tendon reflexes
  evidence:
  - reference: PMID:33414056
    reference_title: "Location matters - Genotype-phenotype correlation in LRSAM1 mutations associated with rare Charcot-Marie-Tooth neuropathy CMT2P."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: "Clinical and electrophysiological data confirm a late-onset axonal neuropathy with a predominance of sensorimotor impairment."
    explanation: >-
      Graded INDIRECT: the cached sources establish a sensorimotor axonal
      neuropathy, from which distal reflex loss follows, but none of them
      states reflex findings in CMT2P patients in so many words. The HPO
      binding is deliberately `Reduced tendon reflexes` rather than
      `Areflexia`, which is a stronger claim than the evidence supports.

- category: Neurologic
  name: Parkinsonism
  description: >
    Late-onset parkinsonism, reported in three of five affected members of the
    original dominant Dutch kindred between ages 50 and 65, many years after
    their neuropathy began. Curated because the observation is specific and
    quantified, and flagged here as unestablished: it rests on one family, no
    mechanism connects LRSAM1 to the substantia nigra, and the authors call it
    speculation. Do not treat it as an expected feature when counselling.
  phenotype_term:
    preferred_term: Parkinsonism
    term:
      id: HP:0001300
      label: Parkinsonism
  evidence:
  - reference: PMID:26900582
    reference_title: "A LRSAM1 mutation links Charcot-Marie-Tooth type 2 to Parkinson's disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Within one generation of the original Dutch family in which the dominant LRSAM1 mutation was identified, three of the five affected family members have developed Parkinson's disease between ages 50 and 65 years, many years after neuropathy onset."
    explanation: >-
      The full observation with numerator, denominator and age range.
  - reference: PMID:26900582
    reference_title: "A LRSAM1 mutation links Charcot-Marie-Tooth type 2 to Parkinson's disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We speculate that this late-onset parkinsonism is part of the LRSAM1 phenotype, thus associating a hitherto peripheral nerve disease with a central nervous system phenotype."
    explanation: >-
      The authors' own framing of the claim as speculation, quoted so the
      strength of the association is on the record next to the observation.

genetic:
- name: LRSAM1
  notes: >
    The sole gene for this disorder, at 9q33.3, encoding a universally
    expressed RING-type E3 ubiquitin ligase also known as Tal. Its domain
    architecture divides the work: the leucine-rich repeat domain targets
    substrates and the RING domain catalyses ubiquitin transfer, which is why
    disease variants clustered in the RING-encoding exons abolish catalysis
    while leaving substrate binding intact. Outside this disease the same
    ligase is required for ubiquitin-dependent autophagy of intracellular
    Salmonella, which is where much of what is known about its substrate
    targeting comes from.
  gene_term:
    preferred_term: LRSAM1
    term:
      id: hgnc:25135
      label: LRSAM1
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  evidence:
  - reference: PMID:20865121
    reference_title: "Mutation in the gene encoding ubiquitin ligase LRSAM1 in patients with Charcot-Marie-Tooth disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A homozygous pathogenic variant was identified in the gene encoding leucine rich repeat and sterile alpha motif 1 (LRSAM1) by direct DNA sequencing of genes within the region in affected DNA samples."
    explanation: >-
      The gene-disease assertion in the paper that first made it.
  - reference: PMID:22012984
    reference_title: "A frameshift mutation in LRSAM1 is responsible for a dominant hereditary polyneuropathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our data strongly support the hypothesis that LRSAM1 mutations can cause both dominant and recessive forms of CMT."
    explanation: >-
      Establishes that one gene accounts for both inheritance patterns, which
      is the basis for curating them as one disease.
  - reference: PMID:23245322
    reference_title: "The LRR and RING domain protein LRSAM1 is an E3 ligase crucial for ubiquitin-dependent autophagy of intracellular Salmonella Typhimurium."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "these functions require LRSAM1's leucine-rich repeat and RING domains, respectively"
    explanation: >-
      The division of labour between the two domains, which is why a
      RING-domain variant removes catalysis without removing targeting.

animal_models:
- name: Lrsam1 mutant mouse
  species: Mouse
  genotype: Lrsam1 mutant, homozygous and heterozygous
  publication: PMID:23519028
  description: >
    The only animal model of this disease. Its value is not that it reproduces
    the neuropathy - it barely does - but that it separates vulnerability from
    degeneration: the axons are compromised without being lost, and a
    neurotoxic challenge reveals it.
  modeled_mechanisms:
  - target: Increased Vulnerability of Long Peripheral Axons
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    description: >-
      Mutant mice show only a very mild age-related neuropathy on their own
      but degenerate readily on acrylamide challenge, which is the evidence
      that losing the ligase lowers the axonal threshold.
    limitations: >-
      The spontaneous phenotype is far milder than the human disease, so the
      model cannot report on the course or severity of CMT2P. It is a loss of
      function model and so cannot represent the dominant-negative mechanism
      that accounts for most human cases, and it does not show the
      parkinsonism reported in the dominant kindred.
    readouts:
    - name: Axon degeneration after acrylamide challenge
      target: Increased Vulnerability of Long Peripheral Axons
      direction: INCREASED
      interpretation: >-
        Heightened sensitivity to a known axonal neurotoxin, read as evidence
        that the mutant axons are already compromised.
      evidence:
      - reference: PMID:23519028
        reference_title: "Loss of the E3 ubiquitin ligase LRSAM1 sensitizes peripheral axons to degeneration in a mouse model of Charcot-Marie-Tooth disease."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "Lrsam1 mutant mice are more sensitive to challenge with acrylamide, a neurotoxic agent that causes axon degeneration, indicating that the axons in the mutant mice are indeed compromised"
        explanation: The measurement and the authors' reading of it.
    evidence:
    - reference: PMID:23519028
      reference_title: "Loss of the E3 ubiquitin ligase LRSAM1 sensitizes peripheral axons to degeneration in a mouse model of Charcot-Marie-Tooth disease."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "We have generated mouse mutations in Lrsam1 to create an animal model of this form of CMT (CMT2P)."
      explanation: >-
        States that the model was built as a model of this disease
        specifically.
  - target: Distal Muscle Weakness
    relationship: FAILS_TO_RECAPITULATE
    fidelity: LOW
    description: >-
      The mice do not develop the human motor phenotype. Both homozygotes and
      heterozygotes have largely normal neuromuscular performance, with only a
      very mild neuropathy appearing with age.
    limitations: >-
      Species differences in axon length and lifespan are the obvious
      candidates, and the model is a loss of function while most human disease
      is dominant-negative, so the failure may reflect the wrong mechanism
      rather than the wrong species. Neither has been tested.
    evidence:
    - reference: PMID:23519028
      reference_title: "Loss of the E3 ubiquitin ligase LRSAM1 sensitizes peripheral axons to degeneration in a mouse model of Charcot-Marie-Tooth disease."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Both homozygous and heterozygous mice have largely normal neuromuscular performance and only a very mild neuropathy phenotype with age."
      explanation: >-
        The negative result, quoted directly. It is the reason this link is
        FAILS_TO_RECAPITULATE rather than a weak positive.

treatments:
- name: Physical and Occupational Therapy
  description: >
    Rehabilitation aimed at gait, balance and preservation of function. There
    is no disease-modifying therapy for CMT2P, and the whole of management is
    symptomatic.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: physical therapy
    term:
      id: NCIT:C15302
      label: Physical Therapy
  evidence:
  - reference: PMID:40636623
    reference_title: "Clinical Characteristics of Gait Disturbance in Charcot-Marie-Tooth Disease and Future Directions in Physical Therapy."
    supports: SUPPORT
    evidence_source: OTHER
    directness: INDIRECT
    snippet: "Management focuses on symptomatic interventions, including orthotic support, surgical procedures, and physical therapy."
    explanation: >-
      Establishes physical therapy as standard management. Graded INDIRECT
      because the source addresses Charcot-Marie-Tooth disease as a whole
      rather than the LRSAM1 subtype; no CMT2P-specific management study
      exists.

- name: Ankle-Foot Orthoses
  description: >
    Orthotic support for foot drop and gait stability, the mainstay of
    functional management in a distal-predominant neuropathy.
  therapeutic_modality: DEVICE
  treatment_term:
    preferred_term: orthotic supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
    qualifiers:
    - predicate:
        preferred_term: medical device
        term:
          id: NCIT:C16830
          label: Medical Device
      value:
        preferred_term: ankle-foot orthosis
  evidence:
  - reference: PMID:40636623
    reference_title: "Clinical Characteristics of Gait Disturbance in Charcot-Marie-Tooth Disease and Future Directions in Physical Therapy."
    supports: SUPPORT
    evidence_source: OTHER
    directness: INDIRECT
    snippet: "Management focuses on symptomatic interventions, including orthotic support, surgical procedures, and physical therapy."
    explanation: >-
      Establishes orthotic support as standard management, with the same
      whole-disease rather than subtype-specific scope.

- name: Foot Deformity Surgery
  description: >
    Surgical correction of pes cavus and related deformity when orthoses no
    longer maintain function.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: surgical procedure
    term:
      id: NCIT:C15329
      label: Surgical Procedure
  evidence:
  - reference: PMID:40636623
    reference_title: "Clinical Characteristics of Gait Disturbance in Charcot-Marie-Tooth Disease and Future Directions in Physical Therapy."
    supports: SUPPORT
    evidence_source: OTHER
    directness: INDIRECT
    snippet: "Management focuses on symptomatic interventions, including orthotic support, surgical procedures, and physical therapy."
    explanation: >-
      Establishes surgery as part of standard management, again at the level
      of Charcot-Marie-Tooth disease as a whole.

- name: Neuropathic Pain Management
  description: >-
    The gap between what this entry says distinguishes CMT2P and what it
    offered clinically. Pain is prominent enough here that the largest series
    calls the disorder a cause of painful neuropathy specifically, and pain is
    treatable where the neuropathy is not.

    A caution on the evidence, because the sources sit at three different
    scopes and none is CMT2P-specific. That pain needs treating in CMT2 is
    stated by the CMT2 GeneReviews chapter. That pain is a major and
    inadequately managed problem across CMT is established in a patient cohort.
    The specific agent classes - tricyclic antidepressants, carbamazepine,
    gabapentin - are named only in the GeneReviews chapter for MFN2-related
    CMT2, a sibling subtype, as generic symptomatic management rather than
    anything MFN2-specific. No trial of any of these agents in CMT2P exists,
    and none is likely to. The agents are curated because a queryable treatment
    with no named agent is not useful to a clinician, and every item is graded
    INDIRECT with its scope stated.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: gabapentin
      term:
        id: CHEBI:42797
        label: gabapentin
    - preferred_term: carbamazepine
      term:
        id: CHEBI:3387
        label: carbamazepine
    - preferred_term: amitriptyline
      term:
        id: CHEBI:2666
        label: amitriptyline
  evidence:
  - reference: PMID:20301462
    reference_title: "Charcot-Marie-Tooth Neuropathy Type 2 - RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY."
    supports: SUPPORT
    evidence_source: OTHER
    directness: INDIRECT
    snippet: "symptomatic treatment of pain, depression, sleep apnea, restless legs syndrome"
    explanation: >-
      The GeneReviews chapter for Charcot-Marie-Tooth neuropathy type 2, the
      group CMT2P belongs to, listing symptomatic treatment of pain in its
      management section. Correct in scope but it names no agents, which is why
      the two further items below are needed.
  - reference: PMID:36793224
    reference_title: "Patient Reported Outcomes Using Medical Cannabis for Managing Pain in Charcot-Marie-Tooth Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: "Chronic pain is a major problem for patients with Charcot-Marie-Tooth (CMT) disease."
    explanation: >-
      Establishes that the problem this treatment addresses is real and common
      across CMT, from a patient cohort rather than expert opinion. Graded
      INDIRECT because the cohort is CMT-wide rather than CMT2P.
  - reference: PMID:20301684
    reference_title: "MFN2 Hereditary Motor and Sensory Neuropathy."
    supports: SUPPORT
    evidence_source: OTHER
    directness: INDIRECT
    snippet: "treatment of neuropathic pain with tricyclic antidepressants or drugs such as carbamazepine or gabapentin"
    explanation: >-
      The only cached source naming agent classes for neuropathic pain in
      axonal CMT. Read the scope carefully before reusing it: this is the
      GeneReviews chapter for MFN2-related CMT2, a different subtype from
      CMT2P. It is cited because the recommendation it makes is generic
      symptomatic management of neuropathic pain in axonal CMT and carries
      nothing MFN2-specific, not because MFN2 disease is a proxy for this one.
      Graded INDIRECT for exactly that reason.

- name: Genetic Counselling
  description: >
    Counselling is unusually consequential here, because the mode of
    inheritance is a property of the variant rather than of the gene:
    recurrence risk depends on whether the family's premature termination
    codon escapes nonsense-mediated decay. Incomplete penetrance and
    asymptomatic carriers complicate family assessment further.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:33414056
    reference_title: "Location matters - Genotype-phenotype correlation in LRSAM1 mutations associated with rare Charcot-Marie-Tooth neuropathy CMT2P."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "ACMG (American College of Medical Genetics and genomics) criteria should be carefully applied in variant interpretation, with special attention to premature termination codon-introducing variants and their location within the gene."
    explanation: >-
      The interpretive care this disease requires, which is the substance of
      what counselling has to convey to a family.

diagnosis:
- name: Nerve conduction studies and electromyography
  description: >
    Establishes that the neuropathy is axonal rather than demyelinating, which
    places the patient in CMT2 and narrows the gene panel. In CMT2P the
    electrophysiology confirms a late-onset axonal sensorimotor process.
  evidence:
  - reference: PMID:33414056
    reference_title: "Location matters - Genotype-phenotype correlation in LRSAM1 mutations associated with rare Charcot-Marie-Tooth neuropathy CMT2P."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Clinical and electrophysiological data confirm a late-onset axonal neuropathy with a predominance of sensorimotor impairment."
    explanation: >-
      Establishes the electrophysiological phenotype the test is looking for.

- name: Lower-limb muscle MRI
  description: >
    Detects fatty atrophy in carriers who are clinically unaffected. In a
    family with a known LRSAM1 variant this is what converts an ambiguous
    pedigree into a resolved one, and it is why the disease's penetrance
    cannot be assessed on clinical examination alone.
  evidence:
  - reference: PMID:27686364
    reference_title: "Charcot-Marie-Tooth disease type 2G redefined by a novel mutation in LRSAM1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Magnetic resonance imaging (MRI) of lower-limb musculature systematically showed fatty atrophy in clinical and subclinical mutation carriers."
    explanation: >-
      The finding and its extension to subclinical carriers, which is what
      makes the test diagnostically useful beyond confirming clinical disease.

- name: LRSAM1 sequencing within a multigene neuropathy panel
  description: >
    Definitive diagnosis. The interpretive difficulty is specific and worth
    stating: because pathogenic variants cluster in the 3-prime exons, whether
    a premature termination codon escapes nonsense-mediated decay determines
    both pathogenicity assessment and the inheritance pattern to counsel on,
    and prediction is not always reliable.
  evidence:
  - reference: PMID:33414056
    reference_title: "Location matters - Genotype-phenotype correlation in LRSAM1 mutations associated with rare Charcot-Marie-Tooth neuropathy CMT2P."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Due to variable inheritance patterns and clustering of pathogenic variants in 3´-prime exons, interpretation of genetic variants in LRSAM1 is challenging."
    explanation: >-
      States the interpretive problem that makes this more than a routine
      panel result.

discussions:
- discussion_id: lrsam1_substrate_gap
  kind: KNOWLEDGE_GAP
  attaches_to:
  - pathophysiology#Impaired TSG101-Dependent Endosomal Sorting
  prompt: >-
    Which LRSAM1 ubiquitylation substrates matter in peripheral axons, and how
    does losing their ubiquitylation cause axonal degeneration?
  rationale: >
    This is the weakest step in an otherwise well-measured chain. TSG101 is
    the only validated substrate, and the reviewers of this gene say so
    explicitly and call it a limit on understanding the protein's cellular
    role. Two results make the endosomal reading harder rather than easier:
    LRSAM1 sits in a post-Golgi perinuclear compartment with little overlap
    with endosome-to-lysosome trafficking machinery, and the p.Cys694Tyr
    allele leaves TSG101 protein levels unchanged in patient cells. Until
    axon-relevant substrates are mapped, the link between the biochemical
    lesion, which is well established, and the clinical phenotype, which is
    well described, is an inference across a gap.
  proposed_experiments:
  - experiment_id: lrsam1_neuronal_ubiquitylome
    name: Ubiquitylation proteomics in LRSAM1-deficient human neurons
    description: >-
      Compare the ubiquitylome of iPSC-derived motor and sensory neurons
      carrying dominant-negative and loss-of-function LRSAM1 alleles against
      isogenic controls, to identify substrates whose ubiquitylation depends
      on LRSAM1 in the cell type the disease affects.
    would_support:
    - pathophysiology#Impaired TSG101-Dependent Endosomal Sorting
    supporting_outcome:
    - >-
      TSG101 ubiquitylation is reduced in mutant neurons, together with other
      substrates in endosomal sorting, supporting the pathway as curated.
    refuting_outcome:
    - >-
      TSG101 ubiquitylation is unchanged while other, non-endosomal substrates
      lose ubiquitylation, which would move this node off the ESCRT pathway
      entirely.

- discussion_id: lrsam1_mouse_severity_mismatch
  kind: HUMAN_MODEL_MISMATCH
  attaches_to:
  - animal_models#Lrsam1 mutant mouse
  - pathophysiology#Increased Vulnerability of Long Peripheral Axons
  prompt: >-
    Why does complete loss of Lrsam1 leave a mouse with almost no neuropathy
    while loss or dominant-negative disruption of LRSAM1 causes a progressive
    neuropathy in people?
  rationale: >
    The mismatch is large and it is not a detail: the mouse is the only animal
    model of this disease and its spontaneous phenotype is very mild in both
    homozygotes and heterozygotes. Two explanations are available and neither
    has been tested. The first is scale, since a mouse sciatic axon is short
    and a mouse lifespan is brief, and this is a length-dependent, late-onset
    degeneration. The second is mechanism, since the mouse models loss of
    function while most human disease is dominant-negative, so the model may
    simply not be modelling the human lesion. Which of the two it is
    determines whether the acrylamide-sensitisation result can be read as
    disease-relevant or only as a general vulnerability assay.
  proposed_experiments:
  - experiment_id: lrsam1_dominant_negative_knockin_mouse
    name: Knock-in mouse carrying a human dominant-negative LRSAM1 allele
    description: >-
      Introduce a human RING-domain frameshift such as p.Leu708Argfs*28 into
      the mouse germline and compare its spontaneous neuropathy with the
      existing Lrsam1 loss-of-function mutant, ageing both cohorts.
    would_support:
    - pathophysiology#Dominant-Negative Truncated RING-Domain Protein
    supporting_outcome:
    - >-
      The knock-in develops a spontaneous progressive neuropathy that the
      loss-of-function mutant does not, which would show the mild mouse
      phenotype reflects the wrong mechanism rather than the wrong species.
    refuting_outcome:
    - >-
      The knock-in is as mild as the existing mutant, which would point to
      axon length and lifespan as the reason and would mean no mouse can model
      this disease's course.

- discussion_id: lrsam1_parkinsonism_association
  kind: KNOWLEDGE_GAP
  attaches_to:
  - pathophysiology#Nigral Neuron Degeneration
  - mechanistic_hypotheses#lrsam1_cns_parkinsonism_extension
  prompt: >-
    Is late-onset parkinsonism part of the LRSAM1 phenotype, and if so what
    connects a peripheral-axon ligase defect to substantia nigra neurons?
  rationale: >
    The observation is striking - three of five affected members of one
    kindred, at ages 50 to 65 - and the authors are careful to call it
    speculation. Two things are unresolved. Whether the association is real
    needs systematic ascertainment across LRSAM1 cohorts rather than
    retrospective notice in the family where it was first seen, since
    Parkinson disease is common enough at those ages that a single pedigree
    cannot settle it. And if it is real, no mechanism exists: nothing links
    this ligase to nigral biology, although the broader ubiquitin-proteostasis
    theme it shares with neurodegeneration makes the idea plausible rather
    than arbitrary. This matters clinically because it determines whether
    LRSAM1 carriers should be watched for parkinsonian features at all.

📚

References & Deep Research

References

2

PMID:20301532

Charcot-Marie-Tooth Hereditary Neuropathy Overview.

No top-level findings curated for this source.

PMID:20301462

Charcot-Marie-Tooth Neuropathy Type 2 - RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY.

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 (2)

Record notes

CMT2G and CMT2P are the same disease. A large pedigree had been classified as a distinct entity, CMT2G, on linkage grounds; re-mapping and sequencing identified LRSAM1 p.Cys694Tyr in it, which collapsed CMT2G into CMT2P. Both designations are carried as synonyms here so a search on either finds this entry. Why this entry has two inheritance blocks rather than two entries. Dominant and recessive CMT2P are one disease with one gene and one functional endpoint, differing in whether the mutant transcript survives nonsense-mediated decay. Splitting them would duplicate the whole pathograph to record a difference that is properly a property of the allele, so the two routes are curated as separate pathophysiology nodes converging on the same ubiquitylation-failure node, with an `inheritance` block for each pattern. A hallucinated identifier caught in preflight, recorded so it is not repeated. The openscientist deep-research report used for this entry proposed MONDO:0013749 as the term for CMT2P. That CURIE resolves, so it does not look like a fabrication, but it is `ventricular septal defect 3`. The report's own term-validation section flagged it, and the correct term, MONDO:0013753, came from the curation stub. The report's reference validation was otherwise clean (20 of 20 identifiers resolved, no quote failures), which is exactly the situation the term check exists for: clean citations tell you nothing about whether the ontology bindings are right. Two of its suggested NCIT treatment terms were wrong in the same way - NCIT:C15224 offered for "pain management" is `Nutrition Research, Fats`, and NCIT:C15633 offered for "genetic counseling" is `Cancer Pain Management` - and neither was used. What this entry deliberately does not claim. No phenotype carries a `frequency`: the literature is a set of pedigrees and small series, the largest being 14 patients from 12 families, and the cohorts include asymptomatic carriers ascertained by family testing, so any percentage would describe who was sequenced rather than the disease. The step from impaired TSG101 ubiquitylation to axon degeneration is marked as inferred in the node that asserts it, and the parkinsonism association is kept out of the canonical hypothesis group.

Create: Charcot-Marie-Tooth Disease Axonal Type 2P (MONDO:0013753, LRSAM1) · 2026-09-02T08:30:04Z · View source

De-novo curation of CMT2P (MONDO:0013753), the LRSAM1-associated axonal hereditary motor and sensory neuropathy. Deep research: one openscientist run (research/Charcot-Marie-Tooth_Disease_Axonal_Type_2P-deep-research-openscientist.md, 20/20 citations resolved, 2/2 quotes valid, confabulation_rate 0.0). Its term validation set needs_review, and the flagged bindings mattered: it proposed MONDO:0013749 for CMT2P, which resolves and is ventricular septal defect 3, and it offered NCIT:C15224 for pain management (actually Nutrition Research, Fats) and NCIT:C15633 for genetic counseling (actually Cancer Pain Management). None were used; the correct MONDO came from the stub and the treatment terms were selected from the cache. This is recorded in the entry notes as a worked case of clean citations coexisting with wrong ontology bindings. just preflight-dr PASSed against MONDO:0013753 with LRSAM1 mentioned 54 times. Curation decisions: dominant and recessive CMT2P are curated as one disease with two inheritance blocks and two upstream pathophysiology nodes converging on a shared ubiquitylation-failure node, because the difference is a property of the allele (whether a 3-prime premature termination codon escapes nonsense-mediated decay) rather than of the disease. The TSG101/ESCRT step carries mechanism_confidence: HYPOTHETICAL and two NO_EVIDENCE items, because the LRSAM1 localisation result and the unchanged TSG101 levels in patient cells both bear on it without supporting it. The parkinsonism association is curated in its own EMERGING hypothesis group and a HYPOTHESIZED node so the peripheral mechanism does not inherit its uncertainty. The mouse model carries one PARTIALLY_RECAPITULATES link and one FAILS_TO_RECAPITULATE link with its own evidence and limitations. HP:0001315 Reduced tendon reflexes was chosen over HP:0001284 Areflexia deliberately; the report wrote areflexia against HP:0001265, which HPO calls Hyporeflexia. Validation: just validate-disorders, validate-terms, check-duplicate-keys, check-entity-refs, check-causal-targets, check-qualifier-terms, check-enum-values all pass. 47/47 snippets verified against cached references.

OpenScientist ▸

Charcot-Marie-Tooth Disease Axonal Type 2P (CMT2P) — Comprehensive Disease Characteristics Report

openscientist-autonomous 20 citations 2026-09-02T07:55:24.236991

Charcot-Marie-Tooth Disease Axonal Type 2P (CMT2P) — Comprehensive Disease Characteristics Report

Disease: Charcot-Marie-Tooth Disease, Axonal, Type 2P OMIM: #614436 | Gene: LRSAM1 (chr9q33.3) | Category: Mendelian Suggested MONDO: MONDO:0013749 (Charcot-Marie-Tooth disease, axonal, type 2P)

Evidence base: literature-derived (human clinical, in vitro/biochemical, model organism, and computational). No primary datasets were provided; all claims are supported by primary literature (PMIDs) and standard disease/gene databases.

Summary

Charcot-Marie-Tooth disease axonal type 2P (CMT2P; OMIM #614436) is a rare, genetically defined form of hereditary axonal sensorimotor peripheral neuropathy caused by pathogenic variants in LRSAM1, a gene on chromosome 9q33.3 encoding a RING-type E3 ubiquitin-protein ligase. It is a member of the large, clinically and genetically heterogeneous Charcot-Marie-Tooth (CMT) family — the most common inherited neuromuscular disorder, affecting roughly 1 in 2,500 people worldwide — but CMT2P itself is one of the rarer axonal (type 2) subtypes. The disease is distinguished by a late/adult onset (typically second to fifth decade), slow progression, lower-limb predominance, frequent neuropathic pain, and marked phenotypic variability that includes asymptomatic mutation carriers.

The molecular pathology centers on loss of LRSAM1 ubiquitin ligase activity. Pathogenic variants cluster in the C-terminal RING domain that mediates the essential E2–E3 interaction required for transferring ubiquitin to substrate proteins (the best-validated target being TSG101, a component of the ESCRT endosomal-trafficking machinery). CMT2P displays a distinctive dual inheritance pattern: recessive alleles that trigger complete loss of protein (e.g., via nonsense-mediated decay, NMD) versus dominant alleles that escape NMD and produce a truncated protein exerting a dominant-negative effect on the RING domain. Whether a 3′-located premature-termination variant escapes or triggers NMD effectively determines whether disease is dominant or recessive — a rare and instructive example of a single gene where variant position dictates inheritance mode.

There is no curative therapy; management is entirely symptomatic and supportive (ankle-foot orthoses, physical/occupational therapy, foot-deformity surgery, neuropathic pain control, and genetic counseling), and life expectancy is normal. An emerging and biologically intriguing finding is that LRSAM1 disease may extend beyond the peripheral nervous system: within the original dominant kindred, several affected members developed late-onset parkinsonism, and additional cases pair CMT2P with parkinsonian features — linking this peripheral neuropathy to a central nervous system phenotype and to ubiquitin-proteostasis themes shared with neurodegeneration.

1. Disease Information

Overview. CMT2P is an axonal (as opposed to demyelinating) hereditary motor and sensory neuropathy. Clinically it presents as a length-dependent, distal, symmetric sensorimotor polyneuropathy with distal weakness and atrophy (legs > arms), distal sensory loss, reduced/absent tendon reflexes, foot deformity (pes cavus), and gait impairment — the classic CMT phenotype — but with a characteristically mild, late-onset, slowly progressive course.

Key identifiers:

Resource	Identifier
OMIM (phenotype)	#614436 (Charcot-Marie-Tooth disease, axonal, type 2P)
OMIM (gene)	LRSAM1 610933
Gene / HGNC	LRSAM1, HGNC:25135
NCBI Gene	90678
UniProt	Q6UWE0
Suggested MONDO	MONDO:0013749
ICD-10	G60.0 (Hereditary motor and sensory neuropathy)
ICD-11	8C20 (Hereditary motor and sensory neuropathy)
MeSH	Charcot-Marie-Tooth Disease (D002607)

Synonyms / alternative names: CMT2P; Charcot-Marie-Tooth disease, axonal, type 2P; CMT2G (a historically separate entity now reclassified as CMT2P after identification of the LRSAM1 p.Cys694Tyr mutation — PMID: 27686364); LRSAM1-related Charcot-Marie-Tooth disease.

Information source type. The knowledge base for CMT2P is derived overwhelmingly from aggregated disease-level resources — OMIM, published family/pedigree studies, and case reports — rather than large EHR cohorts, reflecting its rarity.

2. Etiology

Primary cause — genetic. CMT2P is a monogenic Mendelian disorder caused by pathogenic variants in LRSAM1. The first description came from Guernsey et al. (2010) who used homozygosity mapping in a large recessive eastern Canadian kindred (locus chr9:122–129 Mb) and identified a homozygous intronic splice-acceptor variant (AG→AA) producing a frameshift/truncation and complete loss of protein (PMID: 20865121). Weterman et al. (2012) then identified a dominant frameshift, p.Leu708Argfs*28, in the C-terminal RING domain in a three-generation family with a strong LOD score of 5.12 (PMID: 22012984).

"A homozygous pathogenic variant was identified in the gene encoding leucine rich repeat and sterile alpha motif 1 (LRSAM1) by direct DNA sequencing" — Guernsey et al., PMID: 20865121

"This frameshift mutation (p.Leu708Argfx28) is located in the C-terminal RING finger motif of the encoded protein." — Weterman et al., PMID: 22012984

Genetic risk factors. The causal variants themselves are the risk factors; no additional susceptibility loci are established. Modifier considerations: in a family co-segregating a RAB7A (CMT2B) mutation and a novel LRSAM1 variant, gender and possible RAB7A/LRSAM1 gene interactions were proposed to explain marked variability in age of onset (PMID: 27462242).

Environmental risk / protective factors. No environmental risk or protective factors are established for CMT2P in humans. However, an important gene–environment interaction was demonstrated in the mouse model: Lrsam1 mutant mice are hypersensitive to the axonal neurotoxin acrylamide, indicating that loss of LRSAM1 lowers the axonal threshold for degeneration under toxic stress (PMID: 23519028). This suggests that, mechanistically, neurotoxic exposures could plausibly aggravate an LRSAM1-compromised nervous system, though this has not been shown clinically.

Genetic protective factors. None specifically identified. Incomplete penetrance/asymptomatic carriers imply the existence of unknown modifiers, but none have been mapped.

3. Phenotypes

CMT2P phenotypes are those of a distal, length-dependent axonal sensorimotor polyneuropathy. Onset is typically adult/late (2nd–5th decade), severity is mild to moderate, progression is slow and progressive, and there is variable expressivity including asymptomatic carriers (PMID: 33568173, PMID: 33414056).

"dominant CMT2P is usually characterized by relatively mild, slowly progressive axonal neuropathy, mainly involving lower limbs, with age of onset between the second and fifth decades of life" — Palaima et al., PMID: 33568173

"CMT2P is a rare, but nevertheless relevant cause of adult-onset axonal and painful neuropathy" — Reilich et al., PMID: 33414056

Phenotype	Type	HPO term (suggested)	Onset / severity / progression	Notes
Distal lower-limb muscle weakness	Clinical sign	HP:0009053 / HP:0002460	Adult; mild-moderate; progressive	Legs affected before/more than arms
Distal sensory loss	Symptom/sign	HP:0002936 (distal sensory impairment)	Adult; variable	Length-dependent
Neuropathic / painful neuropathy	Symptom	HP:0009830 (peripheral neuropathy), HP:0012531 (pain)	Adult; variable	Notable feature of CMT2P
Pes cavus (high-arched foot)	Physical manifestation	HP:0001761	Insidious	Classic CMT deformity
Gait instability / disturbance	Clinical sign	HP:0002317 (unsteady gait), HP:0001288	Progressive	Major functional impact
Reduced/absent deep tendon reflexes	Clinical sign	HP:0001265 (areflexia) / HP:0001315	Early	Distal predominance
Foot drop	Clinical sign	HP:0009027	Adult	From distal weakness
Fatty atrophy of lower-limb muscle (MRI)	Laboratory/imaging	HP:0003693 (distal amyotrophy)	Subclinical detectable	Detects subclinical carriers (PMID: 27686364)
Parkinsonism (emerging)	Clinical sign	HP:0001300 (parkinsonism)	Late (5th–7th decade)	CNS extension (PMID: 26900582, PMID: 40721190)

Quality-of-life impact. As with CMT broadly, the dominant burden is on mobility and gait, with foot deformity, falls risk, and — distinctively for CMT2P — chronic neuropathic pain. Supportive care (orthotics, rehabilitation) improves quality of life (PMID: 40014417, PMID: 40636623). Formal EQ-5D/SF-36/PROMIS data specific to CMT2P are not available.

4. Genetic / Molecular Information

Causal gene. LRSAM1 (Leucine Rich Repeat And Sterile Alpha Motif containing 1; also called Tal), HGNC:25135, gene OMIM 610933, NCBI Gene 90678, UniProt Q6UWE0, on chromosome 9q33.3. It encodes a universally expressed RING-type E3 ubiquitin-protein ligase with domain architecture LRR – coiled-coil – SAM – PDZ-binding – RING (PMID: 33568173, PMID: 23245322).

Pathogenic variants cluster in the 3′-prime exons encoding the C-terminal RING domain. Reilich et al. (2021) reported 14 patients from 12 families harboring 10 different LRSAM1 variants (7 novel), predominantly dominant (PMID: 33414056).

Variant	Type	Inheritance	Source
Intronic splice-acceptor AG→AA (frameshift/truncation, complete LOF)	Splice-site	Recessive (homozygous)	PMID: 20865121
p.Leu708Argfs*28	Frameshift (RING domain)	Dominant	PMID: 22012984
p.Pro707Leu	Missense (RING)	Dominant	PMID: 28335037
p.Cys694Tyr	Missense (RING)	Dominant (reclassified CMT2G→CMT2P)	PMID: 27686364

Variant classification (ACMG/AMP). Interpretation is challenging precisely because pathogenic variants cluster at the 3′ end where premature-termination codons may or may not escape NMD; careful application of PVS1 and related criteria is required depending on exact position and predicted NMD outcome (PMID: 33414056).

"Variants at the 3`end may or may not escape from nonsense-mediated decay, thereby defining the pattern of inheritance" — Reilich et al., PMID: 33414056

"clustering of pathogenic variants in 3´-prime exons, interpretation of genetic variants in LRSAM1 is challenging" — Reilich et al., PMID: 33414056

Functional consequences. - Recessive variants → complete loss of LRSAM1 protein → loss of function. - Dominant variants → truncated RING-domain protein escaping NMD → dominant-negative effect on ligase activity (PMID: 33414056).

"the C-terminal RING domain, which exerts a dominant-negative effect on protein function, whenever affected by an altered or truncated protein" — Reilich et al., PMID: 33414056

Allele frequency / somatic vs germline. All disease variants are germline and rare (not established as recurrent population polymorphisms); LRSAM1 mutations are considered rare even within CMT2 (PMID: 28335037). No somatic (COSMIC/cancer) role is relevant.

Modifier genes / epigenetics / chromosomal abnormalities. Possible RAB7A × LRSAM1 interaction and a gender effect were proposed as phenotype modifiers (PMID: 27462242). No epigenetic mechanisms or large chromosomal abnormalities are implicated; transcriptomic changes (upregulation of NEDD4L and TNFRSF21) were seen with the p.Cys694Tyr mutation (PMID: 27686364).

5. Environmental Information

No environmental, lifestyle, or infectious agents cause CMT2P — it is a purely genetic disorder. The only mechanistically relevant environmental link is experimental: LRSAM1-deficient mouse axons are more sensitive to the neurotoxin acrylamide (PMID: 23519028), raising the theoretical possibility that neurotoxic exposures could exacerbate axonal vulnerability. Of interest to the protein's normal biology, LRSAM1 participates in anti-bacterial autophagy (xenophagy) of intracellular Salmonella Typhimurium (PMID: 23245322), but there is no evidence infection triggers the neuropathy.

6. Mechanism / Pathophysiology

Ordered causal chain (initiating lesion → clinical manifestation)

A germline pathogenic variant arises in LRSAM1, clustered in the 3′ exons encoding the C-terminal RING domain.
Depending on variant position and NMD, this leads to one of two states:
(Recessive branch) biallelic loss → NMD/complete absence of LRSAM1 protein → total loss of E3 ligase function; or
(Dominant branch) a truncated protein that escapes NMD → a dominant-negative RING-domain protein that poisons residual ligase activity.
Either state results in disrupted E2–E3 interaction, the essential step for transferring ubiquitin from the E2 conjugating enzyme to substrates — thereby abrogating LRSAM1-mediated ubiquitylation (PMID: 28335037).
Loss of ubiquitylation of the validated target TSG101 (an ESCRT-I component) impairs endosomal sorting / multivesicular-body (MVB) trafficking and receptor endocytosis (PMID: 15256501) — inferred to perturb membrane/protein homeostasis in neurons.
Impaired proteostasis and trafficking lowers the threshold for length-dependent distal axonal degeneration — demonstrated indirectly by heightened axonal vulnerability to neurotoxic stress in the mouse model (PMID: 23519028).
Degeneration of the longest peripheral motor and sensory axons produces distal muscle weakness/atrophy, distal sensory loss, neuropathic pain, areflexia, pes cavus, and gait impairment — the CMT2P phenotype.
(Branch — CNS extension, inferred) In some individuals the same ligase dysfunction is associated with later degeneration affecting the substantia nigra, manifesting as late-onset parkinsonism (PMID: 26900582, PMID: 40721190); the mechanism connecting LRSAM1 to nigral neurons remains undefined.

Causal chain diagram

LRSAM1 pathogenic variant (3' RING-encoding exons, chr9q33.3)
              |
 ┌────────────────────┴────────────────────┐
   (recessive)                                (dominant)
 biallelic, NMD →                       PTC escapes NMD →
 complete loss of LRSAM1               truncated RING protein
|                                        |
└───────────────┬────────────────────────┘
        v
Disrupted E2–E3 interaction  →  loss of ubiquitylation activity
        v
     ↓ Ubiquitination of TSG101 (ESCRT-I)  →  impaired endosomal/MVB trafficking
        v
     Perturbed neuronal proteostasis & membrane homeostasis (inferred)
        v
     ↑ Vulnerability to length-dependent DISTAL AXON DEGENERATION
       (mouse: unmasked by neurotoxic stress; ↑TNFRSF21)
        v
   ┌────────────────────┴──────────────────────────┐
   v                                                v
 PNS phenotype:                          CNS extension (some patients):
 distal weakness, sensory loss,          late-onset parkinsonism
 neuropathic pain, pes cavus,            (substantia nigra; mechanism unknown)
 areflexia, gait impairment

Supporting detail

Molecular pathway / biochemical defect. The core lesion is in the ubiquitin–proteasome / ubiquitin-conjugation pathway. LRSAM1 is a RING E3 ligase; RING-domain variants cause "loss of the E2-E3 interaction that is an essential prerequisite for supporting ubiquitylation of target substrates" (PMID: 28335037).
Protein function. Two functional modules: the LRR domain targets substrates (e.g., cytosolic bacteria) and the RING domain catalyzes ubiquitin transfer — "these functions require LRSAM1's leucine-rich repeat and RING domains, respectively" (PMID: 23245322).
Cellular processes. Endosomal/ESCRT trafficking, MVB and retrovirus budding (via TSG101 monoubiquitination, PMID: 15256501); autophagy/xenophagy; and, downstream, axon degeneration. Transcriptomic profiling of patient cells implicated TNFRSF21 (a regulator of axonal degeneration) and pathways shared with ALS and Alzheimer disease (PMID: 27686364).
Subcellular localization. In transfected cells LRSAM1 localizes to a perinuclear compartment just beyond the Golgi (PMID: 23519028).

Upstream vs downstream: the mutation and lost ubiquitylation are upstream; trafficking/proteostasis defects are intermediate; distal axonal degeneration and clinical signs are downstream.

Suggested ontology terms. GO:0016567 (protein ubiquitination), GO:0004842 (ubiquitin-protein transferase activity), GO:0061630 (ubiquitin protein ligase activity), GO:0007032 (endosome organization), GO:0098930 (axonal transport), GO:0006914 (autophagy). Cell types (CL): CL:0000101 (sensory neuron), CL:0000100 (motor neuron), CL:0002573 (Schwann cell). Cellular components: GO:0005768 (endosome), GO:0000813 (ESCRT-I complex), GO:0005794 (Golgi apparatus).

7. Anatomical Structures Affected

Organ / system level. The peripheral nervous system is primary (UBERON:0000010). Body system: nervous system (UBERON:0001016). Secondary/musculoskeletal involvement includes distal limb muscles and the foot/skeleton (pes cavus, foot deformity); CMT patients also show an under-recognized rate of hip acetabular dysplasia (21% of imaged CMT patients in one series — PMID: 40432997). The emerging CNS extension implicates the substantia nigra / basal ganglia (PMID: 26900582).

Tissue / cell level. Nervous tissue — peripheral motor and sensory axons; LRSAM1 is abundantly expressed in PNS motor and sensory neurons (PMID: 23519028). Affected cells: motor neurons (CL:0000100) and sensory neurons (CL:0000101); skeletal muscle secondarily denervated (CL:0000188).

Subcellular level. Endosome/MVB (GO:0005768), ESCRT-I complex (GO:0000813), Golgi-adjacent perinuclear compartment (GO:0005794).

Localization. Distal, length-dependent, bilateral and symmetric, lower limbs > upper limbs. Suggested UBERON: UBERON:0001322 (sciatic nerve) and distal peroneal/tibial nerve territory; spinal cord and CNS not primarily affected in the classic peripheral phenotype.

8. Temporal Development

Onset: adult/late, typically 2nd to 5th decade; insidious/chronic (PMID: 33568173). A rare early-onset autosomal dominant family has been reported (PMID: 38330802).
Progression: slow and progressive; generally mild ("quiescent") axonal neuropathy (PMID: 27686364).
Course pattern: chronic, lifelong, non-remitting, non-episodic.
Critical periods / CNS window: late-onset parkinsonism appears years after neuropathy onset (ages ~50–65) in some patients (PMID: 26900582).

9. Inheritance and Population

Epidemiology. CMT overall affects ~1:2,500 worldwide with >100 known genetic causes (PMID: 40219666). CMT2P is a rare subtype; LRSAM1 mutations are uncommon even within CMT2 (PMID: 28335037). Precise CMT2P prevalence/incidence are not established.

"Affecting about ~1:2,500 people worldwide, CMT has over 100 known genetic causes, leading to different subtypes with varying disease severity and progression." — Stavrou et al., PMID: 40219666

Inheritance. Both autosomal dominant (predominant) and autosomal recessive, determined by variant location and NMD outcome (see Section 4). Dominant = dominant-negative RING variants escaping NMD; recessive = biallelic complete loss (PMID: 33414056).

Penetrance / expressivity. Incomplete penetrance and variable expressivity, including asymptomatic carriers detectable only by lower-limb muscle MRI (PMID: 27686364, PMID: 33568173).

Founder effects / consanguinity. The original recessive kindred was a large consanguineous eastern Canadian family (homozygous founder-type splice variant) (PMID: 20865121). Carrier status for the recessive LRSAM1 allele has been incidentally detected in idiopathic neuropathy cohorts (PMID: 39290488).

Demographics. No strong ethnic predilection; reported families span Canada, the Netherlands, and others. Sex ratio not clearly skewed, though gender was proposed as a modifier in one family (PMID: 27462242). Genetic anticipation and germline mosaicism are not established.

10. Diagnostics

Clinical / electrophysiology. Diagnosis rests on nerve conduction studies / EMG demonstrating an axonal (rather than demyelinating) sensorimotor neuropathy: reduced amplitudes with relatively preserved conduction velocities (PMID: 40721190). Clinical exam shows distal weakness, sensory loss, areflexia, pes cavus.

Imaging. MRI of lower-limb musculature systematically reveals fatty atrophy in both clinical and subclinical carriers and is useful to detect minimal/subclinical disease (PMID: 27686364).

Genetic testing (definitive). Diagnosis is confirmed by identifying a pathogenic LRSAM1 variant. Recommended approach: multigene neuropathy/CMT panel or exome sequencing, given the >100 CMT genes; targeted LRSAM1 analysis when phenotype/family history suggests it. LRSAM1 is included on inherited neuromuscular gene panels (PMID: 39290488). Careful ACMG interpretation of 3′ PTC variants (NMD escape) is essential (PMID: 33414056). Chromosomal microarray, karyotyping, FISH, mitochondrial and repeat-expansion testing are not relevant to CMT2P.

Omics diagnostics. Not standard; research transcriptome profiling of patient lymphoblasts has shown disease-associated expression changes (PMID: 27686364).

Differential diagnosis. Other axonal CMT2 subtypes (CMT2A/MFN2, CMT2B/RAB7A, CMT2K/GDAP1, etc.), hereditary transthyretin (ATTRv) amyloidosis (important treatable mimic — PMID: 39290488), CMT1 (demyelinating; PMP22), acquired/idiopathic axonal polyneuropathies, and ALS5/SPG11 overlap syndromes (PMID: 26556829).

Screening. Cascade genetic testing of at-risk relatives once a familial variant is known; no population newborn screening.

11. Outcome / Prognosis

Survival / life expectancy: normal. CMT2P is not life-limiting; by analogy to other CMT the disease "reflects a process of normal ageing" with normal life expectancy (PMID: 24646194).
Morbidity / disability. Chronic, slowly progressive mobility impairment, foot deformity, falls risk, and neuropathic pain dominate; wheelchair dependence is uncommon given the mild course.
Complications. Foot deformities requiring surgery; possible hip acetabular dysplasia in CMT broadly (PMID: 40432997); late-onset parkinsonism as a distinct CNS complication in some LRSAM1 patients (PMID: 26900582).
Prognostic factors. Variant type/inheritance (dominant-negative vs LOF), and modifiers such as gender/second-gene interaction (PMID: 27462242). No validated molecular prognostic biomarkers.

12. Treatment

No curative therapy exists; management is symptomatic and supportive.

"Currently, no curative treatment exists for CMT. Management focuses on symptomatic interventions, including orthotic support, surgical procedures, and physical therapy." — Kikuchi, PMID: 40636623

Modality	Intervention	Suggested NCIT
Orthotics	Ankle-foot orthoses (AFOs) for foot drop	NCIT:C50008 (orthotic device)
Rehabilitation	Physical therapy, occupational therapy	NCIT:C15327 (physical therapy)
Surgical	Correction of pes cavus / foot deformity	NCIT:C15329 (surgery)
Pharmacologic (supportive)	Neuropathic pain control (gabapentinoids, duloxetine, TCAs)	NCIT:C15224 (pain management)
Genetic counseling	Family risk assessment	NCIT:C15633 (genetic counseling)

Experimental / disease-modifying (CMT broadly, not LRSAM1-specific). No approved disease-modifying drug for CMT2P. Across CMT, gene therapy (silencing/replacement/editing via AAV vectors) is under active preclinical/early-clinical development but faces blood–nerve/brain-barrier delivery, immunogenicity, and scalability challenges (PMID: 40219666). Other emerging approaches include PMP22 silencers (for CMT1A), HDAC6 inhibitors, and govorestat (aldose reductase inhibitor, CMT-SORD trial) — none specific to LRSAM1 (PMID: 40014417).

"Currently, there are no approved treatments and care focuses on managing symptoms." — Stavrou et al., PMID: 40219666

Pharmacogenomics / personalized medicine. No LRSAM1-specific pharmacogenomic guidance. The dual LOF-vs-dominant-negative mechanism implies different rational strategies (gene replacement for recessive LOF; allele-specific silencing for dominant-negative alleles) — currently conceptual.

13. Prevention

CMT2P cannot be prevented (genetic). Prevention is limited to reproductive/genetic risk management and complication avoidance:

Primary: Genetic counseling, carrier/cascade testing, and reproductive options (prenatal testing, preimplantation genetic diagnosis) for known familial variants (general CMT precedent — PMID: 24646194).
Secondary: Early detection of subclinical carriers via lower-limb muscle MRI (PMID: 27686364); early physiotherapy/orthotics.
Tertiary: Prevent complications — orthotic support to prevent falls/deformity progression, monitoring for hip dysplasia and, given the emerging link, parkinsonian features.
Behavioral: Theoretical avoidance of neurotoxic exposures (extrapolated from acrylamide sensitivity in the mouse model, PMID: 23519028) — not a clinical guideline.

No immunization, public-health, or infectious-control measures apply.

14. Other Species / Natural Disease

Model species: Mus musculus (NCBI Taxon 10090) — the Lrsam1 mutant mouse (PMID: 23519028).
Orthologous gene: mouse Lrsam1, abundantly expressed in PNS motor and sensory neurons.
Natural disease in companion animals/wildlife: No naturally occurring LRSAM1/CMT2P disease documented in other species (OMIA); the LRR–RING E3-ligase function is evolutionarily conserved, and the protein's ubiquitin-dependent xenophagy role is conserved across mammalian cells (PMID: 23245322).
Zoonotic potential: None (non-infectious genetic disease).

15. Model Organisms

Mouse (Lrsam1 mutant). The principal model (PMID: 23519028):

Phenotype recapitulation (partial): Both homozygous and heterozygous mice have largely normal neuromuscular performance and only very mild age-related neuropathy — milder than the human disease.
Key finding — sensitized axons: mutant axons are hypersensitive to axonal neurotoxin challenge.

"Lrsam1 mutant mice are more sensitive to challenge with acrylamide, a neurotoxic agent that causes axon degeneration, indicating that the axons in the mutant mice are indeed compromised" — Bogdanik et al., PMID: 23519028

Localization insight: LRSAM1 localizes to a perinuclear post-Golgi compartment, with little colocalization with endosome-to-lysosome trafficking machinery.
Limitations: Mild phenotype limits modeling of overt human neuropathy; does not capture dominant-negative human biology or the parkinsonism extension.
Cellular / in vitro models: Patient lymphoblasts/fibroblasts for ubiquitylation assays and transcriptomics (PMID: 28335037, PMID: 27686364); in vitro ubiquitylation reconstitution to test E2–E3 interaction defects.
Resources: MGI (mouse) and standard CMT model repositories.

Mechanistic Model / Interpretation

The unifying theme is failure of a RING E3 ubiquitin ligase, converging on impaired proteostasis and endosomal trafficking in neurons. CMT2P is mechanistically distinctive within CMT2 for two reasons: (a) its position-dependent dual inheritance, in which NMD escape/triggering of a 3′ premature-termination codon decides whether disease is dominant (dominant-negative) or recessive (complete loss of function); and (b) a dominant-negative mode operating for most disease alleles. The recurrent link to parkinsonism situates LRSAM1 within broader ubiquitin-proteostasis neurodegeneration biology — echoed by patient-cell transcriptomes sharing pathways with ALS and Alzheimer disease — and suggests the same ligase defect can, over decades, extend from the longest peripheral axons to vulnerable central (nigral) neurons.

Evidence Base

PMID	Study	Contribution
20865121	Guernsey et al. 2010	First identified LRSAM1 as causal (recessive splice variant, complete LOF)
22012984	Weterman et al. 2012	Dominant RING frameshift p.Leu708Argfs*28 (LOD 5.12)
28335037	Hakonen et al. 2017	Biochemical defect: RING variants disrupt E2–E3 interaction, abrogate ubiquitylation
33414056	Reilich et al. 2021	Genotype–phenotype: 3′ clustering, NMD determines inheritance, dominant-negative RING
33568173	Palaima et al. 2021 (review)	Clinical spectrum; TSG101 as main substrate; domain architecture
27686364	2016	CMT2G reclassified as CMT2P (p.Cys694Tyr); MRI subclinical detection; transcriptome
23519028	Bogdanik et al. 2013	Mouse model: mild phenotype, acrylamide sensitization, localization
15256501	Amit et al. 2004	LRSAM1/Tal ubiquitinates TSG101; ESCRT/MVB & retrovirus budding
23245322	Huett et al. 2012	LRR (targeting) + RING (catalytic) domains; anti-bacterial xenophagy
26900582	Aerts et al. 2016	Parkinsonism in 3/5 affected family members — CNS extension
40721190	Ducatel et al. 2025	CMT2P with parkinsonism case — corroborates CNS link
40219666	Stavrou et al. 2025	CMT prevalence (1:2,500); no approved treatments; gene-therapy status
40636623	Kikuchi 2025	Symptomatic management (orthotics, PT, surgery)
40014417	De Grado et al. 2025	Current CMT therapeutics landscape / trials
38330802	2024	Early-onset autosomal dominant CMT2P family
27462242	2016	Gender & RAB7A/LRSAM1 interaction as phenotype modifiers
39290488	2024	LRSAM1 carrier detected on neuropathy gene panel
24646194	2014	CMT precedent: normal life expectancy, symptomatic care
40432997	2025	Hip acetabular dysplasia in CMT (21%)
26556829	2015	ALS5/SPG11 overlap — differential diagnosis context

Evidence source types: human clinical/genetic (family & cohort studies, reviews), model organism (mouse), and in vitro/biochemical (ubiquitylation assays, cell transfection).

Limitations and Knowledge Gaps

Rarity limits epidemiology. No reliable prevalence/incidence, sex ratio, or natural-history quantitation specific to CMT2P; most data come from individual pedigrees and case reports.
Substrate biology is incomplete. TSG101 is the only well-validated LRSAM1 ubiquitylation target relevant to disease; how impaired TSG101/ESCRT function specifically drives axonal degeneration is inferred, not demonstrated.
Genotype–phenotype uncertainty. NMD escape/dominant-negative predictions for 3′ PTC variants are not always experimentally verified, complicating ACMG classification.
Mouse model is mild. The Lrsam1 mouse under-recapitulates overt human neuropathy and does not model the dominant-negative or parkinsonism aspects.
The parkinsonism link is preliminary. Based on one family plus isolated cases; causality, penetrance, and mechanism (LRSAM1 in substantia nigra) are unknown.
No disease-specific therapy or biomarkers. All treatments are symptomatic; no validated prognostic molecular markers.

Proposed Follow-up Experiments / Actions

Functional NMD/dominant-negative assays for each reported 3′ LRSAM1 PTC variant (patient RNA + minigene assays) to firm up ACMG calls and inheritance prediction.
iPSC-derived motor/sensory neurons carrying dominant-negative vs LOF LRSAM1 alleles to test axonal degeneration, ESCRT/TSG101 trafficking, and stress vulnerability — bridging the mild mouse-model gap.
Expand substrate mapping (ubiquitylation proteomics) in neurons to identify axon-relevant LRSAM1 targets beyond TSG101.
Systematic ascertainment of parkinsonism/CNS features across LRSAM1 cohorts (DAT-SPECT imaging, longitudinal follow-up) to establish frequency, penetrance, and mechanism of the CNS extension.
Allele-specific silencing (dominant alleles) and gene replacement (recessive LOF) proof-of-concept in cellular/mouse models, leveraging the AAV gene-therapy platforms being developed for CMT broadly.
Registry-based natural history study to define CMT2P prevalence, progression rate, and disability trajectory, enabling future trial readiness.
Test neurotoxic-exposure interaction clinically/epidemiologically, motivated by acrylamide hypersensitivity in the mouse model.

Report compiled from an autonomous multi-iteration literature investigation (8 confirmed findings, 21 papers reviewed). Evidence is predominantly human genetic/clinical and model-organism; CMT2P remains a rare, symptomatically managed axonal neuropathy with an emerging CNS dimension.

Artifacts

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome	Count
References checked	20
Resolved	20
Unresolved (possible confabulation)	0
Unverifiable	0
Quoted claims checked	2
Quoted claims found in source	2
Quoted claims not found in source	0
References weighed for topical relevance	20
On topic	13
Off topic	0

All extracted references resolved successfully.

Term Validation

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

Outcome	Count
Terms checked	36
Resolved	35
Unresolved (possible confabulation)	0
Obsolete	0
Unverifiable	1
Terms whose name was checked	24
Terms named correctly	17
Terms named as a different term	5
Terms whose name is worth a second look	2

Terms the report names something else

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

MONDO:0013749 (2 mentions) - the report calls it "Charcot-Marie-Tooth disease, axonal, type 2P", "Suggested MONDO"; MONDO calls it ventricular septal defect 3
HP:0001761 (1 mention) - the report calls it "Physical manifestation"; HP calls it Pes cavus
HP:0009027 (1 mention) - the report calls it "Clinical sign"; HP calls it Foot dorsiflexor weakness
NCIT:C15224 (1 mention) - the report calls it "pain management"; NCIT calls it Nutrition Research, Fats
NCIT:C15633 (1 mention) - the report calls it "genetic counseling"; NCIT calls it Cancer Pain Management

Terms whose name is worth a second look

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

NCIT:C50008 (1 mention) - the report calls it "orthotic device"; NCIT calls it Interface Device
NCIT:C15327 (1 mention) - the report calls it "physical therapy"; NCIT calls it Lumbar Puncture, and lists "Spinal Tap" among its other names

Terms named inconsistently

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

MONDO:0013749 - called "Charcot-Marie-Tooth disease, axonal, type 2P", "Suggested MONDO"

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References & Deep Research

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Charcot-Marie-Tooth Disease Axonal Type 2P (CMT2P) — Comprehensive Disease Characteristics Report

Summary

1. Disease Information

2. Etiology

3. Phenotypes

4. Genetic / Molecular Information

5. Environmental Information

6. Mechanism / Pathophysiology

Ordered causal chain (initiating lesion → clinical manifestation)

Causal chain diagram

Supporting detail

7. Anatomical Structures Affected

8. Temporal Development

9. Inheritance and Population

10. Diagnostics

11. Outcome / Prognosis

12. Treatment

13. Prevention

14. Other Species / Natural Disease

15. Model Organisms

Mechanistic Model / Interpretation

Evidence Base

Limitations and Knowledge Gaps

Proposed Follow-up Experiments / Actions

Artifacts

Reference Validation

Term Validation

Terms the report names something else

Terms whose name is worth a second look

Terms named inconsistently