Charcot-Marie-Tooth Disease Type 2
Charcot-Marie-Tooth disease type 2 (CMT2) is a group of inherited peripheral neuropathies characterized by axonal degeneration of peripheral nerves without primary demyelination. Unlike CMT1, which involves Schwann cell dysfunction and demyelination, CMT2 is primarily an axonopathy with normal or near-normal nerve conduction velocities (>38 m/s) but reduced compound muscle action potential amplitudes. CMT2 is genetically heterogeneous, with over 20 subtypes identified. The most common subtype is CMT2A (MFN2 mutations); the remaining subtypes — including CMT2B (RAB7A), CMT2E (NEFL), CMT2F (HSPB1), CMT2K (GDAP1), and the recessive SORD-related form — are each individually rarer, and a large fraction of CMT2 remains genetically unsolved. Clinical features include progressive distal muscle weakness and atrophy, sensory loss, foot deformities, and areflexia, typically with onset in the first to second decade of life.
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Inheritance
2
Autosomal Dominant
HP:0000006
Most CMT2 subtypes follow autosomal dominant inheritance, including CMT2A (MFN2), CMT2B (RAB7A), CMT2D (GARS1), CMT2E (NEFL), and CMT2I/J (MPZ), together with the more recently delineated CMT2FF (CADM3), CMT2HH (JAG1) and CMT2II (heterozygous SLC12A6). De novo mutations occur, particularly in MFN2 and in SLC12A6.
Show evidence (1 reference)
"The majority of CMT2 are autosomal-dominant but autosomal-recessive forms have been described."
Review supports autosomal dominant inheritance as the most common CMT2 inheritance pattern.
Autosomal Recessive
HP:0000007
Some CMT2 subtypes follow autosomal recessive inheritance, including CMT2B1 (LMNA), CMT2B2 (PNKP; originally attributed to MED25), and SORD-CMT2, together with the biallelic subtypes CMT2KK (ARHGAP19), CMT2LL (DARS2) and CMT2MM (COX18). Recessive NEFL mutations also cause a severe early-onset form. Biallelic MFN2 (CMT2A2B) is grouped here by convention, but the carrier parents of the reported probands were not phenotypically normal, so that relationship is better described as semi-dominant. Note: CMT2B2 was initially reported as a MED25 disorder, but re-evaluation of the original family reassigned the cause to a homozygous PNKP variant, so MED25 is no longer considered a CMT gene.
Show evidence (2 references)
"The majority of CMT2 are autosomal-dominant but autosomal-recessive forms have been described."
Review supports the presence of autosomal recessive CMT2 forms.
"Using exome sequencing, we now identified a homozygous nonsense variant (p.Gln517ter) in the last exon of an adjacent gene, the polynucleotide kinase 3'-phosphatase (PNKP) gene."
Re-evaluation of the original CMT2B2 family reassigned the cause from MED25 to a homozygous PNKP variant, so CMT2B2 is a PNKP disorder and MED25 is no longer a CMT gene.
Subtypes
32
CMT2A (MFN2-related)
MONDO:0012231
The most common CMT2 subtype, caused by mutations in the MFN2 gene encoding mitofusin-2. Characterized by early onset, severe distal weakness, and optic atrophy in some cases.
Show evidence (1 reference)
"A causal relationship between Mitofusin (MFN) 2 gene mutations and the hereditary axonal neuropathy Charcot-Marie-Tooth disease type 2A (CMT2A) was described over 15 years ago."
Establishes MFN2 mutations as the causal lesion for CMT2A.
CMT2E (NEFL-related)
MONDO:0011894
Caused by mutations in NEFL encoding neurofilament light chain. Presents with variable severity, from mild to severe neuropathy.
Show evidence (1 reference)
"Here, we demonstrate that allele-specific CRISPR gene editing in a human model of axonal Charcot-Marie-Tooth (CMT) disease rescues pathology caused by a dominant missense mutation in the neurofilament light chain gene (NEFL, CMT type 2E)."
Confirms NEFL mutations as the molecular driver of CMT2E.
CMT2B (RAB7A-related)
MONDO:0010949
Caused by mutations in RAB7A. Distinguished by prominent sensory loss with ulcerations and occasional amputations.
Show evidence (1 reference)
"Missense mutations in RAB7A, the gene encoding the small GTPase Rab7, cause CMT2B and increase Rab7 activity."
Establishes RAB7A mutations as the causal lesion for CMT2B.
CMT2D (GARS1-related)
MONDO:0011091
Caused by mutations in GARS1 encoding glycyl-tRNA synthetase. Predominantly affects the upper extremities.
Show evidence (1 reference)
"Gain-of-function mutations in the housekeeping gene GARS1, which lead to the expression of toxic versions of glycyl-tRNA synthetase (GlyRS), cause the selective motor and sensory pathology characterizing Charcot-Marie-Tooth disease (CMT)."
Links pathogenic GARS1/GlyRS gain-of-function mutations to the motor and sensory pathology modeled in CMT2D.
CMT2I/J (MPZ-related)
MONDO:0011889
MONDO:0011903
Caused by mutations in MPZ encoding myelin protein zero. Late-onset axonal neuropathy with pupillary abnormalities.
Show evidence (1 reference)
"Mutations in MPZ have been associated with different Charcot-Marie-Tooth disease (CMT) phenotypes (CMT1B, CMT2I/J, CMTDI), Dejerine-Sottas syndrome, and congenital hypomyelination neuropathy."
Establishes MPZ mutations as associated with the CMT2I/J phenotype spectrum.
SORD-related axonal CMT2
MONDO:0030055
Autosomal recessive axonal neuropathy caused by biallelic loss-of-function SORD variants. SORD-CMT2 is associated with sorbitol dehydrogenase loss, elevated sorbitol, and distal motor-predominant axonal degeneration.
Show evidence (1 reference)
"Here we report biallelic mutations in the sorbitol dehydrogenase gene (SORD) as the most frequent recessive form of hereditary neuropathy."
Establishes biallelic SORD variants as a common cause of autosomal recessive hereditary neuropathy in the CMT2 spectrum.
CMT2F (HSPB1 / HSP27-related)
MONDO:0011687
Autosomal dominant axonal CMT caused by mutations in HSPB1, encoding the 27-kDa small heat-shock protein B1 (HSP27). Mutant HSP27 disrupts the neurofilament network and axonal transport; the same gene also causes distal hereditary motor neuropathy.
Show evidence (1 reference)
"Here we report a missense mutation in the gene encoding 27-kDa small heat-shock protein B1 (HSPB1, also called HSP27) that segregates in the family with CMT2F."
Establishes HSPB1 (HSP27) missense mutation as the cause of axonal CMT2F.
CMT2Z (MORC2-related)
MONDO:0014736
Axonal CMT caused by mutations in MORC2 (microrchidia CW-type zinc finger 2), a transcriptional regulator. Phenotype is clinically heterogeneous, ranging from early-onset spinal muscular atrophy-like weakness to later-onset axonal neuropathy.
Show evidence (1 reference)
"Here we present a new axonal Charcot-Marie-Tooth disease form, associated with the gene microrchidia family CW-type zinc finger 2 (MORC2)."
Establishes MORC2 mutations as the cause of axonal CMT2Z.
CMT2K (GDAP1-related, axonal)
MONDO:0011916
Axonal CMT caused by mutations in GDAP1, which regulates mitochondrial fission and the mitochondrial network. GDAP1 mutations cause both demyelinating CMT4A and axonal CMT2K; CMT2K occurs in autosomal recessive and (typically milder, later-onset) autosomal dominant forms.
Show evidence (1 reference)
"Mutations in GDAP1 associate with demyelinating (CMT4A) and axonal (CMT2K) forms of CMT."
Establishes GDAP1 mutations as causing axonal CMT2K (alongside demyelinating CMT4A).
CMT2CC (NEFH-related)
MONDO:0014836
Autosomal dominant axonal CMT caused by frameshift variants near the end of NEFH (neurofilament heavy chain) that read through into the 3' UTR, producing a cryptic amyloidogenic element that drives aggresome formation and neuronal death. Phenotype is motor-predominant with early proximal weakness.
Show evidence (1 reference)
"gene was recently identified to cause autosomal dominant axonal Charcot-Marie-Tooth disease (CMT2cc)"
Establishes NEFH as the cause of autosomal dominant axonal CMT2CC.
CMT2L (HSPB8 / HSP22-related)
MONDO:0012096
Autosomal dominant axonal CMT caused by missense mutations in the alpha-crystallin domain of HSPB8, encoding the small heat-shock protein HSP22. The same Lys141 substitutions also cause distal hereditary motor neuropathy, so CMT2L and that motor neuropathy are allelic.
Show evidence (1 reference)
"we report a novel c.423G-->T (Lys141Asn) missense mutation of small heat-shock protein 22-kDa protein 8 (encoded by HSPB8), which is also responsible for distal hereditary motor neuropathy type (dHMN) II"
Establishes an HSPB8 missense mutation as the cause of CMT2L in the pedigree in which the locus was mapped.
CMT2N (AARS1-related)
MONDO:0013212
Autosomal dominant axonal CMT caused by mutations in AARS1, encoding cytoplasmic alanyl-tRNA synthetase. The recurrent p.Arg329His allele has arisen on several independent haplotypes and reduces alanyl-tRNA charging.
Show evidence (2 references)
"Sequencing of candidate genes identified a unique mutation, c.986G>A (p.Arg329His), affecting a totally conserved amino acid in the helical domain of cytoplasmic alanyl-tRNA synthetase (AlaRS)."
Identifies the AARS1 p.Arg329His allele segregating in the large linked CMT2 family in which the locus was mapped.
"Aminoacylation and yeast viability assays showed that p.Arg329His AARS severely reduces enzyme activity."
Functional confirmation that the recurrent CMT2N allele is loss-of-function for aminoacylation.
CMT2Q (DHTKD1-related)
MONDO:0014012
Autosomal dominant axonal CMT attributed to heterozygous loss-of-function variants in DHTKD1, which encodes dehydrogenase E1 and transketolase domain-containing protein 1, part of a 2-oxoglutarate-dehydrogenase-complex-like protein. The defining report is a single five-generation Chinese pedigree with a nonsense allele subject to nonsense-mediated decay; biallelic DHTKD1 variants cause a separate metabolic disease, 2-aminoadipic and 2-oxoadipic aciduria.
Show evidence (2 references)
"Here, we report a five-generation family of eight affected individuals with CMT disease type 2, CMT2."
Defines the extent of the human observation behind CMT2Q - one five-generation family with eight affected individuals.
"We studied two individuals with 2-aminoadipic and 2-oxoadipic aciduria, a metabolic condition that is still unresolved at the molecular level."
Source for the separate biallelic DHTKD1 metabolic disease named in this row's description.
CMT2U (MARS1-related)
MONDO:0014566
Axonal sensorimotor CMT caused by mutations in MARS1, encoding cytoplasmic methionyl-tRNA synthetase. Originally described as adult-onset, the reported spectrum now includes an early-childhood-onset, motor-predominant presentation. Biallelic MARS1 variants cause a separate interstitial lung and liver disease of infancy, which its own authors suggest may have a different mechanism.
Show evidence (4 references)
"The MARS gene was recently reported as the cause of Charcot-Marie-Tooth 2U, a slowly progressive axonal sensorimotor polyneuropathy with adult-onset reported in six patients."
States the MARS1-CMT2U relationship and the size of the reported patient series at the time of this report.
"We report here a patient with a progressive, early childhood-onset, motor-predominant form of Charcot-Marie-Tooth disease."
The early-childhood-onset, motor-predominant presentation that extends the CMT2U spectrum.
"Homozygous or compound heterozygous mutations in MARS gene would cause interstitial lung and liver disease (ILLD), a severe disease onset in infancy or early childhood."
Source for the separate biallelic MARS1 disease named in this row's description.
+ 1 more reference
CMT2V (NAGLU-related)
MONDO:0014665
Dominantly inherited late-onset neuropathy attributed to heterozygous NAGLU variants in two families. In the large French-Canadian family the allele is the missense p.Ile403Thr, the presentation is painful and sensory-predominant, and carriers show a mean 45% decrease in alpha-N-acetylglucosaminidase activity. A second, North-American family was found through a CMT2 patient and carries a nonsense allele, p.Glu123X, segregating in all three available affected members, who had mild muscular weakness and diminished reflexes alongside sensory loss and pain; no enzyme assay was done in that family. Biallelic NAGLU loss causes mucopolysaccharidosis IIIB instead.
Show evidence (4 references)
"Segregation analysis in all 45 recruited individuals has shown that only the p.Ile403Thr variant in the α-N-acetyl-glucosaminidase (NAGLU) gene segregates with the disease."
Segregation of the missense NAGLU allele with the neuropathy across the whole recruited French-Canadian family.
"Using this database we identified, in a CMT2 patient (Case XXII) (Fig. 1B), a nonsense variant (p.Glu123X) creating a premature stop codon"
The second family's truncating NAGLU allele, found in a patient carrying a CMT2 diagnosis.
"Segregation analysis on available DNA from this family confirmed the presence of the NAGLU p.Glu123X in all three available affected members (Cases XXII, XXIII and XXIV)"
Segregation of the nonsense allele in the second family.
+ 1 more reference
CMT2X (SPG11-related)
MONDO:0014726
Autosomal recessive axonal CMT caused by biallelic SPG11 (spatacsin) mutations. SPG11 is better known as a frequent cause of autosomal recessive hereditary spastic paraplegia with thin corpus callosum, and CMT2X is the peripheral-predominant end of that allelic spectrum.
Show evidence (1 reference)
"Our results indicate that ALS5/SPG11/KIAA1840 is the causative gene of a wide spectrum of clinical features, including autosomal recessive axonal Charcot-Marie-Tooth disease."
Concluding claim of the multi-family autosomal recessive axonal CMT screen that defined CMT2X.
CMT2A1 (KIF1B-related, limited validity)
MONDO:0007308
The CMT2A locus was first attributed to a loss-of-function mutation in the motor domain of the kinesin KIF1B; MONDO keeps that attribution as the separate class type 2A1, distinct from the MFN2 class type 2A2. The KIF1B relationship has not accumulated further support, and ClinGen's Charcot-Marie-Tooth Disease Gene Curation Expert Panel classifies it as Limited. It is enumerated here because MONDO retains a distinct class for it, not because dismech treats it as an established cause.
Show evidence (2 references)
"We show that CMT2A patients contain a loss-of-function mutation in the motor domain of the KIF1B gene."
The original report attributing the CMT2A locus to a KIF1B motor-domain loss-of-function allele.
"KIF1B | HGNC:16636 | Charcot-Marie-Tooth disease type 2A1 | MONDO:0007308 | AD | Limited"
ClinGen classifies the KIF1B-CMT2A1 gene-disease relationship as Limited, which is the grading this row records.
CMT2B1 (LMNA-related)
MONDO:0011569
Autosomal recessive axonal CMT caused by a homozygous LMNA mutation, identified through homozygosity mapping in inbred Algerian families sharing a founder haplotype at 1q21.2-q21.3. LMNA encodes lamin A/C, a nuclear-envelope protein whose other alleles cause muscular dystrophy, cardiomyopathy and lipodystrophy.
Show evidence (2 references)
"A unique homozygous mutation in LMNA (which encodes lamin A/C, a component of the nuclear envelope) was identified in all affected members and in additional patients with CMT2 from a third, unrelated family."
Establishes the homozygous LMNA allele as the cause of autosomal recessive CMT2 in the mapped families.
"Homozygosity mapping in inbred Algerian families with autosomal recessive CMT2 (AR-CMT2) provided evidence of linkage to chromosome 1q21.2-q21.3 in two families"
Source for the 1q21.2-q21.3 founder locus named in this row's description.
CMT2R (TRIM2-related)
MONDO:0014208
Autosomal recessive early-onset axonal neuropathy caused by biallelic loss-of-function mutations in TRIM2, an E3 ubiquitin ligase whose substrate includes neurofilament light chain.
Show evidence (1 reference)
"Here, we report compound heterozygous mutations in the tripartite motif containing 2 (TRIM2) gene in a patient with childhood-onset axonal neuropathy, low weight and small muscle mass."
The index report of biallelic TRIM2 mutations in childhood-onset axonal neuropathy.
CMT2Y (VCP-related)
MONDO:0014735
Autosomal dominant axonal CMT caused by mutations in VCP, which facilitates protein degradation by the proteasomal and autophagic pathways. VCP alleles also cause inclusion body myopathy with Paget disease and frontotemporal dementia, hereditary spastic paraplegia, and a minority of familial ALS.
Show evidence (1 reference)
"We identified a novel VCP mutation (p.Glu185Lys) segregating in an autosomal dominant Charcot-Marie-Tooth disease type 2 family."
Establishes a VCP allele segregating with autosomal dominant CMT2.
CMT2EE (MPV17-related)
MONDO:0032728
Autosomal recessive axonal sensorimotor neuropathy caused by biallelic MPV17 variants, without the liver and brain involvement of the MPV17-related mitochondrial DNA depletion syndrome that the same gene causes.
Show evidence (1 reference)
"Here, we describe five additional patients from two unrelated families with sensorimotor axonal neuropathy without hepatocerebral affection caused by homozygous MPV17 variants."
Reports homozygous MPV17 variants causing isolated axonal sensorimotor neuropathy in five further patients.
CMT2DD (ATP1A1-related)
MONDO:0054833
Autosomal dominant axonal CMT caused by missense mutations in ATP1A1, encoding the alpha-1 subunit of the axonal Na+,K+-ATPase. Five of the seven substitutions in the defining cohort fall within a narrow motif of the helical linker between the nucleotide-binding and phosphorylation domains.
Show evidence (1 reference)
"we were able to define mutations in ATP1A1, which encodes the alpha1 subunit of the Na+,K+-ATPase, as a cause of autosomal-dominant CMT2"
Establishes ATP1A1 as a cause of autosomal dominant CMT2 across a multi-country cohort.
DGAT2-related axonal CMT2
MONDO:0044625
Early-onset axonal CMT with sensory ataxia and tremor reported in two members of one Korean family carrying a de novo DGAT2 missense variant. DGAT2 catalyses the final step of triglyceride synthesis at the endoplasmic-reticulum-mitochondrial interface. Support rests on that single family plus cell and zebrafish assays.
Show evidence (1 reference)
"Pedigree analysis and exome sequencing identified a de novo missense mutation (p.Y223H) in the diacylglycerol O-acyltransferase 2 (DGAT2) gene."
The single family in which the DGAT2 allele was identified; recorded as the whole of the human genetic support.
GAN2 (DCAF8-related axonal neuropathy with giant axons)
MONDO:0012411
Axonal hereditary motor and sensory neuropathy with infrequent giant axons and variable cardiomyopathy, caused by a DCAF8 missense variant that weakens DCAF8 binding to DDB1 in the Cullin-4 ubiquitin ligase. It is distinct from giant axonal neuropathy 1, the GAN gene disease, which dismech curates separately at kb/disorders/Giant_Axonal_Neuropathy_1.yaml.
Show evidence (1 reference)
"Our results indicate that DCAF8 p.R317C mutation is responsible for this specific variety of HMSN2 with infrequent giant axons and mild cardiomyopathy."
Establishes the DCAF8 allele as the cause of this axonal HMSN2 with giant axons.
CMT2A2B (autosomal recessive MFN2-related)
MONDO:0014906
The recessively presenting end of the MFN2 spectrum: biallelic (homozygous or compound heterozygous) MFN2 variants producing severe early-onset axonal neuropathy, separated in OMIM/MONDO from dominant CMT2A2A. The heterozygous parents of reported probands were asymptomatic or only minimally affected, so the inheritance is better described as semi-dominant than as strictly recessive.
Show evidence (1 reference)
"Severe early-onset axonal neuropathy due to MFN2 mutations can present as an apparently recessively inherited neuropathy but the minimal phenotype in the parents suggests a semi-dominant mechanism."
Supports the recessive presentation while qualifying it: carrier parents were not phenotypically normal, so the mechanism is semi-dominant.
HMSN VIA (MFN2-related axonal neuropathy with optic atrophy)
MONDO:0011002
Axonal CMT with optic atrophy, caused by MFN2 variants. Curated as an MFN2 subtype rather than a separate disease because optic atrophy is an inconstant feature of the same alleles: in one MFN2 screening series two families with the R364W variant had optic atrophy and two others with the same variant did not, and two early-onset R94W families previously reported as HMSN VI had no visual impairment.
Show evidence (2 references)
"Mutations in the mitofusin 2 (MFN2) gene, which encodes a mitochondrial GTPase mitofusin protein, have recently been reported to cause both Charcot-Marie-Tooth 2A (CMT2A) and hereditary motor and sensory neuropathy VI (HMSN VI)."
Establishes MFN2 as the gene shared by CMT2A and HMSN VI.
"Our findings suggest that HMSN VI might be a variant of the early onset severe CMT2A phenotype."
The authors' own conclusion that HMSN VI is a phenotypic variant of severe early-onset CMT2A, which is why it is curated here as an MFN2 subtype.
CMT2FF (CADM3-related, upper-limb predominant)
MONDO:0030433
Autosomal dominant axonal CMT with marked upper limb involvement, caused by the recurrent CADM3 p.Tyr172Cys variant. CADM3 is the axonal partner of Schwann-cell CADM4 at the axon-glia interface.
Show evidence (1 reference)
"We have identified-by whole exome sequencing-three unrelated families, including one de novo patient, with axonal Charcot-Marie-Tooth disease (CMT2) sharing the same private variant in CADM3, Tyr172Cys."
Establishes the recurrent CADM3 Tyr172Cys variant as the cause of this dominant axonal CMT subtype.
CMT2HH (JAG1-related, with vocal fold paresis)
MONDO:0030458
Autosomal dominant axonal CMT caused by JAG1 variants, distinguished by severe vocal fold paresis from recurrent laryngeal nerve involvement. JAG1 is better known as the Alagille syndrome gene; the reported CMT2 alleles are missense variants that reduce JAG1 cell surface expression.
Show evidence (1 reference)
"Here, we identify autosomal dominant mutations of the canonical Notch ligand Jagged1 (or JAG1) as a cause of peripheral nerve disease in 2 unrelated families with the hereditary axonal neuropathy Charcot-Marie-Tooth disease type 2 (CMT2)."
Establishes dominant JAG1 variants as a cause of axonal CMT2 in two families.
CMT2II (dominant SLC12A6 / KCC3-related)
MONDO:0031068
Heterozygous SLC12A6 variants, acting dominantly, cause inherited neuropathy without the corpus callosum agenesis and neurodevelopmental deficit of the recessive SLC12A6 syndrome (Andermann syndrome). OMIM and MONDO file the dominant form under an axonal CMT2 designation, but the largest reported cohort finds the electrophysiological class is genotype-dependent and spans CMT1, intermediate, CMT2 and pure motor or pure sensory neuropathy; the designation should not be read as a claim that every SLC12A6 kindred is axonal.
Show evidence (2 references)
"Twenty-three individuals from 13 families carried nine variants classified either as pathogenic/likely pathogenic or variants of uncertain significance segregating in multiple family members, including five novel variants."
The largest reported dominant-SLC12A6 cohort, establishing the gene-disease relationship across 13 families.
"Heterozygous variants in SLC12A6 can cause CMT of all clinical phenotypes, severity and age of onset, depending on the genotype."
Supports the caveat in this subtype's description that the axonal designation does not describe the whole dominant SLC12A6 phenotype.
CMT2KK (ARHGAP19-related, motor-predominant)
MONDO:0980963
Autosomal recessive, motor-predominant axonal neuropathy caused by biallelic loss-of-function variants in ARHGAP19, a negative regulator of the RhoA GTPase.
Show evidence (1 reference)
"Here, we identified 16 recessive variants in the RhoGTPase activating protein 19 gene (ARHGAP19) causing motor-predominant neuropathy in 25 individuals from 20 unrelated families."
Establishes biallelic ARHGAP19 variants as a cause of inherited motor-predominant neuropathy across 20 families.
CMT2LL (DARS2-related axonal CMT)
MONDO:0980969
Biallelic DARS2 variants presenting as isolated childhood-onset axonal CMT without the leukoencephalopathy (LBSL) that DARS2 is usually associated with. Reported genotypes pair a hypomorphic allele with a more deleterious one.
Show evidence (2 references)
"Our findings expand the DARS2-related disease spectrum, establishing a novel association with axonal CMT."
Establishes biallelic DARS2 variants as a cause of axonal CMT.
"The 5 individuals, including 4 adults, presented with childhood-onset progressive axonal CMT."
Describes the childhood-onset axonal presentation of the five reported individuals.
CMT2MM (COX18-related axonal CMT)
MONDO:0980971
Autosomal recessive axonal CMT caused by biallelic variants in COX18, an assembly factor for mitochondrial respiratory chain complex IV. Some affected individuals also show central nervous system features such as dystonia and spasticity. This is a primary respiratory-chain cause of CMT rather than a mitochondrial-dynamics one.
Show evidence (2 references)
"Our study presents genetic and functional evidence that supports COX18 as a newly identified gene candidate for autosomal recessive axonal CMT with or without CNS involvement."
Establishes biallelic COX18 variants as a cause of autosomal recessive axonal CMT.
"All eight affected individuals presented with axonal CMT, and some patients also exhibited CNS symptoms, such as dystonia and spasticity."
Describes the axonal presentation and the inconstant CNS involvement recorded in this subtype's description.
Discussions and Knowledge Gaps
1Does MFN2 loss-of-function (shRNA knockdown in hESC-derived motor neurons) faithfully model the pathophysiology of dominant/gain-of-function CMT2A, given that human CMT2A is caused by heterozygous dominant MFN2 missense variants thought to act via dominant-negative or gain-of-function mechanisms rather than simple haploinsufficiency?
Attached to
The two core CMT2A pathophysiology nodes (Mitochondrial Fragmentation and Impaired Mitochondrial Axonal Transport) are evidenced by PMID:34602978, which used MFN2 shRNA knockdown in hESC-derived spinal motor neurons to demonstrate mitochondrial fragmentation and impaired bidirectional axonal transport. However, CMT2A is caused by heterozygous dominant MFN2 missense mutations (e.g., R94W, R364W) that act via dominant-negative or gain-of-function mechanisms — the mutant MFN2 protein competes with wild-type rather than simply being absent. A knockdown model that removes MFN2 protein is mechanistically distinct from a dominant-missense model that produces toxic or dominant-negative MFN2 protein alongside wild-type. Whether the two models converge on identical downstream mitochondrial fragmentation and axonal transport defects in human motor neurons is an open translational question. Relevant context: PMID:42301793 shows that AAV9-mediated overexpression of wild-type MFN2 (MFN2WT) rescues phenotypes in both transgenic dominant-mutation CMT2A mice and patient-derived iPSC motor neurons. If the dominant mutations acted purely as haploinsufficiency, simple knockdown would be expected to model the disease accurately; the rescue by WT overexpression is consistent with dominant-negative action and suggests that the knockdown model may only partially recapitulate the upstream mechanism.
Proposed experiments
Side-by-side mitochondrial phenotype comparison of dominant-negative vs. loss-of-function MFN2 in isogenic iPSC motor neurons
exp_mfn2_dominant_vs_lof_isogenic_comparison
Generate isogenic human iPSC lines carrying (a) heterozygous knock-in of pathogenic CMT2A missense alleles (R94W or R364W), (b) heterozygous MFN2 null (haploinsufficiency control), and (c) homozygous MFN2 null. Differentiate all into motor neurons and compare mitochondrial morphology (aspect ratio, network connectivity), axonal transport kinetics (live imaging of mitochondria in long axons), motor protein (kinesin/dynein) levels, and neurofilament pathology. Convergence of dominant-missense and LOF phenotypes would validate the knockdown data; divergence would indicate that the shRNA model captures only downstream consequences, not the primary disease mechanism.
Wild-type MFN2 overexpression rescue in dominant-missense iPSC motor neurons
exp_mfn2_wt_rescue_in_dominant_missense_neurons
In iPSC-derived motor neurons heterozygous for a pathogenic MFN2 missense allele (not shRNA knockdown), test whether neuronal overexpression of wild-type MFN2 (as in PMID:42301793) rescues axonal transport defects and mitochondrial fragmentation at the single-axon level. Quantitative rescue in dominant-missense neurons would confirm that dominant-negative competition with WT is the operative mechanism and establish that the LOF knockdown model and the dominant-missense model converge on the same downstream transport pathway. Lack of rescue in dominant-missense neurons despite being effective in LOF cells would indicate distinct mechanisms.
Seeded from PMID:34602978 (MFN2 shRNA knockdown hESC motor neurons) and PMID:42301793 (AAV9-MFN2WT rescue in transgenic CMT2A mice and patient iPSC motor neurons). PMID:34602978 itself acknowledges that CMT2A is caused by dominant mutations, providing the context for this translational mismatch.
Pathophysiology
22Mitochondrial Fragmentation
MFN2 mutations impair mitochondrial outer membrane fusion, leading to fragmented mitochondria. Loss of fusion capacity prevents complementation of damaged mitochondrial DNA and proteins, resulting in dysfunctional mitochondrial networks in neurons.
Downstream
Fragmented mitochondria cannot be efficiently transported along axons, as mitofusin-2 also plays a direct role in mitochondrial motility and attachment to motor proteins.
Show evidence (2 references)
"A causal relationship between Mitofusin (MFN) 2 gene mutations and the hereditary axonal neuropathy Charcot-Marie-Tooth disease type 2A (CMT2A) was described over 15 years ago."
Review establishes MFN2 as the causal gene for CMT2A and its role in mitochondrial fusion.
"MFN2 loss did not affect spinal motor neuron differentiation from hESCs but resulted in mitochondrial fragmentation and dysfunction as determined by live-cell imaging."
In vitro evidence that MFN2 deficiency causes mitochondrial fragmentation in human motor neurons.
Impaired Mitochondrial Axonal Transport
Fragmented mitochondria resulting from MFN2 dysfunction fail to be efficiently transported to distal axon terminals. MFN2 also directly regulates mitochondrial transport by interacting with the Miro/Milton motor adaptor complex. Energy deficits at distal terminals result from inadequate mitochondrial delivery.
Downstream
Failure of mitochondrial delivery to distal axon terminals causes energy failure and triggers length-dependent axonal degeneration.
Show evidence (1 reference)
"MFN2 deficit impaired anterograde and retrograde mitochondrial transport within axons, and reduced the mRNA and protein levels of kinesin and dynein, indicating the interfered motor protein expression induced by MFN2 deficiency."
Direct demonstration that MFN2 loss impairs bidirectional mitochondrial transport in human motor neuron axons.
Neurofilament Assembly Disruption
The axonal neurofilament network is disrupted in several CMT2 subtypes, by mutation of a neurofilament subunit or by loss of the ubiquitin ligases that turn neurofilaments over. NEFL mutations cause abnormal neurofilament assembly and accumulation of neurofilament aggregates in neuronal cell bodies and proximal axons. Disrupted neurofilament stoichiometry impairs axonal caliber maintenance and reduces neurofilament density in myelinated axons, particularly affecting large-caliber fibers. NEFH frameshift alleles that read through into the 3' UTR append a cryptic amyloidogenic element, and the resulting protein aggregates. Loss of TRIM2 or weakened assembly of the Cullin-4 ligase complex through DCAF8 removes the degradation arm instead, so neurofilaments accumulate inside axons and, for DCAF8, produce the giant axons that name GAN2.
Downstream
Disrupted neurofilament network impairs axonal caliber and slow axonal transport, contributing to axonal degeneration.
Show evidence (8 references)
"Both mutations disrupted the self-assembly of human NFL."
Direct demonstration that CMT2E NEFL mutations (P8R and Q333P) disrupt neurofilament assembly in cultured cells.
"Diseased motor neurons recapitulated known pathologic phenotypes at early time points of differentiation, including aberrant accumulation of neurofilament light chain protein in neuronal cell bodies."
iPSC-derived motor neurons from CMT2E patient with NEFL N98S mutation show neurofilament accumulation, directly linking NEFL mutations to neurofilament assembly disruption.
"the p.N98S mutation causes a profound reduction of neurofilaments in the myelinated axons of the PNS and CNS, resulting in substantially reduced axonal diameters, particularly of large myelinated axons, and distal axon loss in the PNS."
Mouse model of CMT2E with heterozygous Nefl N98S mutation confirms neurofilament reduction in axons and distal axon loss.
+ 5 more references
Impaired Endosomal Trafficking
RAB7A mutations impair late endosomal trafficking and lysosomal degradation in neurons. Defective endosome-to-lysosome maturation disrupts neurotrophin receptor signaling and cellular waste removal in long axons, particularly sensory neurons.
Downstream
Defective endosomal trafficking impairs neurotrophin receptor signaling and autophagy, leading to sensory axon degeneration.
Show evidence (2 references)
"In Charcot-Marie-Tooth disease 2B (CMT2B), a neuropathy of the peripheral nervous system, this tubulating mechanism is disrupted."
Demonstrates that CMT2B RAB7A mutations disrupt endosomal tubulation and TrkA neurotrophin receptor retrieval.
"Missense mutations in RAB7A, the gene encoding the small GTPase Rab7, cause CMT2B and increase Rab7 activity. Rab7 is ubiquitously expressed and is involved in degradation through the lysosomal pathway."
Drosophila model confirms RAB7A mutations cause CMT2B through altered endosomal/lysosomal trafficking with sensory and motor phenotypes.
Impaired Neurotrophin Signaling Endosome Axonal Transport
GARS1 gain-of-function mutations produce toxic glycyl-tRNA synthetase variants that aberrantly interact with neurotrophin receptor pathways such as BDNF/TrkB. In CMT2D models, this disrupts axonal transport of neurotrophin-containing signaling endosomes, compromising trophic signaling in long peripheral axons.
Downstream
Persistent disruption of neurotrophin signaling endosome transport deprives long axons of trophic support and contributes to distal axonal degeneration.
Show evidence (2 references)
"Through intravital imaging of the sciatic nerve, we show that CMT2D mice displayed early and persistent disturbances in axonal transport of neurotrophin-containing signaling endosomes in vivo."
Directly supports impaired neurotrophin signaling endosome axonal transport in CMT2D mice.
"(BDNF)/TrkB impairments correlated with transport disruption and overall CMT2D neuropathology and that inhibition of this pathway at the nerve-muscle interface perturbed endosome transport in wild-type axons."
Links BDNF/TrkB pathway impairment to transport disruption and CMT2D neuropathology.
SORD Deficiency and Sorbitol Accumulation
Biallelic SORD loss-of-function variants reduce sorbitol dehydrogenase activity in the polyol pathway. Loss of SORD protein causes intracellular and serum sorbitol accumulation, which is linked to peripheral axon degeneration in patient cells and Drosophila models.
Downstream
Sorbitol accumulation and polyol-pathway dysfunction contribute to the length-dependent peripheral axon degeneration seen in SORD-CMT2.
Show evidence (2 references)
"In patient-derived fibroblasts, we found a complete loss of SORD protein and increased intracellular sorbitol."
Patient-derived fibroblast evidence supports SORD protein loss and intracellular sorbitol accumulation.
"In Drosophila, loss of SORD orthologs caused synaptic degeneration and progressive motor impairment."
Model-organism evidence links SORD deficiency to synaptic degeneration and progressive motor impairment.
Small Heat-Shock Protein Chaperone Dysfunction
Mutations in the alpha-crystallin domain of the small heat-shock proteins HSPB1 (HSP27) and HSPB8 (HSP22) convert them from chaperones into aggregation-prone proteins. Mutant HSP27 forms insoluble intracellular aggregates that sequester neurofilament middle chain and the p150 subunit of dynactin, and mutant HSP22 degenerates neurites selectively in motor neurons while leaving sensory and cortical neurons and glial cells largely unaffected. Alleles of both genes are reported in axonal CMT2 and in distal hereditary motor neuropathy.
Downstream
Sequestration of neurofilament and dynactin subunits into mutant small-heat-shock-protein aggregates removes components required for axonal structure and transport, and mutant HSPB8 degenerates neurites directly.
In transgenic C. elegans, pan-neuronal expression of three CMT2F HSPB1 alleles weakened neuromuscular signalling at a young age, and deleting the worm's own small heat-shock protein genes produced the same early aldicarb resistance, so the authors attribute the early defect to a general loss of small-chaperone function rather than to a variant-specific gain.
Show evidence (2 references)
"Mutant (P182L) but not wild-type HSPB1 led to the formation of insoluble intracellular aggregates and to the sequestration in the cytoplasm of selective cellular components, including neurofilament middle chain subunit (NF-M) and p150 dynactin."
Shows that a mutant HSPB1 allele aggregates and sequesters neurofilament and dynactin subunits in primary neurons.
"In motor neurons, expression of both HSPB8 K141N and K141E mutations clearly resulted in neurite degeneration"
Shows that the CMT2L HSPB8 alleles degenerate neurites in motor neurons.
Presynaptic Neuromuscular Transmission Deficit
Pan-neuronal transgenic expression of three CMT2F HSPB1 alleles from different protein domains (G84R in the N-terminal domain, S135F in the alpha-crystallin domain, and the C-terminal truncation Q175X) in C. elegans reduced neuromuscular signalling strength in young adults, read out as aldicarb resistance, while wild-type HSPB1 did not. The defect was attributed to the presynaptic side because postsynaptic levamisole sensitivity showed no consistent change across the three variants. With age the defect was progressive: the age-dependent shift in neuromuscular signalling that control worms show came early in the mutant lines, which had moved from aldicarb resistance to hypersensitivity by adult day 5.
Animal models
Pan-neuronal human HSPB1 CMT2F variant C. elegans
Three CMT2F alleles from different protein domains share an early presynaptic neuromuscular signalling defect that progresses with age.
Downstream
The authors propose that progressive presynaptic failure at the neuromuscular junction is one route from mutant HSPB1 to the progressive distal motor deficit of CMT2F. The worm data show the synaptic defect, not human weakness, so this edge is a proposed mechanism.
Show evidence (3 references)
"Using a transgenic Caenorhabditis elegans model, we examined three distinct HSPB1 variants and determined that mutant HSPB1 caused an early defect in neuromuscular signalling strength as assayed by aldicarb sensitivity."
Mutant HSPB1 alleles caused an early neuromuscular signalling defect in transgenic worms.
"Our data point to the effects being presynaptic in origin and unrelated to differences in expression of mutant HSPB1 compared with that of the wild-type protein."
The defect was localized to the presynaptic side and was not explained by lower expression of the mutant proteins.
"We also identified a progressive effect whereby age-dependent changes to neuromuscular signalling were accelerated in worms expressing mutant HSPB1."
The neuromuscular defect progressed with age faster in worms expressing mutant HSPB1.
Aminoacyl-tRNA Synthetase Loss of Function
Cytoplasmic aminoacyl-tRNA synthetases charge tRNAs with their amino acid. Dominant CMT2 alleles of AARS1 (CMT2N) and MARS1 (CMT2U) behave as loss-of-function in aminoacylation and yeast complementation assays, and the resulting peripheral phenotype is a length-dependent axonal degeneration without central features. The GARS1 disease CMT2D is modeled separately in this entry, because its alleles act through aberrant new interactions rather than through the charging deficit alone.
Downstream
Reduced tRNA charging in long peripheral neurons is followed by distal-predominant axonal degeneration, with the central nervous system spared.
Show evidence (2 references)
"Aminoacylation and yeast viability assays showed that p.Arg329His AARS severely reduces enzyme activity."
Direct assay evidence that the CMT2N allele loses aminoacylation activity.
"p.Ala397Thr MARS supported very little yeast cell growth, consistent with this being a loss-of-function allele."
Yeast complementation evidence that the CMT2U allele loses methionyl-tRNA synthetase function.
Impaired Autophagy-Lysosome Function
Two CMT2 genes converge on the autophagy-lysosome arm of protein and lipid clearance. The CMT2Y VCP allele leaves immature autophagosomes accumulating, and loss of the CMT2X gene product spatacsin leaves lipids uncleared from lysosomes, with motor neuron degeneration in the knockout mouse.
Downstream
Failure of autophagic and lysosomal clearance in long neurons is followed by axonal and motor neuron degeneration.
Show evidence (2 references)
"Functional studies showed that the Glu185Lys variant impaired autophagic function leading to the accumulation of immature autophagosomes."
Direct functional evidence that the CMT2Y VCP allele blocks autophagosome maturation.
"the loss of spatacsin leads to the accumulation of lipids in lysosomes by perturbing their clearance from these organelles"
Establishes the lysosomal clearance defect caused by loss of the CMT2X gene product.
Nuclear Lamina Disruption
Lamin A/C is a component of the nuclear envelope. A homozygous LMNA founder allele causes autosomal recessive axonal CMT2B1, and sciatic nerves of lamin-A/C-null mice show the loss of axons, axonal enlargement and unmyelinated profiles seen in human peripheral axonopathy.
Downstream
Absence of lamin A/C is followed by axonal loss and enlargement in peripheral nerve.
Show evidence (1 reference)
"The finding of site-specific amino acid substitutions in limb-girdle muscular dystrophy type 1B, autosomal dominant Emery-Dreifuss muscular dystrophy, dilated cardiomyopathy type 1A, autosomal dominant partial lipodystrophy, and, now, AR-CMT2 suggests the existence of distinct functional domains"
Places the CMT2B1 allele among the LMNA diseases, supporting a lamina defect as the node's substrate.
Mitochondrial Energy Production Failure
DHTKD1, the gene behind dominant CMT2Q, is part of a 2-oxoglutarate-dehydrogenase-complex-like protein and acts inside the mitochondrion rather than on its shape or transport. Silencing it lowers cellular ATP and NAD(H), and expressing wild-type DHTKD1 in patient fibroblasts normalizes the 2-oxoadipate that accumulates without it.
Downstream
Reduced mitochondrial energy output leaves the longest peripheral axons, which have the largest transport and metabolic demand, unable to sustain their distal segments.
Show evidence (3 references)
"DHTKD1 silencing was found to lead to impaired energy production, evidenced by decreased ATP, total NAD"
Direct measurement that loss of DHTKD1 lowers cellular ATP and NAD(H).
"This gene codes for dehydrogenase E1 and transketolase domain-containing protein 1, which is part of a 2-oxoglutarate-dehydrogenase-complex-like protein."
Source for the description of what DHTKD1 encodes, as stated in this node.
"Increased levels of 2-oxoadipate in individual-derived fibroblasts normalized upon lentiviral expression of the wild-type DHTKD1 mRNA."
Establishes the metabolic step DHTKD1 loss blocks, by rescue in patient fibroblasts.
Impaired Mitochondrial DNA Maintenance
MPV17 is an inner mitochondrial membrane protein serving mitochondrial deoxynucleotide homeostasis. Biallelic MPV17 variants were first described in a mitochondrial DNA depletion syndrome with early-onset liver failure, and can also present as an isolated axonal sensorimotor neuropathy with no liver or brain involvement, which is CMT2EE.
Downstream
Biallelic MPV17 variants can produce a pure axonal sensorimotor neuropathy, with none of the hepatic or cerebral disease the same gene causes in its depletion-syndrome presentation.
Show evidence (2 references)
"MPV17 encodes a putative channel-forming protein of the inner mitochondrial membrane and is involved in mitochondrial deoxynucleotide homeostasis."
States the mitochondrial role of MPV17 that this node describes.
"Here, we describe five additional patients from two unrelated families with sensorimotor axonal neuropathy without hepatocerebral affection caused by homozygous MPV17 variants."
The patients in whom the MPV17 defect produced neuropathy alone.
Impaired Mitochondrial Fission
GDAP1 sits in the mitochondrial outer membrane and drives fission of the mitochondrial network. CMT-associated truncations fail to reach mitochondria and lose fragmentation activity, and point mutations reduce it strongly, so the GDAP1 defect is a loss of fission rather than the loss of fusion produced by MFN2. Both leave the mitochondrial network mishandled, which is why GDAP1 is wired to its own node rather than to Mitochondrial Fragmentation.
Downstream
Loss of control over mitochondrial network dynamics compromises the function of myelinated peripheral nerve and contributes to the axonal degeneration of CMT2K.
Show evidence (2 references)
"GDAP1 truncations that are found in patients who have CMT are not targeted to mitochondria and have lost mitochondrial fragmentation activity."
Patient-derived GDAP1 truncations lose the fission activity this node describes.
"GDAP1 is located in the mitochondrial outer membrane and regulates the mitochondrial network."
Localizes GDAP1 and states the process it regulates.
Axonal Sodium-Potassium ATPase Dysfunction
ATP1A1 encodes the alpha-1 subunit of the Na+,K+-ATPase and is present on the axolemma of myelinated sensory and motor axons and at Schmidt-Lanterman incisures. Several CMT2DD substitutions reduce pump current in a heterologous expression system, pointing to a loss-of-function defect in the sodium-potassium pump.
Downstream
A weakened axonal sodium-potassium pump is proposed as a degenerative pathway in peripheral nerve axons and a candidate therapeutic target.
Show evidence (2 references)
"Immunostaining peripheral nerve axons localized ATP1A1 to the axolemma of myelinated sensory and motor axons and to Schmidt-Lanterman incisures of myelin sheaths."
Places ATP1A1 at the axolemma, the site this node describes.
"demonstrated significant reduction in Na+ current activity in some, but not all, ouabain-insensitive ATP1A1 mutants, suggesting a loss-of-function defect of the Na+,K+ pump"
Two-electrode voltage clamp evidence of reduced pump current, with the authors' own caveat that not all mutants behaved this way.
Axon-Schwann Cell Adhesion Failure
CADM3 is expressed on the axon and binds CADM4 on the myelinating Schwann cell; this pairing organizes the myelinated fibre at the axon-glia interface. The recurrent CMT2FF variant Tyr172Cys introduces a new disulphide bond, retains the mutant protein in the endoplasmic reticulum, reduces its surface expression and lowers its co-localization with CADM4 at intercellular contacts. Knock-in mice show normal nerve conduction and myelin morphology but disordered axonal organization, so the lesion is an adhesion and domain-organization defect in an otherwise normally myelinated axon rather than a demyelinating one.
Downstream
Loss of the CADM3-CADM4 adhesion pairing disorganizes the myelinated axon and converges on the shared length-dependent axonal degeneration of CMT2.
Show evidence (3 references)
"In the peripheral nerve, axon-Schwann cell interaction is essential for the structural organization of myelinated fibres and is primarily mediated by the binding of CADM3, expressed in axons, to CADM4, expressed by myelinating Schwann cells."
States the CADM3-CADM4 axon-glia adhesion pairing that this node asserts is disrupted.
"Our data support a retention of the mutant protein in the endoplasmic reticulum and reduced cell surface expression in vitro."
Supports loss of CADM3 from the axonal surface as the proximate molecular lesion.
"Our findings indicate the involvement of abnormal axon-glia interaction as a disease-causing mechanism in CMT patients with CADM3 mutations."
The authors' own statement that abnormal axon-glia interaction is the disease mechanism in CADM3 CMT.
Reduced JAG1 Cell Surface Expression
JAG1 encodes the canonical Notch ligand Jagged1. The two reported CMT2HH missense variants (p.Ser577Arg, p.Ser650Pro) impair post-translational glycosylation of the protein and reduce the amount of JAG1 reaching the cell surface, where it would otherwise engage Notch receptors on neighbouring cells. Mice heterozygous for the CMT2-associated alleles develop mild peripheral neuropathy.
Downstream
Reduced Jagged1 availability at the cell surface compromises peripheral nerve integrity, particularly of the recurrent laryngeal nerve, and converges on the shared axonal degeneration of CMT2.
Show evidence (2 references)
"Our studies of mutant protein posttranslational modification and localization indicated that the mutations (p.Ser577Arg, p.Ser650Pro) impair protein glycosylation and reduce JAG1 cell surface expression."
Supports impaired glycosylation and reduced surface delivery of the Notch ligand as the molecular lesion.
"Mice harboring heterozygous CMT2-associated mutations exhibited mild peripheral neuropathy, and homozygous expression resulted in embryonic lethality by midgestation."
Model-organism support that the heterozygous CMT2 alleles produce peripheral neuropathy.
Reduced KCC3 Potassium-Chloride Cotransport
SLC12A6 encodes KCC3, a potassium-chloride cotransporter. Dominantly acting de novo missense variants reduce potassium influx through the mutant cotransporter when expressed in Xenopus oocytes. How reduced KCC3 transport injures the peripheral nerve is not established; the largest dominant SLC12A6 cohort states that more work is needed to understand the mechanism, and this node therefore records the measured transport deficit rather than a downstream nerve mechanism.
Downstream
Reduced KCC3 cotransport precedes the length-dependent sensorimotor neuropathy seen in these patients; the intervening steps are not established, so the link is recorded as indirect with unknown intermediates.
Show evidence (2 references)
"Modelling of the mutant KCC3 cotransporter in Xenopus oocytes showed a significant reduction in potassium influx for both changes."
Direct functional measurement of reduced cotransporter activity for the two de novo variants.
"We identified heterozygous de novo variants in SLC12A6 in three unrelated patients with intermediate CMT."
Links the measured transport deficit to the patients whose neuropathy it is invoked to explain.
Impaired RhoA GTPase Inactivation
ARHGAP19 is a GTPase-activating protein that switches RhoA off by stimulating its intrinsic GTP hydrolysis. Biallelic CMT2KK variants both lower ARHGAP19 protein levels and impair its GAP activity, a loss-of-function mechanism. Loss of the orthologue in Drosophila and zebrafish produces motor defects with abnormal axonal and synaptic morphology, and patient-derived motor neurons show the same cellular phenotypes.
Downstream
Failure to inactivate RhoA disrupts axonal and synaptic morphology in motor neurons, converging on the shared motor-predominant axonal degeneration of this subtype.
Show evidence (2 references)
"In vitro biochemical and cellular assays revealed that patient variants impair the GTPase-activating protein (GAP) activity of ARHGAP19 and reduce ARHGAP19 protein levels."
Supports loss of GAP activity and reduced protein level as the molecular lesion.
"LOF in ARHGAP19 orthologues in Drosophila melanogaster and Danio rerio induced motor defects in axonal and synaptic morphology."
Model-organism support that loss of function produces axonal and synaptic pathology.
Mitochondrial Complex IV Assembly Deficiency
COX18 translocates the C-terminal tail of MTCO2 across the mitochondrial inner membrane during assembly of respiratory chain complex IV. The reported CMT2MM splice variant produces a stable but defective COX18 isoform lacking exon 2, which impairs complex IV assembly and activity and lowers the mitochondrial membrane potential. This is a primary respiratory-chain lesion, distinct from the mitochondrial-dynamics lesions of MFN2 and GDAP1 curated above.
Downstream
Reduced complex IV assembly and activity produces a bioenergetic deficit in the axon and, in the fly model, progressive axonal degeneration of sensory neurons.
Show evidence (2 references)
"The mutant protein impairs Complex IV assembly and activity, leading to a reduction in mitochondrial membrane potential."
Supports impaired complex IV assembly and activity as the molecular lesion in this node.
"Downregulation of the COX18 homologue in D. melanogaster resulted in signs of neurodegeneration, including locomotor deficit and progressive axonal degeneration of sensory neurons."
Model-organism support linking COX18 loss to progressive axonal degeneration of sensory neurons.
Mitochondrial Aspartyl-tRNA Aminoacylation Deficiency
DARS2 encodes the mitochondrial aspartyl-tRNA synthetase. Biallelic variants that pair a hypomorphic allele with a more deleterious one lower DARS2 protein levels and impair mitochondrial function without producing the leukoencephalopathy (LBSL) associated with more severe allele combinations. One reported variant reduced DARS2 enzymatic activity by 75 percent in HEK293 cells.
Downstream
Partial loss of mitochondrial aspartyl-tRNA aminoacylation impairs mitochondrial function and converges on the length-dependent axonal degeneration seen in these individuals.
Show evidence (2 references)
"Functional studies revealed reduced DARS2 protein levels, mitochondrial network abnormalities, and impaired mitochondrial function."
Supports reduced DARS2 protein and impaired mitochondrial function as the molecular lesion.
"p.Ser238Phe behaves as a hypomorphic allele, whereas p.Pro503Leu reduced DARS2 enzymatic activity by 75%."
Quantifies the enzymatic deficit and supports the hypomorphic-allele model in this node's description.
Distal Axonal Degeneration
The final common pathway in CMT2 involves dying-back degeneration of peripheral nerve axons. The longest axons are affected first due to their higher metabolic and transport demands, producing the characteristic length-dependent pattern of weakness and sensory loss. This is a Wallerian-like process distinct from neuronal apoptosis.
Downstream
Show evidence (2 references)
"Genetic neuropathies that primarily cause axonal degeneration, as opposed to demyelination, are most often classified as Charcot-Marie-Tooth disease type 2 (CMT2) and are the focus of this review."
Authoritative review establishing CMT2 as defined by axonal degeneration rather than demyelination.
"the challenge of defining the central underlying mechanism(s) linking mitochondrial abnormalities to progressive dying-back of peripheral arm and leg nerves in CMT2A is largely unmet"
Confirms the dying-back pattern of axonal degeneration as the hallmark of CMT2A pathology.
Pathograph
Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Phenotypes
8Eye 1
Optic Atrophy
OCCASIONAL
HP:0000648
Human Phenotype Ontology (HP)
Relation: this clinical feature is this phenotype
This clinical feature is Optic atrophy (HP:0000648). HP:0000648 is a phenotype from the Human Phenotype Ontology.
Show evidence (3 references)
"Charcot-Marie-Tooth (CMT) neuropathy with visual impairment due to optic atrophy has been designated as hereditary motor and sensory neuropathy type VI (HMSN VI)."
Classic HMSN VI paper establishing MFN2 mutations as the cause of optic atrophy in CMT2A across six families; directly supports optic atrophy as an occasional CMT2A phenotype.
"In each pedigree, we identified a unique mutation in the gene mitofusin 2 (MFN2)."
Confirms that each of the six HMSN VI families harbored a distinct MFN2 mutation, establishing the genotype-phenotype link for optic atrophy in CMT2A.
"six HMSN VI families with a subacute onset of optic atrophy and subsequent slow recovery of visual acuity in 60% of the patients"
Directly supports the described subacute onset and slow partial recovery of visual acuity in 60% of affected individuals in the original HMSN VI (CMT2A) series.
Limbs 2
Foot Deformity (Pes Cavus)
VERY_FREQUENT
HP:0001761
Human Phenotype Ontology (HP)
Relation: this clinical feature is this phenotype
This clinical feature is Pes cavus (HP:0001761). HP:0001761 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
"As the disease progresses, individuals often develop foot drop and foot deformities such as pes cavus and equinus, leading to a significant decline in gait function."
Review confirms pes cavus as a hallmark foot deformity in CMT.
Distal Upper Limb Muscle Weakness
FREQUENT
HP:0003484
Human Phenotype Ontology (HP)
Relation: this clinical feature is this phenotype
This clinical feature is Distal upper limb muscle weakness, annotated with Upper limb muscle weakness (HP:0003484). HP:0003484 is a phenotype from the Human Phenotype Ontology.
Musculoskeletal 2
Distal Muscle Weakness
OBLIGATE
HP:0002460
Human Phenotype Ontology (HP)
Relation: this clinical feature is this phenotype
This clinical feature is Distal muscle weakness (HP:0002460). HP:0002460 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
"Inherited peripheral neuropathies are a genetically and phenotypically diverse group of disorders that lead to degeneration of peripheral neurons with resulting sensory and motor dysfunction."
Review confirms motor dysfunction as a core feature of inherited axonal neuropathies including CMT2.
Distal Lower Limb Muscle Atrophy
VERY_FREQUENT
Distal lower limb amyotrophy
HP:0008944
Human Phenotype Ontology (HP)
Relation: this clinical feature is this phenotype
This clinical feature is Distal lower limb amyotrophy (HP:0008944). HP:0008944 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
"All patients presented with distal weakness and atrophy in the lower limb, two of whom had minor clinical sensory abnormalities and small fiber neuropathy."
In an axonal CMT2 (SORD) clinical series, all patients had distal lower-limb weakness and atrophy, directly supporting distal lower-limb amyotrophy as a core CMT2 phenotype.
Nervous System 3
Distal Sensory Loss
VERY_FREQUENT
Distal sensory impairment
HP:0002936
Human Phenotype Ontology (HP)
Relation: this clinical feature is this phenotype
This clinical feature is Distal sensory impairment (HP:0002936). HP:0002936 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
"It is characterised by prominent sensory loss, often complicated by severe ulcero-mutilations of toes or feet, and variable motor involvement."
Clinical characterization of CMT2B from the introduction of the paper, describing the human phenotype.
Reduced Deep Tendon Reflexes
VERY_FREQUENT
Areflexia
HP:0001284
Human Phenotype Ontology (HP)
Relation: this clinical feature is this phenotype
This clinical feature is Areflexia (HP:0001284). HP:0001284 is a phenotype from the Human Phenotype Ontology.
Steppage Gait
FREQUENT
HP:0003376
Human Phenotype Ontology (HP)
Relation: this clinical feature is this phenotype
This clinical feature is Steppage gait (HP:0003376). HP:0003376 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
"One of the hallmark manifestations of CMT is gait disturbance. As the disease progresses, individuals often develop foot drop and foot deformities such as pes cavus and equinus, leading to a significant decline in gait function."
Review confirms gait disturbance including foot drop as a hallmark of CMT.
Genetic Associations
32
MFN2
(Causative)
Show evidence (1 reference)
"A causal relationship between Mitofusin (MFN) 2 gene mutations and the hereditary axonal neuropathy Charcot-Marie-Tooth disease type 2A (CMT2A) was described over 15 years ago."
Establishes MFN2 as the causal gene for CMT2A.
NEFL
(Causative)
Show evidence (2 references)
"Here, we demonstrate that allele-specific CRISPR gene editing in a human model of axonal Charcot-Marie-Tooth (CMT) disease rescues pathology caused by a dominant missense mutation in the neurofilament light chain gene (NEFL, CMT type 2E)."
Patient-derived motor neuron evidence confirms a dominant NEFL missense mutation as causal for CMT2E pathology.
"NEFL | HGNC:7739 | Charcot-Marie-Tooth disease type 2 | MONDO:0018993 | AR | Definitive"
ClinGen classifies the NEFL-Charcot-Marie-Tooth disease type 2 gene-disease relationship as definitive with autosomal recessive inheritance.
RAB7A
(Causative)
Show evidence (2 references)
"Missense mutations in RAB7A, the gene encoding the small GTPase Rab7, cause CMT2B and increase Rab7 activity."
Confirms RAB7A mutations are causal for CMT2B.
"RAB7A | HGNC:9788 | Charcot-Marie-Tooth disease type 2 | MONDO:0018993 | AD | Definitive"
ClinGen classifies the RAB7A-Charcot-Marie-Tooth disease type 2 gene-disease relationship as definitive with autosomal dominant inheritance.
GARS1
(Causative)
Show evidence (1 reference)
"Aberrant interactions between GlyRS mutants and different proteins, including neurotrophin receptor tropomyosin receptor kinase receptor B (TrkB), underlie CMT type 2D (CMT2D); however, our pathomechanistic understanding of this untreatable peripheral neuropathy remains incomplete."
Supports GARS1/GlyRS mutant pathology as the causal basis of CMT2D.
MPZ
(Causative)
Show evidence (1 reference)
"The MPZ mutation Asp121Asn may be associated with late-onset axonal neuropathy, early onset hearing loss and pupil abnormalities."
Human family evidence supports MPZ mutation association with late-onset axonal CMT2I/J features.
SORD
(Causative)
Show evidence (1 reference)
"Here we report biallelic mutations in the sorbitol dehydrogenase gene (SORD) as the most frequent recessive form of hereditary neuropathy."
Establishes biallelic SORD variants as causative for an autosomal recessive hereditary neuropathy in the CMT2 spectrum.
HSPB1
(Causative)
Show evidence (1 reference)
"Here we report a missense mutation in the gene encoding 27-kDa small heat-shock protein B1 (HSPB1, also called HSP27) that segregates in the family with CMT2F."
Establishes HSPB1 (HSP27) as causative for axonal CMT2F.
MORC2
(Causative)
Show evidence (1 reference)
"Here we present a new axonal Charcot-Marie-Tooth disease form, associated with the gene microrchidia family CW-type zinc finger 2 (MORC2)."
Establishes MORC2 as causative for axonal CMT2Z.
GDAP1
(Causative)
Show evidence (1 reference)
"Mutations in GDAP1 associate with demyelinating (CMT4A) and axonal (CMT2K) forms of CMT."
Establishes GDAP1 as causative for axonal CMT2K.
NEFH
(Causative)
Show evidence (1 reference)
"gene was recently identified to cause autosomal dominant axonal Charcot-Marie-Tooth disease (CMT2cc)"
Establishes NEFH as causative for autosomal dominant axonal CMT2CC.
HSPB8
(Causative)
Show evidence (1 reference)
"we report a novel c.423G-->T (Lys141Asn) missense mutation of small heat-shock protein 22-kDa protein 8 (encoded by HSPB8), which is also responsible for distal hereditary motor neuropathy type (dHMN) II"
Establishes HSPB8 as causative for CMT2L in the pedigree that defined the locus.
AARS1
(Causative)
Show evidence (2 references)
"Our report documents in 18 patients the deleterious impact of a mutation in human cytoplasmic AlaRS and broadens the spectrum of defects found in tRNA synthetases."
Human genetic support for AARS1 as the CMT2N gene across two founder-distinct families.
"Our results showed that p.Arg329His AARS also segregated with CMT disease in a large Australian family."
Independent family replicating segregation of the recurrent AARS1 allele with CMT.
DHTKD1
(Causative)
Show evidence (1 reference)
"in exon 8 of dehydrogenase E1 and transketolase domain-containing 1 (DHTKD1) in all eight affected individuals"
Co-segregation of the DHTKD1 nonsense allele with CMT2 in the linked pedigree.
MARS1
(Causative)
Show evidence (1 reference)
"p.Ala397Thr MARS supported very little yeast cell growth, consistent with this being a loss-of-function allele."
Yeast complementation evidence that the CMT2U MARS1 allele is loss-of-function.
NAGLU
(Causative)
Show evidence (2 references)
"A significant 36–54% (mean 45%, P > 0.001) decrease in enzyme activity was observed for all carriers of the mutation"
Quantifies the loss of alpha-N-acetylglucosaminidase activity in carriers of the p.Ile403Thr allele - a mean 45% decrease, so roughly half of normal activity is retained.
"No enzymatic assay was performed on Family 2."
The authors' own statement that the second family's allele was not tested enzymatically, which is part of why no mechanism edge is asserted for NAGLU.
SPG11
(Causative)
Show evidence (1 reference)
"Interestingly, we identified 15 ALS5/SPG11/KIAA1840 mutations in 12 families"
Twelve families with SPG11 alleles among 28 screened autosomal recessive axonal CMT pedigrees.
KIF1B
(Reported cause of CMT2A1, with limited gene-disease validity)
Show evidence (2 references)
"We show that CMT2A patients contain a loss-of-function mutation in the motor domain of the KIF1B gene."
The original human genetic claim for KIF1B at the CMT2A locus.
"As there is a human asserted with a variation in this gene, "Limited" classification must be used. The classification is not disputed at this time."
ClinGen's own summary of why KIF1B-CMT2A1 is graded Limited rather than disputed, which is the basis for the UNKNOWN relationship_type here.
LMNA
(Causative)
Show evidence (1 reference)
"A unique homozygous mutation in LMNA (which encodes lamin A/C, a component of the nuclear envelope) was identified in all affected members and in additional patients with CMT2 from a third, unrelated family."
Establishes LMNA as causative for autosomal recessive CMT2 across three families.
TRIM2
(Causative)
Show evidence (1 reference)
"We show that the patient fibroblasts are practically devoid of TRIM2, through mRNA and protein instability caused by the mutations."
Patient-fibroblast assay demonstrating that the CMT2R TRIM2 alleles leave essentially no TRIM2 protein.
VCP
(Causative)
Show evidence (1 reference)
"We identified a novel VCP mutation (p.Glu185Lys) segregating in an autosomal dominant Charcot-Marie-Tooth disease type 2 family."
The single family establishing VCP as a CMT2Y gene.
MPV17
(Causative)
Show evidence (1 reference)
"Here, we describe five additional patients from two unrelated families with sensorimotor axonal neuropathy without hepatocerebral affection caused by homozygous MPV17 variants."
Two further unrelated families with homozygous MPV17 alleles and isolated axonal neuropathy.
ATP1A1
(Causative)
Show evidence (2 references)
"Seven missense changes were identified that segregated within individual pedigrees"
Seven segregating ATP1A1 missense alleles across the multi-country CMT2 cohort.
"Five mutants fall into a remarkably narrow motif within the helical linker region that couples the nucleotide-binding and phosphorylation domains."
Source for the helical-linker clustering stated in this record's notes.
DGAT2
(Reported in a single family; gene-disease relationship not established)
Show evidence (1 reference)
"We examined a Korean family in which two individuals had an autosomal-dominant axonal CMT with early-onset, sensory ataxia, tremor, and slow disease progression."
Defines the extent of the human observation behind the DGAT2 claim - two affected individuals in one family.
DCAF8
(Causative)
Show evidence (1 reference)
"Six novel variants were identified by WES, but only DCAF8 p.R317C tracked with affected status within the family."
Segregation analysis identifying DCAF8 p.R317C as the only candidate tracking with disease in the family.
MFN2 (biallelic, CMT2A2B)
(Causal)
Show evidence (3 references)
"Severe early-onset axonal neuropathy due to MFN2 mutations can present as an apparently recessively inherited neuropathy but the minimal phenotype in the parents suggests a semi-dominant mechanism."
Establishes the biallelic MFN2 presentation and its semi-dominant rather than fully recessive character.
"All parents were asymptomatic or mildly symptomatic with some signs of peripheral neuropathy indicating a minimal phenotype."
The carrier-parent finding behind the semi-dominant reading recorded in these notes.
"In summary, MFN2 is DEFINITIVELY associated with semidominant axonal hereditary motor and sensory neuropathy due to the presence of both genetic case level evidence and experimental evidence."
ClinGen's Charcot-Marie-Tooth Disease Gene Curation Expert Panel independently classifies the MFN2 neuropathy relationship as semidominant, supporting the semi-dominant reading of the biallelic presentation.
MFN2 (HMSN VIA)
(Causal)
Show evidence (4 references)
"Mutations in the mitofusin 2 (MFN2) gene, which encodes a mitochondrial GTPase mitofusin protein, have recently been reported to cause both Charcot-Marie-Tooth 2A (CMT2A) and hereditary motor and sensory neuropathy VI (HMSN VI)."
Establishes MFN2 as the causal gene for HMSN VI as well as CMT2A.
"We identified two HMSN VI families with the R364W mutation in the early onset group; however, two other families with the same mutation did not have optic atrophy."
Supports the statement in these notes that optic atrophy is not allele-specific in MFN2 neuropathy.
"Phenotype was variable in many studies, even with the same mutation, as some families had optic atrophy, but others did not."
ClinGen's own evidence summary records that optic atrophy varies between families carrying the same MFN2 variant, which is why HMSN VIA is curated as an MFN2 subtype rather than a separate disease.
+ 1 more reference
CADM3 (CMT2FF)
(Causal)
Show evidence (2 references)
"We have identified-by whole exome sequencing-three unrelated families, including one de novo patient, with axonal Charcot-Marie-Tooth disease (CMT2) sharing the same private variant in CADM3, Tyr172Cys."
Establishes CADM3 Tyr172Cys as the causal variant in three unrelated CMT2 families.
"Most CADM3 patients share a similar phenotype consisting of autosomal dominant CMT2 with marked upper limb involvement."
Sources the autosomal dominant inheritance and upper-limb-predominant phenotype recorded here.
JAG1 (CMT2HH)
(Causal)
Show evidence (2 references)
"Here, we identify autosomal dominant mutations of the canonical Notch ligand Jagged1 (or JAG1) as a cause of peripheral nerve disease in 2 unrelated families with the hereditary axonal neuropathy Charcot-Marie-Tooth disease type 2 (CMT2)."
Establishes dominant JAG1 variants as a cause of axonal CMT2.
"Affected individuals in both families exhibited severe vocal fold paresis, a rare feature of peripheral nerve disease that can be life-threatening."
Sources the vocal fold paresis that distinguishes this subtype clinically.
SLC12A6 (CMT2II)
(Causal)
Show evidence (3 references)
"Twenty-three individuals from 13 families carried nine variants classified either as pathogenic/likely pathogenic or variants of uncertain significance segregating in multiple family members, including five novel variants."
The cohort size and variant classification behind the dominant SLC12A6 gene-disease relationship.
"Clinical phenotype varied dramatically with genotype; Arg207His and Ser647Pro caused a severe childhood-onset, sensory and motor, conduction-slowing neuropathy, whereas Gly552Asp caused a mild, adult-onset, sensory-predominant neuropathy, Thr991Ala an infantile-onset motor neuropathy, and the..."
Sources the genotype-dependent electrophysiological class recorded in these notes.
"Our findings expand the genotypic and phenotypic spectrum associated with SLC12A6 variants from autosomal-recessive HMSN/ACC to dominant-acting de novo variants causing a milder clinical presentation with early-onset neuropathy."
Establishes the dominant-acting de novo mechanism and its separation from the recessive HMSN/ACC syndrome.
ARHGAP19 (CMT2KK)
(Causal)
Show evidence (2 references)
"Here, we identified 16 recessive variants in the RhoGTPase activating protein 19 gene (ARHGAP19) causing motor-predominant neuropathy in 25 individuals from 20 unrelated families."
Establishes the biallelic ARHGAP19 gene-disease relationship and the cohort size behind it.
"Through the use of patient lines, in vitro GAP assays and in silico molecular modeling, we provided evidence that CMT-associated ARHGAP19 variants act through a loss-of-function (LOF) mechanism."
Sources the loss-of-function mechanism recorded in these notes.
DARS2 (CMT2LL)
(Causal)
Show evidence (2 references)
"We investigated 5 individuals from 3 unrelated families with axonal CMT and biallelic DARS2 variants."
Establishes the cohort behind the biallelic DARS2 axonal CMT relationship.
"Hypomorphic variants, such as p.Ser238Phe, when paired with more deleterious variants, result in isolated axonal CMT, whereas more severe combinations-although not as deleterious as those seen in leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation-result in..."
Sources the allele-combination model that separates this presentation from DARS2-related leukoencephalopathy.
COX18 (CMT2MM)
(Causal)
Show evidence (2 references)
"Our study presents genetic and functional evidence that supports COX18 as a newly identified gene candidate for autosomal recessive axonal CMT with or without CNS involvement."
Establishes biallelic COX18 variants as a cause of autosomal recessive axonal CMT.
"Exome sequencing coupled with homozygosity mapping revealed a homozygous splice variant c.435-6A>G in COX18 in two siblings with early-onset progressive axonal sensorimotor peripheral neuropathy."
Identifies the index variant and the sibling pair in which the relationship was first established.
Medical Actions
9
Physical Therapy and Rehabilitation
Regular physical therapy to maintain muscle strength, flexibility, and range of motion. Includes stretching exercises, strengthening of unaffected muscles, and balance training.
Show evidence (1 reference)
"While physical therapy may improve muscle strength and physical function, the quality of evidence remains moderate, and no standardized rehabilitation protocols have been firmly established."
Review supports physical therapy for CMT while noting evidence quality is moderate.
Orthotic Devices
Ankle-foot orthoses (AFOs) to compensate for foot drop and improve gait stability. Custom orthopedic shoes for foot deformities.
Show evidence (1 reference)
"Management focuses on symptomatic interventions, including orthotic support, surgical procedures, and physical therapy."
Review confirms orthotic support as a standard management strategy for CMT.
Surgical Management
Corrective surgery for severe foot deformities including tendon transfers, osteotomies, and arthrodesis. Considered when conservative measures fail to maintain functional ambulation.
Avoidance of Neurotoxic Medications
Patients should avoid medications known to worsen peripheral neuropathy, particularly vincristine, which can cause severe deterioration in CMT patients.
Genetic Counseling
Genetic counseling supports inheritance-risk assessment, cascade testing, reproductive counseling, and interpretation of molecular diagnoses for families affected by genetically heterogeneous CMT2.
Show evidence (1 reference)
"Inform genetic counseling of family members of an individual with CMT hereditary neuropathy."
GeneReviews explicitly includes genetic counseling for family members as part of CMT hereditary neuropathy management.
Epalrestat for SORD-CMT2
Epalrestat is an aldose reductase inhibitor under Phase II evaluation for SORD-CMT2. It targets the upstream polyol pathway to reduce sorbitol production in patients with SORD deficiency; clinical efficacy remains investigational.
Show evidence (2 references)
"The primary purpose of this study is to explore the natural history of SORD-CMT2 patients by detecting the ONLS scale score and serum sorbitol level changes at 6th, 12th, 24th, and 36th months and to evaluate the effectiveness and safety of epalrestat."
ClinicalTrials.gov documents a SORD-CMT2 epalrestat study, but results are not yet available.
"normalized intracellular sorbitol levels in patient-derived fibroblasts"
Patient-derived fibroblast evidence supports aldose reductase inhibition as a substrate-reduction strategy for SORD deficiency.
NMD670 for CMT1/CMT2
NMD670 is an investigational small-molecule therapy tested in a completed Phase IIa placebo-controlled trial enrolling ambulatory adults with CMT1 or CMT2. The treatment is modeled with partial support because the trial record establishes clinical evaluation in CMT2 but does not provide outcome results in the cache.
Show evidence (1 reference)
"This Phase 2a study aims to evaluate the efficacy, safety and tolerability of NMD670 vs placebo administered twice a day (BID) for 21 days in ambulatory adult patients with Charcot-Marie-Tooth disease type 1 and type 2."
ClinicalTrials.gov documents completed Phase IIa clinical evaluation of NMD670 in adults with CMT1 or CMT2, but the cache does not include efficacy results.
HDAC6 Inhibition (investigational)
Pharmacological inhibition of histone deacetylase 6 (HDAC6) increases alpha-tubulin acetylation and restores axonal transport. In a mutant-HSPB1 (CMT2F) mouse model, HDAC6 inhibitors corrected axonal transport defects and rescued the neuropathy phenotype, supporting microtubule acetylation as a mechanism-directed therapeutic strategy for axonal CMT. Preclinical/ investigational only.
Show evidence (1 reference)
"acetylation induced by pharmacological inhibition of histone deacetylase 6 (HDAC6) corrected the axonal transport defects caused by HSPB1 mutations and rescued the CMT phenotype of symptomatic mutant HSPB1 mice."
Mouse-model evidence that HDAC6 inhibition rescues axonal transport and the CMT phenotype in mutant-HSPB1 (CMT2F) neuropathy.
NEFL-Targeting Antisense Oligonucleotide (investigational)
Allele-selective antisense oligonucleotide knockdown of the gain-of-function NEFL transcript in CMT2E. In a patient-derived iPSC motor-neuron model of the NEFL p.N98S subtype, ASO treatment targeting the heterozygous gain-of-function variant reduced biomarkers of axonal degeneration. Preclinical/investigational.
Show evidence (1 reference)
"Using an antisense oligonucleotide treatment strategy targeting a heterozygous gain-of-function variant, we aimed to resolve molecular phenotypic changes observed in the CMT2E p.N98S subtype."
iPSC motor-neuron evidence for an allele-selective NEFL-targeting ASO as a candidate therapy for CMT2E.
Diagnosis
1
Nerve Conduction Studies
Motor nerve conduction velocities are normal or near-normal (>38 m/s) in CMT2, distinguishing it from CMT1 where velocities are significantly reduced (<38 m/s). Compound muscle action potential amplitudes are reduced, reflecting axonal loss rather than demyelination.
Key diagnostic criterion distinguishing CMT2 from CMT1
Show evidence (1 reference)
"Median nerve motor nerve conduction velocities (MNCV) were always less than 38 m/s in CMT1A patients, whereas this was also the case in 16% of the CMT2 patients. Sensory nerve conduction velocities showed less overlap. In both CMT1A and CMT2 CMAP and SNAP amplitudes were often reduced or not..."
Comparative electrophysiology supports preserved or overlapping motor conduction velocities and reduced amplitudes as key diagnostic features separating axonal CMT2 from CMT1A.
Clinical Trials
2
NCT05777226
PHASE_II
NOT_RECRUITING
Multicenter Phase II study of SORD-CMT2 natural history and epalrestat treatment, measuring ONLS and serum sorbitol over 36 months in about 30 participants with SORD-CMT2.
Show evidence (1 reference)
"Patients in the drug treatment group take epalrestat (50 mg) orally three times daily."
Trial registry evidence documents epalrestat dosing in SORD-CMT2.
NCT06482437
PHASE_II
COMPLETED
Phase IIa randomized, double-blind, placebo-controlled trial of NMD670 over 21 days in ambulatory adults with genetically confirmed Charcot-Marie-Tooth disease type 1 or type 2.
Show evidence (1 reference)
"This Phase 2a study aims to evaluate the efficacy, safety and tolerability of NMD670 vs placebo administered twice a day (BID) for 21 days in ambulatory adult patients with Charcot-Marie-Tooth disease type 1 and type 2."
Trial registry evidence documents a completed Phase IIa NMD670 trial that included CMT2.
Animal Models
1
Pan-neuronal human HSPB1 CMT2F variant C. elegans
Dominant-type overexpression model of CMT2F in neurons that carry no myelin. All three variants reduced neuromuscular signalling in young adults and accelerated its age-dependent change; wild-type HSPB1 did not, and protected against the age-related change seen in controls.
Species
Caenorhabditis elegans
Genotype
Extrachromosomal Prab-3::HSPB1 arrays expressing human HSPB1 G84R, S135F or Q175X (strains AMG641, AMG647, AMG653) on a Bristol N2 background, compared with Prab-3::HSPB1 wild-type (AMG635) and N2 controls
Publication
Pathograph links
Presynaptic Neuromuscular Transmission Deficit
observes: organism
Three CMT2F alleles from different protein domains share an early presynaptic neuromuscular signalling defect that progresses with age.
Limitations: Invertebrate model with no myelin and no Schwann cells; human HSPB1 is overexpressed from extrachromosomal arrays, which can be mosaic, on top of the worm's own small heat-shock proteins; the signalling defect is inferred from whole-animal aldicarb paralysis timing rather than measured electrophysiologically, and no matching human neuromuscular-junction data exist.
Divergences from the human mechanism
species mismatch
qualifying
C. elegans motor neurons are unmyelinated, so any contribution of Schwann cells or myelin to CMT2F neuromuscular dysfunction, reported in HSPB1 S135F mice, is absent from this model.
proxy quantity
qualifying
The model's quantity is time to paralysis on the acetylcholinesterase inhibitor aldicarb. It stands in for the node's quantity, presynaptic acetylcholine release at the neuromuscular junction, which was not recorded directly.
Readouts
Aldicarb sensitivity in young adults
Direction: DECREASED
Interpretation: Aldicarb resistance at adult day 1 indicates reduced neurotransmitter release in all three variant lines.
Show evidence (1 reference)
"Using a transgenic Caenorhabditis elegans model, we examined three distinct HSPB1 variants and determined that mutant HSPB1 caused an early defect in neuromuscular signalling strength as assayed by aldicarb sensitivity."
Reports the aldicarb assay behind this readout.
Show evidence (2 references)
"Our data point to the effects being presynaptic in origin and unrelated to differences in expression of mutant HSPB1 compared with that of the wild-type protein."
Supports treating the model as informative for a presynaptic defect.
+ 1 more reference
Source YAML
click to showname: Charcot-Marie-Tooth Disease Type 2
creation_date: "2026-04-08T23:00:00Z"
category: Genetic
description: >
Charcot-Marie-Tooth disease type 2 (CMT2) is a group of inherited peripheral
neuropathies characterized by axonal degeneration of peripheral nerves without
primary demyelination. Unlike CMT1, which involves Schwann cell dysfunction and
demyelination, CMT2 is primarily an axonopathy with normal or near-normal nerve
conduction velocities (>38 m/s) but reduced compound muscle action potential
amplitudes. CMT2 is genetically heterogeneous, with over 20 subtypes identified.
The most common subtype is CMT2A (MFN2 mutations); the remaining subtypes —
including CMT2B (RAB7A), CMT2E (NEFL), CMT2F (HSPB1), CMT2K (GDAP1), and the
recessive SORD-related form — are each individually rarer, and a large fraction
of CMT2 remains genetically unsolved.
Clinical features include progressive distal muscle weakness and atrophy,
sensory loss, foot deformities, and areflexia, typically with onset in the
first to second decade of life.
disease_term:
preferred_term: Charcot-Marie-Tooth disease type 2
term:
id: MONDO:0018993
label: Charcot-Marie-Tooth disease type 2
parents:
- Charcot-Marie-Tooth disease
has_subtypes:
- name: CMT2A
subtype_term:
preferred_term: Charcot-Marie-Tooth disease type 2A2
term:
id: MONDO:0012231
label: Charcot-Marie-Tooth disease type 2A2
display_name: CMT2A (MFN2-related)
genes:
- preferred_term: MFN2
term:
id: hgnc:16877
label: MFN2
review_notes: >-
MONDO splits CMT2A into two classes by gene: MONDO:0012231 (type 2A2, MFN2),
bound here, and MONDO:0007308 (type 2A1, KIF1B), which is carried as the
separate CMT2A1 row below.
description: >
The most common CMT2 subtype, caused by mutations in the MFN2 gene encoding
mitofusin-2. Characterized by early onset, severe distal weakness, and optic
atrophy in some cases.
evidence:
- reference: PMID:32733278
reference_title: "Mitofusin 2 Dysfunction and Disease in Mice and Men."
supports: SUPPORT
evidence_source: OTHER
snippet: "A causal relationship between Mitofusin (MFN) 2 gene mutations and the hereditary axonal neuropathy Charcot-Marie-Tooth disease type 2A (CMT2A) was described over 15 years ago."
explanation: Establishes MFN2 mutations as the causal lesion for CMT2A.
- name: CMT2E
subtype_term:
preferred_term: Charcot-Marie-Tooth disease type 2E
term:
id: MONDO:0011894
label: Charcot-Marie-Tooth disease type 2E
display_name: CMT2E (NEFL-related)
genes:
- preferred_term: NEFL
term:
id: hgnc:7739
label: NEFL
description: >
Caused by mutations in NEFL encoding neurofilament light chain. Presents
with variable severity, from mild to severe neuropathy.
evidence:
- reference: PMID:34485306
reference_title: "Allele-Specific Gene Editing Rescues Pathology in a Human Model of Charcot-Marie-Tooth Disease Type 2E."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "Here, we demonstrate that allele-specific CRISPR gene editing in a human model of axonal Charcot-Marie-Tooth (CMT) disease rescues pathology caused by a dominant missense mutation in the neurofilament light chain gene (NEFL, CMT type 2E)."
explanation: Confirms NEFL mutations as the molecular driver of CMT2E.
- name: CMT2B
subtype_term:
preferred_term: Charcot-Marie-Tooth disease type 2B
term:
id: MONDO:0010949
label: Charcot-Marie-Tooth disease type 2B
display_name: CMT2B (RAB7A-related)
genes:
- preferred_term: RAB7A
term:
id: hgnc:9788
label: RAB7A
description: >
Caused by mutations in RAB7A. Distinguished by prominent sensory loss
with ulcerations and occasional amputations.
evidence:
- reference: PMID:24521780
reference_title: "Human Rab7 mutation mimics features of Charcot-Marie-Tooth neuropathy type 2B in Drosophila."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "Missense mutations in RAB7A, the gene encoding the small GTPase Rab7, cause CMT2B and increase Rab7 activity."
explanation: Establishes RAB7A mutations as the causal lesion for CMT2B.
- name: CMT2D
subtype_term:
preferred_term: Charcot-Marie-Tooth disease type 2D
term:
id: MONDO:0011091
label: Charcot-Marie-Tooth disease type 2D
display_name: CMT2D (GARS1-related)
genes:
- preferred_term: GARS1
term:
id: hgnc:4162
label: GARS1
description: >
Caused by mutations in GARS1 encoding glycyl-tRNA synthetase. Predominantly
affects the upper extremities.
evidence:
- reference: PMID:36928301
reference_title: "Boosting peripheral BDNF rescues impaired in vivo axonal transport in CMT2D mice."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "Gain-of-function mutations in the housekeeping gene GARS1, which lead to the expression of toxic versions of glycyl-tRNA synthetase (GlyRS), cause the selective motor and sensory pathology characterizing Charcot-Marie-Tooth disease (CMT)."
explanation: Links pathogenic GARS1/GlyRS gain-of-function mutations to the motor and sensory pathology modeled in CMT2D.
- name: CMT2I/J
subtype_term:
preferred_term: Charcot-Marie-Tooth disease type 2I
term:
id: MONDO:0011889
label: Charcot-Marie-Tooth disease type 2I
mappings:
mondo_mappings:
- term:
id: MONDO:0011903
label: Charcot-Marie-Tooth disease type 2J
mapping_predicate: skos:closeMatch
mapping_source: MONDO
mapping_justification: >-
MONDO carries two classes for late-onset MPZ-related axonal CMT, type 2I
(MONDO:0011889) and type 2J (MONDO:0011903, with pupillary abnormality and
hearing loss). This row covers both, so only type 2I can occupy the single
subtype_term slot and type 2J is recorded here.
display_name: CMT2I/J (MPZ-related)
genes:
- preferred_term: MPZ
term:
id: hgnc:7225
label: MPZ
description: >
Caused by mutations in MPZ encoding myelin protein zero. Late-onset axonal
neuropathy with pupillary abnormalities.
evidence:
- reference: PMID:27774063
reference_title: "A Novel Asp121Asn Mutation of Myelin Protein Zero Is Associated with Late-Onset Axonal Charcot-Marie-Tooth Disease, Hearing Loss and Pupil Abnormalities."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Mutations in MPZ have been associated with different Charcot-Marie-Tooth disease (CMT) phenotypes (CMT1B, CMT2I/J, CMTDI), Dejerine-Sottas syndrome, and congenital hypomyelination neuropathy."
explanation: Establishes MPZ mutations as associated with the CMT2I/J phenotype spectrum.
- name: SORD-CMT2
subtype_term:
preferred_term: SORD-related autosomal recessive distal motor neuropathy
term:
id: MONDO:0030055
label: neuronopathy, distal hereditary motor, autosomal recessive 8
display_name: SORD-related axonal CMT2
genes:
- preferred_term: SORD
term:
id: hgnc:11184
label: SORD
review_notes: >-
MONDO has no SORD class filed under Charcot-Marie-Tooth disease type 2
(MONDO:0018993); its only SORD disease class is MONDO:0030055, filed as a
distal hereditary motor neuronopathy. Searched MONDO via OLS for "SORD" and
"sorbitol dehydrogenase deficiency", and checked the 38 hierarchical
descendants of MONDO:0018993, on 2026-09-23; MONDO:0030055 was the only hit
and is not among those descendants. Bound here because the published
phenotype spans CMT2 and distal HMN.
description: >
Autosomal recessive axonal neuropathy caused by biallelic loss-of-function
SORD variants. SORD-CMT2 is associated with sorbitol dehydrogenase loss,
elevated sorbitol, and distal motor-predominant axonal degeneration.
evidence:
- reference: PMID:32367058
reference_title: "Biallelic mutations in SORD cause a common and potentially treatable hereditary neuropathy with implications for diabetes."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Here we report biallelic mutations in the sorbitol dehydrogenase gene (SORD) as the most frequent recessive form of hereditary neuropathy."
explanation: Establishes biallelic SORD variants as a common cause of autosomal recessive hereditary neuropathy in the CMT2 spectrum.
- name: CMT2F
subtype_term:
preferred_term: Charcot-Marie-Tooth disease axonal type 2F
term:
id: MONDO:0011687
label: Charcot-Marie-Tooth disease axonal type 2F
display_name: CMT2F (HSPB1 / HSP27-related)
genes:
- preferred_term: HSPB1
term:
id: hgnc:5246
label: HSPB1
description: >
Autosomal dominant axonal CMT caused by mutations in HSPB1, encoding the
27-kDa small heat-shock protein B1 (HSP27). Mutant HSP27 disrupts the
neurofilament network and axonal transport; the same gene also causes
distal hereditary motor neuropathy.
evidence:
- reference: PMID:15122254
reference_title: "Mutant small heat-shock protein 27 causes axonal Charcot-Marie-Tooth disease and distal hereditary motor neuropathy."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Here we report a missense mutation in the gene encoding 27-kDa small heat-shock protein B1 (HSPB1, also called HSP27) that segregates in the family with CMT2F."
explanation: Establishes HSPB1 (HSP27) missense mutation as the cause of axonal CMT2F.
- name: CMT2Z
subtype_term:
preferred_term: Charcot-Marie-Tooth disease axonal type 2Z
term:
id: MONDO:0014736
label: Charcot-Marie-Tooth disease axonal type 2Z
display_name: CMT2Z (MORC2-related)
genes:
- preferred_term: MORC2
term:
id: hgnc:23573
label: MORC2
review_notes: >-
A dedicated dismech entry for this subtype exists at
kb/disorders/Charcot-Marie-Tooth_Disease_Axonal_Type_2Z.yaml, anchored to the
same MONDO class; this row is the umbrella summary and that entry is the
detailed home.
description: >
Axonal CMT caused by mutations in MORC2 (microrchidia CW-type zinc finger 2),
a transcriptional regulator. Phenotype is clinically heterogeneous, ranging
from early-onset spinal muscular atrophy-like weakness to later-onset axonal
neuropathy.
evidence:
- reference: PMID:26497905
reference_title: "Mutations in the MORC2 gene cause axonal Charcot-Marie-Tooth disease."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Here we present a new axonal Charcot-Marie-Tooth disease form, associated with the gene microrchidia family CW-type zinc finger 2 (MORC2)."
explanation: Establishes MORC2 mutations as the cause of axonal CMT2Z.
- name: CMT2K
subtype_term:
preferred_term: Charcot-Marie-Tooth disease axonal type 2K
term:
id: MONDO:0011916
label: Charcot-Marie-Tooth disease axonal type 2K
display_name: CMT2K (GDAP1-related, axonal)
genes:
- preferred_term: GDAP1
term:
id: hgnc:15968
label: GDAP1
review_notes: >-
MONDO carries the recessive form as MONDO:0011916, bound here, and the
dominant form separately as MONDO:0020558, which has its own dismech entry at
kb/disorders/Autosomal_Dominant_Charcot-Marie-Tooth_Disease_Type_2K.yaml.
description: >
Axonal CMT caused by mutations in GDAP1, which regulates mitochondrial
fission and the mitochondrial network. GDAP1 mutations cause both
demyelinating CMT4A and axonal CMT2K; CMT2K occurs in autosomal recessive
and (typically milder, later-onset) autosomal dominant forms.
evidence:
- reference: PMID:20685671
reference_title: "The GST domain of GDAP1 is a frequent target of mutations in the dominant form of axonal Charcot Marie Tooth type 2K."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Mutations in GDAP1 associate with demyelinating (CMT4A) and axonal (CMT2K) forms of CMT."
explanation: Establishes GDAP1 mutations as causing axonal CMT2K (alongside demyelinating CMT4A).
- name: CMT2CC
subtype_term:
preferred_term: Charcot-Marie-Tooth disease axonal type 2CC
term:
id: MONDO:0014836
label: Charcot-Marie-Tooth disease axonal type 2CC
display_name: CMT2CC (NEFH-related)
genes:
- preferred_term: NEFH
term:
id: hgnc:7737
label: NEFH
description: >
Autosomal dominant axonal CMT caused by frameshift variants near the end of
NEFH (neurofilament heavy chain) that read through into the 3' UTR, producing
a cryptic amyloidogenic element that drives aggresome formation and neuronal
death. Phenotype is motor-predominant with early proximal weakness.
evidence:
- reference: PMID:28709447
reference_title: "Cryptic amyloidogenic elements in mutant NEFH causing Charcot-Marie-Tooth 2 trigger aggresome formation and neuronal death."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "gene was recently identified to cause autosomal dominant axonal Charcot-Marie-Tooth disease (CMT2cc)"
explanation: Establishes NEFH as the cause of autosomal dominant axonal CMT2CC.
- name: CMT2L
subtype_term:
preferred_term: Charcot-Marie-Tooth disease axonal type 2L
term:
id: MONDO:0012096
label: Charcot-Marie-Tooth disease axonal type 2L
display_name: CMT2L (HSPB8 / HSP22-related)
description: >
Autosomal dominant axonal CMT caused by missense mutations in the
alpha-crystallin domain of HSPB8, encoding the small heat-shock protein
HSP22. The same Lys141 substitutions also cause distal hereditary motor
neuropathy, so CMT2L and that motor neuropathy are allelic.
genes:
- preferred_term: HSPB8
term:
id: hgnc:30171
label: HSPB8
evidence:
- reference: PMID:15565283
reference_title: "Small heat-shock protein 22 mutated in autosomal dominant Charcot-Marie-Tooth disease type 2L."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "we report a novel c.423G-->T (Lys141Asn) missense mutation of small heat-shock protein 22-kDa protein 8 (encoded by HSPB8), which is also responsible for distal hereditary motor neuropathy type (dHMN) II"
explanation: Establishes an HSPB8 missense mutation as the cause of CMT2L in the pedigree in which the locus was mapped.
- name: CMT2N
subtype_term:
preferred_term: Charcot-Marie-Tooth disease axonal type 2N
term:
id: MONDO:0013212
label: Charcot-Marie-Tooth disease axonal type 2N
display_name: CMT2N (AARS1-related)
description: >
Autosomal dominant axonal CMT caused by mutations in AARS1, encoding
cytoplasmic alanyl-tRNA synthetase. The recurrent p.Arg329His allele has
arisen on several independent haplotypes and reduces alanyl-tRNA charging.
genes:
- preferred_term: AARS1
term:
id: hgnc:20
label: AARS1
evidence:
- reference: PMID:20045102
reference_title: "A major determinant for binding and aminoacylation of tRNA(Ala) in cytoplasmic Alanyl-tRNA synthetase is mutated in dominant axonal Charcot-Marie-Tooth disease."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Sequencing of candidate genes identified a unique mutation, c.986G>A (p.Arg329His), affecting a totally conserved amino acid in the helical domain of cytoplasmic alanyl-tRNA synthetase (AlaRS)."
explanation: Identifies the AARS1 p.Arg329His allele segregating in the large linked CMT2 family in which the locus was mapped.
- reference: PMID:22009580
reference_title: "A recurrent loss-of-function alanyl-tRNA synthetase (AARS) mutation in patients with Charcot-Marie-Tooth disease type 2N (CMT2N)."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "Aminoacylation and yeast viability assays showed that p.Arg329His AARS severely reduces enzyme activity."
explanation: Functional confirmation that the recurrent CMT2N allele is loss-of-function for aminoacylation.
- name: CMT2Q
subtype_term:
preferred_term: Charcot-Marie-Tooth disease axonal type 2Q
term:
id: MONDO:0014012
label: Charcot-Marie-Tooth disease axonal type 2Q
display_name: CMT2Q (DHTKD1-related)
description: >
Autosomal dominant axonal CMT attributed to heterozygous loss-of-function
variants in DHTKD1, which encodes dehydrogenase E1 and transketolase
domain-containing protein 1, part of a 2-oxoglutarate-dehydrogenase-complex-like
protein. The defining report is a single five-generation Chinese pedigree
with a nonsense allele subject to nonsense-mediated decay; biallelic DHTKD1
variants cause a separate metabolic disease, 2-aminoadipic and 2-oxoadipic
aciduria.
genes:
- preferred_term: DHTKD1
term:
id: hgnc:23537
label: DHTKD1
evidence:
- reference: PMID:23141294
reference_title: "A nonsense mutation in DHTKD1 causes Charcot-Marie-Tooth disease type 2 in a large Chinese pedigree."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Here, we report a five-generation family of eight affected individuals with CMT disease type 2, CMT2."
explanation: Defines the extent of the human observation behind CMT2Q - one five-generation family with eight affected individuals.
- reference: PMID:23141293
reference_title: "DHTKD1 mutations cause 2-aminoadipic and 2-oxoadipic aciduria."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "We studied two individuals with 2-aminoadipic and 2-oxoadipic aciduria, a metabolic condition that is still unresolved at the molecular level."
explanation: Source for the separate biallelic DHTKD1 metabolic disease named in this row's description.
- name: CMT2U
subtype_term:
preferred_term: Charcot-Marie-Tooth disease axonal type 2U
term:
id: MONDO:0014566
label: Charcot-Marie-Tooth disease axonal type 2U
display_name: CMT2U (MARS1-related)
description: >
Axonal sensorimotor CMT caused by mutations in MARS1, encoding cytoplasmic
methionyl-tRNA synthetase. Originally described as adult-onset, the reported
spectrum now includes an early-childhood-onset, motor-predominant
presentation. Biallelic MARS1 variants cause a separate interstitial lung
and liver disease of infancy, which its own authors suggest may have a
different mechanism.
genes:
- preferred_term: MARS1
term:
id: hgnc:6898
label: MARS1
evidence:
- reference: PMID:31356216
reference_title: "A Novel Mutation in MARS in a Patient with Charcot-Marie-Tooth Disease, Axonal, Type 2U with Congenital Onset."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: BACKGROUND
snippet: "The MARS gene was recently reported as the cause of Charcot-Marie-Tooth 2U, a slowly progressive axonal sensorimotor polyneuropathy with adult-onset reported in six patients."
explanation: States the MARS1-CMT2U relationship and the size of the reported patient series at the time of this report.
- reference: PMID:31356216
reference_title: "A Novel Mutation in MARS in a Patient with Charcot-Marie-Tooth Disease, Axonal, Type 2U with Congenital Onset."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "We report here a patient with a progressive, early childhood-onset, motor-predominant form of Charcot-Marie-Tooth disease."
explanation: The early-childhood-onset, motor-predominant presentation that extends the CMT2U spectrum.
- reference: PMID:28148924
reference_title: "Mutations in methionyl-tRNA synthetase gene in a Chinese family with interstitial lung and liver disease, postnatal growth failure and anemia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Homozygous or compound heterozygous mutations in MARS gene would cause interstitial lung and liver disease (ILLD), a severe disease onset in infancy or early childhood."
explanation: Source for the separate biallelic MARS1 disease named in this row's description.
- reference: PMID:28148924
reference_title: "Mutations in methionyl-tRNA synthetase gene in a Chinese family with interstitial lung and liver disease, postnatal growth failure and anemia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "ILLD and CMT2U might have different disease mechanism."
explanation: The authors' own caution that the two MARS1 diseases may not share a mechanism.
- name: CMT2V
subtype_term:
preferred_term: Charcot-Marie-Tooth disease axonal type 2V
term:
id: MONDO:0014665
label: Charcot-Marie-Tooth disease axonal type 2V
display_name: CMT2V (NAGLU-related)
description: >
Dominantly inherited late-onset neuropathy attributed to heterozygous NAGLU
variants in two families. In the large French-Canadian family the allele is
the missense p.Ile403Thr, the presentation is painful and sensory-predominant,
and carriers show a mean 45% decrease in alpha-N-acetylglucosaminidase
activity. A second, North-American family was found through a CMT2 patient and
carries a nonsense allele, p.Glu123X, segregating in all three available
affected members, who had mild muscular weakness and diminished reflexes
alongside sensory loss and pain; no enzyme assay was done in that family.
Biallelic NAGLU loss causes mucopolysaccharidosis IIIB instead.
genes:
- preferred_term: NAGLU
term:
id: hgnc:7632
label: NAGLU
evidence:
- reference: PMID:25818867
reference_title: "Adult-onset painful axonal polyneuropathy caused by a dominant NAGLU mutation."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Segregation analysis in all 45 recruited individuals has shown that only the p.Ile403Thr variant in the α-N-acetyl-glucosaminidase (NAGLU) gene segregates with the disease."
explanation: Segregation of the missense NAGLU allele with the neuropathy across the whole recruited French-Canadian family.
- reference: PMID:25818867
reference_title: "Adult-onset painful axonal polyneuropathy caused by a dominant NAGLU mutation."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Using this database we identified, in a CMT2 patient (Case XXII) (Fig. 1B), a nonsense variant (p.Glu123X) creating a premature stop codon"
explanation: The second family's truncating NAGLU allele, found in a patient carrying a CMT2 diagnosis.
- reference: PMID:25818867
reference_title: "Adult-onset painful axonal polyneuropathy caused by a dominant NAGLU mutation."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Segregation analysis on available DNA from this family confirmed the presence of the NAGLU p.Glu123X in all three available affected members (Cases XXII, XXIII and XXIV)"
explanation: Segregation of the nonsense allele in the second family.
- reference: PMID:25818867
reference_title: "Adult-onset painful axonal polyneuropathy caused by a dominant NAGLU mutation."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Affected family members had mild muscular weakness, but diminished reflexes in the neurological examination in their early 40s."
explanation: The motor component in the second family, which is why this row does not argue that the CMT2 label overstates the phenotype.
- name: CMT2X
subtype_term:
preferred_term: Charcot-Marie-Tooth disease axonal type 2X
term:
id: MONDO:0014726
label: Charcot-Marie-Tooth disease axonal type 2X
display_name: CMT2X (SPG11-related)
description: >
Autosomal recessive axonal CMT caused by biallelic SPG11 (spatacsin)
mutations. SPG11 is better known as a frequent cause of autosomal recessive
hereditary spastic paraplegia with thin corpus callosum, and CMT2X is the
peripheral-predominant end of that allelic spectrum.
genes:
- preferred_term: SPG11
term:
id: hgnc:11226
label: SPG11
evidence:
- reference: PMID:26556829
reference_title: "ALS5/SPG11/KIAA1840 mutations cause autosomal recessive axonal Charcot-Marie-Tooth disease."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Our results indicate that ALS5/SPG11/KIAA1840 is the causative gene of a wide spectrum of clinical features, including autosomal recessive axonal Charcot-Marie-Tooth disease."
explanation: Concluding claim of the multi-family autosomal recessive axonal CMT screen that defined CMT2X.
- name: CMT2A1
subtype_term:
preferred_term: Charcot-Marie-Tooth disease type 2A1
term:
id: MONDO:0007308
label: Charcot-Marie-Tooth disease type 2A1
display_name: CMT2A1 (KIF1B-related, limited validity)
description: >
The CMT2A locus was first attributed to a loss-of-function mutation in the
motor domain of the kinesin KIF1B; MONDO keeps that attribution as the
separate class type 2A1, distinct from the MFN2 class type 2A2. The KIF1B
relationship has not accumulated further support, and ClinGen's
Charcot-Marie-Tooth Disease Gene Curation Expert Panel classifies it as
Limited. It is enumerated here because MONDO retains a
distinct class for it, not because dismech treats it as an established
cause.
genes:
- preferred_term: KIF1B
term:
id: hgnc:16636
label: KIF1B
evidence:
- reference: PMID:11389829
reference_title: "Charcot-Marie-Tooth disease type 2A caused by mutation in a microtubule motor KIF1Bbeta."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "We show that CMT2A patients contain a loss-of-function mutation in the motor domain of the KIF1B gene."
explanation: The original report attributing the CMT2A locus to a KIF1B motor-domain loss-of-function allele.
- reference: CGGV:assertion_ae6ffeae-9609-47bf-89a9-4863cf6ef05c-2026-06-12T160000.000Z
reference_title: "KIF1B / Charcot-Marie-Tooth disease type 2A1 (Limited)"
supports: SUPPORT
evidence_source: OTHER
snippet: "KIF1B | HGNC:16636 | Charcot-Marie-Tooth disease type 2A1 | MONDO:0007308 | AD | Limited"
explanation: ClinGen classifies the KIF1B-CMT2A1 gene-disease relationship as Limited, which is the grading this row records.
- name: CMT2B1
subtype_term:
preferred_term: Charcot-Marie-Tooth disease type 2B1
term:
id: MONDO:0011569
label: Charcot-Marie-Tooth disease type 2B1
display_name: CMT2B1 (LMNA-related)
description: >
Autosomal recessive axonal CMT caused by a homozygous LMNA mutation,
identified through homozygosity mapping in inbred Algerian families sharing
a founder haplotype at 1q21.2-q21.3. LMNA encodes lamin A/C, a
nuclear-envelope protein whose other alleles cause muscular dystrophy,
cardiomyopathy and lipodystrophy.
genes:
- preferred_term: LMNA
term:
id: hgnc:6636
label: LMNA
evidence:
- reference: PMID:11799477
reference_title: "Homozygous defects in LMNA, encoding lamin A/C nuclear-envelope proteins, cause autosomal recessive axonal neuropathy in human (Charcot-Marie-Tooth disorder type 2) and mouse."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "A unique homozygous mutation in LMNA (which encodes lamin A/C, a component of the nuclear envelope) was identified in all affected members and in additional patients with CMT2 from a third, unrelated family."
explanation: Establishes the homozygous LMNA allele as the cause of autosomal recessive CMT2 in the mapped families.
- reference: PMID:11799477
reference_title: "Homozygous defects in LMNA, encoding lamin A/C nuclear-envelope proteins, cause autosomal recessive axonal neuropathy in human (Charcot-Marie-Tooth disorder type 2) and mouse."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Homozygosity mapping in inbred Algerian families with autosomal recessive CMT2 (AR-CMT2) provided evidence of linkage to chromosome 1q21.2-q21.3 in two families"
explanation: Source for the 1q21.2-q21.3 founder locus named in this row's description.
- name: CMT2R
subtype_term:
preferred_term: Charcot-Marie-Tooth disease type 2R
term:
id: MONDO:0014208
label: Charcot-Marie-Tooth disease type 2R
display_name: CMT2R (TRIM2-related)
description: >
Autosomal recessive early-onset axonal neuropathy caused by biallelic
loss-of-function mutations in TRIM2, an E3 ubiquitin ligase whose substrate
includes neurofilament light chain.
genes:
- preferred_term: TRIM2
term:
id: hgnc:15974
label: TRIM2
evidence:
- reference: PMID:23562820
reference_title: "Deficiency of the E3 ubiquitin ligase TRIM2 in early-onset axonal neuropathy."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Here, we report compound heterozygous mutations in the tripartite motif containing 2 (TRIM2) gene in a patient with childhood-onset axonal neuropathy, low weight and small muscle mass."
explanation: The index report of biallelic TRIM2 mutations in childhood-onset axonal neuropathy.
- name: CMT2Y
subtype_term:
preferred_term: Charcot-Marie-Tooth disease type 2Y
term:
id: MONDO:0014735
label: Charcot-Marie-Tooth disease type 2Y
display_name: CMT2Y (VCP-related)
description: >
Autosomal dominant axonal CMT caused by mutations in VCP, which facilitates
protein degradation by the proteasomal and autophagic pathways. VCP alleles also cause
inclusion body myopathy with Paget disease and frontotemporal dementia,
hereditary spastic paraplegia, and a minority of familial ALS.
genes:
- preferred_term: VCP
term:
id: hgnc:12666
label: VCP
evidence:
- reference: PMID:25125609
reference_title: "A novel mutation in VCP causes Charcot-Marie-Tooth Type 2 disease."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "We identified a novel VCP mutation (p.Glu185Lys) segregating in an autosomal dominant Charcot-Marie-Tooth disease type 2 family."
explanation: Establishes a VCP allele segregating with autosomal dominant CMT2.
- name: CMT2EE
subtype_term:
preferred_term: Charcot-Marie-Tooth disease, axonal, type 2EE
term:
id: MONDO:0032728
label: Charcot-Marie-Tooth disease, axonal, type 2EE
display_name: CMT2EE (MPV17-related)
description: >
Autosomal recessive axonal sensorimotor neuropathy caused by biallelic
MPV17 variants, without the liver and brain involvement of the
MPV17-related mitochondrial DNA depletion syndrome that the same gene
causes.
genes:
- preferred_term: MPV17
term:
id: hgnc:7224
label: MPV17
evidence:
- reference: PMID:30298599
reference_title: "MPV17 mutations in juvenile- and adult-onset axonal sensorimotor polyneuropathy."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Here, we describe five additional patients from two unrelated families with sensorimotor axonal neuropathy without hepatocerebral affection caused by homozygous MPV17 variants."
explanation: Reports homozygous MPV17 variants causing isolated axonal sensorimotor neuropathy in five further patients.
- name: CMT2DD
subtype_term:
preferred_term: Charcot-Marie-tooth disease, axonal, type 2DD
term:
id: MONDO:0054833
label: Charcot-Marie-tooth disease, axonal, type 2DD
display_name: CMT2DD (ATP1A1-related)
description: >
Autosomal dominant axonal CMT caused by missense mutations in ATP1A1,
encoding the alpha-1 subunit of the axonal Na+,K+-ATPase. Five of the seven
substitutions in the defining cohort fall within a narrow motif of the
helical linker between the nucleotide-binding and phosphorylation domains.
genes:
- preferred_term: ATP1A1
term:
id: hgnc:799
label: ATP1A1
evidence:
- reference: PMID:29499166
reference_title: "Mutations in ATP1A1 Cause Dominant Charcot-Marie-Tooth Type 2."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "we were able to define mutations in ATP1A1, which encodes the alpha1 subunit of the Na+,K+-ATPase, as a cause of autosomal-dominant CMT2"
explanation: Establishes ATP1A1 as a cause of autosomal dominant CMT2 across a multi-country cohort.
- name: DGAT2-CMT2
subtype_term:
preferred_term: autosomal dominant Charcot-Marie-Tooth disease type 2 due to DGAT2 mutation
term:
id: MONDO:0044625
label: autosomal dominant charcot-marie-tooth disease type 2 due to DGAT2 mutation
display_name: DGAT2-related axonal CMT2
description: >
Early-onset axonal CMT with sensory ataxia and tremor reported in two
members of one Korean family carrying a de novo DGAT2 missense variant.
DGAT2 catalyses the final step of triglyceride synthesis at the
endoplasmic-reticulum-mitochondrial interface. Support rests on that single
family plus cell and zebrafish assays.
genes:
- preferred_term: DGAT2
term:
id: hgnc:16940
label: DGAT2
review_notes: >-
MONDO carries this class but records no causal gene edge for it: queried via
the Monarch API on 2026-09-23, DGAT2 (hgnc:16940) is attached to
MONDO:0044625 only as biolink:gene_associated_with_condition, with no
biolink:CausalGeneToDiseaseAssociation. Enumerated here with that grading
rather than as an established CMT2 gene.
evidence:
- reference: PMID:26786738
reference_title: "DGAT2 Mutation in a Family with Autosomal-Dominant Early-Onset Axonal Charcot-Marie-Tooth Disease."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Pedigree analysis and exome sequencing identified a de novo missense mutation (p.Y223H) in the diacylglycerol O-acyltransferase 2 (DGAT2) gene."
explanation: The single family in which the DGAT2 allele was identified; recorded as the whole of the human genetic support.
- name: GAN2
subtype_term:
preferred_term: giant axonal neuropathy 2
term:
id: MONDO:0012411
label: giant axonal neuropathy 2
display_name: GAN2 (DCAF8-related axonal neuropathy with giant axons)
description: >
Axonal hereditary motor and sensory neuropathy with infrequent giant axons
and variable cardiomyopathy, caused by a DCAF8 missense variant that weakens
DCAF8 binding to DDB1 in the Cullin-4 ubiquitin ligase. It is distinct from
giant axonal neuropathy 1, the GAN gene disease, which dismech curates
separately at kb/disorders/Giant_Axonal_Neuropathy_1.yaml.
genes:
- preferred_term: DCAF8
term:
id: hgnc:24891
label: DCAF8
evidence:
- reference: PMID:24500646
reference_title: "Ubiquitin ligase defect by DCAF8 mutation causes HMSN2 with giant axons."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Our results indicate that DCAF8 p.R317C mutation is responsible for this specific variety of HMSN2 with infrequent giant axons and mild cardiomyopathy."
explanation: Establishes the DCAF8 allele as the cause of this axonal HMSN2 with giant axons.
- name: CMT2A2B
display_name: CMT2A2B (autosomal recessive MFN2-related)
subtype_term:
preferred_term: autosomal recessive MFN2-related axonal CMT (CMT2A2B)
term:
id: MONDO:0014906
label: "Charcot-Marie-Tooth disease, axonal, autosomal recessive, type 2a2b;"
description: >-
The recessively presenting end of the MFN2 spectrum: biallelic (homozygous or
compound heterozygous) MFN2 variants producing severe early-onset axonal
neuropathy, separated in OMIM/MONDO from dominant CMT2A2A. The heterozygous
parents of reported probands were asymptomatic or only minimally affected, so
the inheritance is better described as semi-dominant than as strictly recessive.
genes:
- preferred_term: MFN2
term:
id: hgnc:16877
label: MFN2
evidence:
- reference: PMID:18458227
reference_title: "Severe early-onset axonal neuropathy with homozygous and compound heterozygous MFN2 mutations."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Severe early-onset axonal neuropathy due to MFN2 mutations can present as an apparently recessively inherited neuropathy but the minimal phenotype in the parents suggests a semi-dominant mechanism."
explanation: >-
Supports the recessive presentation while qualifying it: carrier parents were
not phenotypically normal, so the mechanism is semi-dominant.
- name: HMSN6A
display_name: HMSN VIA (MFN2-related axonal neuropathy with optic atrophy)
subtype_term:
preferred_term: hereditary motor and sensory neuropathy type 6A
term:
id: MONDO:0011002
label: "neuropathy, hereditary motor and sensory, type 6A"
description: >-
Axonal CMT with optic atrophy, caused by MFN2 variants. Curated as an MFN2
subtype rather than a separate disease because optic atrophy is an inconstant
feature of the same alleles: in one MFN2 screening series two families with the
R364W variant had optic atrophy and two others with the same variant did not, and
two early-onset R94W families previously reported as HMSN VI had no visual
impairment.
genes:
- preferred_term: MFN2
term:
id: hgnc:16877
label: MFN2
evidence:
- reference: PMID:16835246
reference_title: "Early onset severe and late-onset mild Charcot-Marie-Tooth disease with mitofusin 2 (MFN2) mutations."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Mutations in the mitofusin 2 (MFN2) gene, which encodes a mitochondrial GTPase mitofusin protein, have recently been reported to cause both Charcot-Marie-Tooth 2A (CMT2A) and hereditary motor and sensory neuropathy VI (HMSN VI)."
explanation: Establishes MFN2 as the gene shared by CMT2A and HMSN VI.
- reference: PMID:16835246
reference_title: "Early onset severe and late-onset mild Charcot-Marie-Tooth disease with mitofusin 2 (MFN2) mutations."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Our findings suggest that HMSN VI might be a variant of the early onset severe CMT2A phenotype."
explanation: >-
The authors' own conclusion that HMSN VI is a phenotypic variant of severe
early-onset CMT2A, which is why it is curated here as an MFN2 subtype.
- name: CMT2FF
display_name: CMT2FF (CADM3-related, upper-limb predominant)
subtype_term:
preferred_term: Charcot-Marie-Tooth disease, axonal, type 2FF
term:
id: MONDO:0030433
label: "Charcot-Marie-Tooth disease, axonal, type 2FF"
description: >-
Autosomal dominant axonal CMT with marked upper limb involvement, caused by the
recurrent CADM3 p.Tyr172Cys variant. CADM3 is the axonal partner of Schwann-cell
CADM4 at the axon-glia interface.
genes:
- preferred_term: CADM3
term:
id: hgnc:17601
label: CADM3
evidence:
- reference: PMID:33889941
reference_title: "A CADM3 variant causes Charcot-Marie-Tooth disease with marked upper limb involvement."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "We have identified-by whole exome sequencing-three unrelated families, including one de novo patient, with axonal Charcot-Marie-Tooth disease (CMT2) sharing the same private variant in CADM3, Tyr172Cys."
explanation: Establishes the recurrent CADM3 Tyr172Cys variant as the cause of this dominant axonal CMT subtype.
- name: CMT2HH
display_name: CMT2HH (JAG1-related, with vocal fold paresis)
subtype_term:
preferred_term: Charcot-Marie-Tooth disease, axonal, type 2HH
term:
id: MONDO:0030458
label: "Charcot-Marie-Tooth disease, axonal, Type 2HH"
description: >-
Autosomal dominant axonal CMT caused by JAG1 variants, distinguished by severe
vocal fold paresis from recurrent laryngeal nerve involvement. JAG1 is better
known as the Alagille syndrome gene; the reported CMT2 alleles are missense
variants that reduce JAG1 cell surface expression.
genes:
- preferred_term: JAG1
term:
id: hgnc:6188
label: JAG1
evidence:
- reference: PMID:32065591
reference_title: "Dominant mutations of the Notch ligand Jagged1 cause peripheral neuropathy."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Here, we identify autosomal dominant mutations of the canonical Notch ligand Jagged1 (or JAG1) as a cause of peripheral nerve disease in 2 unrelated families with the hereditary axonal neuropathy Charcot-Marie-Tooth disease type 2 (CMT2)."
explanation: Establishes dominant JAG1 variants as a cause of axonal CMT2 in two families.
- name: CMT2II
display_name: CMT2II (dominant SLC12A6 / KCC3-related)
subtype_term:
preferred_term: Charcot-Marie-Tooth disease, axonal, type 2II
term:
id: MONDO:0031068
label: "Charcot-Marie-Tooth disease, axonal, IIa 2II"
description: >-
Heterozygous SLC12A6 variants, acting dominantly, cause inherited neuropathy
without the corpus callosum agenesis and neurodevelopmental deficit of the
recessive SLC12A6 syndrome (Andermann syndrome). OMIM and MONDO file the
dominant form under an axonal CMT2 designation, but the largest reported cohort
finds the electrophysiological class is genotype-dependent and spans CMT1,
intermediate, CMT2 and pure motor or pure sensory neuropathy; the designation
should not be read as a claim that every SLC12A6 kindred is axonal.
genes:
- preferred_term: SLC12A6
term:
id: hgnc:10914
label: SLC12A6
evidence:
- reference: PMID:41500801
reference_title: "Spectrum of dominant Charcot-Marie-Tooth disease due to SLC12A6 variants."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Twenty-three individuals from 13 families carried nine variants classified either as pathogenic/likely pathogenic or variants of uncertain significance segregating in multiple family members, including five novel variants."
explanation: The largest reported dominant-SLC12A6 cohort, establishing the gene-disease relationship across 13 families.
- reference: PMID:41500801
reference_title: "Spectrum of dominant Charcot-Marie-Tooth disease due to SLC12A6 variants."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Heterozygous variants in SLC12A6 can cause CMT of all clinical phenotypes, severity and age of onset, depending on the genotype."
explanation: >-
Supports the caveat in this subtype's description that the axonal designation
does not describe the whole dominant SLC12A6 phenotype.
- name: CMT2KK
display_name: CMT2KK (ARHGAP19-related, motor-predominant)
subtype_term:
preferred_term: Charcot-Marie-Tooth disease, axonal, type 2KK
term:
id: MONDO:0980963
label: "Charcot-Marie-Tooth disease, axonal, type 2KK"
description: >-
Autosomal recessive, motor-predominant axonal neuropathy caused by biallelic
loss-of-function variants in ARHGAP19, a negative regulator of the RhoA GTPase.
genes:
- preferred_term: ARHGAP19
term:
id: hgnc:23724
label: ARHGAP19
evidence:
- reference: PMID:41086021
reference_title: "Biallelic variants in ARHGAP19 cause a progressive inherited motor-predominant neuropathy."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Here, we identified 16 recessive variants in the RhoGTPase activating protein 19 gene (ARHGAP19) causing motor-predominant neuropathy in 25 individuals from 20 unrelated families."
explanation: Establishes biallelic ARHGAP19 variants as a cause of inherited motor-predominant neuropathy across 20 families.
- name: CMT2LL
display_name: CMT2LL (DARS2-related axonal CMT)
subtype_term:
preferred_term: Charcot-Marie-Tooth disease, axonal, type 2LL
term:
id: MONDO:0980969
label: "Charcot-Marie-Tooth disease, axonal, type 2LL"
description: >-
Biallelic DARS2 variants presenting as isolated childhood-onset axonal CMT
without the leukoencephalopathy (LBSL) that DARS2 is usually associated with.
Reported genotypes pair a hypomorphic allele with a more deleterious one.
genes:
- preferred_term: DARS2
term:
id: hgnc:25538
label: DARS2
evidence:
- reference: PMID:40814755
reference_title: "Biallelic Variants in the DARS2 Gene as a Novel Cause of Axonal Charcot-Marie-Tooth Disease."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Our findings expand the DARS2-related disease spectrum, establishing a novel association with axonal CMT."
explanation: Establishes biallelic DARS2 variants as a cause of axonal CMT.
- reference: PMID:40814755
reference_title: "Biallelic Variants in the DARS2 Gene as a Novel Cause of Axonal Charcot-Marie-Tooth Disease."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The 5 individuals, including 4 adults, presented with childhood-onset progressive axonal CMT."
explanation: Describes the childhood-onset axonal presentation of the five reported individuals.
- name: CMT2MM
display_name: CMT2MM (COX18-related axonal CMT)
subtype_term:
preferred_term: Charcot-Marie-Tooth disease, axonal, type 2MM
term:
id: MONDO:0980971
label: "charcot-marie-tooth disease, axonal, type 2MM"
description: >-
Autosomal recessive axonal CMT caused by biallelic variants in COX18, an
assembly factor for mitochondrial respiratory chain complex IV. Some affected
individuals also show central nervous system features such as dystonia and
spasticity. This is a primary respiratory-chain cause of CMT rather than a
mitochondrial-dynamics one.
genes:
- preferred_term: COX18
term:
id: hgnc:26801
label: COX18
evidence:
- reference: PMID:40830826
reference_title: "Biallelic variants in COX18 cause a mitochondrial disorder primarily manifesting as peripheral neuropathy."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Our study presents genetic and functional evidence that supports COX18 as a newly identified gene candidate for autosomal recessive axonal CMT with or without CNS involvement."
explanation: Establishes biallelic COX18 variants as a cause of autosomal recessive axonal CMT.
- reference: PMID:40830826
reference_title: "Biallelic variants in COX18 cause a mitochondrial disorder primarily manifesting as peripheral neuropathy."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "All eight affected individuals presented with axonal CMT, and some patients also exhibited CNS symptoms, such as dystonia and spasticity."
explanation: Describes the axonal presentation and the inconstant CNS involvement recorded in this subtype's description.
pathophysiology:
- name: Mitochondrial Fragmentation
description: >
MFN2 mutations impair mitochondrial outer membrane fusion, leading to
fragmented mitochondria. Loss of fusion capacity prevents complementation
of damaged mitochondrial DNA and proteins, resulting in dysfunctional
mitochondrial networks in neurons.
cell_types:
- preferred_term: Motor neuron
term:
id: CL:0000100
label: motor neuron
- preferred_term: Sensory neuron
term:
id: CL:0000101
label: sensory neuron
biological_processes:
- preferred_term: Mitochondrial fusion
term:
id: GO:0008053
label: mitochondrial fusion
modifier: DECREASED
genes:
- preferred_term: MFN2
term:
id: hgnc:16877
label: MFN2
downstream:
- target: Impaired Mitochondrial Axonal Transport
description: >
Fragmented mitochondria cannot be efficiently transported along
axons, as mitofusin-2 also plays a direct role in mitochondrial
motility and attachment to motor proteins.
evidence:
- reference: PMID:32733278
reference_title: "Mitofusin 2 Dysfunction and Disease in Mice and Men."
supports: SUPPORT
evidence_source: OTHER
snippet: "A causal relationship between Mitofusin (MFN) 2 gene mutations and the hereditary axonal neuropathy Charcot-Marie-Tooth disease type 2A (CMT2A) was described over 15 years ago."
explanation: Review establishes MFN2 as the causal gene for CMT2A and its role in mitochondrial fusion.
- reference: PMID:34602978
reference_title: "MFN2 Deficiency Impairs Mitochondrial Transport and Downregulates Motor Protein Expression in Human Spinal Motor Neurons."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "MFN2 loss did not affect spinal motor neuron differentiation from hESCs but resulted in mitochondrial fragmentation and dysfunction as determined by live-cell imaging."
explanation: In vitro evidence that MFN2 deficiency causes mitochondrial fragmentation in human motor neurons.
notes: Subtype CMT2A (MFN2 mutations) is the most common CMT2 subtype
- name: Impaired Mitochondrial Axonal Transport
description: >
Fragmented mitochondria resulting from MFN2 dysfunction fail to be
efficiently transported to distal axon terminals. MFN2 also directly
regulates mitochondrial transport by interacting with the Miro/Milton
motor adaptor complex. Energy deficits at distal terminals result from
inadequate mitochondrial delivery.
cell_types:
- preferred_term: Motor neuron
term:
id: CL:0000100
label: motor neuron
- preferred_term: Sensory neuron
term:
id: CL:0000101
label: sensory neuron
biological_processes:
- preferred_term: Axonal transport of mitochondria
term:
id: GO:0019896
label: axonal transport of mitochondrion
modifier: DECREASED
genes:
- preferred_term: MFN2
term:
id: hgnc:16877
label: MFN2
downstream:
- target: Distal Axonal Degeneration
description: >
Failure of mitochondrial delivery to distal axon terminals causes
energy failure and triggers length-dependent axonal degeneration.
evidence:
- reference: PMID:34602978
reference_title: "MFN2 Deficiency Impairs Mitochondrial Transport and Downregulates Motor Protein Expression in Human Spinal Motor Neurons."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "MFN2 deficit impaired anterograde and retrograde mitochondrial transport within axons, and reduced the mRNA and protein levels of kinesin and dynein, indicating the interfered motor protein expression induced by MFN2 deficiency."
explanation: Direct demonstration that MFN2 loss impairs bidirectional mitochondrial transport in human motor neuron axons.
- name: Neurofilament Assembly Disruption
description: >
The axonal neurofilament network is disrupted in several CMT2 subtypes,
by mutation of a neurofilament subunit or by loss of the ubiquitin
ligases that turn neurofilaments over. NEFL mutations cause abnormal
neurofilament assembly and accumulation of neurofilament aggregates in
neuronal cell bodies and proximal axons. Disrupted neurofilament
stoichiometry impairs axonal caliber maintenance and reduces
neurofilament density in myelinated axons, particularly affecting
large-caliber fibers. NEFH frameshift alleles that read through into the
3' UTR append a cryptic amyloidogenic element, and the resulting protein
aggregates. Loss of TRIM2 or weakened assembly of the Cullin-4 ligase
complex through DCAF8 removes the degradation arm instead, so
neurofilaments accumulate inside axons and, for DCAF8, produce the giant
axons that name GAN2.
biological_scale: CELLULAR
cell_types:
- preferred_term: Motor neuron
term:
id: CL:0000100
label: motor neuron
biological_processes:
- preferred_term: Neurofilament cytoskeleton organization
term:
id: GO:0060052
label: neurofilament cytoskeleton organization
modifier: ABNORMAL
genes:
- preferred_term: NEFL
term:
id: hgnc:7739
label: NEFL
- preferred_term: NEFH
term:
id: hgnc:7737
label: NEFH
- preferred_term: TRIM2
term:
id: hgnc:15974
label: TRIM2
- preferred_term: DCAF8
term:
id: hgnc:24891
label: DCAF8
downstream:
- target: Distal Axonal Degeneration
description: >
Disrupted neurofilament network impairs axonal caliber and slow
axonal transport, contributing to axonal degeneration.
evidence:
- reference: PMID:12432080
reference_title: "Effects of Charcot-Marie-Tooth-linked mutations of the neurofilament light subunit on intermediate filament formation."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "Both mutations disrupted the self-assembly of human NFL."
explanation: Direct demonstration that CMT2E NEFL mutations (P8R and Q333P) disrupt neurofilament assembly in cultured cells.
- reference: PMID:34485306
reference_title: "Allele-Specific Gene Editing Rescues Pathology in a Human Model of Charcot-Marie-Tooth Disease Type 2E."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "Diseased motor neurons recapitulated known pathologic phenotypes at early time points of differentiation, including aberrant accumulation of neurofilament light chain protein in neuronal cell bodies."
explanation: iPSC-derived motor neurons from CMT2E patient with NEFL N98S mutation show neurofilament accumulation, directly linking NEFL mutations to neurofilament assembly disruption.
- reference: PMID:29940160
reference_title: "Myelinated axons fail to develop properly in a genetically authentic mouse model of Charcot-Marie-Tooth disease type 2E."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "the p.N98S mutation causes a profound reduction of neurofilaments in the myelinated axons of the PNS and CNS, resulting in substantially reduced axonal diameters, particularly of large myelinated axons, and distal axon loss in the PNS."
explanation: Mouse model of CMT2E with heterozygous Nefl N98S mutation confirms neurofilament reduction in axons and distal axon loss.
- reference: PMID:28709447
reference_title: "Cryptic amyloidogenic elements in mutant NEFH causing Charcot-Marie-Tooth 2 trigger aggresome formation and neuronal death."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "Consistently, we show that these mutations cause protein aggregation which are recognised by the autophagic pathway in motoneurons and triggered caspase 3 activation leading to apoptosis in neuroblastoma cells."
explanation: CMT2CC NEFH frameshift products aggregate in motoneurons and kill neuroblastoma cells, the NEFH arm of this node.
- reference: PMID:23562820
reference_title: "Deficiency of the E3 ubiquitin ligase TRIM2 in early-onset axonal neuropathy."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "Trim2-gene trap mice showed axonopathy with accumulations of neurofilaments inside axons."
explanation: Loss of the TRIM2 ligase produces intra-axonal neurofilament accumulation, the CMT2R arm of this node.
- reference: PMID:23562820
reference_title: "Deficiency of the E3 ubiquitin ligase TRIM2 in early-onset axonal neuropathy."
supports: SUPPORT
evidence_source: IN_VITRO
quote_role: BACKGROUND
snippet: "TRIM2 is an E3 ubiquitin ligase that ubiquitinates neurofilament light chain, a component of the intermediate filament in axons."
explanation: States the substrate relationship that makes TRIM2 loss a neurofilament-handling defect.
- reference: PMID:24500646
reference_title: "Ubiquitin ligase defect by DCAF8 mutation causes HMSN2 with giant axons."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "This mutation results in decreased DDB1-DCAF8 association, leading to an E3 ubiquitin ligase defect that is likely associated with neurofilament degradation."
explanation: Co-immunoprecipitation evidence that the GAN2 DCAF8 allele weakens the Cullin-4 ligase that turns neurofilaments over.
- reference: PMID:24500646
reference_title: "Ubiquitin ligase defect by DCAF8 mutation causes HMSN2 with giant axons."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Giant axons with neurofilament accumulations were found in 3 affected persons who had undergone nerve biopsy evaluations."
explanation: Nerve-biopsy confirmation that neurofilaments accumulate in axons of DCAF8 patients.
notes: >-
Subtypes reaching this node - CMT2E (NEFL), CMT2CC (NEFH), CMT2R (TRIM2)
and GAN2 (DCAF8). The four differ in where the neurofilament network fails:
subunit assembly for NEFL, aggregation of an extended NEFH product, and loss
of neurofilament turnover for the two ubiquitin-ligase genes.
- name: Impaired Endosomal Trafficking
description: >
RAB7A mutations impair late endosomal trafficking and lysosomal
degradation in neurons. Defective endosome-to-lysosome maturation
disrupts neurotrophin receptor signaling and cellular waste removal
in long axons, particularly sensory neurons.
cell_types:
- preferred_term: Sensory neuron
term:
id: CL:0000101
label: sensory neuron
biological_processes:
- preferred_term: Endosome to lysosome transport
term:
id: GO:0008333
label: endosome to lysosome transport
modifier: ABNORMAL
genes:
- preferred_term: RAB7A
term:
id: hgnc:9788
label: RAB7A
downstream:
- target: Distal Axonal Degeneration
description: >
Defective endosomal trafficking impairs neurotrophin receptor
signaling and autophagy, leading to sensory axon degeneration.
evidence:
- reference: PMID:34486665
reference_title: "Tubular microdomains of Rab7-positive endosomes retrieve TrkA, a mechanism disrupted in Charcot-Marie-Tooth disease 2B."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "In Charcot-Marie-Tooth disease 2B (CMT2B), a neuropathy of the peripheral nervous system, this tubulating mechanism is disrupted."
explanation: Demonstrates that CMT2B RAB7A mutations disrupt endosomal tubulation and TrkA neurotrophin receptor retrieval.
- reference: PMID:24521780
reference_title: "Human Rab7 mutation mimics features of Charcot-Marie-Tooth neuropathy type 2B in Drosophila."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "Missense mutations in RAB7A, the gene encoding the small GTPase Rab7, cause CMT2B and increase Rab7 activity. Rab7 is ubiquitously expressed and is involved in degradation through the lysosomal pathway."
explanation: Drosophila model confirms RAB7A mutations cause CMT2B through altered endosomal/lysosomal trafficking with sensory and motor phenotypes.
notes: Subtype CMT2B with prominent sensory involvement and ulcerations
- name: Impaired Neurotrophin Signaling Endosome Axonal Transport
description: >
GARS1 gain-of-function mutations produce toxic glycyl-tRNA synthetase
variants that aberrantly interact with neurotrophin receptor pathways such
as BDNF/TrkB. In CMT2D models, this disrupts axonal transport of
neurotrophin-containing signaling endosomes, compromising trophic signaling
in long peripheral axons.
cell_types:
- preferred_term: Motor neuron
term:
id: CL:0000100
label: motor neuron
- preferred_term: Sensory neuron
term:
id: CL:0000101
label: sensory neuron
biological_processes:
- preferred_term: Axonal transport
term:
id: GO:0098930
label: axonal transport
modifier: DECREASED
genes:
- preferred_term: GARS1
term:
id: hgnc:4162
label: GARS1
downstream:
- target: Distal Axonal Degeneration
description: >
Persistent disruption of neurotrophin signaling endosome transport
deprives long axons of trophic support and contributes to distal axonal
degeneration.
evidence:
- reference: PMID:36928301
reference_title: "Boosting peripheral BDNF rescues impaired in vivo axonal transport in CMT2D mice."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "Through intravital imaging of the sciatic nerve, we show that CMT2D mice displayed early and persistent disturbances in axonal transport of neurotrophin-containing signaling endosomes in vivo."
explanation: Directly supports impaired neurotrophin signaling endosome axonal transport in CMT2D mice.
- reference: PMID:36928301
reference_title: "Boosting peripheral BDNF rescues impaired in vivo axonal transport in CMT2D mice."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "(BDNF)/TrkB impairments correlated with transport disruption and overall CMT2D neuropathology and that inhibition of this pathway at the nerve-muscle interface perturbed endosome transport in wild-type axons."
explanation: Links BDNF/TrkB pathway impairment to transport disruption and CMT2D neuropathology.
notes: Subtype CMT2D (GARS1 mutations)
- name: SORD Deficiency and Sorbitol Accumulation
description: >
Biallelic SORD loss-of-function variants reduce sorbitol dehydrogenase
activity in the polyol pathway. Loss of SORD protein causes intracellular
and serum sorbitol accumulation, which is linked to peripheral axon
degeneration in patient cells and Drosophila models.
cell_types:
- preferred_term: Motor neuron
term:
id: CL:0000100
label: motor neuron
- preferred_term: Sensory neuron
term:
id: CL:0000101
label: sensory neuron
biological_processes:
- preferred_term: Carbohydrate metabolic process
term:
id: GO:0005975
label: carbohydrate metabolic process
modifier: ABNORMAL
genes:
- preferred_term: SORD
term:
id: hgnc:11184
label: SORD
downstream:
- target: Distal Axonal Degeneration
description: >
Sorbitol accumulation and polyol-pathway dysfunction contribute to the
length-dependent peripheral axon degeneration seen in SORD-CMT2.
evidence:
- reference: PMID:32367058
reference_title: "Biallelic mutations in SORD cause a common and potentially treatable hereditary neuropathy with implications for diabetes."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "In patient-derived fibroblasts, we found a complete loss of SORD protein and increased intracellular sorbitol."
explanation: Patient-derived fibroblast evidence supports SORD protein loss and intracellular sorbitol accumulation.
- reference: PMID:32367058
reference_title: "Biallelic mutations in SORD cause a common and potentially treatable hereditary neuropathy with implications for diabetes."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "In Drosophila, loss of SORD orthologs caused synaptic degeneration and progressive motor impairment."
explanation: Model-organism evidence links SORD deficiency to synaptic degeneration and progressive motor impairment.
notes: SORD-related axonal neuropathy / autosomal recessive CMT2
- name: Small Heat-Shock Protein Chaperone Dysfunction
description: >
Mutations in the alpha-crystallin domain of the small heat-shock proteins
HSPB1 (HSP27) and HSPB8 (HSP22) convert them from chaperones into
aggregation-prone proteins. Mutant HSP27 forms insoluble intracellular
aggregates that sequester neurofilament middle chain and the p150 subunit
of dynactin, and mutant HSP22 degenerates neurites selectively in motor
neurons while leaving sensory and cortical neurons and glial cells largely
unaffected. Alleles of both genes are reported in axonal CMT2 and in distal
hereditary motor neuropathy.
biological_scale: MOLECULAR
cell_types:
- preferred_term: Motor neuron
term:
id: CL:0000100
label: motor neuron
biological_processes:
- preferred_term: Protein folding
term:
id: GO:0006457
label: protein folding
modifier: ABNORMAL
molecular_functions:
- preferred_term: protein folding chaperone
term:
id: GO:0044183
label: protein folding chaperone
modifier: LOSS_OF_FUNCTION
genes:
- preferred_term: HSPB1
term:
id: hgnc:5246
label: HSPB1
- preferred_term: HSPB8
term:
id: hgnc:30171
label: HSPB8
downstream:
- target: Distal Axonal Degeneration
description: >
Sequestration of neurofilament and dynactin subunits into mutant
small-heat-shock-protein aggregates removes components required for axonal
structure and transport, and mutant HSPB8 degenerates neurites directly.
evidence:
- reference: PMID:16368711
reference_title: "A mutation in the small heat-shock protein HSPB1 leading to distal hereditary motor neuronopathy disrupts neurofilament assembly and the axonal transport of specific cellular cargoes."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "These findings suggest a possible pathogenic mechanism for HSPB1 whereby the mutation may lead to preferential motor neuron loss by disrupting selective components essential for axonal structure and transport."
explanation: Proposes the sequestration-to-axonal-failure step this edge asserts.
- target: Presynaptic Neuromuscular Transmission Deficit
description: >
In transgenic C. elegans, pan-neuronal expression of three CMT2F HSPB1
alleles weakened neuromuscular signalling at a young age, and deleting the
worm's own small heat-shock protein genes produced the same early aldicarb
resistance, so the authors attribute the early defect to a general loss of
small-chaperone function rather than to a variant-specific gain.
evidence:
- reference: PMID:42489084
reference_title: "Charcot-Marie-Tooth disease variants of HSPB1 progressively alter neuromuscular signalling."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
quote_role: PRIMARY_RESULT
directness: INDIRECT
snippet: "In contrast, the early defect in neuromuscular signalling may be a result of a general loss of small chaperone function."
explanation: The authors infer from the phenocopy by endogenous small heat-shock protein deletions that the early synaptic defect reflects loss of small-chaperone function; the inference is drawn in worms.
evidence:
- reference: PMID:16368711
reference_title: "A mutation in the small heat-shock protein HSPB1 leading to distal hereditary motor neuronopathy disrupts neurofilament assembly and the axonal transport of specific cellular cargoes."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "Mutant (P182L) but not wild-type HSPB1 led to the formation of insoluble intracellular aggregates and to the sequestration in the cytoplasm of selective cellular components, including neurofilament middle chain subunit (NF-M) and p150 dynactin."
explanation: Shows that a mutant HSPB1 allele aggregates and sequesters neurofilament and dynactin subunits in primary neurons.
- reference: PMID:20538880
reference_title: "Mutant HSPB8 causes motor neuron-specific neurite degeneration."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "In motor neurons, expression of both HSPB8 K141N and K141E mutations clearly resulted in neurite degeneration"
explanation: Shows that the CMT2L HSPB8 alleles degenerate neurites in motor neurons.
notes: >-
Subtypes reaching this node - CMT2F (HSPB1) and CMT2L (HSPB8). The HSPB1
experiment quoted here used the P182L allele, which was reported in distal
hereditary motor neuronopathy rather than in a CMT2F family; it is cited for
the chaperone-to-aggregate mechanism the two phenotypes share, not as CMT2F
patient evidence.
- name: Presynaptic Neuromuscular Transmission Deficit
description: >
Pan-neuronal transgenic expression of three CMT2F HSPB1 alleles from
different protein domains (G84R in the N-terminal domain, S135F in the
alpha-crystallin domain, and the C-terminal truncation Q175X) in
C. elegans reduced neuromuscular signalling strength in young adults, read
out as aldicarb resistance, while wild-type HSPB1 did not. The defect was
attributed to the presynaptic side because postsynaptic levamisole
sensitivity showed no consistent change across the three variants. With age the defect was
progressive: the age-dependent shift in neuromuscular signalling that
control worms show came early in the mutant lines, which had moved from
aldicarb resistance to hypersensitivity by adult day 5.
biological_scale: CELLULAR
cell_types:
- preferred_term: Motor neuron
term:
id: CL:0000100
label: motor neuron
biological_processes:
- preferred_term: neuromuscular synaptic transmission
term:
id: GO:0007274
label: neuromuscular synaptic transmission
modifier: ABNORMAL
genes:
- preferred_term: HSPB1
term:
id: hgnc:5246
label: HSPB1
downstream:
- target: Distal Muscle Weakness
description: >
The authors propose that progressive presynaptic failure at the
neuromuscular junction is one route from mutant HSPB1 to the progressive
distal motor deficit of CMT2F. The worm data show the synaptic defect, not
human weakness, so this edge is a proposed mechanism.
evidence:
- reference: PMID:42489084
reference_title: "Charcot-Marie-Tooth disease variants of HSPB1 progressively alter neuromuscular signalling."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
quote_role: PRIMARY_RESULT
directness: INDIRECT
snippet: "These results indicate a possible progressive mechanism for HSPB1-dependent neuromuscular defects."
explanation: The authors present the worm neuromuscular phenotype as a possible progressive mechanism for HSPB1-related neuromuscular disease; the link to human weakness is their inference.
evidence:
- reference: PMID:42489084
reference_title: "Charcot-Marie-Tooth disease variants of HSPB1 progressively alter neuromuscular signalling."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
quote_role: PRIMARY_RESULT
snippet: "Using a transgenic Caenorhabditis elegans model, we examined three distinct HSPB1 variants and determined that mutant HSPB1 caused an early defect in neuromuscular signalling strength as assayed by aldicarb sensitivity."
explanation: Mutant HSPB1 alleles caused an early neuromuscular signalling defect in transgenic worms.
- reference: PMID:42489084
reference_title: "Charcot-Marie-Tooth disease variants of HSPB1 progressively alter neuromuscular signalling."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
quote_role: PRIMARY_RESULT
snippet: "Our data point to the effects being presynaptic in origin and unrelated to differences in expression of mutant HSPB1 compared with that of the wild-type protein."
explanation: The defect was localized to the presynaptic side and was not explained by lower expression of the mutant proteins.
- reference: PMID:42489084
reference_title: "Charcot-Marie-Tooth disease variants of HSPB1 progressively alter neuromuscular signalling."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
quote_role: PRIMARY_RESULT
snippet: "We also identified a progressive effect whereby age-dependent changes to neuromuscular signalling were accelerated in worms expressing mutant HSPB1."
explanation: The neuromuscular defect progressed with age faster in worms expressing mutant HSPB1.
notes: >-
Subtype reaching this node - CMT2F (HSPB1). The only evidence is a
C. elegans model. Worm motor neurons have no myelin, which the authors chose
on purpose to separate axonal and synaptic effects from myelination, and the
human protein was expressed from extrachromosomal arrays on a wild-type
background. No human neuromuscular-junction study of CMT2F was found in the
entry's references.
- name: Aminoacyl-tRNA Synthetase Loss of Function
description: >
Cytoplasmic aminoacyl-tRNA synthetases charge tRNAs with their amino acid.
Dominant CMT2 alleles of AARS1 (CMT2N) and MARS1 (CMT2U) behave as
loss-of-function in aminoacylation and yeast complementation assays, and the
resulting peripheral phenotype is a length-dependent axonal degeneration
without central features. The GARS1 disease CMT2D is modeled separately in
this entry, because its alleles act through aberrant new interactions rather
than through the charging deficit alone.
biological_scale: MOLECULAR
cell_types:
- preferred_term: Motor neuron
term:
id: CL:0000100
label: motor neuron
- preferred_term: Sensory neuron
term:
id: CL:0000101
label: sensory neuron
biological_processes:
- preferred_term: tRNA aminoacylation for protein translation
term:
id: GO:0006418
label: tRNA aminoacylation for protein translation
modifier: DECREASED
genes:
- preferred_term: AARS1
term:
id: hgnc:20
label: AARS1
- preferred_term: MARS1
term:
id: hgnc:6898
label: MARS1
downstream:
- target: Distal Axonal Degeneration
description: >
Reduced tRNA charging in long peripheral neurons is followed by
distal-predominant axonal degeneration, with the central nervous system
spared.
evidence:
- reference: PMID:20045102
reference_title: "A major determinant for binding and aminoacylation of tRNA(Ala) in cytoplasmic Alanyl-tRNA synthetase is mutated in dominant axonal Charcot-Marie-Tooth disease."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Patients present with sensory-motor distal degeneration secondary to predominant axonal neuropathy, slight demyelination, and no atypical or additional CNS features."
explanation: Describes the distal axonal degeneration that follows the AARS1 charging deficit in patients.
evidence:
- reference: PMID:22009580
reference_title: "A recurrent loss-of-function alanyl-tRNA synthetase (AARS) mutation in patients with Charcot-Marie-Tooth disease type 2N (CMT2N)."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "Aminoacylation and yeast viability assays showed that p.Arg329His AARS severely reduces enzyme activity."
explanation: Direct assay evidence that the CMT2N allele loses aminoacylation activity.
- reference: PMID:31356216
reference_title: "A Novel Mutation in MARS in a Patient with Charcot-Marie-Tooth Disease, Axonal, Type 2U with Congenital Onset."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "p.Ala397Thr MARS supported very little yeast cell growth, consistent with this being a loss-of-function allele."
explanation: Yeast complementation evidence that the CMT2U allele loses methionyl-tRNA synthetase function.
notes: Subtypes reaching this node - CMT2N (AARS1) and CMT2U (MARS1).
- name: Impaired Autophagy-Lysosome Function
description: >
Two CMT2 genes converge on the autophagy-lysosome arm of protein and lipid
clearance. The CMT2Y VCP allele leaves immature autophagosomes accumulating,
and loss of the CMT2X gene product spatacsin leaves lipids uncleared from
lysosomes, with motor neuron degeneration in the knockout mouse.
biological_scale: CELLULAR
cell_types:
- preferred_term: Motor neuron
term:
id: CL:0000100
label: motor neuron
biological_processes:
- preferred_term: Autophagosome maturation
term:
id: GO:0097352
label: autophagosome maturation
modifier: DECREASED
- preferred_term: Lysosome organization
term:
id: GO:0007040
label: lysosome organization
modifier: ABNORMAL
genes:
- preferred_term: VCP
term:
id: hgnc:12666
label: VCP
- preferred_term: SPG11
term:
id: hgnc:11226
label: SPG11
downstream:
- target: Distal Axonal Degeneration
description: >
Failure of autophagic and lysosomal clearance in long neurons is followed
by axonal and motor neuron degeneration.
evidence:
- reference: PMID:28237315
reference_title: "Loss of spatacsin function alters lysosomal lipid clearance leading to upper and lower motor neuron degeneration."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "Spinal motor neurons also degenerated and this was accompanied by fragmentation of neuromuscular junctions and muscle atrophy."
explanation: Spatacsin-null mice degenerate spinal motor neurons and their neuromuscular junctions, the degeneration step of this edge.
evidence:
- reference: PMID:25125609
reference_title: "A novel mutation in VCP causes Charcot-Marie-Tooth Type 2 disease."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "Functional studies showed that the Glu185Lys variant impaired autophagic function leading to the accumulation of immature autophagosomes."
explanation: Direct functional evidence that the CMT2Y VCP allele blocks autophagosome maturation.
- reference: PMID:28237315
reference_title: "Loss of spatacsin function alters lysosomal lipid clearance leading to upper and lower motor neuron degeneration."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "the loss of spatacsin leads to the accumulation of lipids in lysosomes by perturbing their clearance from these organelles"
explanation: Establishes the lysosomal clearance defect caused by loss of the CMT2X gene product.
notes: >-
Subtypes reaching this node - CMT2Y (VCP) and CMT2X (SPG11). NAGLU (CMT2V)
is also a lysosomal gene but is deliberately not wired here - the cited
report establishes only a partial enzyme deficiency in carriers, and no step
from that deficiency to peripheral axonal degeneration is demonstrated.
- name: Nuclear Lamina Disruption
description: >
Lamin A/C is a component of the nuclear envelope. A
homozygous LMNA founder allele causes autosomal recessive axonal CMT2B1, and
sciatic nerves of lamin-A/C-null mice show the loss of axons, axonal
enlargement and unmyelinated profiles seen in human peripheral axonopathy.
biological_scale: CELLULAR
cell_types:
- preferred_term: Motor neuron
term:
id: CL:0000100
label: motor neuron
- preferred_term: Sensory neuron
term:
id: CL:0000101
label: sensory neuron
biological_processes:
- preferred_term: Nuclear envelope organization
term:
id: GO:0006998
label: nuclear envelope organization
modifier: ABNORMAL
genes:
- preferred_term: LMNA
term:
id: hgnc:6636
label: LMNA
downstream:
- target: Distal Axonal Degeneration
description: >
Absence of lamin A/C is followed by axonal loss and enlargement in
peripheral nerve.
evidence:
- reference: PMID:11799477
reference_title: "Homozygous defects in LMNA, encoding lamin A/C nuclear-envelope proteins, cause autosomal recessive axonal neuropathy in human (Charcot-Marie-Tooth disorder type 2) and mouse."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "Ultrastructural exploration of sciatic nerves of LMNA null (i.e., -/-) mice was performed and revealed a strong reduction of axon density, axonal enlargement, and the presence of nonmyelinated axons, all of which were highly similar to the phenotypes of human peripheral axonopathies."
explanation: Sciatic-nerve ultrastructure in the lamin-A/C-null mouse, the degeneration step of this edge.
evidence:
- reference: PMID:11799477
reference_title: "Homozygous defects in LMNA, encoding lamin A/C nuclear-envelope proteins, cause autosomal recessive axonal neuropathy in human (Charcot-Marie-Tooth disorder type 2) and mouse."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The finding of site-specific amino acid substitutions in limb-girdle muscular dystrophy type 1B, autosomal dominant Emery-Dreifuss muscular dystrophy, dilated cardiomyopathy type 1A, autosomal dominant partial lipodystrophy, and, now, AR-CMT2 suggests the existence of distinct functional domains"
explanation: Places the CMT2B1 allele among the LMNA diseases, supporting a lamina defect as the node's substrate.
notes: >-
Subtype reaching this node - CMT2B1 (LMNA). The mouse evidence is a null
allele, whereas CMT2B1 patients are homozygous for a missense allele, so the
model is a loss-of-function approximation rather than a genocopy.
- name: Mitochondrial Energy Production Failure
description: >
DHTKD1, the gene behind dominant CMT2Q, is part of a
2-oxoglutarate-dehydrogenase-complex-like protein and acts inside the
mitochondrion rather than on its shape or transport. Silencing it lowers
cellular ATP and NAD(H), and expressing wild-type DHTKD1 in patient
fibroblasts normalizes the 2-oxoadipate that accumulates without it.
biological_scale: MOLECULAR
cell_types:
- preferred_term: Motor neuron
term:
id: CL:0000100
label: motor neuron
- preferred_term: Sensory neuron
term:
id: CL:0000101
label: sensory neuron
biological_processes:
- preferred_term: ATP biosynthetic process
term:
id: GO:0006754
label: ATP biosynthetic process
modifier: DECREASED
genes:
- preferred_term: DHTKD1
term:
id: hgnc:23537
label: DHTKD1
downstream:
- target: Distal Axonal Degeneration
description: >
Reduced mitochondrial energy output leaves the longest peripheral axons,
which have the largest transport and metabolic demand, unable to sustain
their distal segments.
evidence:
- reference: PMID:23141294
reference_title: "A nonsense mutation in DHTKD1 causes Charcot-Marie-Tooth disease type 2 in a large Chinese pedigree."
supports: SUPPORT
evidence_source: OTHER
snippet: "implicating an important role for DHTKD1 in mitochondrial energy production and neurological development"
explanation: The authors' own conclusion tying the DHTKD1 energy defect to the neurological phenotype.
evidence:
- reference: PMID:23141294
reference_title: "A nonsense mutation in DHTKD1 causes Charcot-Marie-Tooth disease type 2 in a large Chinese pedigree."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "DHTKD1 silencing was found to lead to impaired energy production, evidenced by decreased ATP, total NAD"
explanation: Direct measurement that loss of DHTKD1 lowers cellular ATP and NAD(H).
- reference: PMID:23141293
reference_title: "DHTKD1 mutations cause 2-aminoadipic and 2-oxoadipic aciduria."
supports: SUPPORT
evidence_source: OTHER
quote_role: BACKGROUND
snippet: "This gene codes for dehydrogenase E1 and transketolase domain-containing protein 1, which is part of a 2-oxoglutarate-dehydrogenase-complex-like protein."
explanation: Source for the description of what DHTKD1 encodes, as stated in this node.
- reference: PMID:23141293
reference_title: "DHTKD1 mutations cause 2-aminoadipic and 2-oxoadipic aciduria."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "Increased levels of 2-oxoadipate in individual-derived fibroblasts normalized upon lentiviral expression of the wild-type DHTKD1 mRNA."
explanation: Establishes the metabolic step DHTKD1 loss blocks, by rescue in patient fibroblasts.
notes: >-
Subtype reaching this node - CMT2Q (DHTKD1). MPV17 (CMT2EE) is also a
mitochondrial gene but has its own node, Impaired Mitochondrial DNA
Maintenance, because the cited evidence for it concerns deoxynucleotide
homeostasis and mitochondrial DNA rather than energy output.
- name: Impaired Mitochondrial DNA Maintenance
description: >
MPV17 is an inner mitochondrial membrane protein serving mitochondrial
deoxynucleotide homeostasis. Biallelic MPV17 variants were first described
in a mitochondrial DNA depletion syndrome with early-onset liver failure,
and can also present as an isolated axonal sensorimotor neuropathy with no
liver or brain involvement, which is CMT2EE.
biological_scale: MOLECULAR
cell_types:
- preferred_term: Motor neuron
term:
id: CL:0000100
label: motor neuron
- preferred_term: Sensory neuron
term:
id: CL:0000101
label: sensory neuron
biological_processes:
- preferred_term: Mitochondrial DNA metabolic process
term:
id: GO:0032042
label: mitochondrial DNA metabolic process
modifier: ABNORMAL
genes:
- preferred_term: MPV17
term:
id: hgnc:7224
label: MPV17
downstream:
- target: Distal Axonal Degeneration
description: >
Biallelic MPV17 variants can produce a pure axonal sensorimotor
neuropathy, with none of the hepatic or cerebral disease the same gene
causes in its depletion-syndrome presentation.
evidence:
- reference: PMID:30298599
reference_title: "MPV17 mutations in juvenile- and adult-onset axonal sensorimotor polyneuropathy."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "This report provides further evidence that MPV17 mutations should be considered in patients with pure, non-syndromic axonal neuropathy."
explanation: Establishes that the MPV17 defect can present as an isolated axonal neuropathy.
evidence:
- reference: PMID:30298599
reference_title: "MPV17 mutations in juvenile- and adult-onset axonal sensorimotor polyneuropathy."
supports: SUPPORT
evidence_source: OTHER
quote_role: BACKGROUND
snippet: "MPV17 encodes a putative channel-forming protein of the inner mitochondrial membrane and is involved in mitochondrial deoxynucleotide homeostasis."
explanation: States the mitochondrial role of MPV17 that this node describes.
- reference: PMID:30298599
reference_title: "MPV17 mutations in juvenile- and adult-onset axonal sensorimotor polyneuropathy."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Here, we describe five additional patients from two unrelated families with sensorimotor axonal neuropathy without hepatocerebral affection caused by homozygous MPV17 variants."
explanation: The patients in whom the MPV17 defect produced neuropathy alone.
notes: >-
Subtype reaching this node - CMT2EE (MPV17). Split from Mitochondrial Energy
Production Failure because no cited source measures reduced energy output for
MPV17; what the sources support is a defect in deoxynucleotide supply and
mitochondrial DNA maintenance.
- name: Impaired Mitochondrial Fission
description: >
GDAP1 sits in the mitochondrial outer membrane and drives fission of the
mitochondrial network. CMT-associated truncations fail to reach
mitochondria and lose fragmentation activity, and point mutations reduce it
strongly, so the GDAP1 defect is a loss of fission rather than the loss of
fusion produced by MFN2. Both leave the mitochondrial network mishandled,
which is why GDAP1 is wired to its own node rather than to Mitochondrial
Fragmentation.
biological_scale: CELLULAR
cell_types:
- preferred_term: Motor neuron
term:
id: CL:0000100
label: motor neuron
- preferred_term: Sensory neuron
term:
id: CL:0000101
label: sensory neuron
biological_processes:
- preferred_term: Mitochondrial fission
term:
id: GO:0000266
label: mitochondrial fission
modifier: DECREASED
genes:
- preferred_term: GDAP1
term:
id: hgnc:15968
label: GDAP1
downstream:
- target: Distal Axonal Degeneration
description: >
Loss of control over mitochondrial network dynamics compromises the
function of myelinated peripheral nerve and contributes to the axonal
degeneration of CMT2K.
evidence:
- reference: PMID:16172208
reference_title: "Ganglioside-induced differentiation associated protein 1 is a regulator of the mitochondrial network: new implications for Charcot-Marie-Tooth disease."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "Our data indicate that an exquisitely tight control of mitochondrial dynamics, regulated by GDAP1, is crucial for the proper function of myelinated peripheral nerves."
explanation: States the step from disturbed GDAP1-controlled mitochondrial dynamics to peripheral nerve dysfunction.
evidence:
- reference: PMID:16172208
reference_title: "Ganglioside-induced differentiation associated protein 1 is a regulator of the mitochondrial network: new implications for Charcot-Marie-Tooth disease."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "GDAP1 truncations that are found in patients who have CMT are not targeted to mitochondria and have lost mitochondrial fragmentation activity."
explanation: Patient-derived GDAP1 truncations lose the fission activity this node describes.
- reference: PMID:16172208
reference_title: "Ganglioside-induced differentiation associated protein 1 is a regulator of the mitochondrial network: new implications for Charcot-Marie-Tooth disease."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "GDAP1 is located in the mitochondrial outer membrane and regulates the mitochondrial network."
explanation: Localizes GDAP1 and states the process it regulates.
notes: Subtype reaching this node - CMT2K (GDAP1).
- name: Axonal Sodium-Potassium ATPase Dysfunction
description: >
ATP1A1 encodes the alpha-1 subunit of the Na+,K+-ATPase and is present on
the axolemma of myelinated sensory and motor axons and at Schmidt-Lanterman
incisures. Several CMT2DD substitutions reduce pump current in a
heterologous expression system, pointing to a loss-of-function defect in the
sodium-potassium pump.
biological_scale: MOLECULAR
cell_types:
- preferred_term: Motor neuron
term:
id: CL:0000100
label: motor neuron
- preferred_term: Sensory neuron
term:
id: CL:0000101
label: sensory neuron
molecular_functions:
- preferred_term: P-type sodium:potassium-exchanging transporter activity
term:
id: GO:0005391
label: P-type sodium:potassium-exchanging transporter activity
modifier: DECREASED
genes:
- preferred_term: ATP1A1
term:
id: hgnc:799
label: ATP1A1
downstream:
- target: Distal Axonal Degeneration
description: >
A weakened axonal sodium-potassium pump is proposed as a degenerative
pathway in peripheral nerve axons and a candidate therapeutic target.
evidence:
- reference: PMID:29499166
reference_title: "Mutations in ATP1A1 Cause Dominant Charcot-Marie-Tooth Type 2."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "These findings identify a CMT pathway and a potential target for therapy development in degenerative diseases of peripheral nerve axons."
explanation: The authors' own framing of the ATP1A1 defect as a degenerative pathway in peripheral nerve axons.
evidence:
- reference: PMID:29499166
reference_title: "Mutations in ATP1A1 Cause Dominant Charcot-Marie-Tooth Type 2."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "Immunostaining peripheral nerve axons localized ATP1A1 to the axolemma of myelinated sensory and motor axons and to Schmidt-Lanterman incisures of myelin sheaths."
explanation: Places ATP1A1 at the axolemma, the site this node describes.
- reference: PMID:29499166
reference_title: "Mutations in ATP1A1 Cause Dominant Charcot-Marie-Tooth Type 2."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "demonstrated significant reduction in Na+ current activity in some, but not all, ouabain-insensitive ATP1A1 mutants, suggesting a loss-of-function defect of the Na+,K+ pump"
explanation: Two-electrode voltage clamp evidence of reduced pump current, with the authors' own caveat that not all mutants behaved this way.
notes: Subtype reaching this node - CMT2DD (ATP1A1).
- name: Axon-Schwann Cell Adhesion Failure
biological_scale: CELLULAR
description: >
CADM3 is expressed on the axon and binds CADM4 on the myelinating Schwann
cell; this pairing organizes the myelinated fibre at the axon-glia interface.
The recurrent CMT2FF variant Tyr172Cys introduces a new disulphide bond,
retains the mutant protein in the endoplasmic reticulum, reduces its surface
expression and lowers its co-localization with CADM4 at intercellular
contacts. Knock-in mice show normal nerve conduction and myelin morphology
but disordered axonal organization, so the lesion is an adhesion and
domain-organization defect in an otherwise normally myelinated axon rather
than a demyelinating one.
cell_types:
- preferred_term: Schwann cell
term:
id: CL:0002573
label: Schwann cell
- preferred_term: sensory neuron
term:
id: CL:0000101
label: sensory neuron
molecular_functions:
- preferred_term: cell adhesion molecule binding
term:
id: GO:0050839
label: cell adhesion molecule binding
modifier: DECREASED
genes:
- preferred_term: CADM3
term:
id: hgnc:17601
label: CADM3
evidence:
- reference: PMID:33889941
reference_title: "A CADM3 variant causes Charcot-Marie-Tooth disease with marked upper limb involvement."
supports: SUPPORT
evidence_source: OTHER
snippet: "In the peripheral nerve, axon-Schwann cell interaction is essential for the structural organization of myelinated fibres and is primarily mediated by the binding of CADM3, expressed in axons, to CADM4, expressed by myelinating Schwann cells."
quote_role: BACKGROUND
explanation: States the CADM3-CADM4 axon-glia adhesion pairing that this node asserts is disrupted.
- reference: PMID:33889941
reference_title: "A CADM3 variant causes Charcot-Marie-Tooth disease with marked upper limb involvement."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "Our data support a retention of the mutant protein in the endoplasmic reticulum and reduced cell surface expression in vitro."
explanation: Supports loss of CADM3 from the axonal surface as the proximate molecular lesion.
- reference: PMID:33889941
reference_title: "A CADM3 variant causes Charcot-Marie-Tooth disease with marked upper limb involvement."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Our findings indicate the involvement of abnormal axon-glia interaction as a disease-causing mechanism in CMT patients with CADM3 mutations."
explanation: The authors' own statement that abnormal axon-glia interaction is the disease mechanism in CADM3 CMT.
downstream:
- target: Distal Axonal Degeneration
description: >
Loss of the CADM3-CADM4 adhesion pairing disorganizes the myelinated axon
and converges on the shared length-dependent axonal degeneration of CMT2.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
notes: CMT2FF (CADM3-related axonal CMT)
- name: Reduced JAG1 Cell Surface Expression
biological_scale: MOLECULAR
description: >
JAG1 encodes the canonical Notch ligand Jagged1. The two reported CMT2HH
missense variants (p.Ser577Arg, p.Ser650Pro) impair post-translational
glycosylation of the protein and reduce the amount of JAG1 reaching the cell
surface, where it would otherwise engage Notch receptors on neighbouring
cells. Mice heterozygous for the CMT2-associated alleles develop mild
peripheral neuropathy.
molecular_functions:
- preferred_term: Notch binding
term:
id: GO:0005112
label: Notch binding
modifier: DECREASED
biological_processes:
- preferred_term: Notch signaling pathway
term:
id: GO:0007219
label: Notch signaling pathway
modifier: DECREASED
genes:
- preferred_term: JAG1
term:
id: hgnc:6188
label: JAG1
evidence:
- reference: PMID:32065591
reference_title: "Dominant mutations of the Notch ligand Jagged1 cause peripheral neuropathy."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "Our studies of mutant protein posttranslational modification and localization indicated that the mutations (p.Ser577Arg, p.Ser650Pro) impair protein glycosylation and reduce JAG1 cell surface expression."
explanation: Supports impaired glycosylation and reduced surface delivery of the Notch ligand as the molecular lesion.
- reference: PMID:32065591
reference_title: "Dominant mutations of the Notch ligand Jagged1 cause peripheral neuropathy."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "Mice harboring heterozygous CMT2-associated mutations exhibited mild peripheral neuropathy, and homozygous expression resulted in embryonic lethality by midgestation."
explanation: Model-organism support that the heterozygous CMT2 alleles produce peripheral neuropathy.
downstream:
- target: Distal Axonal Degeneration
description: >
Reduced Jagged1 availability at the cell surface compromises peripheral
nerve integrity, particularly of the recurrent laryngeal nerve, and
converges on the shared axonal degeneration of CMT2.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
notes: CMT2HH (JAG1-related axonal CMT)
- name: Reduced KCC3 Potassium-Chloride Cotransport
biological_scale: MOLECULAR
description: >
SLC12A6 encodes KCC3, a potassium-chloride cotransporter. Dominantly acting
de novo missense variants reduce potassium influx through the mutant
cotransporter when expressed in Xenopus oocytes. How reduced KCC3 transport
injures the peripheral nerve is not established; the largest dominant
SLC12A6 cohort states that more work is needed to understand the mechanism,
and this node therefore records the measured transport deficit rather than a
downstream nerve mechanism.
molecular_functions:
- preferred_term: potassium:chloride symporter activity
term:
id: GO:0015379
label: potassium:chloride symporter activity
modifier: DECREASED
genes:
- preferred_term: SLC12A6
term:
id: hgnc:10914
label: SLC12A6
evidence:
- reference: PMID:31439721
reference_title: "De novo variants in SLC12A6 cause sporadic early-onset progressive sensorimotor neuropathy."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "Modelling of the mutant KCC3 cotransporter in Xenopus oocytes showed a significant reduction in potassium influx for both changes."
explanation: Direct functional measurement of reduced cotransporter activity for the two de novo variants.
- reference: PMID:31439721
reference_title: "De novo variants in SLC12A6 cause sporadic early-onset progressive sensorimotor neuropathy."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "We identified heterozygous de novo variants in SLC12A6 in three unrelated patients with intermediate CMT."
explanation: Links the measured transport deficit to the patients whose neuropathy it is invoked to explain.
downstream:
- target: Distal Axonal Degeneration
description: >
Reduced KCC3 cotransport precedes the length-dependent sensorimotor
neuropathy seen in these patients; the intervening steps are not
established, so the link is recorded as indirect with unknown intermediates.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
notes: CMT2II (dominant SLC12A6 / KCC3-related CMT)
- name: Impaired RhoA GTPase Inactivation
biological_scale: MOLECULAR
description: >
ARHGAP19 is a GTPase-activating protein that switches RhoA off by stimulating
its intrinsic GTP hydrolysis. Biallelic CMT2KK variants both lower ARHGAP19
protein levels and impair its GAP activity, a loss-of-function mechanism.
Loss of the orthologue in Drosophila and zebrafish produces motor defects
with abnormal axonal and synaptic morphology, and patient-derived motor
neurons show the same cellular phenotypes.
molecular_functions:
- preferred_term: GTPase activator activity
term:
id: GO:0005096
label: GTPase activator activity
modifier: DECREASED
cell_types:
- preferred_term: motor neuron
term:
id: CL:0000100
label: motor neuron
genes:
- preferred_term: ARHGAP19
term:
id: hgnc:23724
label: ARHGAP19
evidence:
- reference: PMID:41086021
reference_title: "Biallelic variants in ARHGAP19 cause a progressive inherited motor-predominant neuropathy."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "In vitro biochemical and cellular assays revealed that patient variants impair the GTPase-activating protein (GAP) activity of ARHGAP19 and reduce ARHGAP19 protein levels."
explanation: Supports loss of GAP activity and reduced protein level as the molecular lesion.
- reference: PMID:41086021
reference_title: "Biallelic variants in ARHGAP19 cause a progressive inherited motor-predominant neuropathy."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "LOF in ARHGAP19 orthologues in Drosophila melanogaster and Danio rerio induced motor defects in axonal and synaptic morphology."
explanation: Model-organism support that loss of function produces axonal and synaptic pathology.
downstream:
- target: Distal Axonal Degeneration
description: >
Failure to inactivate RhoA disrupts axonal and synaptic morphology in
motor neurons, converging on the shared motor-predominant axonal
degeneration of this subtype.
causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
notes: CMT2KK (ARHGAP19-related motor-predominant axonal CMT)
- name: Mitochondrial Complex IV Assembly Deficiency
biological_scale: MOLECULAR
description: >
COX18 translocates the C-terminal tail of MTCO2 across the mitochondrial
inner membrane during assembly of respiratory chain complex IV. The reported
CMT2MM splice variant produces a stable but defective COX18 isoform lacking
exon 2, which impairs complex IV assembly and activity and lowers the
mitochondrial membrane potential. This is a primary respiratory-chain lesion,
distinct from the mitochondrial-dynamics lesions of MFN2 and GDAP1 curated
above.
biological_processes:
- preferred_term: mitochondrial respiratory chain complex IV assembly
term:
id: GO:0033617
label: mitochondrial respiratory chain complex IV assembly
modifier: DECREASED
genes:
- preferred_term: COX18
term:
id: hgnc:26801
label: COX18
evidence:
- reference: PMID:40830826
reference_title: "Biallelic variants in COX18 cause a mitochondrial disorder primarily manifesting as peripheral neuropathy."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "The mutant protein impairs Complex IV assembly and activity, leading to a reduction in mitochondrial membrane potential."
explanation: Supports impaired complex IV assembly and activity as the molecular lesion in this node.
- reference: PMID:40830826
reference_title: "Biallelic variants in COX18 cause a mitochondrial disorder primarily manifesting as peripheral neuropathy."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "Downregulation of the COX18 homologue in D. melanogaster resulted in signs of neurodegeneration, including locomotor deficit and progressive axonal degeneration of sensory neurons."
explanation: Model-organism support linking COX18 loss to progressive axonal degeneration of sensory neurons.
downstream:
- target: Distal Axonal Degeneration
description: >
Reduced complex IV assembly and activity produces a bioenergetic deficit in
the axon and, in the fly model, progressive axonal degeneration of sensory
neurons.
causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
notes: CMT2MM (COX18-related axonal CMT)
- name: Mitochondrial Aspartyl-tRNA Aminoacylation Deficiency
biological_scale: MOLECULAR
description: >
DARS2 encodes the mitochondrial aspartyl-tRNA synthetase. Biallelic variants
that pair a hypomorphic allele with a more deleterious one lower DARS2
protein levels and impair mitochondrial function without producing the
leukoencephalopathy (LBSL) associated with more severe allele combinations.
One reported variant reduced DARS2 enzymatic activity by 75 percent in
HEK293 cells.
biological_processes:
- preferred_term: mitochondrial aspartyl-tRNA aminoacylation
term:
id: GO:0070146
label: mitochondrial aspartyl-tRNA aminoacylation
modifier: DECREASED
genes:
- preferred_term: DARS2
term:
id: hgnc:25538
label: DARS2
evidence:
- reference: PMID:40814755
reference_title: "Biallelic Variants in the DARS2 Gene as a Novel Cause of Axonal Charcot-Marie-Tooth Disease."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "Functional studies revealed reduced DARS2 protein levels, mitochondrial network abnormalities, and impaired mitochondrial function."
explanation: Supports reduced DARS2 protein and impaired mitochondrial function as the molecular lesion.
- reference: PMID:40814755
reference_title: "Biallelic Variants in the DARS2 Gene as a Novel Cause of Axonal Charcot-Marie-Tooth Disease."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "p.Ser238Phe behaves as a hypomorphic allele, whereas p.Pro503Leu reduced DARS2 enzymatic activity by 75%."
explanation: Quantifies the enzymatic deficit and supports the hypomorphic-allele model in this node's description.
downstream:
- target: Distal Axonal Degeneration
description: >
Partial loss of mitochondrial aspartyl-tRNA aminoacylation impairs
mitochondrial function and converges on the length-dependent axonal
degeneration seen in these individuals.
causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
notes: CMT2LL (DARS2-related axonal CMT)
- name: Distal Axonal Degeneration
conforms_to: "peripheral_axonal_degeneration#Distal Axonal Degeneration and Demyelination"
description: >
The final common pathway in CMT2 involves dying-back degeneration of
peripheral nerve axons. The longest axons are affected first due to
their higher metabolic and transport demands, producing the characteristic
length-dependent pattern of weakness and sensory loss. This is a
Wallerian-like process distinct from neuronal apoptosis.
cell_types:
- preferred_term: Motor neuron
term:
id: CL:0000100
label: motor neuron
- preferred_term: Sensory neuron
term:
id: CL:0000101
label: sensory neuron
biological_processes:
- preferred_term: Autophagy
term:
id: GO:0006914
label: autophagy
modifier: DYSREGULATED
evidence:
- reference: PMID:34606075
reference_title: "Axonal Charcot-Marie-Tooth Disease: from Common Pathogenic Mechanisms to Emerging Treatment Opportunities."
supports: SUPPORT
evidence_source: OTHER
snippet: "Genetic neuropathies that primarily cause axonal degeneration, as opposed to demyelination, are most often classified as Charcot-Marie-Tooth disease type 2 (CMT2) and are the focus of this review."
explanation: Authoritative review establishing CMT2 as defined by axonal degeneration rather than demyelination.
- reference: PMID:32733278
reference_title: "Mitofusin 2 Dysfunction and Disease in Mice and Men."
supports: SUPPORT
evidence_source: OTHER
snippet: "the challenge of defining the central underlying mechanism(s) linking mitochondrial abnormalities to progressive dying-back of peripheral arm and leg nerves in CMT2A is largely unmet"
explanation: Confirms the dying-back pattern of axonal degeneration as the hallmark of CMT2A pathology.
downstream:
- target: Distal Muscle Weakness
- target: Distal Sensory Loss
- target: Foot Deformity (Pes Cavus)
- target: Distal Lower Limb Muscle Atrophy
- target: Reduced Deep Tendon Reflexes
- target: Steppage Gait
- target: Distal Upper Limb Muscle Weakness
discussions:
- discussion_id: mismatch_mfn2_lof_model_dominant_cmt2a
kind: HUMAN_MODEL_MISMATCH
status: OPEN
prompt: >-
Does MFN2 loss-of-function (shRNA knockdown in hESC-derived motor neurons)
faithfully model the pathophysiology of dominant/gain-of-function CMT2A,
given that human CMT2A is caused by heterozygous dominant MFN2 missense
variants thought to act via dominant-negative or gain-of-function
mechanisms rather than simple haploinsufficiency?
attaches_to:
- pathophysiology#Mitochondrial Fragmentation
- pathophysiology#Impaired Mitochondrial Axonal Transport
rationale: >-
The two core CMT2A pathophysiology nodes (Mitochondrial Fragmentation and
Impaired Mitochondrial Axonal Transport) are evidenced by PMID:34602978,
which used MFN2 shRNA knockdown in hESC-derived spinal motor neurons to
demonstrate mitochondrial fragmentation and impaired bidirectional axonal
transport. However, CMT2A is caused by heterozygous dominant MFN2 missense
mutations (e.g., R94W, R364W) that act via dominant-negative or
gain-of-function mechanisms — the mutant MFN2 protein competes with
wild-type rather than simply being absent. A knockdown model that removes
MFN2 protein is mechanistically distinct from a dominant-missense model that
produces toxic or dominant-negative MFN2 protein alongside wild-type. Whether
the two models converge on identical downstream mitochondrial fragmentation
and axonal transport defects in human motor neurons is an open translational
question. Relevant context: PMID:42301793 shows that AAV9-mediated
overexpression of wild-type MFN2 (MFN2WT) rescues phenotypes in both
transgenic dominant-mutation CMT2A mice and patient-derived iPSC motor
neurons. If the dominant mutations acted purely as haploinsufficiency, simple
knockdown would be expected to model the disease accurately; the rescue by
WT overexpression is consistent with dominant-negative action and suggests
that the knockdown model may only partially recapitulate the upstream
mechanism.
proposed_experiments:
- experiment_id: exp_mfn2_dominant_vs_lof_isogenic_comparison
name: Side-by-side mitochondrial phenotype comparison of dominant-negative vs. loss-of-function MFN2 in isogenic iPSC motor neurons
description: >-
Generate isogenic human iPSC lines carrying (a) heterozygous knock-in
of pathogenic CMT2A missense alleles (R94W or R364W), (b) heterozygous
MFN2 null (haploinsufficiency control), and (c) homozygous MFN2 null.
Differentiate all into motor neurons and compare mitochondrial morphology
(aspect ratio, network connectivity), axonal transport kinetics (live
imaging of mitochondria in long axons), motor protein (kinesin/dynein)
levels, and neurofilament pathology. Convergence of dominant-missense and
LOF phenotypes would validate the knockdown data; divergence would
indicate that the shRNA model captures only downstream consequences, not
the primary disease mechanism.
- experiment_id: exp_mfn2_wt_rescue_in_dominant_missense_neurons
name: Wild-type MFN2 overexpression rescue in dominant-missense iPSC motor neurons
description: >-
In iPSC-derived motor neurons heterozygous for a pathogenic MFN2 missense
allele (not shRNA knockdown), test whether neuronal overexpression of
wild-type MFN2 (as in PMID:42301793) rescues axonal transport defects and
mitochondrial fragmentation at the single-axon level. Quantitative rescue
in dominant-missense neurons would confirm that dominant-negative
competition with WT is the operative mechanism and establish that the LOF
knockdown model and the dominant-missense model converge on the same
downstream transport pathway. Lack of rescue in dominant-missense neurons
despite being effective in LOF cells would indicate distinct mechanisms.
notes: >-
Seeded from PMID:34602978 (MFN2 shRNA knockdown hESC motor neurons) and
PMID:42301793 (AAV9-MFN2WT rescue in transgenic CMT2A mice and patient iPSC
motor neurons). PMID:34602978 itself acknowledges that CMT2A is caused by
dominant mutations, providing the context for this translational mismatch.
phenotypes:
- name: Distal Muscle Weakness
category: Musculoskeletal
frequency: OBLIGATE
description: >
Progressive weakness of distal limb muscles, particularly affecting
the peroneal muscles of the lower legs and intrinsic hand muscles.
Leads to difficulty with foot dorsiflexion (foot drop) and fine
motor tasks.
phenotype_term:
preferred_term: Distal muscle weakness
term:
id: HP:0002460
label: Distal muscle weakness
evidence:
- reference: PMID:34606075
reference_title: "Axonal Charcot-Marie-Tooth Disease: from Common Pathogenic Mechanisms to Emerging Treatment Opportunities."
supports: SUPPORT
evidence_source: OTHER
snippet: "Inherited peripheral neuropathies are a genetically and phenotypically diverse group of disorders that lead to degeneration of peripheral neurons with resulting sensory and motor dysfunction."
explanation: Review confirms motor dysfunction as a core feature of inherited axonal neuropathies including CMT2.
- name: Distal Sensory Loss
category: Neurological
frequency: VERY_FREQUENT
description: >
Progressive sensory loss in a stocking-glove distribution, affecting
vibration and proprioception more than pain and temperature in most
subtypes.
phenotype_term:
preferred_term: Distal sensory impairment
term:
id: HP:0002936
label: Distal sensory impairment
evidence:
- reference: PMID:24521780
reference_title: "Human Rab7 mutation mimics features of Charcot-Marie-Tooth neuropathy type 2B in Drosophila."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "It is characterised by prominent sensory loss, often complicated by severe ulcero-mutilations of toes or feet, and variable motor involvement."
explanation: Clinical characterization of CMT2B from the introduction of the paper, describing the human phenotype.
- name: Foot Deformity (Pes Cavus)
category: Musculoskeletal
frequency: VERY_FREQUENT
description: >
High-arched feet (pes cavus) resulting from imbalance between
intrinsic and extrinsic foot muscles. Often accompanied by
hammer toes and equinovarus deformity.
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
snippet: "As the disease progresses, individuals often develop foot drop and foot deformities such as pes cavus and equinus, leading to a significant decline in gait function."
explanation: Review confirms pes cavus as a hallmark foot deformity in CMT.
- name: Distal Lower Limb Muscle Atrophy
category: Musculoskeletal
frequency: VERY_FREQUENT
description: >
Wasting of distal leg muscles producing the characteristic inverted
champagne bottle or stork leg appearance.
phenotype_term:
preferred_term: Distal lower limb amyotrophy
term:
id: HP:0008944
label: Distal lower limb amyotrophy
evidence:
- reference: PMID:34819907
reference_title: "Clinical and Genetic Features of Biallelic Mutations in SORD in a Series of Chinese Patients With Charcot-Marie-Tooth and Distal Hereditary Motor Neuropathy."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "All patients presented with distal weakness and atrophy in the lower limb, two of whom had minor clinical sensory abnormalities and small fiber neuropathy."
explanation: In an axonal CMT2 (SORD) clinical series, all patients had distal lower-limb weakness and atrophy, directly supporting distal lower-limb amyotrophy as a core CMT2 phenotype.
- name: Reduced Deep Tendon Reflexes
category: Neurological
frequency: VERY_FREQUENT
description: >
Absent or reduced deep tendon reflexes, particularly at the ankles,
reflecting loss of the afferent sensory arc.
phenotype_term:
preferred_term: Areflexia
term:
id: HP:0001284
label: Areflexia
- name: Steppage Gait
category: Neurological
frequency: FREQUENT
description: >
Characteristic high-stepping gait due to foot drop from peroneal
muscle weakness, requiring exaggerated hip and knee flexion during
the swing phase of walking.
phenotype_term:
preferred_term: Steppage gait
term:
id: HP:0003376
label: Steppage 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
snippet: "One of the hallmark manifestations of CMT is gait disturbance. As the disease progresses, individuals often develop foot drop and foot deformities such as pes cavus and equinus, leading to a significant decline in gait function."
explanation: Review confirms gait disturbance including foot drop as a hallmark of CMT.
- name: Distal Upper Limb Muscle Weakness
category: Musculoskeletal
frequency: FREQUENT
description: >
Weakness of intrinsic hand muscles developing later in the disease
course, affecting grip strength and fine motor skills.
phenotype_term:
preferred_term: Distal upper limb muscle weakness
term:
id: HP:0003484
label: Upper limb muscle weakness
- name: Optic Atrophy
category: Neurological
frequency: OCCASIONAL
subtype: CMT2A
description: >
Visual impairment due to optic nerve degeneration, occurring in a subset
of CMT2A (MFN2) patients. This phenotype defines the HMSN VI (hereditary
motor and sensory neuropathy type VI) syndrome. Onset is typically
subacute, with subsequent slow recovery of visual acuity in a majority
(60%) of affected individuals in the original HMSN VI series. Optic
atrophy in CMT2A reflects the shared role of mitochondrial dynamics in
both peripheral neurons and retinal ganglion cells.
phenotype_term:
preferred_term: Optic atrophy
term:
id: HP:0000648
label: Optic atrophy
evidence:
- reference: PMID:16437557
reference_title: "Axonal neuropathy with optic atrophy is caused by mutations in mitofusin 2."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Charcot-Marie-Tooth (CMT) neuropathy with visual impairment due to optic atrophy has been designated as hereditary motor and sensory neuropathy type VI (HMSN VI)."
explanation: >-
Classic HMSN VI paper establishing MFN2 mutations as the cause of optic
atrophy in CMT2A across six families; directly supports optic atrophy as
an occasional CMT2A phenotype.
- reference: PMID:16437557
reference_title: "Axonal neuropathy with optic atrophy is caused by mutations in mitofusin 2."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "In each pedigree, we identified a unique mutation in the gene mitofusin 2 (MFN2)."
explanation: >-
Confirms that each of the six HMSN VI families harbored a distinct MFN2
mutation, establishing the genotype-phenotype link for optic atrophy in
CMT2A.
- reference: PMID:16437557
reference_title: "Axonal neuropathy with optic atrophy is caused by mutations in mitofusin 2."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "six HMSN VI families with a subacute onset of optic atrophy and subsequent slow recovery of visual acuity in 60% of the patients"
explanation: >-
Directly supports the described subacute onset and slow partial recovery
of visual acuity in 60% of affected individuals in the original HMSN VI
(CMT2A) series.
genetic:
- name: MFN2
gene_term:
preferred_term: MFN2
term:
id: hgnc:16877
label: MFN2
association: Causative
features: Most common CMT2 gene, accounting for ~20% of CMT2 cases with severe early-onset phenotype and optic atrophy in some patients
subtype: CMT2A
evidence:
- reference: PMID:32733278
reference_title: "Mitofusin 2 Dysfunction and Disease in Mice and Men."
supports: SUPPORT
evidence_source: OTHER
snippet: "A causal relationship between Mitofusin (MFN) 2 gene mutations and the hereditary axonal neuropathy Charcot-Marie-Tooth disease type 2A (CMT2A) was described over 15 years ago."
explanation: Establishes MFN2 as the causal gene for CMT2A.
- name: NEFL
gene_term:
preferred_term: NEFL
term:
id: hgnc:7739
label: NEFL
association: Causative
notes: Both dominant missense and recessive null mutations described causing CMT2E
subtype: CMT2E
evidence:
- reference: PMID:34485306
reference_title: "Allele-Specific Gene Editing Rescues Pathology in a Human Model of Charcot-Marie-Tooth Disease Type 2E."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "Here, we demonstrate that allele-specific CRISPR gene editing in a human model of axonal Charcot-Marie-Tooth (CMT) disease rescues pathology caused by a dominant missense mutation in the neurofilament light chain gene (NEFL, CMT type 2E)."
explanation: Patient-derived motor neuron evidence confirms a dominant NEFL missense mutation as causal for CMT2E pathology.
- reference: CGGV:assertion_49d4cf82-b365-456e-9e35-2b28a66b71ec-2023-01-10T170000.000Z
reference_title: "NEFL / Charcot-Marie-Tooth disease type 2 (Definitive)"
supports: SUPPORT
evidence_source: OTHER
snippet: "NEFL | HGNC:7739 | Charcot-Marie-Tooth disease type 2 | MONDO:0018993 | AR | Definitive"
explanation: ClinGen classifies the NEFL-Charcot-Marie-Tooth disease type 2 gene-disease relationship as definitive with autosomal recessive inheritance.
- name: RAB7A
gene_term:
preferred_term: RAB7A
term:
id: hgnc:9788
label: RAB7A
association: Causative
notes: RAB7A regulates late endosomal and lysosomal trafficking; mutations cause CMT2B with prominent sensory involvement
subtype: CMT2B
evidence:
- reference: PMID:24521780
reference_title: "Human Rab7 mutation mimics features of Charcot-Marie-Tooth neuropathy type 2B in Drosophila."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "Missense mutations in RAB7A, the gene encoding the small GTPase Rab7, cause CMT2B and increase Rab7 activity."
explanation: Confirms RAB7A mutations are causal for CMT2B.
- reference: CGGV:assertion_222dbfa6-db75-42a0-bab6-338b46a316c3-2022-02-10T021034.172Z
reference_title: "RAB7A / Charcot-Marie-Tooth disease type 2 (Definitive)"
supports: SUPPORT
evidence_source: OTHER
snippet: "RAB7A | HGNC:9788 | Charcot-Marie-Tooth disease type 2 | MONDO:0018993 | AD | Definitive"
explanation: ClinGen classifies the RAB7A-Charcot-Marie-Tooth disease type 2 gene-disease relationship as definitive with autosomal dominant inheritance.
- name: GARS1
gene_term:
preferred_term: GARS1
term:
id: hgnc:4162
label: GARS1
association: Causative
notes: Encodes glycyl-tRNA synthetase; mutations cause CMT2D with predominantly upper extremity involvement
subtype: CMT2D
evidence:
- reference: PMID:36928301
reference_title: "Boosting peripheral BDNF rescues impaired in vivo axonal transport in CMT2D mice."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "Aberrant interactions between GlyRS mutants and different proteins, including neurotrophin receptor tropomyosin receptor kinase receptor B (TrkB), underlie CMT type 2D (CMT2D); however, our pathomechanistic understanding of this untreatable peripheral neuropathy remains incomplete."
explanation: Supports GARS1/GlyRS mutant pathology as the causal basis of CMT2D.
- name: MPZ
gene_term:
preferred_term: MPZ
term:
id: hgnc:7225
label: MPZ
association: Causative
notes: Myelin protein zero mutations can cause late-onset axonal CMT2I/J with pupillary abnormalities
review_notes: >-
Deliberately not wired to a pathophysiology node in this entry. MPZ is a
Schwann cell myelin protein, and the axonal CMT2I/J phenotype arises from
altered myelin rather than from a primary neuronal lesion, so the mechanism
belongs with the demyelinating CMT1B entry rather than with the axonal
mechanism nodes curated here.
subtype: CMT2I/J
evidence:
- reference: PMID:27774063
reference_title: "A Novel Asp121Asn Mutation of Myelin Protein Zero Is Associated with Late-Onset Axonal Charcot-Marie-Tooth Disease, Hearing Loss and Pupil Abnormalities."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The MPZ mutation Asp121Asn may be associated with late-onset axonal neuropathy, early onset hearing loss and pupil abnormalities."
explanation: Human family evidence supports MPZ mutation association with late-onset axonal CMT2I/J features.
- name: SORD
gene_term:
preferred_term: SORD
term:
id: hgnc:11184
label: SORD
association: Causative
notes: Biallelic SORD loss-of-function variants cause autosomal recessive SORD-related axonal CMT2 / distal hereditary motor neuropathy.
subtype: SORD-CMT2
evidence:
- reference: PMID:32367058
reference_title: "Biallelic mutations in SORD cause a common and potentially treatable hereditary neuropathy with implications for diabetes."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Here we report biallelic mutations in the sorbitol dehydrogenase gene (SORD) as the most frequent recessive form of hereditary neuropathy."
explanation: Establishes biallelic SORD variants as causative for an autosomal recessive hereditary neuropathy in the CMT2 spectrum.
- name: HSPB1
gene_term:
preferred_term: HSPB1
term:
id: hgnc:5246
label: HSPB1
association: Causative
notes: Encodes the small heat-shock protein HSP27; dominant mutations cause axonal CMT2F and overlap with distal hereditary motor neuropathy.
subtype: CMT2F
evidence:
- reference: PMID:15122254
reference_title: "Mutant small heat-shock protein 27 causes axonal Charcot-Marie-Tooth disease and distal hereditary motor neuropathy."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Here we report a missense mutation in the gene encoding 27-kDa small heat-shock protein B1 (HSPB1, also called HSP27) that segregates in the family with CMT2F."
explanation: Establishes HSPB1 (HSP27) as causative for axonal CMT2F.
- name: MORC2
gene_term:
preferred_term: MORC2
term:
id: hgnc:23573
label: MORC2
association: Causative
notes: Encodes a CW-type zinc finger transcriptional regulator; mutations cause axonal CMT2Z with a clinically heterogeneous, sometimes SMA-like, phenotype.
review_notes: >-
Deliberately not wired to a pathophysiology node in this entry. The
mechanism by which MORC2 alleles injure peripheral axons is modeled in the
dedicated subtype entry at
kb/disorders/Charcot-Marie-Tooth_Disease_Axonal_Type_2Z.yaml; duplicating it
on the umbrella would restate that model without adding evidence.
subtype: CMT2Z
evidence:
- reference: PMID:26497905
reference_title: "Mutations in the MORC2 gene cause axonal Charcot-Marie-Tooth disease."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Here we present a new axonal Charcot-Marie-Tooth disease form, associated with the gene microrchidia family CW-type zinc finger 2 (MORC2)."
explanation: Establishes MORC2 as causative for axonal CMT2Z.
- name: GDAP1
gene_term:
preferred_term: GDAP1
term:
id: hgnc:15968
label: GDAP1
association: Causative
notes: Regulates mitochondrial fission; mutations cause both demyelinating CMT4A and axonal CMT2K (recessive and dominant).
subtype: CMT2K
evidence:
- reference: PMID:20685671
reference_title: "The GST domain of GDAP1 is a frequent target of mutations in the dominant form of axonal Charcot Marie Tooth type 2K."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Mutations in GDAP1 associate with demyelinating (CMT4A) and axonal (CMT2K) forms of CMT."
explanation: Establishes GDAP1 as causative for axonal CMT2K.
- name: NEFH
gene_term:
preferred_term: NEFH
term:
id: hgnc:7737
label: NEFH
association: Causative
notes: Neurofilament heavy chain; 3' UTR read-through frameshift variants create a cryptic amyloidogenic element causing autosomal dominant axonal CMT2CC.
subtype: CMT2CC
evidence:
- reference: PMID:28709447
reference_title: "Cryptic amyloidogenic elements in mutant NEFH causing Charcot-Marie-Tooth 2 trigger aggresome formation and neuronal death."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "gene was recently identified to cause autosomal dominant axonal Charcot-Marie-Tooth disease (CMT2cc)"
explanation: Establishes NEFH as causative for autosomal dominant axonal CMT2CC.
- name: HSPB8
gene_term:
preferred_term: HSPB8
term:
id: hgnc:30171
label: HSPB8
association: Causative
relationship_type: CAUSATIVE
notes: >-
Encodes the small heat-shock protein HSP22. Substitutions at Lys141 in the
alpha-crystallin domain cause CMT2L and, allelically, distal hereditary
motor neuropathy; mutant HSP22 is degeneration-inducing selectively in motor
neurons.
subtype: CMT2L
evidence:
- reference: PMID:15565283
reference_title: "Small heat-shock protein 22 mutated in autosomal dominant Charcot-Marie-Tooth disease type 2L."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "we report a novel c.423G-->T (Lys141Asn) missense mutation of small heat-shock protein 22-kDa protein 8 (encoded by HSPB8), which is also responsible for distal hereditary motor neuropathy type (dHMN) II"
explanation: Establishes HSPB8 as causative for CMT2L in the pedigree that defined the locus.
- name: AARS1
gene_term:
preferred_term: AARS1
term:
id: hgnc:20
label: AARS1
association: Causative
relationship_type: CAUSATIVE
notes: >-
Cytoplasmic alanyl-tRNA synthetase. The recurrent p.Arg329His allele has
arisen on more than one founder background and reduces tRNA(Ala) charging.
subtype: CMT2N
evidence:
- reference: PMID:20045102
reference_title: "A major determinant for binding and aminoacylation of tRNA(Ala) in cytoplasmic Alanyl-tRNA synthetase is mutated in dominant axonal Charcot-Marie-Tooth disease."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Our report documents in 18 patients the deleterious impact of a mutation in human cytoplasmic AlaRS and broadens the spectrum of defects found in tRNA synthetases."
explanation: Human genetic support for AARS1 as the CMT2N gene across two founder-distinct families.
- reference: PMID:22009580
reference_title: "A recurrent loss-of-function alanyl-tRNA synthetase (AARS) mutation in patients with Charcot-Marie-Tooth disease type 2N (CMT2N)."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Our results showed that p.Arg329His AARS also segregated with CMT disease in a large Australian family."
explanation: Independent family replicating segregation of the recurrent AARS1 allele with CMT.
- name: DHTKD1
gene_term:
preferred_term: DHTKD1
term:
id: hgnc:23537
label: DHTKD1
association: Causative
relationship_type: CAUSATIVE
notes: >-
Dehydrogenase E1 and transketolase domain-containing protein 1, part of a
2-oxoglutarate-dehydrogenase-complex-like protein. The human genetic support
for CMT2Q that this entry cites is a single linked five-generation pedigree
with a nonsense allele degraded by nonsense-mediated decay; biallelic DHTKD1
variants cause 2-aminoadipic and 2-oxoadipic aciduria instead.
subtype: CMT2Q
evidence:
- reference: PMID:23141294
reference_title: "A nonsense mutation in DHTKD1 causes Charcot-Marie-Tooth disease type 2 in a large Chinese pedigree."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "in exon 8 of dehydrogenase E1 and transketolase domain-containing 1 (DHTKD1) in all eight affected individuals"
explanation: Co-segregation of the DHTKD1 nonsense allele with CMT2 in the linked pedigree.
- name: MARS1
gene_term:
preferred_term: MARS1
term:
id: hgnc:6898
label: MARS1
association: Causative
relationship_type: CAUSATIVE
notes: >-
Cytoplasmic methionyl-tRNA synthetase. Reported in a small number of CMT2U
families; the CMT2U alleles behave as loss-of-function in yeast
complementation. Biallelic MARS1 variants cause an interstitial lung and
liver disease of infancy instead.
subtype: CMT2U
evidence:
- reference: PMID:31356216
reference_title: "A Novel Mutation in MARS in a Patient with Charcot-Marie-Tooth Disease, Axonal, Type 2U with Congenital Onset."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "p.Ala397Thr MARS supported very little yeast cell growth, consistent with this being a loss-of-function allele."
explanation: Yeast complementation evidence that the CMT2U MARS1 allele is loss-of-function.
- name: NAGLU
gene_term:
preferred_term: NAGLU
term:
id: hgnc:7632
label: NAGLU
association: Causative
relationship_type: CAUSATIVE
notes: >-
Lysosomal alpha-N-acetylglucosaminidase. The CMT2V claim rests on two
families in the defining report: a large French-Canadian family in which the
heterozygous missense allele p.Ile403Thr segregates with a late-onset painful
sensory-predominant neuropathy and carriers show a mean 45% decrease in
enzyme activity, and a North-American family carrying the nonsense allele
p.Glu123X, in which affected members also had mild muscular weakness and
diminished reflexes. Biallelic loss causes mucopolysaccharidosis IIIB
instead. No enzyme assay was performed in the second family, and how a
partial enzyme deficiency produces the neuropathy is not established in
nerve, so no mechanism edge to axonal degeneration is asserted for this gene.
subtype: CMT2V
evidence:
- reference: PMID:25818867
reference_title: "Adult-onset painful axonal polyneuropathy caused by a dominant NAGLU mutation."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "A significant 36–54% (mean 45%, P > 0.001) decrease in enzyme activity was observed for all carriers of the mutation"
explanation: Quantifies the loss of alpha-N-acetylglucosaminidase activity in carriers of the p.Ile403Thr allele - a mean 45% decrease, so roughly half of normal activity is retained.
- reference: PMID:25818867
reference_title: "Adult-onset painful axonal polyneuropathy caused by a dominant NAGLU mutation."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "No enzymatic assay was performed on Family 2."
explanation: The authors' own statement that the second family's allele was not tested enzymatically, which is part of why no mechanism edge is asserted for NAGLU.
- name: SPG11
gene_term:
preferred_term: SPG11
term:
id: hgnc:11226
label: SPG11
association: Causative
relationship_type: CAUSATIVE
notes: >-
Encodes spatacsin. Biallelic alleles span autosomal recessive hereditary
spastic paraplegia with thin corpus callosum, juvenile ALS, and the axonal
CMT2X end of that spectrum; loss of spatacsin impairs clearance of lipids
from lysosomes.
subtype: CMT2X
evidence:
- reference: PMID:26556829
reference_title: "ALS5/SPG11/KIAA1840 mutations cause autosomal recessive axonal Charcot-Marie-Tooth disease."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Interestingly, we identified 15 ALS5/SPG11/KIAA1840 mutations in 12 families"
explanation: Twelve families with SPG11 alleles among 28 screened autosomal recessive axonal CMT pedigrees.
- name: KIF1B
gene_term:
preferred_term: KIF1B
term:
id: hgnc:16636
label: KIF1B
association: Reported cause of CMT2A1, with limited gene-disease validity
relationship_type: UNKNOWN
notes: >-
Kinesin family member 1B. The CMT2A locus was originally attributed to a
KIF1B motor-domain loss-of-function allele, but the relationship has not
been corroborated and ClinGen's Charcot-Marie-Tooth Disease Gene Curation
Expert Panel classifies KIF1B-CMT2A1 as Limited. Graded UNKNOWN rather than
CAUSATIVE for that reason, and deliberately not wired to a pathophysiology
node: asserting a mechanism edge would commit this entry to a gene-disease
relationship the cited curation does not support.
subtype: CMT2A1
evidence:
- reference: PMID:11389829
reference_title: "Charcot-Marie-Tooth disease type 2A caused by mutation in a microtubule motor KIF1Bbeta."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "We show that CMT2A patients contain a loss-of-function mutation in the motor domain of the KIF1B gene."
explanation: The original human genetic claim for KIF1B at the CMT2A locus.
- reference: CGGV:assertion_ae6ffeae-9609-47bf-89a9-4863cf6ef05c-2026-06-12T160000.000Z
reference_title: "KIF1B / Charcot-Marie-Tooth disease type 2A1 (Limited)"
supports: SUPPORT
evidence_source: OTHER
snippet: "As there is a human asserted with a variation in this gene, \"Limited\" classification must be used. The classification is not disputed at this time."
explanation: ClinGen's own summary of why KIF1B-CMT2A1 is graded Limited rather than disputed, which is the basis for the UNKNOWN relationship_type here.
- name: LMNA
gene_term:
preferred_term: LMNA
term:
id: hgnc:6636
label: LMNA
association: Causative
relationship_type: CAUSATIVE
notes: >-
Lamin A/C, a nuclear-envelope intermediate filament protein. A homozygous
founder allele causes autosomal recessive axonal CMT2B1; other LMNA alleles
cause muscular dystrophy, dilated cardiomyopathy and partial lipodystrophy.
subtype: CMT2B1
evidence:
- reference: PMID:11799477
reference_title: "Homozygous defects in LMNA, encoding lamin A/C nuclear-envelope proteins, cause autosomal recessive axonal neuropathy in human (Charcot-Marie-Tooth disorder type 2) and mouse."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "A unique homozygous mutation in LMNA (which encodes lamin A/C, a component of the nuclear envelope) was identified in all affected members and in additional patients with CMT2 from a third, unrelated family."
explanation: Establishes LMNA as causative for autosomal recessive CMT2 across three families.
- name: TRIM2
gene_term:
preferred_term: TRIM2
term:
id: hgnc:15974
label: TRIM2
association: Causative
relationship_type: CAUSATIVE
notes: >-
E3 ubiquitin ligase whose substrates include neurofilament light chain.
Biallelic loss-of-function alleles cause early-onset axonal neuropathy
(CMT2R); the index report describes a single patient, with the phenotypic
spectrum extended by later series.
subtype: CMT2R
evidence:
- reference: PMID:23562820
reference_title: "Deficiency of the E3 ubiquitin ligase TRIM2 in early-onset axonal neuropathy."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "We show that the patient fibroblasts are practically devoid of TRIM2, through mRNA and protein instability caused by the mutations."
explanation: Patient-fibroblast assay demonstrating that the CMT2R TRIM2 alleles leave essentially no TRIM2 protein.
- name: VCP
gene_term:
preferred_term: VCP
term:
id: hgnc:12666
label: VCP
association: Causative
relationship_type: CAUSATIVE
notes: >-
Facilitates protein degradation by the proteasomal and autophagic
pathways. The CMT2Y claim
rests on one autosomal dominant family whose p.Glu185Lys allele impairs
autophagic flux; other VCP alleles cause inclusion body myopathy with Paget
disease and frontotemporal dementia, hereditary spastic paraplegia and a
minority of familial ALS.
subtype: CMT2Y
evidence:
- reference: PMID:25125609
reference_title: "A novel mutation in VCP causes Charcot-Marie-Tooth Type 2 disease."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "We identified a novel VCP mutation (p.Glu185Lys) segregating in an autosomal dominant Charcot-Marie-Tooth disease type 2 family."
explanation: The single family establishing VCP as a CMT2Y gene.
- name: MPV17
gene_term:
preferred_term: MPV17
term:
id: hgnc:7224
label: MPV17
association: Causative
relationship_type: CAUSATIVE
notes: >-
Mitochondrial inner-membrane protein involved in deoxynucleotide
homeostasis. Biallelic alleles cause the axonal sensorimotor neuropathy
CMT2EE as well as the hepatocerebral mitochondrial DNA depletion syndrome;
the neuropathy-only presentations reported so far lack liver and brain
involvement.
subtype: CMT2EE
evidence:
- reference: PMID:30298599
reference_title: "MPV17 mutations in juvenile- and adult-onset axonal sensorimotor polyneuropathy."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Here, we describe five additional patients from two unrelated families with sensorimotor axonal neuropathy without hepatocerebral affection caused by homozygous MPV17 variants."
explanation: Two further unrelated families with homozygous MPV17 alleles and isolated axonal neuropathy.
- name: ATP1A1
gene_term:
preferred_term: ATP1A1
term:
id: hgnc:799
label: ATP1A1
association: Causative
relationship_type: CAUSATIVE
notes: >-
Alpha-1 subunit of the Na+,K+-ATPase, localized to the axolemma of
myelinated sensory and motor axons. Five of the seven substitutions in the
defining cohort fall in the helical linker coupling the nucleotide-binding
and phosphorylation domains.
subtype: CMT2DD
evidence:
- reference: PMID:29499166
reference_title: "Mutations in ATP1A1 Cause Dominant Charcot-Marie-Tooth Type 2."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Seven missense changes were identified that segregated within individual pedigrees"
explanation: Seven segregating ATP1A1 missense alleles across the multi-country CMT2 cohort.
- reference: PMID:29499166
reference_title: "Mutations in ATP1A1 Cause Dominant Charcot-Marie-Tooth Type 2."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Five mutants fall into a remarkably narrow motif within the helical linker region that couples the nucleotide-binding and phosphorylation domains."
explanation: Source for the helical-linker clustering stated in this record's notes.
- name: DGAT2
gene_term:
preferred_term: DGAT2
term:
id: hgnc:16940
label: DGAT2
association: Reported in a single family; gene-disease relationship not established
relationship_type: UNKNOWN
notes: >-
Diacylglycerol O-acyltransferase 2, catalysing the final step of
triglyceride synthesis. The whole of the human genetic support is one Korean
family with two affected members and a de novo missense allele, supported by
cell-proliferation and zebrafish assays. Graded UNKNOWN, and not wired to a
pathophysiology node.
subtype: DGAT2-CMT2
evidence:
- reference: PMID:26786738
reference_title: "DGAT2 Mutation in a Family with Autosomal-Dominant Early-Onset Axonal Charcot-Marie-Tooth Disease."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "We examined a Korean family in which two individuals had an autosomal-dominant axonal CMT with early-onset, sensory ataxia, tremor, and slow disease progression."
explanation: Defines the extent of the human observation behind the DGAT2 claim - two affected individuals in one family.
- name: DCAF8
gene_term:
preferred_term: DCAF8
term:
id: hgnc:24891
label: DCAF8
association: Causative
relationship_type: CAUSATIVE
notes: >-
Substrate receptor of the Cullin-4-DDB1 E3 ubiquitin ligase. A single
missense allele reported in one family weakens DCAF8-DDB1 binding and is
associated with axonal neuropathy carrying infrequent giant axons with
neurofilament accumulation.
subtype: GAN2
evidence:
- reference: PMID:24500646
reference_title: "Ubiquitin ligase defect by DCAF8 mutation causes HMSN2 with giant axons."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Six novel variants were identified by WES, but only DCAF8 p.R317C tracked with affected status within the family."
explanation: Segregation analysis identifying DCAF8 p.R317C as the only candidate tracking with disease in the family.
- name: MFN2 (biallelic, CMT2A2B)
gene_term:
preferred_term: MFN2
term:
id: hgnc:16877
label: MFN2
association: Causal
relationship_type: CAUSATIVE
subtype: CMT2A2B
notes: >-
Homozygous or compound heterozygous MFN2 variants produce severe early-onset
axonal neuropathy, designated CMT2A2B and separated in OMIM/MONDO from the
dominant CMT2A2A. The heterozygous parents of the reported probands carried
the single variants and were asymptomatic or only minimally affected, which
the authors read as semi-dominant rather than strictly recessive inheritance.
ClinGen's Charcot-Marie-Tooth Disease Gene Curation Expert Panel reaches the
same conclusion independently, classifying MFN2 as Definitive for
semidominant axonal hereditary motor and sensory neuropathy.
evidence:
- reference: PMID:18458227
reference_title: "Severe early-onset axonal neuropathy with homozygous and compound heterozygous MFN2 mutations."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Severe early-onset axonal neuropathy due to MFN2 mutations can present as an apparently recessively inherited neuropathy but the minimal phenotype in the parents suggests a semi-dominant mechanism."
explanation: Establishes the biallelic MFN2 presentation and its semi-dominant rather than fully recessive character.
- reference: PMID:18458227
reference_title: "Severe early-onset axonal neuropathy with homozygous and compound heterozygous MFN2 mutations."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "All parents were asymptomatic or mildly symptomatic with some signs of peripheral neuropathy indicating a minimal phenotype."
explanation: The carrier-parent finding behind the semi-dominant reading recorded in these notes.
- reference: CGGV:assertion_a04350b3-5fe9-438a-9e90-db0055ed15e7-2022-10-10T160000.000Z
reference_title: "MFN2 / obsolete axonal hereditary motor and sensory neuropathy (Definitive)"
supports: SUPPORT
evidence_source: OTHER
snippet: "In summary, MFN2 is DEFINITIVELY associated with semidominant axonal hereditary motor and sensory neuropathy due to the presence of both genetic case level evidence and experimental evidence."
explanation: >-
ClinGen's Charcot-Marie-Tooth Disease Gene Curation Expert Panel independently
classifies the MFN2 neuropathy relationship as semidominant, supporting the
semi-dominant reading of the biallelic presentation.
- name: MFN2 (HMSN VIA)
gene_term:
preferred_term: MFN2
term:
id: hgnc:16877
label: MFN2
association: Causal
relationship_type: CAUSATIVE
subtype: HMSN6A
notes: >-
MFN2 is the gene behind hereditary motor and sensory neuropathy type VI,
axonal CMT accompanied by optic atrophy. Optic atrophy is not allele-specific:
in a 62-family screen two R364W families had optic atrophy and two others with
the same variant did not, and two early-onset R94W families previously reported
as HMSN VI had no visual impairment. This record is kept separate from the
dominant CMT2A record only so that the OMIM/MONDO HMSN6A concept has a
reciprocal gene assertion; the gene and its mechanism are the same.
evidence:
- reference: PMID:16835246
reference_title: "Early onset severe and late-onset mild Charcot-Marie-Tooth disease with mitofusin 2 (MFN2) mutations."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Mutations in the mitofusin 2 (MFN2) gene, which encodes a mitochondrial GTPase mitofusin protein, have recently been reported to cause both Charcot-Marie-Tooth 2A (CMT2A) and hereditary motor and sensory neuropathy VI (HMSN VI)."
explanation: Establishes MFN2 as the causal gene for HMSN VI as well as CMT2A.
- reference: PMID:16835246
reference_title: "Early onset severe and late-onset mild Charcot-Marie-Tooth disease with mitofusin 2 (MFN2) mutations."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "We identified two HMSN VI families with the R364W mutation in the early onset group; however, two other families with the same mutation did not have optic atrophy."
explanation: Supports the statement in these notes that optic atrophy is not allele-specific in MFN2 neuropathy.
- reference: CGGV:assertion_a04350b3-5fe9-438a-9e90-db0055ed15e7-2022-10-10T160000.000Z
reference_title: "MFN2 / obsolete axonal hereditary motor and sensory neuropathy (Definitive)"
supports: SUPPORT
evidence_source: OTHER
snippet: "Phenotype was variable in many studies, even with the same mutation, as some families had optic atrophy, but others did not."
explanation: >-
ClinGen's own evidence summary records that optic atrophy varies between
families carrying the same MFN2 variant, which is why HMSN VIA is curated as
an MFN2 subtype rather than a separate disease.
- reference: PMID:16835246
reference_title: "Early onset severe and late-onset mild Charcot-Marie-Tooth disease with mitofusin 2 (MFN2) mutations."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "In addition, two early onset families with R94W mutations, previously reported for HMSN VI, did not have visual impairment."
explanation: >-
The second discordant observation behind the statement that optic atrophy is
not allele-specific, in families whose variant had been reported as HMSN VI.
- name: CADM3 (CMT2FF)
gene_term:
preferred_term: CADM3
term:
id: hgnc:17601
label: CADM3
association: Causal
relationship_type: CAUSATIVE
subtype: CMT2FF
notes: >-
A single recurrent CADM3 variant, Tyr172Cys, was found in three unrelated
families including one de novo case, and is absent from 230,000 control
chromosomes in gnomAD. CADM3 is the axonal member of the CADM adhesion pair
that organizes the myelinated fibre with Schwann-cell CADM4. Inheritance is
autosomal dominant. A search of the approved symbol CADM3 in the
ClinGen Gene-Disease Validity CSV (snapshot 2026-08-13) returns no row, so no
expert panel has yet classified this relationship.
evidence:
- reference: PMID:33889941
reference_title: "A CADM3 variant causes Charcot-Marie-Tooth disease with marked upper limb involvement."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "We have identified-by whole exome sequencing-three unrelated families, including one de novo patient, with axonal Charcot-Marie-Tooth disease (CMT2) sharing the same private variant in CADM3, Tyr172Cys."
explanation: Establishes CADM3 Tyr172Cys as the causal variant in three unrelated CMT2 families.
- reference: PMID:33889941
reference_title: "A CADM3 variant causes Charcot-Marie-Tooth disease with marked upper limb involvement."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Most CADM3 patients share a similar phenotype consisting of autosomal dominant CMT2 with marked upper limb involvement."
explanation: Sources the autosomal dominant inheritance and upper-limb-predominant phenotype recorded here.
- name: JAG1 (CMT2HH)
gene_term:
preferred_term: JAG1
term:
id: hgnc:6188
label: JAG1
association: Causal
relationship_type: CAUSATIVE
subtype: CMT2HH
notes: >-
Autosomal dominant JAG1 missense variants cause axonal CMT2 with severe vocal
fold paresis. JAG1 is far better known as the Alagille syndrome gene, and
the only JAG1 row in the ClinGen Gene-Disease Validity CSV
(snapshot 2026-08-13) is Definitive for Alagille syndrome due to a JAG1 point
mutation; that CSV carries no JAG1 row for any neuropathy concept. The neuropathy
claim therefore rests on the two-family report and its functional and mouse
data rather than on an expert-panel classification.
evidence:
- reference: PMID:32065591
reference_title: "Dominant mutations of the Notch ligand Jagged1 cause peripheral neuropathy."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Here, we identify autosomal dominant mutations of the canonical Notch ligand Jagged1 (or JAG1) as a cause of peripheral nerve disease in 2 unrelated families with the hereditary axonal neuropathy Charcot-Marie-Tooth disease type 2 (CMT2)."
explanation: Establishes dominant JAG1 variants as a cause of axonal CMT2.
- reference: PMID:32065591
reference_title: "Dominant mutations of the Notch ligand Jagged1 cause peripheral neuropathy."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Affected individuals in both families exhibited severe vocal fold paresis, a rare feature of peripheral nerve disease that can be life-threatening."
explanation: Sources the vocal fold paresis that distinguishes this subtype clinically.
- name: SLC12A6 (CMT2II)
gene_term:
preferred_term: SLC12A6
term:
id: hgnc:10914
label: SLC12A6
association: Causal
relationship_type: CAUSATIVE
subtype: CMT2II
notes: >-
Heterozygous SLC12A6 variants act dominantly, including as de novo variants in
sporadic cases, and cause inherited neuropathy without the corpus callosum
agenesis of the biallelic SLC12A6 syndrome. The largest cohort to date reports
23 individuals from 13 families carrying nine variants, with the
electrophysiological class tracking the genotype rather than being uniformly
axonal, so the OMIM/MONDO axonal CMT2 designation understates the phenotypic
range. A search of the approved symbol SLC12A6 in the ClinGen
Gene-Disease Validity CSV (snapshot 2026-08-13) returns no row.
evidence:
- reference: PMID:41500801
reference_title: "Spectrum of dominant Charcot-Marie-Tooth disease due to SLC12A6 variants."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Twenty-three individuals from 13 families carried nine variants classified either as pathogenic/likely pathogenic or variants of uncertain significance segregating in multiple family members, including five novel variants."
explanation: The cohort size and variant classification behind the dominant SLC12A6 gene-disease relationship.
- reference: PMID:41500801
reference_title: "Spectrum of dominant Charcot-Marie-Tooth disease due to SLC12A6 variants."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Clinical phenotype varied dramatically with genotype; Arg207His and Ser647Pro caused a severe childhood-onset, sensory and motor, conduction-slowing neuropathy, whereas Gly552Asp caused a mild, adult-onset, sensory-predominant neuropathy, Thr991Ala an infantile-onset motor neuropathy, and the Met282Lys/Gly286Cys locus a complex, axonal neuropathy."
explanation: Sources the genotype-dependent electrophysiological class recorded in these notes.
- reference: PMID:31439721
reference_title: "De novo variants in SLC12A6 cause sporadic early-onset progressive sensorimotor neuropathy."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Our findings expand the genotypic and phenotypic spectrum associated with SLC12A6 variants from autosomal-recessive HMSN/ACC to dominant-acting de novo variants causing a milder clinical presentation with early-onset neuropathy."
explanation: Establishes the dominant-acting de novo mechanism and its separation from the recessive HMSN/ACC syndrome.
- name: ARHGAP19 (CMT2KK)
gene_term:
preferred_term: ARHGAP19
term:
id: hgnc:23724
label: ARHGAP19
association: Causal
relationship_type: CAUSATIVE
subtype: CMT2KK
notes: >-
Biallelic ARHGAP19 variants cause motor-predominant axonal neuropathy in 25
individuals from 20 unrelated families. The mechanism is loss of function:
variants lower ARHGAP19 protein levels and impair its GTPase-activating
activity towards RhoA. A search of the approved symbol ARHGAP19 in the ClinGen
Gene-Disease Validity CSV (snapshot 2026-08-13) returns no row, which is
expected for a relationship first reported in 2025.
evidence:
- reference: PMID:41086021
reference_title: "Biallelic variants in ARHGAP19 cause a progressive inherited motor-predominant neuropathy."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Here, we identified 16 recessive variants in the RhoGTPase activating protein 19 gene (ARHGAP19) causing motor-predominant neuropathy in 25 individuals from 20 unrelated families."
explanation: Establishes the biallelic ARHGAP19 gene-disease relationship and the cohort size behind it.
- reference: PMID:41086021
reference_title: "Biallelic variants in ARHGAP19 cause a progressive inherited motor-predominant neuropathy."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "Through the use of patient lines, in vitro GAP assays and in silico molecular modeling, we provided evidence that CMT-associated ARHGAP19 variants act through a loss-of-function (LOF) mechanism."
explanation: Sources the loss-of-function mechanism recorded in these notes.
- name: DARS2 (CMT2LL)
gene_term:
preferred_term: DARS2
term:
id: hgnc:25538
label: DARS2
association: Causal
relationship_type: CAUSATIVE
subtype: CMT2LL
notes: >-
Biallelic DARS2 variants can present as isolated childhood-onset axonal CMT
without leukoencephalopathy. The ClinGen Gene-Disease Validity CSV (snapshot
2026-08-13) carries a single DARS2 row, Definitive for mitochondrial disease
(MONDO:0044970) from the Mitochondrial Diseases Gene Curation Expert Panel, and
no row against a CMT or hereditary neuropathy concept; the CMT phenotype rests
on the 2025 three-family report and its functional work.
evidence:
- reference: PMID:40814755
reference_title: "Biallelic Variants in the DARS2 Gene as a Novel Cause of Axonal Charcot-Marie-Tooth Disease."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "We investigated 5 individuals from 3 unrelated families with axonal CMT and biallelic DARS2 variants."
explanation: Establishes the cohort behind the biallelic DARS2 axonal CMT relationship.
- reference: PMID:40814755
reference_title: "Biallelic Variants in the DARS2 Gene as a Novel Cause of Axonal Charcot-Marie-Tooth Disease."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Hypomorphic variants, such as p.Ser238Phe, when paired with more deleterious variants, result in isolated axonal CMT, whereas more severe combinations-although not as deleterious as those seen in leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation-result in axonal CMT with central nervous system involvement, albeit without leukoencephalopathy."
explanation: Sources the allele-combination model that separates this presentation from DARS2-related leukoencephalopathy.
- name: COX18 (CMT2MM)
gene_term:
preferred_term: COX18
term:
id: hgnc:26801
label: COX18
association: Causal
relationship_type: CAUSATIVE
variant_origin: GERMLINE
subtype: CMT2MM
notes: >-
Biallelic COX18 variants cause autosomal recessive axonal CMT, in some
individuals with additional central nervous system features. COX18 is an
assembly factor for respiratory chain complex IV, so this is a primary
respiratory-chain rather than a mitochondrial-dynamics cause of CMT. A search of the approved symbol COX18 in the
ClinGen Gene-Disease Validity CSV (snapshot 2026-08-13) returns no row.
evidence:
- reference: PMID:40830826
reference_title: "Biallelic variants in COX18 cause a mitochondrial disorder primarily manifesting as peripheral neuropathy."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Our study presents genetic and functional evidence that supports COX18 as a newly identified gene candidate for autosomal recessive axonal CMT with or without CNS involvement."
explanation: Establishes biallelic COX18 variants as a cause of autosomal recessive axonal CMT.
- reference: PMID:40830826
reference_title: "Biallelic variants in COX18 cause a mitochondrial disorder primarily manifesting as peripheral neuropathy."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Exome sequencing coupled with homozygosity mapping revealed a homozygous splice variant c.435-6A>G in COX18 in two siblings with early-onset progressive axonal sensorimotor peripheral neuropathy."
explanation: Identifies the index variant and the sibling pair in which the relationship was first established.
inheritance:
- name: Autosomal Dominant
inheritance_term:
preferred_term: Autosomal dominant inheritance
term:
id: HP:0000006
label: Autosomal dominant inheritance
description: >
Most CMT2 subtypes follow autosomal dominant inheritance, including
CMT2A (MFN2), CMT2B (RAB7A), CMT2D (GARS1), CMT2E (NEFL), and
CMT2I/J (MPZ), together with the more recently delineated CMT2FF (CADM3),
CMT2HH (JAG1) and CMT2II (heterozygous SLC12A6). De novo mutations occur,
particularly in MFN2 and in SLC12A6.
evidence:
- reference: PMID:21327736
reference_title: "Recent advances in the genetics of hereditary axonal sensory-motor neuropathies type 2."
supports: SUPPORT
evidence_source: OTHER
snippet: "The majority of CMT2 are autosomal-dominant but autosomal-recessive forms have been described."
explanation: Review supports autosomal dominant inheritance as the most common CMT2 inheritance pattern.
- name: Autosomal Recessive
inheritance_term:
preferred_term: Autosomal recessive inheritance
term:
id: HP:0000007
label: Autosomal recessive inheritance
description: >
Some CMT2 subtypes follow autosomal recessive inheritance, including
CMT2B1 (LMNA), CMT2B2 (PNKP; originally attributed to MED25), and SORD-CMT2,
together with the biallelic subtypes CMT2KK (ARHGAP19), CMT2LL (DARS2) and
CMT2MM (COX18). Recessive NEFL mutations also cause a severe early-onset form.
Biallelic MFN2 (CMT2A2B) is grouped here by convention, but the carrier parents
of the reported probands were not phenotypically normal, so that relationship is
better described as semi-dominant. Note: CMT2B2
was initially reported as a MED25 disorder, but re-evaluation of the original
family reassigned the cause to a homozygous PNKP variant, so MED25 is no longer
considered a CMT gene.
evidence:
- reference: PMID:21327736
reference_title: "Recent advances in the genetics of hereditary axonal sensory-motor neuropathies type 2."
supports: SUPPORT
evidence_source: OTHER
snippet: "The majority of CMT2 are autosomal-dominant but autosomal-recessive forms have been described."
explanation: Review supports the presence of autosomal recessive CMT2 forms.
- reference: PMID:30039206
reference_title: "The polynucleotide kinase 3'-phosphatase gene (PNKP) is involved in Charcot-Marie-Tooth disease (CMT2B2) previously related to MED25."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Using exome sequencing, we now identified a homozygous nonsense variant (p.Gln517ter) in the last exon of an adjacent gene, the polynucleotide kinase 3'-phosphatase (PNKP) gene."
explanation: Re-evaluation of the original CMT2B2 family reassigned the cause from MED25 to a homozygous PNKP variant, so CMT2B2 is a PNKP disorder and MED25 is no longer a CMT gene.
diagnosis:
- name: Nerve Conduction Studies
description: >
Motor nerve conduction velocities are normal or near-normal (>38 m/s)
in CMT2, distinguishing it from CMT1 where velocities are significantly
reduced (<38 m/s). Compound muscle action potential amplitudes are
reduced, reflecting axonal loss rather than demyelination.
notes: Key diagnostic criterion distinguishing CMT2 from CMT1
evidence:
- reference: PMID:16941080
reference_title: "Comparison of CMT1A and CMT2: similarities and differences."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Median nerve motor nerve conduction velocities (MNCV) were always less than 38 m/s in CMT1A patients, whereas this was also the case in 16% of the CMT2 patients. Sensory nerve conduction velocities showed less overlap. In both CMT1A and CMT2 CMAP and SNAP amplitudes were often reduced or not obtainable in the legs."
explanation: Comparative electrophysiology supports preserved or overlapping motor conduction velocities and reduced amplitudes as key diagnostic features separating axonal CMT2 from CMT1A.
treatments:
- name: Physical Therapy and Rehabilitation
description: >
Regular physical therapy to maintain muscle strength, flexibility,
and range of motion. Includes stretching exercises, strengthening
of unaffected muscles, and balance training.
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
snippet: "While physical therapy may improve muscle strength and physical function, the quality of evidence remains moderate, and no standardized rehabilitation protocols have been firmly established."
explanation: Review supports physical therapy for CMT while noting evidence quality is moderate.
- name: Orthotic Devices
description: >
Ankle-foot orthoses (AFOs) to compensate for foot drop and improve
gait stability. Custom orthopedic shoes for foot deformities.
treatment_term:
preferred_term: orthotic supportive care
term:
id: NCIT:C15747
label: Supportive Care
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
snippet: "Management focuses on symptomatic interventions, including orthotic support, surgical procedures, and physical therapy."
explanation: Review confirms orthotic support as a standard management strategy for CMT.
- name: Surgical Management
description: >
Corrective surgery for severe foot deformities including tendon
transfers, osteotomies, and arthrodesis. Considered when conservative
measures fail to maintain functional ambulation.
therapeutic_modality: SURGERY
treatment_term:
preferred_term: orthopedic surgical procedure
term:
id: NCIT:C16186
label: Orthopedic Surgical Procedure
- name: Avoidance of Neurotoxic Medications
description: >
Patients should avoid medications known to worsen peripheral
neuropathy, particularly vincristine, which can cause severe
deterioration in CMT patients.
treatment_term:
preferred_term: supportive care
term:
id: NCIT:C15747
label: Supportive Care
- name: Genetic Counseling
description: >
Genetic counseling supports inheritance-risk assessment, cascade testing,
reproductive counseling, and interpretation of molecular diagnoses for
families affected by genetically heterogeneous CMT2.
treatment_term:
preferred_term: Genetic Counseling
term:
id: NCIT:C15240
label: Genetic Counseling
evidence:
- reference: PMID:20301532
reference_title: "Charcot-Marie-Tooth Hereditary Neuropathy Overview."
supports: SUPPORT
evidence_source: OTHER
snippet: "Inform genetic counseling of family members of an individual with CMT hereditary neuropathy."
explanation: GeneReviews explicitly includes genetic counseling for family members as part of CMT hereditary neuropathy management.
- name: Epalrestat for SORD-CMT2
description: >
Epalrestat is an aldose reductase inhibitor under Phase II evaluation for
SORD-CMT2. It targets the upstream polyol pathway to reduce sorbitol
production in patients with SORD deficiency; clinical efficacy remains
investigational.
treatment_term:
preferred_term: Pharmacotherapy
term:
id: NCIT:C15986
label: Pharmacotherapy
therapeutic_agent:
- preferred_term: epalrestat
term:
id: CHEBI:31539
label: epalrestat
target_phenotypes:
- preferred_term: Distal muscle weakness
term:
id: HP:0002460
label: Distal muscle weakness
target_mechanisms:
- target: SORD Deficiency and Sorbitol Accumulation
description: >
Epalrestat inhibits aldose reductase upstream of SORD, aiming to reduce
sorbitol accumulation caused by SORD deficiency.
evidence:
- reference: clinicaltrials:NCT05777226
reference_title: "Multi-center Study of Natural History of SORD-related Charcot-Marie-Tooth Disease and Epalrestat Treatment"
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The primary purpose of this study is to explore the natural history of SORD-CMT2 patients by detecting the ONLS scale score and serum sorbitol level changes at 6th, 12th, 24th, and 36th months and to evaluate the effectiveness and safety of epalrestat."
explanation: ClinicalTrials.gov documents a SORD-CMT2 epalrestat study, but results are not yet available.
- reference: PMID:32367058
reference_title: "Biallelic mutations in SORD cause a common and potentially treatable hereditary neuropathy with implications for diabetes."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "normalized intracellular sorbitol levels in patient-derived fibroblasts"
explanation: Patient-derived fibroblast evidence supports aldose reductase inhibition as a substrate-reduction strategy for SORD deficiency.
- name: NMD670 for CMT1/CMT2
description: >
NMD670 is an investigational small-molecule therapy tested in a completed
Phase IIa placebo-controlled trial enrolling ambulatory adults with CMT1 or
CMT2. The treatment is modeled with partial support because the trial record
establishes clinical evaluation in CMT2 but does not provide outcome results
in the cache.
treatment_term:
preferred_term: Pharmacotherapy
term:
id: NCIT:C15986
label: Pharmacotherapy
target_phenotypes:
- preferred_term: Steppage gait
term:
id: HP:0003376
label: Steppage gait
- preferred_term: Distal muscle weakness
term:
id: HP:0002460
label: Distal muscle weakness
evidence:
- reference: clinicaltrials:NCT06482437
reference_title: "A Phase 2a, Randomised, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy, Safety, and Tolerability of NMD670 Over 21 Days in Ambulatory Adult Patients With Type 1 and Type 2 Charcot-Marie-Tooth Disease"
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "This Phase 2a study aims to evaluate the efficacy, safety and tolerability of NMD670 vs placebo administered twice a day (BID) for 21 days in ambulatory adult patients with Charcot-Marie-Tooth disease type 1 and type 2."
explanation: ClinicalTrials.gov documents completed Phase IIa clinical evaluation of NMD670 in adults with CMT1 or CMT2, but the cache does not include efficacy results.
- name: HDAC6 Inhibition (investigational)
description: >
Pharmacological inhibition of histone deacetylase 6 (HDAC6) increases
alpha-tubulin acetylation and restores axonal transport. In a mutant-HSPB1
(CMT2F) mouse model, HDAC6 inhibitors corrected axonal transport defects and
rescued the neuropathy phenotype, supporting microtubule acetylation as a
mechanism-directed therapeutic strategy for axonal CMT. Preclinical/
investigational only.
therapeutic_modality: SMALL_MOLECULE
treatment_term:
preferred_term: Pharmacotherapy
term:
id: NCIT:C15986
label: Pharmacotherapy
target_mechanisms:
- target: Impaired Mitochondrial Axonal Transport
description: >
HDAC6 inhibition raises alpha-tubulin acetylation, correcting the impaired
axonal transport that drives distal axonal degeneration in axonal CMT.
evidence:
- reference: PMID:21785432
reference_title: "HDAC6 inhibitors reverse axonal loss in a mouse model of mutant HSPB1-induced Charcot-Marie-Tooth disease."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "acetylation induced by pharmacological inhibition of histone deacetylase 6 (HDAC6) corrected the axonal transport defects caused by HSPB1 mutations and rescued the CMT phenotype of symptomatic mutant HSPB1 mice."
explanation: Mouse-model evidence that HDAC6 inhibition rescues axonal transport and the CMT phenotype in mutant-HSPB1 (CMT2F) neuropathy.
- name: NEFL-Targeting Antisense Oligonucleotide (investigational)
description: >
Allele-selective antisense oligonucleotide knockdown of the gain-of-function
NEFL transcript in CMT2E. In a patient-derived iPSC motor-neuron model of the
NEFL p.N98S subtype, ASO treatment targeting the heterozygous gain-of-function
variant reduced biomarkers of axonal degeneration. Preclinical/investigational.
therapeutic_modality: ANTISENSE_OLIGONUCLEOTIDE
oligonucleotide_details:
oligonucleotide_mechanism: RNASE_H_KNOCKDOWN
target_gene:
preferred_term: NEFL
term:
id: hgnc:7739
label: NEFL
target_transcript: NEFL mRNA (p.N98S gain-of-function allele)
treatment_term:
preferred_term: Pharmacotherapy
term:
id: NCIT:C15986
label: Pharmacotherapy
target_mechanisms:
- target: Neurofilament Assembly Disruption
description: >
Knockdown of the gain-of-function NEFL allele aims to reverse the
neurofilament assembly disruption underlying CMT2E.
evidence:
- reference: PMID:39008620
reference_title: "Customized antisense oligonucleotide-based therapy for neurofilament-associated Charcot-Marie-Tooth disease."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "Using an antisense oligonucleotide treatment strategy targeting a heterozygous gain-of-function variant, we aimed to resolve molecular phenotypic changes observed in the CMT2E p.N98S subtype."
explanation: iPSC motor-neuron evidence for an allele-selective NEFL-targeting ASO as a candidate therapy for CMT2E.
animal_models:
- name: Pan-neuronal human HSPB1 CMT2F variant C. elegans
species: Caenorhabditis elegans
genotype: >-
Extrachromosomal Prab-3::HSPB1 arrays expressing human HSPB1 G84R, S135F or
Q175X (strains AMG641, AMG647, AMG653) on a Bristol N2 background, compared
with Prab-3::HSPB1 wild-type (AMG635) and N2 controls
publication: PMID:42489084
description: >-
Dominant-type overexpression model of CMT2F in neurons that carry no myelin.
All three variants reduced neuromuscular signalling in young adults and
accelerated its age-dependent change; wild-type HSPB1 did not, and protected
against the age-related change seen in controls.
modeled_mechanisms:
- target: Presynaptic Neuromuscular Transmission Deficit
relationship: PARTIALLY_RECAPITULATES
fidelity: LOW
model_scale: ORGANISM
description: >-
Three CMT2F alleles from different protein domains share an early
presynaptic neuromuscular signalling defect that progresses with age.
limitations: >-
Invertebrate model with no myelin and no Schwann cells; human HSPB1 is
overexpressed from extrachromosomal arrays, which can be mosaic, on top of the worm's own
small heat-shock proteins; the signalling defect is inferred from
whole-animal aldicarb paralysis timing rather than measured
electrophysiologically, and no matching human neuromuscular-junction data
exist.
divergences:
- divergence_type: SPECIES_MISMATCH
materiality: QUALIFYING
description: >-
C. elegans motor neurons are unmyelinated, so any contribution of
Schwann cells or myelin to CMT2F neuromuscular dysfunction, reported in
HSPB1 S135F mice, is absent from this model.
- divergence_type: PROXY_QUANTITY
materiality: QUALIFYING
description: >-
The model's quantity is time to paralysis on the acetylcholinesterase
inhibitor aldicarb. It stands in for the node's quantity, presynaptic
acetylcholine release at the neuromuscular junction, which was not
recorded directly.
readouts:
- name: Aldicarb sensitivity in young adults
target: Presynaptic Neuromuscular Transmission Deficit
direction: DECREASED
interpretation: >-
Aldicarb resistance at adult day 1 indicates reduced neurotransmitter
release in all three variant lines.
evidence:
- reference: PMID:42489084
reference_title: "Charcot-Marie-Tooth disease variants of HSPB1 progressively alter neuromuscular signalling."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
quote_role: PRIMARY_RESULT
snippet: "Using a transgenic Caenorhabditis elegans model, we examined three distinct HSPB1 variants and determined that mutant HSPB1 caused an early defect in neuromuscular signalling strength as assayed by aldicarb sensitivity."
explanation: Reports the aldicarb assay behind this readout.
evidence:
- reference: PMID:42489084
reference_title: "Charcot-Marie-Tooth disease variants of HSPB1 progressively alter neuromuscular signalling."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
quote_role: PRIMARY_RESULT
snippet: "Our data point to the effects being presynaptic in origin and unrelated to differences in expression of mutant HSPB1 compared with that of the wild-type protein."
explanation: Supports treating the model as informative for a presynaptic defect.
- reference: PMID:42489084
reference_title: "Charcot-Marie-Tooth disease variants of HSPB1 progressively alter neuromuscular signalling."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
quote_role: PRIMARY_RESULT
snippet: "We also identified a progressive effect whereby age-dependent changes to neuromuscular signalling were accelerated in worms expressing mutant HSPB1."
explanation: Supports the progressive component of the modeled node.
clinical_trials:
- name: NCT05777226
phase: PHASE_II
status: NOT_RECRUITING
description: >
Multicenter Phase II study of SORD-CMT2 natural history and epalrestat
treatment, measuring ONLS and serum sorbitol over 36 months in about 30
participants with SORD-CMT2.
target_phenotypes:
- preferred_term: Distal muscle weakness
term:
id: HP:0002460
label: Distal muscle weakness
evidence:
- reference: clinicaltrials:NCT05777226
reference_title: "Multi-center Study of Natural History of SORD-related Charcot-Marie-Tooth Disease and Epalrestat Treatment"
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Patients in the drug treatment group take epalrestat (50 mg) orally three times daily."
explanation: Trial registry evidence documents epalrestat dosing in SORD-CMT2.
notes: ClinicalTrials.gov reports NOT_YET_RECRUITING; mapped to NOT_RECRUITING because the schema has no separate not-yet-recruiting enum.
- name: NCT06482437
phase: PHASE_II
status: COMPLETED
description: >
Phase IIa randomized, double-blind, placebo-controlled trial of NMD670 over
21 days in ambulatory adults with genetically confirmed Charcot-Marie-Tooth
disease type 1 or type 2.
target_phenotypes:
- preferred_term: Steppage gait
term:
id: HP:0003376
label: Steppage gait
- preferred_term: Distal muscle weakness
term:
id: HP:0002460
label: Distal muscle weakness
evidence:
- reference: clinicaltrials:NCT06482437
reference_title: "A Phase 2a, Randomised, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy, Safety, and Tolerability of NMD670 Over 21 Days in Ambulatory Adult Patients With Type 1 and Type 2 Charcot-Marie-Tooth Disease"
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "This Phase 2a study aims to evaluate the efficacy, safety and tolerability of NMD670 vs placebo administered twice a day (BID) for 21 days in ambulatory adult patients with Charcot-Marie-Tooth disease type 1 and type 2."
explanation: Trial registry evidence documents a completed Phase IIa NMD670 trial that included CMT2.
references:
- reference: PMID:20301532
title: "Charcot-Marie-Tooth Hereditary Neuropathy Overview."
tags:
- GeneReviews
findings: []
datasets: []
References & Deep Research
References
1Charcot-Marie-Tooth Hereditary Neuropathy Overview.
No top-level findings curated for this source.
Deep Research
1Deep 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.
Falcon
▸
Charcot–Marie–Tooth Disease Type 2 (CMT2) — Comprehensive Disease Characteristics Report
Target disease: Charcot–Marie–Tooth disease type 2 (CMT2)
MONDO: MONDO:0018993 / MONDO_0018993 (Open Targets) (OpenTargets Search: Charcot-Marie-Tooth disease type 2,Charcot-Marie-Tooth disease)
Category: Genetic (inherited peripheral neuropathy; predominantly axonal) (okamoto2023thecurrentstate pages 1-2, kalninaUnknownyearclinicalvariabilityof pages 11-15)
Executive summary (current understanding)
CMT2 refers to the axonal forms of Charcot–Marie–Tooth disease, in which peripheral nerve dysfunction is driven primarily by axonal degeneration rather than primary demyelination; electrodiagnostically, it is commonly distinguished by relatively preserved nerve conduction velocity (NCV) with reduced compound action potential amplitudes (reflecting axon loss) (kalninaUnknownyearclinicalvariabilityof pages 11-15, okamoto2023thecurrentstate pages 1-2). CMT2 is genetically heterogeneous: one recent review notes axonal CMT (CMT2) is caused by dominant mutations in >30 genes (medina2024customizedantisenseoligonucleotidebased pages 1-2). Recent (2023–2024) advances are concentrated in: (i) diagnostic uplift via WGS in specialist neuropathy pathways, (ii) quantitative imaging biomarkers (e.g., Dixon MRI fat fraction), and (iii) precision genetic therapeutics such as antisense oligonucleotides (ASOs) for gain-of-function neurofilament disease and gene therapy trials for specific recessive CMT2 subtypes (record2024wholegenomesequencing pages 1-2, sun2024quantifiedfatfraction pages 1-2, medina2024customizedantisenseoligonucleotidebased pages 1-2, grado2024willnewinvestigational pages 1-3).
1. Disease information
1.1 Concise overview
CMT is a hereditary motor and sensory neuropathy characterized clinically by distal muscle weakness/atrophy, frequent foot deformities (pes cavus), and distal sensory loss with reduced reflexes (okamoto2023thecurrentstate pages 1-2, sun2024quantifiedfatfraction pages 1-2). CMT2 specifically is the axonal category, typically showing NCV >38 m/s in common clinical classification schemes (okamoto2023thecurrentstate pages 1-2, sun2024quantifiedfatfraction pages 1-2).
1.2 Key identifiers
- MONDO: MONDO:0018993 (Open Targets disease object MONDO_0018993) (OpenTargets Search: Charcot-Marie-Tooth disease type 2,Charcot-Marie-Tooth disease)
- OMIM / Orphanet / ICD-10/ICD-11 / MeSH: not retrieved in the current evidence set; therefore not reported here to avoid speculation.
1.3 Synonyms / alternative names
- “CMT2”
- “Axonal Charcot–Marie–Tooth disease” / “axonal CMT” (okamoto2023thecurrentstate pages 1-2, kalninaUnknownyearclinicalvariabilityof pages 11-15)
- Subtype naming by gene (examples): CMT2A (MFN2), CMT2E (NEFL), CMT2D (GARS), CMT2F (HSPB1), CMT2S (IGHMBP2), CMT2CC (NEFH) (dong2024currenttreatmentmethods pages 2-4, sarno2024charcotmarietoothtype2cc pages 1-3, medina2024customizedantisenseoligonucleotidebased pages 1-2).
1.4 Evidence provenance (patient-level vs aggregated)
This report integrates:
Aggregated disease-level resources: Open Targets gene–disease associations (OpenTargets Search: Charcot-Marie-Tooth disease type 2,Charcot-Marie-Tooth disease).
Aggregated cohorts/registries: UCL specialist center cohort (2009–2023) with 1515 patients (record2024wholegenomesequencing pages 1-2) and a Chinese pediatric cohort (2007–2021) with 181 patients (ma2023clinicalandmutational pages 1-2, ma2023clinicalandmutational pages 2-3).
Primary clinical research and mechanistic model systems:* patient iPSC-derived neurons, mouse models, imaging biomarkers, and clinical trials/registries (medina2024customizedantisenseoligonucleotidebased pages 1-2, abati2024invivoanda pages 111-114, sun2024quantifiedfatfraction pages 1-2, NCT05777226 chunk 1).
2. Etiology
2.1 Disease causal factors
Primary cause: inherited pathogenic variants affecting peripheral nerve axons (genetic axonopathy) (kalninaUnknownyearclinicalvariabilityof pages 11-15, okamoto2023thecurrentstate pages 1-2). CMT2 encompasses autosomal dominant and autosomal recessive forms (kalninaUnknownyearclinicalvariabilityof pages 11-15, dong2024currenttreatmentmethods pages 2-4).
Electrophysiologic definition (clinical classification):
Review-based criterion: demyelinating CMT1 often has arm NCV <38 m/s, whereas axonal CMT2 is distinctive with NCV >38 m/s; intermediate velocities (25–45 m/s) can occur in transitional forms (okamoto2023thecurrentstate pages 1-2).
Specialist-center phenotype binning used a stricter CMT1 definition (upper-limb MNCV <25 m/s) (record2024wholegenomesequencing pages 1-2).
2.2 Risk factors
Genetic risk (major driver): family history and inherited pathogenic variants. In a pediatric cohort, de novo mutations were detected in 12.7% (23/181) of patients, underscoring that absence of family history does not exclude genetic CMT (ma2023clinicalandmutational pages 2-3).
Environmental / lifestyle risk factors: no specific environmental causal risk factors for CMT2 were identified in the retrieved evidence. (Clinical relevance: exposures can worsen neuropathy symptoms, but disease causation is genetic; evidence not retrieved here.)
2.3 Protective factors
No genetic or environmental protective factors were identified in the retrieved evidence.
2.4 Gene–environment interactions
Not identified in the retrieved evidence.
3. Phenotypes
3.1 Core clinical phenotype spectrum (with suggested HPO terms)
Common presentations span motor, sensory, and musculoskeletal domains:
1) Distal muscle weakness and atrophy (often legs > arms; progressive) (kalninaUnknownyearclinicalvariabilityof pages 11-15, okamoto2023thecurrentstate pages 1-2, sun2024quantifiedfatfraction pages 1-2)
* Suggested HPO: Distal muscle weakness (HP:0002460); Muscle atrophy (HP:0003202)
2) Foot deformities including pes cavus; may include hammertoes (okamoto2023thecurrentstate pages 1-2, sun2024quantifiedfatfraction pages 1-2)
* Suggested HPO: Pes cavus (HP:0001761); Hammer toe (HP:0001838)
3) Distal sensory loss (often stocking–glove) (okamoto2023thecurrentstate pages 1-2)
* Suggested HPO: Distal sensory impairment (HP:0002936); Hypoesthesia (HP:0001251)
4) Areflexia / reduced deep tendon reflexes (okamoto2023thecurrentstate pages 1-2, sarno2024charcotmarietoothtype2cc pages 1-3)
* Suggested HPO: Areflexia (HP:0001284)
5) Gait abnormalities / foot drop from distal weakness (sun2024quantifiedfatfraction pages 1-2)
* Suggested HPO: Abnormal gait (HP:0001288); Foot drop (HP:0001763)
6) Atypical/proximal weakness phenotype (CMT2CC): proximal lower-limb weakness may be prominent and can mimic CIDP, with conduction block-like features on NCS (sarno2024charcotmarietoothtype2cc pages 1-3)
* Suggested HPO: Proximal muscle weakness (HP:0003323)
3.2 Phenotype characteristics: onset, severity, progression
- Onset: broad, from childhood to late adulthood (including “childhood to >60 years” in a CMT2-focused review) (kalninaUnknownyearclinicalvariabilityof pages 11-15). Pediatric cohort mean age at onset was 8.3 ± 5.7 years (ma2023clinicalandmutational pages 1-2).
- Progression: typically slowly progressive and lifelong; clinical suspicion in specialist center included “slowly progressive disease course, often with foot deformity” (record2024wholegenomesequencing pages 1-2).
- Severity: variable; pediatric cohort used CMTPedS to stratify severity, with genotype–severity differences noted (e.g., PMP22 point mutations severe) (ma2023clinicalandmutational pages 1-2, ma2023clinicalandmutational pages 3-4).
3.3 Quality of life impact
Direct QoL instrument statistics (EQ-5D/SF-36/PROMIS) specific to CMT2 were not retrieved; however, disability and gait limitations are reflected in frequent use of functional outcome measures (CMTNSv2/CMTES/ONLS/6MWT/10MWT) in studies and trials (sun2024quantifiedfatfraction pages 8-10, NCT05777226 chunk 1, NCT06482437 chunk 1).
4. Genetic / molecular information
4.1 Causal genes (examples; gene heterogeneity)
Open Targets lists multiple associated targets for MONDO:0018993 including MPZ, MFN2, GDAP1, NEFL, HSPB1, TRPV4, RAB7A, MORC2, GARS1, DYNC1H1, AARS1 (OpenTargets Search: Charcot-Marie-Tooth disease type 2,Charcot-Marie-Tooth disease). Large cohort studies further support MFN2, NEFL, GDAP1, GARS and HSPB1 as recurrent diagnoses (record2024wholegenomesequencing pages 3-5).
Cohort-based frequency snapshots (useful for prioritizing gene testing):
* UCL specialist center (1515 patients with CMT/related disorders; 2009–2023): the most common diagnoses were PMP22 duplication, GJB1, PMP22 deletion, and MFN2 (CMT2A) (record2024wholegenomesequencing pages 1-2). CMT2 remained “unsolved in around half” with 48.6% (143/294) solved in that cohort (record2024wholegenomesequencing pages 3-5).
Chinese pediatric cohort (181 patients; 2007–2021): among axonal cases, common genes included MFN2 (16.5%; 14/85), IGHMBP2 (7.1%; 6/85) and MORC2 (7.1%; 6/85)* (ma2023clinicalandmutational pages 2-3).
A compact comparison table is provided below.
| Finding type | Metric/value | Population | Source (paper + year + DOI) | Notes |
|---|---|---|---|---|
| Electrophysiologic definition | CMT1: NCV in arms <38 m/s | General CMT classification | Okamoto & Takashima 2023, Genes, DOI: 10.3390/genes14071391 (okamoto2023thecurrentstate pages 1-2) | Review states a consistent slow NCV <38 m/s represents demyelinating CMT1. |
| Electrophysiologic definition | CMT2: NCV >38 m/s | General CMT classification | Okamoto & Takashima 2023, Genes, DOI: 10.3390/genes14071391 (okamoto2023thecurrentstate pages 1-2) | Review states NCV >38 m/s is distinctive of axonal CMT2. |
| Electrophysiologic definition | Transitional/intermediate NCV 25–45 m/s | General CMT classification; often CMTX1/transition forms | Okamoto & Takashima 2023, Genes, DOI: 10.3390/genes14071391 (okamoto2023thecurrentstate pages 1-2) | Useful differential context when values are not clearly demyelinating or axonal. |
| Electrophysiologic definition | CMT1: upper-limb MNCV <25 m/s | UCL inherited neuropathy centre phenotype definition | Record et al. 2024, Brain, DOI: 10.1093/brain/awae064 (record2024wholegenomesequencing pages 1-2) | Centre-specific research definition for demyelinating CMT1. |
| Electrophysiologic definition | CMT2: axonal neuropathy (threshold not fully visible in excerpt) | UCL inherited neuropathy centre phenotype definition | Record et al. 2024, Brain, DOI: 10.1093/brain/awae064 (record2024wholegenomesequencing pages 1-2) | Excerpt explicitly labels CMT2 as axonal neuropathy; exact numeric cutoff is truncated in the provided text. |
| Diagnostic yield | 76.9% (1165/1515) overall genetic diagnosis rate | Entire CMT and related disorders cohort | Record et al. 2024, Brain, DOI: 10.1093/brain/awae064 (record2024wholegenomesequencing pages 1-2) | Excluding hereditary ATTR amyloidosis. |
| Diagnostic yield | 48.6% (143/294) solved | CMT2 subgroup | Record et al. 2024, Brain, DOI: 10.1093/brain/awae064 (record2024wholegenomesequencing pages 3-5) | Confirms that axonal CMT remains unsolved in about half of cases. |
| Diagnostic yield | 31.8% (74/233) achieved a diagnosis in 100KGP | Cases recruited to UK 100,000 Genomes Project | Record et al. 2024, Brain, DOI: 10.1093/brain/awae064 (record2024wholegenomesequencing pages 1-2) | Includes cases later diagnosed outside the original 100KGP report. |
| Diagnostic yield | 19.7% (46/233) true WGS diagnostic rate | Cases recruited to UK 100,000 Genomes Project | Record et al. 2024, Brain, DOI: 10.1093/brain/awae064 (record2024wholegenomesequencing pages 1-2) | “True” rate after excluding 28 otherwise-diagnosed cases. |
| Diagnostic yield | 3.5% overall diagnostic uplift from WGS | Entire cohort | Record et al. 2024, Brain, DOI: 10.1093/brain/awae064 (record2024wholegenomesequencing pages 1-2) | Incremental improvement attributed to WGS. |
| Common gene (adult/mixed cohort) | PMP22 duplication 43.3% (505/1165 solved); 33.3% (505/1515 total) | Entire Record cohort | Record et al. 2024, Brain, DOI: 10.1093/brain/awae064 (record2024wholegenomesequencing pages 1-2, record2024wholegenomesequencing pages 3-5) | Most common overall diagnosis. |
| Common gene (adult/mixed cohort) | GJB1 13.0% (151/1165 solved); 10.0% (151/1515 total) | Entire Record cohort | Record et al. 2024, Brain, DOI: 10.1093/brain/awae064 (record2024wholegenomesequencing pages 1-2, record2024wholegenomesequencing pages 3-5) | Second most common overall diagnosis. |
| Common gene (adult/mixed cohort) | PMP22 deletion 6.2% (72/1165 solved); 4.8% (72/1515 total) | Entire Record cohort | Record et al. 2024, Brain, DOI: 10.1093/brain/awae064 (record2024wholegenomesequencing pages 1-2, record2024wholegenomesequencing pages 3-5) | HNPP-associated. |
| Common gene (adult/mixed cohort) | MFN2 3.9% (46/1165 solved); 3.0% (46/1515 total) | Entire Record cohort | Record et al. 2024, Brain, DOI: 10.1093/brain/awae064 (record2024wholegenomesequencing pages 1-2, record2024wholegenomesequencing pages 3-5) | Most common single genetic diagnosis in CMT2 overall. |
| Common gene (adult/mixed cohort) | MFN2 30.1% (43/143 solved CMT2) | Solved CMT2 cases in Record cohort | Record et al. 2024, Brain, DOI: 10.1093/brain/awae064 (record2024wholegenomesequencing pages 3-5) | Dominant contributor within solved axonal CMT2. |
| Common gene (pediatric cohort) | PMP22 duplication 18.2% (33/181) | Chinese pediatric CMT cohort | Ma et al. 2023, Frontiers in Genetics, DOI: 10.3389/fgene.2023.1188361 (ma2023clinicalandmutational pages 1-2, ma2023clinicalandmutational pages 2-3) | Most frequent genetic diagnosis overall in this pediatric series. |
| Common gene (pediatric cohort) | MFN2 7.7% (14/181) | Chinese pediatric CMT cohort | Ma et al. 2023, Frontiers in Genetics, DOI: 10.3389/fgene.2023.1188361 (ma2023clinicalandmutational pages 1-2, ma2023clinicalandmutational pages 2-3) | Most frequent cause of axonal CMT in this cohort. |
| Common gene (pediatric cohort) | GJB1 6.6% (12/181) | Chinese pediatric CMT cohort | Ma et al. 2023, Frontiers in Genetics, DOI: 10.3389/fgene.2023.1188361 (ma2023clinicalandmutational pages 1-2, ma2023clinicalandmutational pages 2-3) | Most common cause of CMTX in this cohort. |
| Common gene (pediatric cohort) | GDAP1 5.0% (9/181) | Chinese pediatric CMT cohort | Ma et al. 2023, Frontiers in Genetics, DOI: 10.3389/fgene.2023.1188361 (ma2023clinicalandmutational pages 2-3) | Among next most frequent genes in pediatric series. |
| Common gene (pediatric cohort) | PMP22 point mutations 4.4% (8/181) | Chinese pediatric CMT cohort | Ma et al. 2023, Frontiers in Genetics, DOI: 10.3389/fgene.2023.1188361 (ma2023clinicalandmutational pages 2-3) | Reported as severe genotypes, often de novo. |
| Common gene (pediatric cohort) | IGHMBP2 3.3% (6/181); MORC2 3.3% (6/181) | Chinese pediatric CMT cohort | Ma et al. 2023, Frontiers in Genetics, DOI: 10.3389/fgene.2023.1188361 (ma2023clinicalandmutational pages 2-3) | Both among the top recurrent pediatric diagnoses. |
Table: This table summarizes key electrophysiologic cutoffs, diagnostic-yield metrics, and recurrent gene frequencies for Charcot-Marie-Tooth disease type 2 and related CMT cohorts. It is useful for quickly comparing how CMT2 is defined clinically and how often major genes and testing strategies contribute to diagnosis.
4.2 Pathogenic variants and molecular classes (selected examples)
MFN2 (CMT2A): missense variants can impair mitochondrial outer membrane GTPase function, contribute to mtDNA instability, and disrupt mitochondrial fusion/OXPHOS (dong2024currenttreatmentmethods pages 2-4).
NEFL (CMT2E): >30 pathogenic variants reported; many are dominant missense changes with gain-of-function effects disrupting neurofilament assembly and organelle transport, while rare recessive LoF variants cause severe early-onset phenotypes (marina2024novelgeneticand pages 1-3, medina2024customizedantisenseoligonucleotidebased pages 1-2).
NEFH (CMT2CC): frameshift variants may produce abnormal proteins that form axonal aggregates disrupting neurofilament organization and axonal transport, and can lead to misdiagnosis as CIDP (sarno2024charcotmarietoothtype2cc pages 1-3).
GARS (CMT2D): altered GlyRS conformation can bind Nrp1 and disturb VEGF–Nrp1 signaling with selective peripheral axon degeneration (dong2024currenttreatmentmethods pages 2-4).
HSPB1/Hsp27 (CMT2F): mutant Hsp27 can alter mitochondria and contribute to neurofilament hyperphosphorylation and reduced anterograde transport of neurofilaments (dong2024currenttreatmentmethods pages 2-4).
4.3 Modifier genes / protective alleles
Not identified in the retrieved evidence.
4.4 Epigenetic and chromosomal abnormalities
Not identified in the retrieved evidence.
5. Environmental information
No specific environmental or infectious causative contributors were identified in the retrieved evidence. CMT2 is primarily genetic in etiology (kalninaUnknownyearclinicalvariabilityof pages 11-15, okamoto2023thecurrentstate pages 1-2).
6. Mechanism / pathophysiology
6.1 Unifying pathophysiologic concept: length-dependent axon degeneration
A major conceptual framework is that axonal transport is required to maintain long peripheral axons, and transport dysregulation contributes to axonal degeneration. A high-impact 2023 review states: “Disruption of axonal transport occurs early in neurodegenerative diseases and plays a key role in axonal degeneration.” (berth2023disruptionofaxonal pages 1-2). In CMT2, this can manifest as impaired trafficking of mitochondria, signaling endosomes, autophagosomes, and cytoskeletal cargo, leading to distal axonal energy failure, impaired proteostasis, and progressive denervation.
6.2 Major mechanistic classes linked to CMT2 genes
A. Axonal transport & microtubule state (therapeutic angle: microtubule acetylation)
Microtubule acetylation supports axonal transport; Berth & Lloyd describe that increasing acetylation via ATAT1 or preventing deacetylation by HDAC6 can rescue axonal transport deficits in models: “increasing microtubule acetylation via increasing ATAT1 or preventing deacetylation by HDAC6 rescued axonal transport deficits in disease models.” (berth2023disruptionofaxonal pages 1-2).
Suggested GO terms: microtubule-based transport (GO:0007018); axon development (GO:0061564); protein transport (GO:0015031)
Suggested CL (cell types): motor neuron (CL:0000100); Schwann cell (CL:0000218)
Suggested UBERON (anatomy): peripheral nerve (UBERON:0001021); sciatic nerve (UBERON:0001323)*
B. Mitochondrial dynamics, ER–mitochondria contacts, and mitochondrial axonal trafficking (MFN2/CMT2A)
MFN2 regulates mitochondrial fusion and ER–mitochondria interface; CMT2A is associated with mitochondrial transport defects and clustering. Patient-derived neuron data show “reduced speeds in both anterograde and retrograde trafficking” with “accumulation of mitochondria in perinuclear clusters” and distal axon clustering (abati2024invivoand pages 16-20, abati2024invivoand pages 11-16).
Suggested GO: mitochondrial fusion (GO:0008053); mitochondrion organization (GO:0007005); mitophagy (GO:0000422); oxidative phosphorylation (GO:0006119)
Suggested GO cellular component: mitochondrion (GO:0005739); endoplasmic reticulum (GO:0005783)
C. Cytoskeletal integrity / neurofilament biology (NEFL/NEFH)
NEFL-related disease affects neurofilament assembly, axonal caliber, and organelle transport (marina2024novelgeneticand pages 1-3, medina2024customizedantisenseoligonucleotidebased pages 1-2). NEFH frameshift variants can cause axonal aggregates and axonal transport interference (sarno2024charcotmarietoothtype2cc pages 1-3).
* Suggested GO: intermediate filament organization (GO:0045109); axonogenesis (GO:0007409)
D. Aminoacyl-tRNA synthetase toxic gain-of-function signaling (GARS)
GARS mutations can enable aberrant receptor binding (Nrp1) and disturb VEGF–Nrp1 signaling, causing selective axon degeneration (dong2024currenttreatmentmethods pages 2-4).
Suggested GO: tRNA aminoacylation for protein translation (GO:0006418); VEGF receptor signaling pathway (GO:0048010)*
6.3 Molecular profiling / multi-omics (availability)
Transcriptomic pathway enrichment (e.g., oxidative phosphorylation/respiratory chain) is reported in iPSC motor neuron models across CMT2 subtypes (abati2024invivoand pages 16-20, abati2024invivoand pages 11-16). Comprehensive proteomics/metabolomics signatures for CMT2 were not retrieved in this evidence set.
7. Anatomical structures affected
7.1 Organ/system level
- Primary system: peripheral nervous system; peripheral motor and sensory axons (kalninaUnknownyearclinicalvariabilityof pages 11-15, okamoto2023thecurrentstate pages 1-2).
- Secondary tissues: distal skeletal muscle affected by denervation and fatty replacement (quantified by MRI fat fraction) (sun2024quantifiedfatfraction pages 1-2, sun2024quantifiedfatfraction media 864be787).
7.2 Tissue/cell level (suggested terms)
- Tissue: peripheral nerve; skeletal muscle (lower limb compartments) (sun2024quantifiedfatfraction pages 1-2).
- Cells: motor neurons and sensory neurons; Schwann cells contribute depending on subtype (berth2023disruptionofaxonal pages 1-2, dong2024currenttreatmentmethods pages 2-4).
- Suggested CL: motor neuron (CL:0000100); sensory neuron (CL:0000101); Schwann cell (CL:0000218)
7.3 Subcellular level
Mitochondrial networks and transport machinery; neurofilament cytoskeleton; microtubules (abati2024invivoand pages 16-20, berth2023disruptionofaxonal pages 1-2).
8. Temporal development
8.1 Onset
Variable. Reviews describe onset from childhood to late adulthood (kalninaUnknownyearclinicalvariabilityof pages 11-15). Pediatric cohort mean onset age 8.3 ± 5.7 years (ma2023clinicalandmutational pages 1-2).
8.2 Progression
Typically slowly progressive, length-dependent neuropathy leading to distal disability; “slowly progressive disease course” was part of criteria for inherited neuropathy classification at a specialist center (record2024wholegenomesequencing pages 1-2).
9. Inheritance and population
9.1 Epidemiology (statistics)
- Prevalence (CMT overall): estimated 1 in 2500 to 1 in 10,000 (record2024wholegenomesequencing pages 1-2).
- Incidence (CMT overall): 10 to 40 per 100,000 individuals (okamoto2023thecurrentstate pages 1-2).
- Subtype distribution in a large specialist cohort (UCL, 2009–2023; n=1515): CMT2 constituted 19.4% (294/1515); CMT1 41.0% (621/1515) (record2024wholegenomesequencing pages 1-2).
- Subtype distribution in a Chinese pediatric cohort (2007–2021; n=181): axonal CMT was 47% (85/181) (ma2023clinicalandmutational pages 2-3).
9.2 Inheritance patterns
Both autosomal dominant and autosomal recessive CMT2 exist (kalninaUnknownyearclinicalvariabilityof pages 11-15, dong2024currenttreatmentmethods pages 2-4). In one pediatric cohort: AD 33.7% (61/181), AR 16.6% (30/181), X-linked 6.6% (12/181) (ma2023clinicalandmutational pages 2-3).
9.3 Founder effects / sex ratio / carrier frequency
Not identified in the retrieved evidence.
10. Diagnostics
10.1 Clinical and electrophysiologic diagnostics
- Electrodiagnostics: clinical classification frequently uses NCV thresholds: CMT2 NCV >38 m/s (okamoto2023thecurrentstate pages 1-2). CMT2 is described as axonal disease with reduced amplitudes and preserved velocities (kalninaUnknownyearclinicalvariabilityof pages 11-15).
- Diagnostic pitfall: CMT2CC (NEFH) can show misleading electrophysiology (non-uniform slowing, partial conduction block) and be misdiagnosed as CIDP; targeted NGS identified NEFH c.3057dupG (p.K1020fs*43) in a case report (sarno2024charcotmarietoothtype2cc pages 1-3).
10.2 Genetic testing approach and yield (real-world implementation)
A specialist-center series (UCL) spanning 2009–2023 used serial testing strategies (single gene/MLPA, NGS panels, WES, WGS) and reported:
Overall genetic diagnosis in 76.9% (1165/1515) (record2024wholegenomesequencing pages 1-2).
CMT2 remained harder to solve: 48.6% (143/294) (record2024wholegenomesequencing pages 3-5).
WGS diagnostic uplift across entire cohort: 3.5%; UK 100KGP “true” diagnostic rate 19.7% (46/233)* (record2024wholegenomesequencing pages 1-2).
A pediatric workflow (China, 2007–2021) used PMP22 CNV pre-exclusion by MLPA, then Sanger sequencing or NGS/WES, achieving 68% (123/181) diagnostic rate; in axonal CMT, solved fraction was 60% (51/85) (ma2023clinicalandmutational pages 2-3).
10.3 Imaging/biopsy
MRI and quantified fat fraction are emerging as severity biomarkers (below); biopsies and CSF were used as ancillary investigations in specialist pathways when needed (record2024wholegenomesequencing pages 1-2).
11. Outcome / prognosis
11.1 Prognosis
CMT2 is generally chronic and slowly progressive with disability; in CMT broadly, “effective pharmacological treatments have not established” (okamoto2023thecurrentstate pages 1-2). Survival/life expectancy statistics were not retrieved.
11.2 Outcome measures and biomarkers (recent quantitative data)
A. Quantified muscle fat fraction (FF) by multi-echo Dixon MRI (Frontiers in Neurology; published 29 Jan 2024)
Sun et al. recruited 25 CMT2 patients (plus 34 CMT1A and 10 controls) and quantified calf muscle FF across levels and compartments (DOI: 10.3389/fneur.2023.1334976; URL: https://doi.org/10.3389/fneur.2023.1334976) (sun2024quantifiedfatfraction pages 1-2). Selected quantitative findings:
* Soleus FF was higher in CMT2 than CMT1 at proximal level (34.8 ± 25.1% vs 19.1 ± 14.7%; p=0.034) and medial level (38.0 ± 25.6% vs 23.5 ± 21%; p=0.044) (sun2024quantifiedfatfraction pages 1-2).
In subtype comparison, MFN2 (CMT2A) vs PMP22 duplication showed higher soleus FF (54.7 ± 20.2% vs 23.5 ± 21.0%; p=0.039) (sun2024quantifiedfatfraction pages 1-2, sun2024quantifiedfatfraction pages 3-5).
Correlations in CMT2: CMTNSv2 correlated with TA/EHL FF (r=0.469; p<0.05) and lower-limb motor subscores correlated more strongly (e.g., TA/EHL r=0.659; p<0.01) (sun2024quantifiedfatfraction pages 8-10). Dorsiflexion strength inversely correlated with TA/EHL FF (r=−0.653; p<0.01) (sun2024quantifiedfatfraction pages 8-10).
Visual evidence (Figure 1 ROI and fat fraction maps; and key tables): Sun et al. provide calf-level FF maps and ROI definitions and quantitative FF tables (sun2024quantifiedfatfraction media 864be787, sun2024quantifiedfatfraction media 736ba65c).
B. Neurofilament light chain (NfL) and other biomarker candidates
Recent mechanistic work and reviews discuss plasma neurofilament light chain increases across CMT forms (abati2024invivoand pages 16-20) and highlight NfL as a clinically relevant biomarker for axonal degeneration in NEFL-related CMT2E contexts (medina2024customizedantisenseoligonucleotidebased pages 1-2). Candidate mitochondrial stress biomarkers (e.g., GDF15) and circulating cell-free mtDNA have been proposed in MFN2-related disease contexts (abati2024invivoand pages 16-20).
12. Treatment
12.1 Current standard of care (real-world implementation)
Recent review literature emphasizes that there are no approved disease-curative treatments and that rehabilitation, orthotics, and surgery remain key symptom-focused management approaches (dong2024currenttreatmentmethods pages 2-4). (This statement is directly supported by the 2024 review abstract.)
MAXO suggestions (supportive care examples):
Physical therapy / rehabilitation: MAXO:0000011 (rehabilitation therapy; term label may differ by implementation)
Orthotic device use: MAXO:0000763 (orthotic therapy/device)
Corrective surgery for foot deformities: MAXO:0000004* (surgical procedure)
12.2 Recent developments (2023–2024) and emerging therapies
A. Precision ASO therapy for NEFL CMT2E (published July 2024, Brain; DOI: 10.1093/brain/awae225)
Medina et al. provide a patient-specific iPSC motor neuron platform and report: “Our findings demonstrated a significant decrease in clinically relevant biomarkers of axonal degeneration, presenting the first clinically viable genetic therapeutic for CMT2E.” (medina2024customizedantisenseoligonucleotidebased pages 1-2). This is a major 2024 advance toward allele-specific therapy for gain-of-function CMT2.
MAXO suggestion: antisense oligonucleotide therapy (ASO) — MAXO:0000877 (oligonucleotide therapy; exact code may vary across MAXO releases).
B. MFN2 (CMT2A) RNAi + gene therapy concepts (preclinical, 2024)
Abati et al. describe a combined RNAi and gene-therapy approach that “effectively silenced the mutant MFN2 and restored functional wild-type MFN2 levels,” correcting mitochondrial phenotypes in patient-derived motor neurons; however, early interventions were toxic in a mouse model, highlighting translational safety constraints (abati2024invivoanda pages 111-114).
MAXO suggestion: gene therapy / RNA interference therapy (MAXO gene therapy class).
C. Active/ongoing clinical trials relevant to CMT2 (with identifiers)
1) SORD-CMT natural history and epalrestat treatment (Phase 2)
ClinicalTrials.gov NCT05777226 (first posted/record year 2023; start ~Apr 2023). Non-randomized, open-label, parallel design, n≈30, ages 14–50, oral epalrestat 50 mg TID up to 36 months. Primary endpoints include serum sorbitol and ONLS change at 6–36 months; secondary includes 10-meter walk test (NCT05777226 chunk 1).
URL: https://clinicaltrials.gov/study/NCT05777226 (trial page; ID cited from record) (NCT05777226 chunk 1).
2) INSPIRE trial (SORD-CMT; aldose reductase inhibitor AT-007) (Phase II/III)
Expert-opinion review cites ongoing NCT05397665 for CMT-SORD targeting sorbitol lowering with AT-007 (grado2024willnewinvestigational pages 1-3).
URL: https://clinicaltrials.gov/study/NCT05397665 (not retrieved as a full trial record here; ID supported by review) (grado2024willnewinvestigational pages 1-3).
3) CMT2S (IGHMBP2) gene replacement (Phase I/IIa)
Expert-opinion review cites NCT05152823, intrathecal AAV9-mediated IGHMBP2 replacement (grado2024willnewinvestigational pages 1-3).
URL: https://clinicaltrials.gov/study/NCT05152823 (not retrieved as a full trial record here; ID supported by review) (grado2024willnewinvestigational pages 1-3).
4) NMD670 in adult CMT1/CMT2 (Phase 2a randomized DBPC)
ClinicalTrials.gov NCT06482437 tests oral NMD670 vs placebo for 21 days, n=81, with primary endpoint change in 6MWT distance; secondary endpoints include CMT-FOM, ONLS, CMT-HI, and SF-36 among others (NCT06482437 chunk 1).
URL: https://clinicaltrials.gov/study/NCT06482437 (NCT06482437 chunk 1).
13. Prevention
13.1 Primary prevention
Not applicable in the classic sense because CMT2 is genetic; there is no vaccine or exposure avoidance strategy identified in retrieved evidence.
13.2 Secondary/tertiary prevention (real-world implementation)
- Early genetic diagnosis is positioned as essential for emerging gene/allele-specific therapies and for avoiding misdiagnosis and ineffective immunotherapies (e.g., CIDP vs genetic neuropathy) (record2024wholegenomesequencing pages 1-2, sarno2024charcotmarietoothtype2cc pages 1-3).
- Rehabilitation/orthotics to mitigate secondary complications such as falls and progressive deformities aligns with standard management discussions (dong2024currenttreatmentmethods pages 2-4).
13.3 Genetic counseling and screening
Evidence in the retrieved set supports the importance of accounting for de novo disease (12.7% in one pediatric cohort) and using tiered genetic testing approaches (MLPA → NGS/WES/WGS) (ma2023clinicalandmutational pages 2-3, record2024wholegenomesequencing pages 1-2).
14. Other species / natural disease
Naturally occurring CMT2-like disease in non-human species was not identified in the retrieved evidence.
15. Model organisms / experimental models
15.1 Human iPSC-based models (2024 focus)
A 2024 review highlights iPSC-derived motor neuron models for CMT2 variants, including NEFL (CMT2E) N98S causing intracellular accumulation/release of NFL, and GARS (CMT2D) with neuronal functional phenotypes (lent2024advancesandchallenges pages 4-5). Another 2024 synthesis reports “progressive axonal transport and mitochondrial deficits” across multiple CMT2 iPSC motor neuron lines (lent2024advancesandchallenges pages 6-7). The same review emphasizes limitations: immaturity, variability, challenges with purity, lack of axo-glial and NMJ interactions, and difficulty modeling late-onset features; animal models remain important for delivery/biodistribution assessments (abati2024invivoanda pages 27-31, lent2024advancesandchallenges pages 13-14).
15.2 Mouse models for MFN2 (CMT2A)
Preclinical work cited includes Thy1.2-MFN2R94Q and Mitocharc1 models; an RNAi+gene therapy strategy showed molecular efficacy but early toxicity in Thy1.2-MFN2R94Q, emphasizing safety constraints (abati2024invivoanda pages 111-114).
Expert opinion / authoritative analysis (2023–2024)
- Therapeutic state-of-the-field: 2023 and 2024 reviews emphasize the lack of established pharmacologic disease-modifying therapy, and highlight gene-based approaches (gene replacement, exon skipping/ASOs, knockdown) as emerging strategies (okamoto2023thecurrentstate pages 1-2, dong2024currenttreatmentmethods pages 2-4).
- Outcome-measure bottleneck: Expert commentary stresses challenges in responsive outcome measures and biomarkers due to slow progression and genetic heterogeneity, and notes that only a limited number of gene therapies have reached clinical trial stage, including for specific CMT2 subtypes (dong2024currenttreatmentmethods pages 2-4, grado2024willnewinvestigational pages 1-3).
Key data gaps (based on retrieved evidence)
1) OMIM/Orphanet/ICD/MeSH identifiers were not retrieved here; integrating those requires additional database queries.
2) Variant-level penetrance/expressivity, founder effects, sex ratios, and protective alleles were not captured in the current evidence set.
3) Survival/life expectancy and formal QoL instrument statistics specific to CMT2 were not retrieved.
4) Environmental modifiers and gene–environment interactions were not identified in the retrieved evidence.
Primary sources (URLs and publication dates)
- Record CJ et al. Whole genome sequencing increases the diagnostic rate in Charcot-Marie-Tooth disease. Brain (Advance access Mar 14, 2024). DOI/URL: https://doi.org/10.1093/brain/awae064 (record2024wholegenomesequencing pages 1-2)
- Sun X et al. Quantified fat fraction as biomarker assessing disease severity in rare Charcot–Marie–Tooth subtypes. Frontiers in Neurology (Published 29 Jan 2024). DOI/URL: https://doi.org/10.3389/fneur.2023.1334976 (sun2024quantifiedfatfraction pages 1-2)
- Medina J et al. Customized antisense oligonucleotide-based therapy for neurofilament-associated Charcot–Marie–Tooth disease. Brain (Advance access 15 Jul 2024). DOI/URL: https://doi.org/10.1093/brain/awae225 (medina2024customizedantisenseoligonucleotidebased pages 1-2)
- Berth SH, Lloyd TE. Disruption of axonal transport in neurodegeneration. J Clin Invest (Jun 2023). DOI/URL: https://doi.org/10.1172/jci168554 (berth2023disruptionofaxonal pages 1-2)
- Okamoto Y, Takashima H. The Current State of Charcot–Marie–Tooth Disease Treatment. Genes (Published 1 Jul 2023). DOI/URL: https://doi.org/10.3390/genes14071391 (okamoto2023thecurrentstate pages 1-2)
- Ma Y et al. Clinical and mutational spectrum of paediatric Charcot-Marie-Tooth disease in a large cohort of Chinese patients. Frontiers in Genetics (Published 13 Jul 2023). DOI/URL: https://doi.org/10.3389/fgene.2023.1188361 (ma2023clinicalandmutational pages 1-2)
- Dong H et al. Current Treatment Methods for Charcot–Marie–Tooth Diseases. Biomolecules (Sep 2024). DOI/URL: https://doi.org/10.3390/biom14091138 (dong2024currenttreatmentmethods pages 2-4)
- ClinicalTrials.gov NCT05777226 (SORD-CMT natural history + epalrestat): https://clinicaltrials.gov/study/NCT05777226 (record year 2023; status in record: UNKNOWN) (NCT05777226 chunk 1)
- ClinicalTrials.gov NCT06482437 (NMD670 in CMT1/CMT2): https://clinicaltrials.gov/study/NCT06482437 (record year 2024; status: COMPLETED) (NCT06482437 chunk 1)
References
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(abati2024invivoanda pages 27-31): E Abati. In vivo and in vitro evaluation of the combination of rna interfering and gene therapy for treating mitofusin2-related diseases. Unknown journal, 2024.
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(lent2024advancesandchallenges pages 13-14): Jonas Van Lent, Robert Prior, Gonzalo Pérez Siles, Anthony N. Cutrupi, Marina L. Kennerson, Tim Vangansewinkel, Esther Wolfs, Bipasha Mukherjee-Clavin, Zachary Nevin, Luke Judge, Bruce Conklin, Henna Tyynismaa, Alex J. Clark, David L. Bennett, Ludo Van Den Bosch, Mario Saporta, and Vincent Timmerman. Advances and challenges in modeling inherited peripheral neuropathies using ipscs. Experimental & Molecular Medicine, 56:1348-1364, Jun 2024. URL: https://doi.org/10.1038/s12276-024-01250-x, doi:10.1038/s12276-024-01250-x. This article has 30 citations and is from a peer-reviewed journal.
