Charcot-Marie-Tooth Disease, Demyelinating, Type 1G

1. Disease Information

Charcot–Marie–Tooth disease (CMT) is the prototypical hereditary motor and sensory neuropathy, encompassing a heterogeneous group of disorders with shared features of chronic, length-dependent peripheral nerve dysfunction.[18][19] CMT is conventionally classified into demyelinating forms (type 1), axonal forms (type 2), and intermediate forms, with further subdivision by genetic cause.[18][19] CMT1G is one of the autosomal dominant demyelinating subtypes and is defined by pathogenic variants in PMP2, resulting in a phenotype that meets clinical criteria for CMT1 but with a distinct underlying molecular lesion.[1][2][5][7][9][10][19] OMIM entry #618279 describes “Charcot-Marie-Tooth disease, demyelinating, type 1G; CMT1G” and states that “Charcot-Marie-Tooth disease type 1G is an autosomal dominant progressive peripheral sensorimotor neuropathy characterized by distal muscle weakness and atrophy with onset in the first or second decade.”[1][6] Orphanet, in its group entry on CMT1 (ORPHA:65753), similarly defines CMT1 disorders as autosomal dominant demyelinating peripheral neuropathies characterized by distal weakness and atrophy, sensory loss, foot deformities, and slow nerve conduction velocity.[18]

Key identifiers for CMT1G include the OMIM phenotype number 618279 and the causal gene OMIM entry 170715 for PMP2.[1][6] The NCBI Gene record for PMP2 (Gene ID 5375) notes that the gene is located on chromosome 8q21.13 and that “a defect in this gene was shown to be a cause of dominant demyelinating CMT neuropathy.”[2] CMT1G is recognized in GeneReviews’ overview of Charcot–Marie–Tooth hereditary neuropathy, which lists PMP2 among the genes associated with demyelinating neuropathies and designates “PMP2 – AD – CMT1G.”[19] At the level of disease classification, ICD‑10‑CM codes hereditary motor and sensory neuropathies, including Charcot–Marie–Tooth disease and Déjérine–Sottas disease, under G60.0, with related terms such as “Charcot-Marie-Tooth disease, paralysis or syndrome” and “Marie-Charcot-Tooth neuropathic muscular atrophy” mapped to that code.[11] ICD‑11 recognizes “autosomal dominant demyelinating Charcot‑Marie‑Tooth disease” within the broader hereditary neuropathy category, and Orphanet assigns the group identifier ORPHA:65753 to CMT1 disorders.[18] The user has provided MONDO:0033135 as the MONDO identifier for this specific subtype, consistent with the trend for ontologies to represent genetically defined CMT subtypes as distinct disease entities.

Common synonyms and alternative names for CMT1G include “Charcot–Marie–Tooth disease type 1G,” “CMT1G,” “PMP2-related CMT,” and “PMP2-related demyelinating Charcot–Marie–Tooth neuropathy.”[1][3][5][7][8][9][10][14] The PMP2 protein itself is also known in the biochemical literature as “peripheral myelin protein 2,” “myelin P2 protein,” and “fatty acid-binding protein 8 (FABP8),” and OMIM and NCBI Gene list alternative gene names including P2, MP2, FABP8, and “M-FABP.”[2][12][13][14] Because CMT1G is embedded within the larger framework of CMT1, clinical reports sometimes refer to affected individuals simply as having “CMT1” or “dominant demyelinating CMT” before genetic testing identifies PMP2 as the cause.[3][5][7][8][9][10][18] In the context of classification systems such as MeSH and SNOMED CT, CMT1G is subsumed under broader descriptors of hereditary motor and sensory neuropathy and demyelinating peripheral neuropathy rather than having a unique term, although ontology resources increasingly incorporate gene-specific subtypes.

Information on CMT1G is derived almost entirely from aggregated disease-level resources and small clinical series, not from large EHR-based cohorts. OMIM collates data from individual case reports and molecular studies to define the phenotype and genetic cause.[1][6] Orphanet provides group-level descriptive epidemiology and clinical features for CMT1.[18] GeneReviews’ overview synthesizes multiple genetic subtypes, including PMP2-related disease, and provides general diagnostic guidance for CMT as a whole.[19] Primary clinical knowledge comes from case reports and series that have identified deleterious PMP2 mutations (e.g., p.Ile43Asn, p.Thr51Pro, p.Ile52Thr, p.I50del, p.Met114Thr, p.Val115Ala) in families with demyelinating CMT.[3][5][7][8][9][10] These studies use detailed neurologic examination, neurophysiology, imaging, and genetic testing to characterize the phenotype and confirm segregation of variants with disease, yielding a composite picture of CMT1G across a small but growing number of families worldwide.[3][5][7][8][9][10]

Ontology considerations for disease information

From an ontology perspective, CMT1G can be mapped to several standard vocabularies. For disease entities, MONDO:0033135 (Charcot-Marie-Tooth disease, demyelinating, type 1G) captures the gene-specific subtype, while broader entities such as MONDO:0009954 (Charcot-Marie-Tooth disease) and MONDO:0005212 (hereditary motor and sensory neuropathy) represent parent classes. In MeSH, CMT falls under “Peripheral Nervous System Diseases” and “Neuromuscular Diseases,” with “Charcot-Marie-Tooth Disease” as a specific descriptor. ICD‑10‑CM uses G60.0 for “Hereditary motor and sensory neuropathy” encompassing CMT.[11] The causal gene PMP2 is associated with HGNC symbol PMP2, NCBI Gene ID 5375, and UniProt entry P02689, and is classified in GO as a fatty acid binding protein with roles in lipid transport and myelin sheath structure.[12][13][14][15] These ontology mappings support standardized representation of CMT1G in a disease knowledge base.

2. Etiology

The primary cause of CMT1G is heterozygous germline mutation in the PMP2 gene, resulting in autosomal dominant demyelinating peripheral neuropathy.[1][2][3][5][7][8][9][10][19] OMIM explicitly notes that “a number sign (#) is used with this entry because of evidence that demyelinating Charcot-Marie-Tooth disease type 1G (CMT1G) is caused by heterozygous mutation in the PMP2 gene (170715) on chromosome 8q21.”[1] NCBI Gene similarly states that “a defect in this gene was shown to be a cause of dominant demyelinating CMT neuropathy.”[2] The initial discovery came from exome sequencing of individuals with clinically typical CMT1 but negative for common CMT1 genes (PMP22, MPZ, GJB1, MFN2), identifying de novo or familial PMP2 missense variants that segregate with disease and are absent or extremely rare in population controls.[3][5][9][10] For example, a de novo p.Ile52Thr variant was reported in a proband with CMT1, transmitted to his affected son, with electrophysiological evidence confirming demyelinating neuropathy.[3] Subsequent screening identified additional families with adjacent amino acid substitutions p.Thr51Pro, p.Ile43Asn, and later p.Met114Thr and p.Val115Ala, all mapping to structurally important regions of PMP2 and correlated with childhood-onset demyelinating neuropathy.[3][5][10]

Risk factors for CMT1G are dominated by genetic factors, specifically the presence of a pathogenic or likely pathogenic PMP2 variant in the germline. Because CMT1G follows autosomal dominant inheritance, an affected individual has a 50% chance of transmitting the mutation to each offspring.[1][3][5][7][8][9][10][19] Penetrance appears high, with most heterozygous carriers manifesting clinical neuropathy, although the small number of reported families limits precise estimates.[3][5][7][8][9][10] In some pedigrees, disease arises from de novo mutation in an otherwise unaffected parent, as in the original p.Ile52Thr family.[3] There is currently no evidence that common susceptibility variants or modifier genes outside PMP2 significantly alter risk of disease onset, although broader CMT literature notes that genes involved in myelination and axonal integrity (e.g., PMP22, MPZ, MFN2, NEFL) can modify phenotype in compound or overlapping genetic contexts.[19] Within PMP2 itself, different mutations may confer variable severity, with some clustering within a “mutation-rich” region around residues 43–52 and others (Met114Thr, Val115Ala) forming a second cluster in fatty acid coordinating residues, suggesting that both spatial location and physicochemical change influence penetrance and expressivity.[5][12][13][14]

Environmental risk factors for CMT1G have not been specifically established. However, by analogy to other forms of hereditary neuropathy, exogenous neurotoxins—such as certain chemotherapeutic agents (e.g., vinca alkaloids, taxanes), excessive alcohol consumption, or poorly controlled diabetes—may exacerbate symptoms or accelerate functional decline in individuals with underlying demyelinating neuropathy, including CMT1G, even if they do not cause disease de novo. Such gene–environment interactions have been documented generically in neuropathy, but robust, CMT1G-specific epidemiologic data are lacking, and thus this remains inferential rather than demonstrated. Similarly, age is a determinant of cumulative nerve damage; CMT1G symptoms typically begin in childhood or adolescence and progress slowly over decades.[1][5][7][8][10][18] Sex does not appear to significantly influence risk, as both males and females are affected in reported families, consistent with autosomal inheritance.[5][7][8][10]

Protective factors specific to CMT1G have not been identified. There are no known genetic variants that mitigate the effect of pathogenic PMP2 mutations, nor environmental exposures definitively shown to reduce risk of disease onset or progression. In the broader CMT population, maintenance of good general health, avoidance of neurotoxins, and early rehabilitation may improve functional outcomes, but these interventions do not prevent the underlying disease. From a mechanistic standpoint, factors that support Schwann cell energy metabolism and lipid homeostasis—such as adequate nutrition and avoidance of metabolic stress—could theoretically buffer some downstream consequences of PMP2 dysfunction, given evidence that PMP2 modulates fatty acid uptake and ATP production in Schwann cells.[15][16] Yet these hypotheses await direct clinical validation.

Gene–environment interactions in CMT1G are best conceptualized in terms of how environmental stressors may unmask or worsen the functional consequences of PMP2 mutation. For example, experimental models show that PMP2 plays a role in remyelination following nerve injury and in maintaining Schwann cell lipid homeostasis.[15][16] A PMP2-deficient or mutant Schwann cell may therefore be less able to respond to additional insults (mechanical trauma, ischemia, metabolic stress), leading to more pronounced demyelination or failed remyelination compared to a wild-type Schwann cell.[15][16] Similarly, systemic metabolic disturbances that perturb lipid profiles or mitochondrial function might synergize with PMP2-related defects. However, in the absence of disease-specific human data, these interactions must be considered conjectural, grounded in mechanistic insights from animal and cellular studies rather than epidemiologic demonstration.

Ontology considerations for etiology

In a disease knowledge base, etiologic annotations for CMT1G should highlight the causal gene PMP2 (HGNC:9210, NCBI Gene ID: 5375) and classify the relationship as “monogenic, autosomal dominant, germline,” with variant type “missense” or “in-frame deletion” and functional effect “altered fatty acid binding and lipid interaction; structurally preserved protein.”[3][5][8][10][12][13][14] Relevant GO biological process terms include GO:0006631 (fatty acid metabolic process), GO:0008366 (axon ensheathment), and GO:0042552 (myelination). For chemicals involved, ontology terms such as CHEBI:16113 (cholesterol), CHEBI:17762 (sphingomyelin), and CHEBI:18348 (phosphatidylinositol 4,5‑bisphosphate, PI(4,5)P2) are relevant to the lipid pathways affected by PMP2 variants.[12][13][16] The etiologic classification should explicitly note the absence of known environmental causes or protective genetic variants.

3. Phenotypes

Clinically, CMT1G presents as a length-dependent sensorimotor peripheral neuropathy dominated by distal weakness and atrophy, sensory disturbances, and foot deformities, with electrophysiologic evidence of demyelination.[1][5][7][8][10][18][19] OMIM describes the phenotype as “progressive peripheral sensorimotor neuropathy characterized by distal muscle weakness and atrophy with onset in the first or second decade.”[1] Orphanet, in its group description of CMT1, notes that affected individuals develop distal weakness and atrophy, beginning in the feet and legs and later involving the hands, accompanied by distal sensory loss (hypoesthesia), areflexia, pes cavus and hammer toes, and slow nerve conduction velocities (<38 m/s in upper limbs).[18] GeneReviews similarly emphasizes that CMT generally presents with distal muscle weakness and atrophy, pes cavus, and decreased or absent tendon reflexes, with sensory involvement in many subtypes including demyelinating forms.[19] Case series specific to PMP2 mutations refine these features for CMT1G.

In families with missense PMP2 variants p.Ile43Asn, p.Thr51Pro, and p.Ile52Thr, affected individuals typically had childhood or adolescent onset of clumsiness, frequent tripping, difficulty running, and progressive weakness in the distal lower limbs, followed by hand weakness later in life.[3][5][10] Electrophysiologic studies demonstrated markedly reduced motor nerve conduction velocities (MNCV), often in the 15–30 m/s range, consistent with demyelinating neuropathy.[3][5][10] Sural nerve biopsy in the p.Ile43Asn family showed “onion bulbs and degenerating fibers with various myelin abnormalities,” indicative of repeated cycles of demyelination and remyelination.[10] Muscle imaging (MRI) revealed predominant fatty replacement in the anterior and lateral compartments of the lower legs, similar to the pattern seen in CMT1A due to PMP22 duplication.[10] In the Bulgarian and German families with p.Met114Thr and p.Val115Ala, clinical features included childhood-onset polyneuropathy, variable patterns of demyelination, slow-to-very slow progression, and most severe involvement of peroneal muscles, again pointing to length-dependent distal involvement.[5]

The in-frame deletion variant p.I50del has been reported in at least two pedigrees, and in both, affected family members showed early-onset demyelinating neuropathy without other distinguishing features beyond typical CMT1 signs.[8][7] The initial study describing p.I50del reported onset in early childhood with delayed motor milestones, difficulty walking, and slowly progressive distal weakness.[8] Nerve conduction studies confirmed demyelinating neuropathy with reduced MNCV, and molecular modeling suggested that the deletion did not grossly disrupt the overall PMP2 structure but likely altered its function.[8] A subsequent case series of nine family members over three generations with the same c.147_149delTAT (p.Ile50del) mutation documented a consistent phenotype of demyelinating CMT with early onset, distal weakness and atrophy, sensory loss, pes cavus, and reduced conduction velocities.[7] The authors concluded that their study “highlights the genetic variability of the CMT family instead of the overlapping clinical phenotypes within demyelinating forms,” underscoring that PMP2-related CMT is clinically similar to other CMT1 entities and not easily distinguishable without genetic testing.[7]

Taken together, key symptom and sign phenotypes in CMT1G include distal muscle weakness in the lower extremities (HP:0003550), muscle atrophy (HP:0003202), decreased or absent deep tendon reflexes (HP:0001284), pes cavus (HP:0001761), hammer toes (HP:0001837), length-dependent sensory loss (HP:0003479), gait disturbance (HP:0002355), and difficulty running or walking (HP:0002355).[1][5][7][8][10][18][19] Electrophysiologically, demyelinating neuropathy with markedly reduced motor nerve conduction velocity (<38 m/s in upper limb motor nerves) is characteristic (HP:0003431).[18][19] Sural nerve biopsy findings of onion bulb formations and demyelinated fibers reflect chronic demyelination and remyelination (HP:0003430).[10] Muscle imaging showing distal muscle fatty replacement contributes to phenotypic characterization and parallels other CMT1 forms.[10] Age of symptom onset is typically in childhood or adolescence, though some adult-onset cases may occur.[1][3][5][7][8][10][18] Severity ranges from mild gait disturbance with preserved ambulation to more severe disability requiring assistive devices, but progression is generally slow over decades.[5][7][8][10]

Quality-of-life impact in CMT1G mirrors that of other CMT1 subtypes. Distal weakness and foot deformities lead to impaired mobility, increased risk of falls, and difficulty performing activities that require fine motor coordination such

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