CMT Insights

Charcot-Marie-Tooth Disease (CMT): Sub-types

Charcot-Marie-Tooth disease (CMT) is named after the three physicians who first described it in 1886: Jean-Martin Charcot, Pierre Marie, and Howard Henry Tooth. Also known as Hereditary Motor and Sensory Neuropathy (HMSN), CMT refers to a group of inherited peripheral neuropathies caused by genetic mutations that damage the peripheral nerves—the nerves linking the brain and spinal cord to muscles and sensory organs. These mutations disrupt nerve signals, causing progressive muscle weakness, sensory loss, foot deformities (such as high arches or hammertoes), and mobility challenges.

CMT is highly diverse, with over 160 recognized subtypes linked to mutations in more than 130 genes. In India and across Asia, studies reveal unique genetic variants (such as those in the MFN2 and SH3TC2 genes) and a higher prevalence of recessive forms, frequently associated with consanguineous marriages in certain communities.

To simplify this complexity, CMT (or HMSN) subtypes are grouped into broader categories based on inheritance pattern, type of nerve damage (demyelinating or axonal), and primary clinical features.

Main Classifications (Most Common Types)

Most CMT cases worldwide—fall into these core groups:

• CMT1 (also called HMSN I): Autosomal dominant demyelinating neuropathy The myelin sheath (the protective covering around nerves) is primarily damaged, slowing nerve conduction. This is the most common category, with symptoms often starting in childhood or adolescence.

• CMT2 (also called HMSN II): Axonal neuropathy The nerve axons (the long fibers transmitting signals) are directly affected, reducing signal strength. Onset is typically in adulthood, with noticeable muscle wasting.

• CMT4: Autosomal recessive demyelinating neuropathy Similar to CMT1 but requires mutations in both gene copies (one from each parent). These rarer, often more severe forms are more prevalent in regions with consanguineous marriages, including parts of India and Asia.

• CMTX: X-linked neuropathy Caused by mutations in genes on the X chromosome. Males are usually more severely affected, while females may have milder or variable symptoms.

• CMTDI: Dominant Intermediate CMT (CMTDI / DI-CMT) Rare mixed axonal-demyelinating subtypes (25–45 m/s NCS); autosomal dominant; genes include DNM2, YARS1, MPZ, INF2, GNB4, NEFL; symptoms: distal weakness, sensory loss, foot deformities; research overlaps broader CMT gene therapies.

• CMTRI: Recessive Intermediate CMT (CMTRI / RI-CMT) Rare mixed subtypes; autosomal recessive (common in consanguineous families in India/Asia); genes include GDAP1, KARS1, PLEKHG5, COX6A1, KCTD11; symptoms: early distal weakness, foot deformities, possible scoliosis; research limited, GDAP1 gene replacement preclinical.

Sub-Classifications

CMT1: Autosomal Dominant Demyelinating Neuropathy (often childhood onset)

These subtypes primarily affect the myelin sheath, slowing nerve signals.

• CMT1A Mutant Gene: PMP22 (duplication) Symptoms: Childhood–Teens onset; classic features like foot drop, high arches, weakness, sensory loss (Moderate severity). Research Projects: PXT3003 Clinical Trial (Phase III for CMT1A, NCT02579759, researchers: Shahram Attarian et al.); VM202 (Engensis) Gene Therapy (Phase I/II, NCT05361031, Helixmith Co., Ltd.); scAAV1.tMCK.NTF3 Gene Therapy (Phase I/II, NCT03520751, Nationwide Children's Hospital).

• CMT1B Mutant Gene: MPZ Symptoms: Childhood–Adulthood onset; similar to CMT1A but variable (Moderate–Severe). Research Projects: PXT3003 in CMT1B (Preclinical on neuregulin pathways, researchers: Alessandra Bolino)

• CMT1C Mutant Gene: LITAF Symptoms: Infancy–Childhood onset; early onset, similar to CMT1A (Moderate). Research Projects: No specific trials found; included in broader CMT gene therapy reviews.

• CMT1D Mutant Gene: EGR2 Symptoms: Infancy onset; severe, Dejerine-Sottas-like (Severe). Research Projects: No specific trials found; EGR2 mutations studied in preclinical models (researchers: Byung-Ok Choi).

• CMT1E Mutant Gene: PMP22 (point mutation) Symptoms: Childhood onset; severe, similar to CMT1A but earlier (Severe). Research Projects: EN001 Stem Cell Therapy (Preclinical, Encell, South Korea).

• CMT1F Mutant Gene: NEFL Symptoms: Childhood–Teens onset; tremor, ataxia, intermediate NCV (Moderate). Research Projects: NEFL ASO (ASO Approaches for CMT2E, researchers: Chris Lorson, Michael Garcia)

• CMT1G Mutant Gene: PMP2 Symptoms: Childhood onset; classic demyelinating (Moderate). Research Projects: No specific trials found; PMP2 mutations (researchers: Byung-Ok Choi).

• CMT1H Mutant Gene: Various Symptoms: Variable onset; emerging features (Variable).

CMT2: Axonal Neuropathy (Mostly Autosomal Dominant, often adult onset)

These subtypes damage nerve axons, reducing signal strength.

• CMT2A1/A2 Mutant Gene: MFN2 Symptoms: Childhood–Teens onset; severe distal weakness, possible optic atrophy (Moderate to Severe). Research Projects: CRISPR-based Strategy for CMT2A (Genetic therapy, researchers: Bruce Conklin); AGT-100216 for CMT2A (Phase I, Augustine Therapeutics); Small Molecule Targeting Mitofusin (Preclinical, Mitochondria in Motion).

• CMT2B Mutant Gene: RAB7A Symptoms: Teens–20s onset; sensory loss, ulcers, amputation risk (Moderate–Severe). Research Projects: No specific trials found; RAB7A mutations (researchers: Byung-Ok Choi).

• CMT2C Mutant Gene: TRPV4 Symptoms: Variable onset; vocal cord/diaphragm paralysis, hearing loss (Variable). Research Projects: ABS-0871 for CMT2C (Phase I, Actio Biosciences); AGT-100216 for CMT2C (Phase I, Augustine Therapeutics).

• CMT2D Mutant Gene: GARS1 Symptoms: Teens–Adulthood onset; prominent hand weakness (Mild–Moderate). Research Projects: XtRNA Bio Gene Therapy for CMT2D (Preclinical, XtRNA Bio).

• CMT2E Mutant Gene: NEFL Symptoms: Childhood–Teens onset; ataxia, tremor (Moderate). Research Projects: ASO Therapy for CMT2E (CMTA-STAR).

• CMT2F Mutant Gene: HSPB1 Symptoms: Adulthood onset; distal weakness, cramps (Mild–Moderate). Research Projects: HDAC6 Inhibitors (CKD504, Preclinical).

• CMT2G Mutant Gene: Locus only Symptoms: Adulthood onset; classic axonal (Mild–Moderate).

• CMT2H Mutant Gene: Locus only Symptoms: Variable onset; rare (Variable).

• CMT2I/J Mutant Gene: MPZ (late-onset) Symptoms: Adulthood onset; late-onset axonal (Mild).

• CMT2K Mutant Gene: GDAP1 Symptoms: Childhood onset; severe, vocal cord involvement (Severe). Research Projects: Gene Replacement for GDAP1 (Preclinical, researchers: Xin Chen, Steven Gray)

• CMT2L Mutant Gene: HSPB8 Symptoms: Adulthood onset; distal weakness (Mild–Moderate).

• CMT2M Mutant Gene: DYNC1H1 Symptoms: Childhood onset; severe weakness (Moderate–Severe).

• CMT2N Mutant Gene: AARS1 Symptoms: Adulthood onset; distal weakness (Mild).

• CMT2O Mutant Gene: DYNC1H1 (overlap) Symptoms: Variable onset; similar to 2M (Variable).

• CMT2P Mutant Gene: LRSAM1 Symptoms: Adulthood onset; mild distal (Mild).

• CMT2Q Mutant Gene: DHTKD1 Symptoms: Childhood onset; metabolic overlap (Moderate).

• CMT2R Mutant Gene: Various Symptoms: Variable onset; rare (Variable).

• CMT2S Mutant Gene: IGHMBP2 Symptoms: Childhood onset; severe, respiratory (Severe). Research Projects: Gene Therapy for IGHMBP2 (Phase I/II, NCT05152823, Nationwide Children's Hospital/Megan Waldrop).

• CMT2T Mutant Gene: Various Symptoms: Variable onset; rare (Variable).

• CMT2U Mutant Gene: Various Symptoms: Variable onset; rare (Variable).

• CMT2V Mutant Gene: Various Symptoms: Variable onset; rare (Variable).

• CMT2W Mutant Gene: Various Symptoms: Variable onset; rare (Variable).

• CMT2X Mutant Gene: Various Symptoms: Variable onset; rare (Variable).

• CMT2Y Mutant Gene: Various Symptoms: Variable onset; rare (Variable).

• CMT2Z Mutant Gene: MORC2 Symptoms: Childhood–Adulthood onset; rapid progression, severe (Severe). Research Projects: No specific trials found; MORC2 mutations (researchers: Byung-Ok Choi).

CMT4: Autosomal Recessive Demyelinating Neuropathy (Often severe, infancy/childhood onset)

Similar to CMT1 but recessive; more common in consanguineous populations like parts of India.

• CMT4A Mutant Gene: GDAP1 Symptoms: Infancy–Childhood onset; severe weakness, hoarseness, diaphragm involvement (Very Severe). Research Projects: Gene Replacement Therapy for CMT4A (Preclinical, researchers: Xin Chen, Steven Gray).

• CMT4B1 Mutant Gene: MTMR2 Symptoms: Infancy–Childhood onset; severe demyelination, facial weakness, scoliosis (Severe). Research Projects: AAV9-Mediated Gene Therapy for CMT4B1 (Preclinical, researchers: Alessandra Bolino).

• CMT4B2 Mutant Gene: MTMR13 Symptoms: Childhood onset; glaucoma, severe weakness, scoliosis (Severe). Research Projects: Included in broader CMT4B gene therapy (researchers: Alessandra Bolino).

• CMT4B3 Mutant Gene: MTMR5 Symptoms: Childhood onset; severe weakness (Severe). Research Projects: Gene Therapy - MiniGene/Split Vector for CMT4B3 (Preclinical, researchers: Stephan Zuchner, Scott Harper).

• CMT4C Mutant Gene: SH3TC2 Symptoms: Early Childhood onset; kyphoscoliosis, foot drop, hearing loss (Moderate to Severe). Research Projects: AAV9-Mediated SH3TC2 Gene Therapy (Preclinical, researchers: Kleopa KA ); AAV1.NT-3 Gene Therapy (Preclinical, researchers: Zarife Sahenk).

• CMT4D Mutant Gene: NDRG1 Symptoms: Childhood onset; severe sensory loss, deafness, tongue atrophy (Severe).

• CMT4E Mutant Gene: EGR2 Symptoms: Infancy onset; Dejerine-Sottas-like, very severe (Extremely Severe).

• CMT4F Mutant Gene: PRX Symptoms: Childhood onset; severe sensory, pain (Severe).

• CMT4G Mutant Gene: Locus only Symptoms: Childhood onset; severe (Severe).

• CMT4H Mutant Gene: FGD4 Symptoms: Infancy–Childhood onset; severe early weakness, scoliosis (Severe).

• CMT4J Mutant Gene: FIG4 Symptoms: Childhood–Teens onset; asymmetric, rapid, CNS involvement (Very Severe). Research Projects: ELP-02 Gene Therapy (Planned Phase I/II, Elpida Therapeutics, NCT06151600); AAV9-mediated FIG4 Delivery (Preclinical, researchers: Steven Gray).

• CMT4K Mutant Gene: Various Symptoms: Variable onset; rare (Variable).

CMTX: X-Linked Neuropathy (Mixed demyelinating/axonal, variable severity)

Often more severe in males; may involve CNS.

• CMTX1 Mutant Gene: GJB1 (Connexin-32) Symptoms: Childhood–Teens onset; demyelinating, CNS involvement (white matter) (Moderate–Severe, males worse). Research Projects: Nanoparticle-based Gene Delivery for CMTX1 (Preclinical, researchers: Alexia Kagiava); AAVrh10-hMPZ.GJB1 Gene Therapy (Preclinical, researchers: Kleopas Kleopa).

• CMTX2 Mutant Gene: Various Symptoms: Childhood onset; severe, early onset (Severe).

• CMTX3 Mutant Gene: Locus only Symptoms: Childhood onset; demyelinating (Moderate).

• CMTX4 Mutant Gene: AIFM1 Symptoms: Childhood onset; deafness, cognitive impairment (Moderate).

• CMTX5 Mutant Gene: PRPS1 Symptoms: Childhood onset; hearing loss, optic atrophy (Moderate).

• CMTX6 Mutant Gene: Various Symptoms: Childhood onset; rare (Variable). Research Projects: No specific trials found.

Dominant Intermediate CMT (CMTDI / DI-CMT)

• Definition: Rare CMT subtypes with mixed axonal-demyelinating features; intermediate nerve conduction velocities (typically 25–45 m/s). Autosomal dominant inheritance.

• Subtypes & Genes (main ones):

  • CMTDIB: DNM2

  • CMTDIC: YARS1

  • CMTDID: MPZ

  • CMTDIE: INF2 (often with kidney issues)

  • CMTDIF: GNB4

  • CMTDIG: NEFL

• Symptoms: Progressive distal weakness/atrophy (feet/legs first), sensory loss, foot deformities (pes cavus, hammertoes), gait issues, reduced reflexes. Variable severity; onset childhood to adulthood.

• Research: Limited subtype-specific trials; overlaps with broader CMT gene therapy, ASO approaches, and preclinical models (e.g., for NEFL/MPZ).

Recessive Intermediate CMT (CMTRI / RI-CMT)

• Definition: Rare mixed axonal-demyelinating subtypes with intermediate NCS velocities. Autosomal recessive inheritance (more common in consanguineous families, relevant in India/Asia).

• Subtypes & Genes (main ones):

  • CMTRIA: GDAP1

  • CMTRIB: KARS1

  • CMTRIC: PLEKHG5

  • CMTRID: COX6A1

  • CMTRIE (newer, ~2025): KCTD11

• Symptoms: Early/moderate-severe distal weakness (lower limbs prominent), sensory loss, foot deformities (pes cavus/equinovarus), balance/gait problems. Onset often childhood; may include scoliosis or respiratory issues in severe cases.

• Research: No large subtype-specific trials; GDAP1 overlaps with gene replacement preclinical work. Expanding genetic panels aid diagnosis in Asia.

Additional Classifications

These include historical or overlapping types mentioned in research.

• CMT3 Mutant Gene: Not specified (overlaps with CMT1/4) Symptoms: Not detailed (severe form).

• HNPP Mutant Gene: Not specified Symptoms: Not detailed. Research Projects: Niacin-Niaspan Therapy (Preclinical for myelin regulation).

• dHMN Mutant Gene: Not specified Symptoms: Not detailed. Research Projects: HDAC6 Inhibitors (Preclinical for dHMN2).

If you or a loved one has CMT, genetic testing can provide clarity on the exact subtype, guide management, and connect you to research opportunities. At CMT Association Asia-India, we're committed to raising awareness, supporting patients across India and Asia, and advancing research toward better treatments and a cure. Contact us or register in our patient data repository to help drive progress!