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Condition report · Neurological

Charcot-Marie-Tooth Disease

Whole genome sequencing identifies the specific genetic cause of CMT, enabling accurate subtype diagnosis, prognosis, medication guidance, and access to gene-specific clinical trials.

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About this condition

A group of inherited conditions that damage the peripheral nerves, causing slowly progressive weakness, muscle wasting and loss of sensation, mainly in the feet, lower legs and hands. It includes the demyelinating (type 1) and axonal (type 2) forms and distal hereditary motor neuropathies.

Charcot-Marie-Tooth disease (CMT) is the most common inherited peripheral neuropathy, affecting approximately 1 in 2,500 people. It is characterized by progressive distal muscle weakness and atrophy (typically starting in feet and legs), sensory loss, decreased reflexes, and progressive foot deformities (pes cavus, hammer toes). Onset is typically in the first or second decade of life but varies widely across individuals and genetic subtypes. Severity ranges from mild foot drop to wheelchair dependence, with highly variable progression rates.

The genetic landscape of CMT is profoundly heterogeneous: over 100 distinct genetic subtypes have been described involving more than 45 causative genes. Major inheritance categories include CMT1 (demyelinating, autosomal dominant, ~50% of cases), CMT2 (axonal, ~15-30%, mostly autosomal dominant), and CMTX (X-linked, ~10-15%). The four most commonly mutated genes (PMP22, GJB1, MPZ, and MFN2) account for approximately 90% of positive molecular diagnoses. PMP22 1.5-Mb duplication causes CMT1A (the most common form); MFN2 mutations cause CMT2A; GJB1 mutations cause CMTX1 with X-linked inheritance patterns.

A genetic diagnosis in CMT is essential for clinical management: accurate subtype classification determines prognosis and progression rate; specific inheritance patterns enable genetic counseling with precise recurrence risks; medication safety changes (vincristine is contraindicated in PMP22-related CMT and can cause severe neuropathy); gene-specific clinical trials (PXT3003 for CMT1A, gene therapy approaches) become accessible; and connection to natural history studies enables informed surveillance and planning. For the substantial portion of CMT patients without a genetic diagnosis, WGS may provide the answer that ends their diagnostic odyssey.

CMT comprises over 100 genetic subtypes with demyelinating, axonal, intermediate, and X-linked forms. The four most common genes account for 90% of diagnoses, but the remaining 10% require comprehensive genetic sequencing.

The 2 conditions we analyse

Charcot-Marie-Tooth Disease

A group of inherited peripheral neuropathies causing progressive weakness and wasting of the distal muscles and loss of sensation, mainly in the feet and hands.

What a diagnosis changes

Genetic counseling, subtype-specific monitoring, physical therapy, orthotics, neurotoxic drug avoidance, gene-specific clinical trials, surveillance for associated features

Genes analysed

Also known as

Charcot Marie Tooth muscular atrophy; Charcot-Marie-Tooth hereditary neuropathy; CMT; CMT/HMSN; hereditary motor and sensory neuropathy; hereditary sensorimotor neuropathy; peroneal muscular atrophy

Includes 102 related subtypes ↓
  • autosomal dominant charcot-marie-tooth disease type 2 due to DGAT2 mutation
  • autosomal dominant Charcot-Marie-Tooth disease type 2 due to KIF5A mutation
  • autosomal dominant Charcot-Marie-Tooth disease type 2 due to TFG mutation
  • autosomal dominant Charcot-Marie-Tooth disease type 2K
  • autosomal dominant Charcot-Marie-Tooth disease type 2M
  • autosomal dominant Charcot-Marie-Tooth disease type 2W
  • autosomal dominant intermediate Charcot-Marie-Tooth disease
  • autosomal dominant intermediate Charcot-Marie-Tooth disease with neuropathic pain
  • autosomal recessive intermediate Charcot-Marie-Tooth disease
  • Charcot-Marie-Tooth disease axonal type 2C
  • Charcot-Marie-Tooth disease axonal type 2CC
  • Charcot-Marie-Tooth disease axonal type 2F
  • Charcot-Marie-Tooth disease axonal type 2H
  • Charcot-Marie-Tooth disease axonal type 2K
  • Charcot-Marie-Tooth disease axonal type 2L
  • Charcot-Marie-Tooth disease axonal type 2N
  • Charcot-Marie-Tooth disease axonal type 2O
  • Charcot-Marie-Tooth disease axonal type 2P
  • Charcot-Marie-Tooth disease axonal type 2Q
  • Charcot-Marie-Tooth disease axonal type 2S
  • Charcot-Marie-Tooth disease axonal type 2U
  • Charcot-Marie-Tooth disease axonal type 2V
  • Charcot-Marie-Tooth disease axonal type 2X
  • Charcot-Marie-Tooth disease axonal type 2Z
  • Charcot-Marie-Tooth disease dominant intermediate B
  • Charcot-Marie-Tooth disease dominant intermediate C
  • Charcot-Marie-Tooth disease dominant intermediate D
  • Charcot-Marie-Tooth disease dominant intermediate E
  • Charcot-Marie-Tooth disease dominant intermediate F
  • Charcot-Marie-Tooth disease recessive intermediate A
  • Charcot-Marie-Tooth disease recessive intermediate B
  • Charcot-Marie-Tooth disease recessive intermediate C
  • Charcot-Marie-Tooth disease recessive intermediate D
  • Charcot-Marie-Tooth disease type 1
  • Charcot-Marie-Tooth disease type 1A
  • Charcot-Marie-Tooth disease type 1B
  • Charcot-Marie-Tooth disease type 1C
  • Charcot-Marie-Tooth disease type 1D
  • Charcot-Marie-Tooth disease type 1E
  • Charcot-Marie-Tooth disease type 1F
  • Charcot-Marie-Tooth disease type 2
  • Charcot-Marie-Tooth disease type 2A1
  • Charcot-Marie-Tooth disease type 2A2
  • Charcot-Marie-Tooth disease type 2B
  • Charcot-Marie-Tooth disease type 2B1
  • Charcot-Marie-Tooth disease type 2B2
  • Charcot-Marie-Tooth disease type 2B5
  • Charcot-Marie-Tooth disease type 2D
  • Charcot-Marie-Tooth disease type 2E
  • Charcot-Marie-Tooth disease type 2I
  • Charcot-Marie-Tooth disease type 2J
  • Charcot-Marie-Tooth disease type 2R
  • Charcot-Marie-Tooth disease type 2T
  • Charcot-Marie-Tooth disease type 2Y
  • Charcot-Marie-Tooth disease type 3
  • Charcot-Marie-Tooth disease type 4
  • Charcot-Marie-Tooth disease type 4A
  • Charcot-Marie-Tooth disease type 4B1
  • Charcot-Marie-Tooth disease type 4B2
  • Charcot-Marie-Tooth disease type 4B3
  • Charcot-Marie-Tooth disease type 4C
  • Charcot-Marie-Tooth disease type 4D
  • Charcot-Marie-Tooth disease type 4E
  • Charcot-Marie-Tooth disease type 4F
  • Charcot-Marie-Tooth disease type 4G
  • Charcot-Marie-Tooth disease type 4H
  • Charcot-Marie-Tooth disease type 4J
  • Charcot-Marie-Tooth disease type 4K
  • Charcot-Marie-Tooth disease type X
  • Charcot-Marie-Tooth disease with ptosis and parkinsonism
  • Charcot-Marie-Tooth disease X-linked dominant 1
  • Charcot-Marie-Tooth disease X-linked dominant 6
  • Charcot-Marie-Tooth disease X-linked recessive 2
  • Charcot-Marie-Tooth disease X-linked recessive 3
  • Charcot-Marie-Tooth disease X-linked recessive 4
  • Charcot-Marie-Tooth disease X-linked recessive 5
  • Charcot-Marie-Tooth disease, axonal, autosomal recessive, type 2a2b;
  • Charcot-Marie-Tooth disease, axonal, IIa 2II
  • Charcot-Marie-Tooth disease, axonal, mitochondrial form, 1
  • Charcot-Marie-tooth disease, axonal, type 2DD
  • Charcot-Marie-Tooth disease, axonal, type 2EE
  • Charcot-Marie-Tooth disease, axonal, type 2FF
  • Charcot-Marie-Tooth Disease, axonal, type 2GG
  • Charcot-Marie-Tooth disease, axonal, Type 2HH
  • Charcot-Marie-tooth disease, axonal, type 2JJ
  • Charcot-Marie-Tooth disease, axonal, type 2KK
  • Charcot-Marie-Tooth disease, axonal, type 2LL
  • charcot-marie-tooth disease, axonal, type 2MM
  • Charcot-Marie-Tooth disease, axonal, with vocal cord paresis, autosomal recessive
  • Charcot-Marie-Tooth disease, demyelinating, IIA 1H
  • Charcot-Marie-Tooth disease, demyelinating, IIA 1I
  • Charcot-Marie-Tooth disease, demyelinating, type 1G
  • Charcot-Marie-Tooth disease, demyelinating, type 1J
  • Charcot-Marie-Tooth disease, dominant intermediate A
  • Charcot-Marie-Tooth disease, dominant intermediate G
  • Charcot-Marie-Tooth disease, Guadalajara neuronal type
  • demyelinating hereditary motor and sensory neuropathy
  • giant axonal neuropathy 2
  • intermediate Charcot-Marie-Tooth disease
  • MME-related autosomal dominant Charcot Marie Tooth disease type 2
  • neuronopathy, distal hereditary motor, autosomal dominant 1
  • neuropathy, hereditary motor and sensory, type 6A
MONDO:0015626Orphanet 166MedGen 2980

Distal Hereditary Motor Neuropathy

Inherited neuropathies that mainly affect motor nerves, causing weakness and wasting of the hands and feet, including SORD-related neuropathy.

Genes analysed

Also known as

dHMN; distal spinal muscular atrophy; dSMA; neuronopathy, distal hereditary motor

Includes 35 related subtypes ↓
  • autosomal recessive distal spinal muscular atrophy 1
  • autosomal recessive distal spinal muscular atrophy 2
  • distal hereditary motor neuropathy type 2
  • distal hereditary motor neuropathy type 7
  • early-onset progressive encephalopathy-spastic ataxia-distal spinal muscular atrophy syndrome
  • hereditary spastic paraplegia 17
  • myopathy, myofibrillar, 13, with rimmed vacuoles
  • neuronopathy, distal hereditary motor, autosomal dominant
  • neuronopathy, distal hereditary motor, autosomal dominant 1
  • neuronopathy, distal hereditary motor, autosomal dominant 10
  • neuronopathy, distal hereditary motor, autosomal dominant 11
  • neuronopathy, distal hereditary motor, autosomal dominant 15
  • neuronopathy, distal hereditary motor, autosomal dominant 8
  • neuronopathy, distal hereditary motor, autosomal recessive
  • neuronopathy, distal hereditary motor, autosomal recessive 10
  • neuronopathy, distal hereditary motor, autosomal recessive 11, with spasticity
  • neuronopathy, distal hereditary motor, autosomal recessive 3
  • neuronopathy, distal hereditary motor, autosomal recessive 4
  • neuronopathy, distal hereditary motor, autosomal recessive 5
  • neuronopathy, distal hereditary motor, autosomal recessive 7
  • neuronopathy, distal hereditary motor, autosomal recessive 8
  • neuronopathy, distal hereditary motor, autosomal recessive 9
  • neuronopathy, distal hereditary motor, type 2A
  • neuronopathy, distal hereditary motor, type 2B
  • neuronopathy, distal hereditary motor, type 2C
  • neuronopathy, distal hereditary motor, type 2D
  • neuronopathy, distal hereditary motor, type 5
  • neuronopathy, distal hereditary motor, type 5A
  • neuronopathy, distal hereditary motor, type 5B
  • neuronopathy, distal hereditary motor, type 5C
  • neuronopathy, distal hereditary motor, type 7A
  • neuronopathy, distal hereditary motor, type 7B
  • neuronopathy, distal hereditary motor, type 9
  • spinal muscular atrophy, distal, autosomal recessive, 6
  • X-linked distal spinal muscular atrophy type 3
MONDO:0018894Orphanet 53739MedGen 98274

Why whole genome sequencing

Standard panels cover 8-20 genes. CMT has 45+ known causes. Step-wise single-gene testing leaves 20-40% undiagnosed.

CMT's extreme genetic heterogeneity defeats step-wise panel testing

CMT genetic testing has historically relied on step-wise approaches: first, PMP22 duplication/deletion analysis (identifies only ~50% of CMT); then, targeted gene panels (8-20 genes, identifying an additional ~30-40%). This leaves 20-40% of patients without a molecular diagnosis. Even comprehensive panels cannot detect all 45+ known CMT genes, rare subtypes, copy number variants beyond PMP22, or intronic variants. Copy number variant detection for the critical PMP22 duplication requires separate analysis not always performed. Whole genome sequencing with proper CNV detection and bioinformatic depth captures all known CMT genes, the PMP22 duplication, intronic variants, and novel candidate genes in a single test.

A genetic diagnosis enables subtype-specific care and clinical trials

Accurate genetic subtyping is transformative: CMT1A (PMP22 duplication) qualifies for gene therapy trials (PXT3003, Phocéa trial); CMT2A (MFN2) qualifies for emerging mitochondrial-targeted therapies in development; CMTX1 (GJB1) requires X-linked inheritance counseling and may qualify for gap junction-targeted approaches. All diagnosed subtypes enable avoidance of neurotoxic medications (vincristine contraindication in PMP22-related disease), accurate prognostic counseling, and surveillance for associated complications. For undiagnosed CMT patients (approximately 40%), WGS often provides the genetic answer that explains their neuropathy and opens access to targeted interventions.

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