Charcot–Marie–Tooth disease (CMT) refers to a group of genetically heterogeneous disorders affecting peripheral nerve function.

Charcot–Marie–Tooth disease (CMT)

Definition:

• Charcot–Marie–Tooth disease (CMT) refers to a group of genetically heterogeneous disorders affecting peripheral nerve function.
• Named after Jean-Martin Charcot, Pierre Marie, and Henry Tooth, who described the disorder in 1886.

Epidemiology

• Prevalence:
  • Most common inherited neuromuscular disorder.
  • Affects approximately 1 in 2500 individuals (Skre 1974).

  Pathophysiology

  • Accounts for ~40% of childhood chronic neuropathies.

  Genetic Basis

  • Nature of Disease:
    • Characterized by degeneration of:
      • Axon.
      • Myelin sheath.
      • Or both.

      Classic Phenotype

      • Progressive, symmetrical distal weakness.
      • Sensory loss.
      • Areflexia (loss of reflexes).

      Clinical Presentation in Children

      • Causative Mechanisms:
        • Disorders of genes affecting:
          • Myelin compaction and maintenance.
          • Cytoskeletal formation.
          • Axonal transport.
          • Mitochondrial metabolism.

          Sensory Involvement

          • Autosomal dominant.
          • Autosomal recessive.
          • X-linked.
          • Mitochondrial.

          Associated Symptoms

          • Core Symptoms:
            • Gait difficulties.
            • Foot deformity (e.g., pes cavus or pes planus with valgus deviation).
            • Sensory loss.
            • Wasting of distal muscles in hands and feet.

            Key Points for Examination

            • Symptoms typically begin distally and in lower limbs before progressing to upper limbs.
            • Slow progression often delays medical attention.

            Overview of Classification

            • Highly variable: from birth to the sixth/seventh decades.
            • Most commonly presents in the first two decades of life.

            Advances in Genetic Testing

            • Affects longest fibres first, correlating with weakness severity.

            Traditional Classification

            1. CMT1 (Demyelinating CMT):

               • Motor conduction velocity (MCV): < 38 m/s in adults.
               • Subtype CMT1A:
                 • Most common demyelinating disorder (70% of cases).
                 • Genetic cause:
                   • Duplication of the PMP22 gene on chromosome 17p11.2.
                   • Results in overexpression of peripheral myelin protein 22.
                   • Often caused by unequal crossing-over during meiosis.
                 • Clinical features:
                   • Onset in the first decade, though neonatal onset possible.
                   • Weakness, sensory loss, calf hypertrophy, scoliosis, and tremor.
                   • Slow progression; most remain ambulant.
                   • Exacerbations: Pregnancy, rapid growth, infections, or exposure to vincristine.
                   • Rare response to steroid treatment in specific cases.
                 • Diagnostic markers:
                   • Elevated CSF protein in over half of cases.
                   • Nerve enlargement detected via ultrasound neurography.
               • CMT1B-F: Other subtypes linked to mutations in different myelin-related genes.

            2. CMT2 (Axonal CMT):

               • MCV: > 38 m/s in adults.
               • Characterized by axonal degeneration rather than demyelination.

            3. CMT4 (Autosomal Recessive Demyelinating CMT):

               • Rare subtype with severe presentations and early onset.

            4. CMT3 (Déjerine–Sottas Neuropathy):

               • Severe early-onset form of demyelinating neuropathy.
               • Features:
                 • Delayed motor milestones.
                 • Hypomyelination on nerve biopsy.
                 • Linked to point mutations in genes causing CMT1.

            5. Intermediate CMT:

               • MCV range: 25–45 m/s.
               • Features between CMT1 and CMT2.

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            Information

            Published:03 January 2025 Last Updated:03 January 2025