Aetiology

Charcot-Marie-Tooth (CMT) is a genetic condition, and there are no known risk factors for the condition, other than a family history. Depending on the inheritance pattern of the CMT subtype, the risk of passing the condition on to the next generation differs. In autosomal dominant forms (CMT1 [defined as both demyelinating conductions and dominant inheritance], CMT2 [axonal conductions and dominant inheritance], or dominant-intermediate [intermediate conduction velocities and dominant inheritance]), one parent with the genetic disorder is sufficient to pass on the condition, and each child has a 50% chance of inheriting the disorder. In autosomal recessive forms (CMT4 [any conduction velocity, with recessive inheritance]), both parents carry the genetic mutation, but do not usually have clinical manifestations of the disease, as they have one working copy of the gene. In such cases, each child has a 25% chance of getting the disorder, a 50% chance of being a carrier, and a 25% chance of inheriting two working copies of the gene and being an unaffected non-carrier. Females with an X-linked form of CMT have a 50% chance of passing on the condition, and males with an X-linked form have a 100% chance of passing on the condition to daughters but a 0% chance of passing it on to sons.

CMT is a genetically heterogeneous condition, with over 90 genes and loci known to cause the condition when mutated. The most common subtype is CMT1A, caused by a duplication of the PMP22 gene. The second most common subtype is CMT1X, caused by a mutation in the GJB1 gene. The most common subtype of axonal CMT (CMT type 2) is CMT2A, caused by mutations in the MFN2 gene. The reciprocal mutation to CMT1A, a deletion of the PMP22 gene, causes hereditary neuropathy with liability to pressure palsies (HNPP), and is the third most common type of CMT overall.[7]

Pathophysiology

The pathophysiology of the different disorders that comprise CMT is dependent on the specific genetic disorder. Genetic mutations primarily affecting the Schwann cell and myelin lead to demyelinating CMT (CMT1), while those affecting axons lead to axonal CMT (CMT2). Clinical disability correlates primarily with axonal loss. Research is focused on understanding the interaction between the Schwann cell and the axon.

Classification

Subtypes of Charcot-Marie-Tooth (CMT) disease

CMT type 1 (CMT1)

  • Autosomal dominant with slow nerve conduction velocity, showing demyelination.

CMT type 2 (CMT2)

  • Autosomal dominant or recessive inheritance with normal nerve conduction velocity and reduced amplitudes, showing axonal degeneration.

CMT type 4 (CMT4)

  • Autosomal recessive inheritance, regardless of nerve conduction study features.

CMT type X

  • X-linked inheritance, regardless of nerve conduction study features.

Dominant intermediate CMT (DI-CMT)

  • Autosomal dominant inheritance with intermediately slowed nerve conduction velocity of 30-45 m/second in the median or ulnar nerves.

Hereditary motor neuropathy (HMN)

  • Only findings of a hereditary motor neuropathy, with little to no sensory involvement.

Hereditary sensory neuropathy (HSN)

  • Predominantly and strongly pronounced sensory symptoms and signs, with mild motor deficits.

Hereditary sensory and autonomic neuropathies (HSAN)

  • Predominant sensory and autonomic symptoms and signs, possible motor involvement.

Hereditary neuropathy with liability to pressure palsies (HNPP)

  • Transient sensory and motor symptoms after minor compression or stretching of a nerve.

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