A hereditary peripheral polyneuropathy presenting with progressive distal weakness and muscular atrophy (myopathy) affecting all four limbs.
Hereditary Motor and Sensory Neuropathy Type I; Peroneal Muscular Atrophy.
This disorder was first described in 1886 in Paris by the two French neurologists Jean Martin Charcot and Pierre Marie, who identified it as a primary muscle disease, and independently in Cambridge by the English physician Howard Henry Tooth, who correctly interpreted his findings as a primary neurologic disease.
Charcot-Marie-Tooth (CMT) Syndrome is the most common genetic cause of neuropathy. Estimates vary widely between 1:2,500 and 1:10,000 live births, in part because of the broad range of the clinical presentation (even within the same family). Around half of all CMT patients suffer from CMT 1 with CMT 1A accounting for approximately two-thirds of all CMT 1 cases. Mutations in the gap junction β-1 gene (GJB1) are responsible for CMTX1 and make up approximately 10 to 20% of CMT cases, while CMT1B, associated with myelin protein zero gene (MPZ) mutations accounts for less than 5% of CMT cases. Approximately 20% of CMT cases are classified as CMT 2, which has numerous subtypes and accordingly can be caused by different mutations. No racial or sexual predilection could be identified. More than 50 different (sub-) types of CMT are known today.
CMT can be inherited in different patterns: autosomal dominant, autosomal recessive, and X-linked transmission have been described. The dominant form is most common one. More than 1,000 different mutations in more than 80 disease-associated genes have been detected, and new ones are added on a regular basis thanks to next-generation sequencing, which has allowed for the identification of several previously unknown involved genes and genetic defects. Mutations in one of the following genes are responsible for approximately 90% of genetically confirmed CMT cases: PMP22 (peripheral myelin protein-22, mapped to chromosome 17p12), MPZ (myelin protein zero; 1q23.3), GJB1 (gap junction β-1, mapped to chromosome Xq13.1), MFN2 (Mitofusin 2, located on chromosome 1p36.22), and GDAP1 (Ganglioside-induced Differentiation-Associated Protein 1, mapped to chromosome 8q21.11).
The syndrome can be divided into two types based on electrophysiologic, clinical, and genetic features. CMT 1 is a demyelinating form of peripheral polyneuropathy characterized by decreased motor nerve conduction velocities, hypertrophy of peripheral nerves with typical onion bulb formation and segmental demyelination. As a result of a mutation in the PMP22 gene, the myelin that is formed is unstable and breaks down easily. Larger motor and sensory axons may be involved. CMT 2, the so-called neuronal form or axonal neuropathy, is characterized by normal or only slightly diminished motor nerve conduction velocities and normal myelination and nerve size. The pathoanatomical correlate is direct axonal death with Wallerian degeneration. Since most patients also ...