Center for Human Genetics and Laboratory Diagnostics, Dr. Klein, Dr. Rost and Colleagues

Charcot-Marie-Tooth Neuropathy Type 1A (CMT1A, Hereditary Motor and Sensory Neuropathy, HMSN1A ), X chromosomal (CMTX1; HMSNX), CMT1B and CMT1E [G60.0]

OMIM numbers: 118220 CMT1A, 601097 (PMP22), 118200 CMT1B, 159440 (MPZ), 302800 CMTX1, 304040 (GJB1), 118300 CMT1E, 601097 (PMP22)

Dr. rer. biol. hum. Soheyla Chahrokh-Zadeh

Scientific Background

CMT neuropathies are the most frequently occurring hereditary peripheral neuropathies with clinical and genetic heterogeneity (prevalence approx. 1 in 3,300). Inheritance is predominantly autosomal dominant; however, it may also be autosomal recessive or X chromosomal. Age of manifestation is first to third decade of life. Affected patients typically show slow progressive weakness and atrophy of the distal muscles (arms and legs), which is usually accompanied by mild to moderate sensory loss. Furthermore, depressed tendon reflexes and high-arched feet are observed.

CMT neuropathies are classified through genetic, electrophysiological and neuropathological criteria. With a proportion of 40-50% of all CMT neuropathies, autosomal dominant CMT1 is the most frequent form and is divided into several subtypes according to the affected gene and type of mutation. Of all CMT1 cases 70-85% are of the subtype CMT1A. The genetic cause is a 1.5 Mb tandem duplication on chromosome 17p11.2 (CMT1A duplication), which, among others, includes the PMP22 gene. In approximately one third of all patients, this duplication arises de novo.

CMT1 is a mainly motor, primary peripheral demyelinating polyneuropathy with distal paresis, especially in the lower extremities. The motor nerve conduction velocity is severely decreased (<38m/s). Approx. 20% of all patients with an unclassified, chronic, peripheral neuropathy have CMT1A. A recent large study with german patients with CMT1 phenotype found the following distribution: CMT1A (51%), CMTX1 (9%) and CMT1B (5%).