Molecular genetics of distal hereditary motor neuropathies

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Abstract from Hum Mol Genet. 2004 Oct 1;13 Suppl 2:R195-202.

Molecular genetics of distal hereditary motor neuropathies.

Irobi J, De Jonghe P, Timmerman V.

Inherited peripheral neuropathies comprise a wide variety of diseases

primarily affecting the peripheral nervous system. The best-known

peripheral neuropathy is Charcot-Marie-Tooth disease (CMT) described in

1886 by J.-M. Charcot, P. Marie and H.H. Tooth. In 1980, A.E. Harding

and P.K. showed that in a large group of individuals with CMT,

several only had motor abnormalities on clinical and

electrophysiological examination, whereas sensory abnormalities were

absent. This exclusively motor variant of CMT was designated as spinal

CMT or hereditary distal spinal muscular atrophy, and included in the

distal hereditary motor neuropathies (distal HMN). The distal HMN are

clinically and genetically heterogeneous and are subdivided according to

the mode of inheritance, age at onset and clinical evolution. Since the

introduction of positional cloning, 12 chromosomal loci and seven

disease-causing genes have been identified for autosomal dominant and

recessive distal HMN. Most of the genes involved have housekeeping

functions, as in RNA processing, translation synthesis, glycosylation,

stress response, apoptosis, but also axonal trafficking and editing.

Functional characterization of the mutations will help to unravel the

cellular processes that underlie the specificity of motor neuropathies

leading to neurogenic muscular atrophy of distal limb muscles. Here we

review the recent progress of the molecular genetics of distal HMN and

discuss the genes implicated.