A molecular genetic update of inherited distal motor neuropathies

[Guest guest]

Verh K Acad Geneeskd Belg. 2008;70(1):25-46.

A molecular genetic update of inherited distal motor neuropathies.

Irobi-Devolder J.

Molecular Genetics Department, Flanders Interuniversity Institute for

Biotechnology, University of Antwerp, Antwerpen.

Inherited peripheral neuropathies belong to the most common

neuromuscular disorders and occur worldwide (1/2500). The best known

is Charcot Marie Tooth (CMT), an inherited disorder first described

in 1886. Most patients have progressive weakness and wasting of foot

and hand muscles. Treatment is currently supportive (braces and foot

surgery) and a therapy that fundamentally alters the course of these

diseases is still lacking.

The involvement of a specific subset of neurons is a key hallmark in

the disease process. One subgroup, distal hereditary motor neuropathy

(distal HMN) is characterized by the selective loss of motor neurons

and/or their long axons in the peripheral nervous system. Apart from

the absence of sensory abnormalities, distal HMN closely resembles

axonal CMT2.

A better understanding of the molecular architecture of the

peripheral nerve, the functional pathways, the myelination process

and the complex interaction between the axon, the myelinating Schwann

cells and muscle is crucial to identify targets for therapeutic

interventions.

Identification of loci, genes and disease-causing mutations is the

first step in this understanding and opens new perspectives for

molecular genetic diagnosis. Genotype-phenotype correlations guide

the selection of specific mutations suitable for functional analysis

in cellular and animal models. The knowledge gained from the

molecular genetic and biological research will also help to make

progress in the study of acquired peripheral neuropathies. Some of

these neuropathies are often therapy-resistant, have a profound

influence on the quality of life of the patients, and constitute a

financial burden for both the individual and the community.