A molecular genetic update of inherited distal motor neuropathies.

Abstract

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.