Molecular Genetics of Charcot-Marie-Tooth Disease: From Genes to Genomes

Abstract

Charcot-Marie-Tooth disease (CMT) is a heterogeneous group of disorders of the peripheral nervous system, mainly characterized by distal muscle weakness and atrophy leading to motor handicap. With an estimated prevalence of 1 in 2,500, this condition is one of the most commonly inherited neurological disorders. Mutations in more than 30 genes affecting glial and/or neuronal functions have been associated with different forms of CMT leading to a substantial improvement in diagnostics of the disease and in the understanding of implicated pathophysiological mechanisms. However, recent data from systematic genetic screening performed in large cohorts of CMT patients indicated that molecular diagnosis could be established only in ∼50–70% of them, suggesting that additional genes are involved in this disease. In addition to providing an overview of genetic and functional data concerning various CMT forms, this review focuses on recent data generated through the use of highly parallel genetic technologies (SNP chips, sequence capture and next-generation DNA sequencing) in CMT families, and the current and future impact of these technologies on gene discovery and diagnostics of CMTs.

The scales and tales of myelination: using zebrafish and mouse to study myelinating glia

“…Loss of myelin and myelinating glia in the CNS and PNS of patients with diseases such as multiple sclerosis and Charcot-Marie-Tooth disease results in devastating symptoms including chronic pain and paralysis (Runia et al, 2012; Azzedine et al, 2012). It is therefore important to be able to assess behavioral defects in animal models that attempt to represent these complex neurological diseases in order to test how well the animal model mimics the human disease state.…”

Exome Sequence Analysis Suggests that Genetic Burden Contributes to Phenotypic Variability and Complex Neuropathy

“…Cellular functions include myelin assembly ( PMP22, MPZ, PRX, Cx32 ), membrane and endocytic trafficking ( MTMR2, SBF2, FIG4, SH3TC2 ) and mitochondrial dynamics ( MFN2, GDAP1 ) [Niemann et al, 2005; Azzedine et al, 2012]. Another predominant contributing gene group is that of aminoacyl-tRNA synthetases, an essential class of enzymes that ligate amino acids onto cognate tRNA molecules [reviewed in Wallen and Antonellis, 2013].…”

Charcot–Marie–Tooth diseases: an update and some new proposals for the classification

“…It is now possible to test all known CMT genes for several patients in a single experiment 59. A new problem arising from these techniques is the interpretation of the identified variants: for example, the causative nature of a new sequence variant or the presence of several genetic variants in the same individual (oligogenic inheritance or rare ‘private’ polymorphisms in more than one CMT gene).…”