Vincent Timmerman

Peripheral Neuropathy
VIB Department of Molecular Genetics, University of Antwerp

Inherited peripheral neuropathies belong to the most common neuromuscular disorders and occur worldwide (1/2500). The best known is Charcot-Marie-Tooth disease (CMT), an inherited disorder first described in 1886. Most patients have a progressive weakness and wasting of foot and hand muscles. Sometimes patients need walking aids or become wheelchair dependent even at a young age. The clinical variability and genetic heterogeneity often poses difficult diagnostic problems. Treatment is currently supportive (braces and foot surgery) and a therapy that fundamentally alters the course of these diseases is still lacking. 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. The identification of loci, genes and disease-causing mutations involved in the inherited peripheral neuropathies is the first step in this understanding. Over the years, we have assembled a unique collection of unrelated pedigrees, clinical data and DNA samples. Genotype/phenotype correlations are made using clinical, neurophysiological and neuropathological data provided by clinicians and pathologists. The molecular genetic methods used in our laboratory include: genome-wide searches and genetic linkage analyses in extended families, identification of novel genes using DNA cloning techniques, gene prediction, mutation analysis of candidate genes and functional analysis of some of the genes. Our research group has been successful in the identification and confirmation of several genes and mutations responsible for various types of inherited peripheral neuropathies. Everything started with the identification of the CMT1A duplication as the most frequent mutation in CMT neuropathies. And in the past 5 years we were able to identify 7 loci through genome-wide linkage studies and we identified 5 novel genes: ARHGEF10, RAB7, HSP22, SEPT9 and YARS. In addition, we contributed to the identification of 7 other genes through international collaboration (HSP27, MFN2, DNM2, BSCL2, SETX, SH3TC2 and FGD4). Although many genes still need to be identified, we have initiated functional studies in selected genes in order to understand the pathomechanism of mutations, the biology of myelination and axonal transport, and the differential gene expression in motor and sensory neurons. The current focus is to gain knowledge on distal hereditary motor neuropathies (distal HMN), hereditary sensory and autonomic neuropathies (HSAN) and intermediate types of CMT.