Mitochondrial dysfunction and pathophysiology of CMT involving GDAP1 mutations

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Exp Neurol. 2010 Sep 14

Mitochondrial dysfunction and pathophysiology of Charcot-Marie-Tooth disease

involving GDAP1 mutations.

Cassereau J, Chevrollier A, Gueguen N, Desquiret V, Verny C, Nicolas G, Dubas F,

Amati-Bonneau P, Reynier P, Bonneau D, Procaccio V.

UMR INSERM, U771-CNRS6214, F-49933 Angers, France; University Hospital of

Angers, Department of Neurology, Angers, F-49933, France; University of Angers,

School of Medicine, Angers, F-49933, France.

Abstract

Charcot-Marie-Tooth (CMT) disease represents a large group of clinically and

genetically heterogeneous disorders leading to inherited peripheral neuropathies

affecting motor and sensory neurons. Mutations in the ganglioside-induced

differentiation-associated-protein 1 gene (GDAP1), which encodes a protein

anchored to the mitochondrial outer membrane, are usually associated with the

recessive forms of CMT disease and only rarely with the autosomal dominant

forms.

function of GDAP1 is not fully understood but it plays a role in mitochondrial

dynamics by promoting fission events. We present an overview of GDAP1 and the

corresponding protein together with the complete spectrum of the 41 gene

mutations described so far. We examine the relationship between the genotype and

the phenotype in the various forms of CMT disease related to GDAP1 mutations,

and discuss the pathophysiological hypotheses that link peripheral neuropathies

to mitochondrial dysfunction and GDAP1 mutations.

The meta-analysis of the literature reveals the great heterogeneity of

phenotypic presentations and shows that the recessive forms of CMT disease, i.e.

CMT4A and AR-CMT2, are far more severe than the dominant form, i.e. CMT2K.

Among patients with recessive forms of the disease, those carrying truncating

mutations are more seriously affected, often becoming wheelchair-bound before

the end of the third decade. At the neuronal level, GDAP1 mutations may lead to

perturbed axonal transport and impaired energy production as in other

neurodegenerative diseases due to mutations in genes involved in mitochondrial

dynamics.