CMT Type 2: MFN2 mutation distribution and genotype/phenotype correlation

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Brain. 2006 May 19

MFN2 mutation distribution and genotype/phenotype correlation in

Charcot-Marie- Tooth type 2.

Verhoeven K, Claeys KG, Zuchner S, Schroder JM, Weis J, Ceuterick C,

Jordanova A, Nelis E, De Vriendt E, Van Hul M, Seeman P, Mazanec R,

Saifi GM, Szigeti K, Mancias P, IJ, Kochanski A, Ryniewicz B,

De Bleecker J, Van den Bergh P, Verellen C, Van Coster R, Goemans N,

Auer-Grumbach M, Robberecht W, Rasic VM, Nevo Y, Tournev I,

Guergueltcheva V, Roelens F, Vieregge P, Vinci P, Moreno MT, Christen

HJ, Shy ME, Lupski JR, Vance JM, De Jonghe P, Timmerman V.

Peripheral Neuropathy Group, Department of Molecular Genetics,

Flanders Interuniversity Institute for Biotechnology, Antwerpen,

Belgium.

Mutations in mitofusin 2 (MFN2) have been reported in Charcot-Marie-

Tooth type 2 (CMT2) families. To study the distribution of mutations

in MFN2 we screened 323 families and isolated patients with distinct

CMT phenotypes. In 29 probands, we identified 22 distinct MFN2

mutations, and 14 of these mutations have not been reported before.

All mutations were located in the cytoplasmic domains of the MFN2

protein. Patients presented with a classical but rather severe CMT

phenotype, since 28% of them were wheelchair-dependent. Some had

additional features as optic atrophy. Most patients had an early

onset and severe disease status, whereas a smaller group experienced

a later onset and milder disease course. Electrophysiological data

showed in the majority of patients normal to slightly reduced nerve

conduction velocities with often severely reduced amplitudes of the

compound motor and sensory nerve action potentials. Examination of

sural nerve specimens showed loss of large myelinated fibres and

degenerative mitochondrial changes. In patients with a documented

family history of CMT2 the frequency of MFN2 mutations was 33%

indicating that MFN2 mutations are a major cause in this population.