Abstract
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.
Highlights
HMSN are a clinically and genetically heterogeneous group of disorders of the peripheral nervous system
In 29 probands, we identified an mitofusin 2 (MFN2) mutation
Patients with an MFN2 mutation presented with a classical CMT phenotype but more severe (28% of our CMT2A patients were wheelchair-dependent) compared to e.g. the CMT1A-duplication phenotype (Fig. 2B, C)
Summary
HMSN are a clinically and genetically heterogeneous group of disorders of the peripheral nervous system. The clinical features of HMSN include progressive distal muscle weakness and atrophy, starting in the lower limbs and later on affecting the upper extremities, steppage gait, foot deformities, distal sensory loss, and decreased or absent tendon reflexes (Harding and Thomas, 1980). HMSN is divided into two main subtypes: HMSN I, called Charcot–Marie–Tooth disease type 1 (CMT1), is a primarily demyelinating neuropathy with severely reduced motor nerve conduction velocities (NCV < 38 m/s), and HMSN II (CMT2) with primarily axonal loss characterized by normal or slightly reduced NCV but decreased amplitudes. In some CMT families, patients have been difficult to classify using these strict electrophysiological criteria, leading to the concept of intermediate CMT with median motor NCVs between 25 and 45 m/s (Davis et al, 1978). In CMT2 patients, nerve biopsies typically show axonal loss and regenerative sprouting (Schroder, 2001)
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