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Charcot-Marie-Tooth disease (CMT) is a hereditary peripheral neuropathy characterised by length-dependent degeneration of the motor and sensory nerve fibres with consequent distal muscle weakness, atrophy and mild sensory loss, primarily in lower limbs. The historic prevalence of CMT in the general population is 1 in 2500 individuals,1 while the present prevalence is 1 in 1214 individuals.2 Missense mutations in the mitofusion 2 gene (MFN2; OMIM*608506) have been found in most axonal forms (CMT type 2; CMT2) with autosomal dominant inheritance, and truncation mutations can be found in a few cases with seemingly autosomal recessive inheritance or sporadic cases. A dominant negative or toxic gain-of-function mechanism has been postulated in the autosomal dominant mode; however, the biological effect(s) by mutant MFN2 may vary depending on the nature of the mutations.3 This report describes a unique pathomechanism identified in a large Japanese MFN2-CMT2A2 family.
The currently living family members were examined by movement disorder specialists (TK, RM, HN, YN and YI). Neurological assessments, including the Charcot-Marie-Tooth disease neuropathy score V.2, electrophysiology of peripheral nerves and neuroimaging analyses, were carried out. Genetic analyses were conducted as described in online supplementary data, including targeted resequencing, Sanger sequencing, restriction fragment length polymorphism (RFLP) analysis and semiquantitative reverse-transcription (RT)-PCR. Peripheral T-cells were cultured with a nonsense-mediated decay (NMD) inhibitor, emetine, in order to evaluate the effect by NMD system. A bioinformatic analysis and literature review were also carried out. The details are described in online supplementary data.
The family is composed of a three-generation kindred, with autosomal dominant inheritance (figure 1A). Nine individuals were diagnosed as ‘certainly affected’ and classified as having Charcot-Marie-Tooth disease. Clinical and laboratory features of all affected individuals are summarised in online supplementary tables S1 and S2, and figure S1. Age-at-onset was 5 …
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