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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 …
Contributors TK conceived the study, obtained the research fund and drafted the manuscript. KY and RO helped with the genetic experiments. YO, NT, AM, CB and HN performed the electrophysiological and neurosonographical studies. RM, YN and YI performed follow-up evaluations and coordinated the clinical studies. LP and AO performed the mutation surveillance in Italian patients and critical revision of the manuscript. AH, YH and HT co-ordinated the genetic experiments, including the experiment using a GeneChip CustomSeq Resequencing Array, and performed critical revision of the manuscript. RK obtained the research funding and provided study supervision. All the authors read and approved the final manuscript.
Funding This work was supported by the Japan Society for the Promotion of Science (JSPS KAKENHI Grant number 26461294 to TK), the Ministry of Health, Labour, and Welfare of Japan (Grants for Evidence-based Early Diagnosis and Treatment Strategies for Neuroimmunological Diseases to RK), the Intramural Research Grant (25-4) for Neurological and Psychiatric Disorders of the National Centre of Neurology and Psychiatry (NCNP), Japan (Grant to HN and RK), the Research programme for conquering intractable disease (Grant to HT), and Grant-in-Aid for Research on Rare and Intractable Diseases, the Research Committee on Establishment of Novel Treatments for Amyotrophic Lateral Sclerosis (Grant to TK, RM, RO, YI and RK) from the Japan Agency for Medical Research and development, AMED, the Italian Ministero della Salute (Grant number GR09.109 to AO), and a grant from the Università di Roma ‘Tor Vergata’, Rome, Italy (Grant number E82I15000190005 to AO). KY is a recipient of a scholarship for medical students, provided by Tokushima Prefecture. CB is supported by the Fujii-Otsuka International Education and Research Exchange Fund.
Competing interests None declared.
Patient consent Obtained.
Ethics approval Approved by the Institutional Review Boards (IRBs) of the Tokushima University Hospital, as well as local IRBs of the referring institutions.
Provenance and peer review Not commissioned; externally peer reviewed.