Recessive axonal Charcot-Marie-Tooth disease due to compound heterozygous mitofusin 2 mutations

• DOI: 10.1212/wnl.0b013e3182242d4d
• Publication Date: 2011-06-30T04:35:21Z
• Authors: J.M. Polke; M. Laurá; D. Pareyson; F. Taroni; M. Milani; G. Bergamin; V.S. Gibbons; H. Houlden; S.C. Chamley; J. Blake; C. DeVile; R. Sandford; M.G. Sweeney; M.B. Davis; M.M. Reilly
• Keywords: Compound heterozygosity; Nonsense mutation; Nonsense

Mutations in mitofusin 2 (MFN2) are the most common cause of axonal Charcot-Marie-Tooth disease (CMT2). Over 50 mutations have been reported, mainly causing autosomal dominant disease, though families with homozygous or compound heterozygous described. We present 3 early-onset CMT2 associated MFN2 mutations. Transcriptional analysis was performed to investigate effects mutations.Patients were examined clinically and electrophysiologically; parents also where available. Genetic investigations included DNA sequencing dosage by multiplex ligation-dependent probe amplification. mRNA transcripts from blood lymphocytes analyzed families.Compound heterozygosity for varying severity between pedigrees. Parents, examined, unaffected expected Four novel detected (one missense, one nonsense, an intragenic deletion exons 7 + 8, a 3-base pair deletion), as well previously reported missense demonstrated aberrant splicing exonic indicated nonsense-mediated decay mutant alleles premature truncating mutations.Our findings confirm that can apparent recessive inheritance. Novel genetic include decay. Carrier asymptomatic, suggesting null be nonpathogenic unless coinherited another mutation.