Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Charcot–Marie–Tooth disease type 2A with an autosomal-recessive inheritance: the first report of an adult-onset disease


Axonal Charcot–Marie–Tooth disease (CMT) is most frequently caused by mutations in the MFN2 gene (CMT2A) that can lead to various clinical phenotypes. The age at disease onset varies, but most cases occur before adolescence. We report two Japanese sisters who presented with middle-age-onset peripheral neuropathy with distinct clinical features. In the affected sisters, a homozygous missense mutation, c.1894C>T, p.R632W, corresponding to the transmembrane domain of MFN2 was identified; this mutation was heterozygous in another non-affected sibling, demonstrating co-segregation of the genotype and phenotype. The patients developed adult-onset slowly progressive muscle weakness that was predominant in the calf muscles and sensory disturbance. Magnetic resonance imaging revealed diffuse atrophy of the spinal cord, especially in the thoracic segment, and mild atrophy of the parietal lobe and the cerebellum in both patients. Electron microscopy of the sural nerve revealed clusters of round and swollen mitochondria. This is the first case report of adult-onset CMT2A with an autosomal-recessive inheritance pattern. The phenotype caused by the MFN2 mutation in these cases is very mild, considering that the mutation causes middle-aged-onset Charcot–Marie–Tooth even in the homozygous state. The mechanism of MFN2 mutation-induced toxicity is an interesting theme that awaits further investigations.

This is a preview of subscription content, access via your institution

Access options

Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Fig. 1
Fig. 2
Fig. 3


  1. Chung KW, Kim SB, Park KD, Choi KG, Lee JH, Eun HW, et al. Early onset severe and late-onset mild Charcot-Marie-Tooth disease with mitofusin 2 (MFN2) mutations. Brain. 2006;129:2103–18.

    CAS  Article  Google Scholar 

  2. Verhoeven K, Claeys KG, Zuchner S, Schroder JM, Weis J, Ceuterick C, et al. MFN2 mutation distribution and genotype/phenotype correlation in Charcot-Marie-Tooth type 2. Brain. 2006;129:2093–102.

    Article  Google Scholar 

  3. Calvo J, Funalot B, Ouvrier RA, Lazaro L, Toutain A, De Mas P, et al. Genotype-phenotype correlations in Charcot-Marie-Tooth disease type 2 caused by mitofusin 2 mutations. Arch Neurol. 2009;66:1511–6.

    Article  Google Scholar 

  4. Choi BO, Nakhro K, Park HJ, Hyun YS, Lee JH, Kanwal S, et al. A cohort study of MFN2 mutations and phenotypic spectrums in Charcot-Marie-Tooth disease 2A patients. Clin Genet. 2015;87:594–8.

    CAS  Article  Google Scholar 

  5. Abe A, Numakura C, Kijima K, Hayashi M, Hashimoto T, Hayasaka K. Molecular diagnosis and clinical onset of Charcot-Marie-Tooth disease in Japan. J Hum Genet. 2011;56:364–8.

    CAS  Article  Google Scholar 

  6. Rojo M, Legros F, Chateau D, Lombès A. Membrane topology and mitochondrial targeting of mitofusins, ubiquitous mammalian homologs of the transmembrane GTPase Fzo. J Cell Sci. 2002;115:1663–74.

    CAS  PubMed  Google Scholar 

  7. Nicholson GA, Magdelaine C, Zhu D, Grew S, Ryan MM, Sturtz F, et al. Severe early-onset axonal neuropathy with homozygous and compound heterozygous MFN2 mutations. Neurology. 2008;70:1678–81.

    CAS  Article  Google Scholar 

  8. Polke JM, Laurá M, Pareyson D, Taroni F, Milani M, Bergamin G, et al. Recessive axonal Charcot-Marie-Tooth disease due to compound heterozygous mitofusin 2 mutations. Neurology. 2011;77:168–73.

    CAS  Article  Google Scholar 

  9. Vallat J-M, Ouvrier RA, Pollard JD, Magdelaine C, Zhu D, Nicholson GA, et al. Histopathological findings in hereditary motor and sensory neuropathy of axonal type with onset in early childhood associated with mitofusin 2 mutations. J Neuropathol Exp Neurol. 2008;67:1097–102.

    Article  Google Scholar 

  10. Carr AS, Polke JM, Wilson J, Pelayo-Negro AL, Laura M, Nanji T, et al. MFN2 deletion of exons 7 and 8: founder mutation in the UK population. J Peripher Nerv Syst. 2015;20:67–71.

    CAS  Article  Google Scholar 

  11. Sun Y, Hu G, Luo J, Fang D, Yu Y, Wang X et al. Mutations in methionyl-tRNA synthetase gene in a Chinese family with interstitial lung and liver disease, postnatal growth failure and anemia. J Hum Genet. 2017;62:647–51.

  12. Bombelli F, Stojkovic T, Dubourg O, Echaniz-Laguna A, Tardieu S, Larcher K, et al. Charcot-Marie-Tooth disease type 2A: from typical to rare phenotypic and genotypic features. JAMA Neurol. 2014;71:1036–42.

    Article  Google Scholar 

  13. Itoh K, Nakamura K, Iijima M, Sesaki H. Mitochondrial dynamics in neurodegeneration. Trends Cell Biol. 2013;23:64–71.

    CAS  Article  Google Scholar 

Download references


We thank the family for their participation in this study and Dr. Sachiko Kasai, Department of Neurology, Kyoto Kizugawa Hospital, who provided us the clinical information of a patient. This study was supported, in part, by grants from the research on the Nervous and Mental Disorders and Research Committee for Charcot–Marie–Tooth Disease, Neuropathy, Ataxic Disease and Applying Health and Technology of Ministry of Health, Welfare and Labour, Japan. This research is also supported by the research program for conquering intractable disease from Japan Agency for Medical Research and Development (AMED).

Author information

Authors and Affiliations


Corresponding author

Correspondence to Hirofumi Yamashita.

Ethics declarations

Conficlt of interests

The authors declare that they have no competing financial interests.

Electronic supplementary material

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Hikiami, R., Yamashita, H., Koita, N. et al. Charcot–Marie–Tooth disease type 2A with an autosomal-recessive inheritance: the first report of an adult-onset disease. J Hum Genet 63, 89–92 (2018).

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:


Quick links