Early onset severe and late-onset mild Charcot-Marie-Tooth disease with mitofusin 2 (MFN2) mutations

K. W. Chung, S. B. Kim, K. D. Park, K. G. Choi, J. H. Lee, H. W. Eun, J. S. Suh, J. H. Hwang, W. K. Kim, B. C. Seo, S. H. Kim, I. H. Son, S. M. Kim, I. N. Sunwoo, B. O. Choi

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234 Scopus citations


Mutations in the mitofusin 2 (MFN2) gene, which encodes a mitochondrial GTPase mitofusin protein, have recently been reported to cause both Charcot-Marie-Tooth 2A (CMT2A) and hereditary motor and sensory neuropathy VI (HMSN VI). It is well known that HMSN VI is an axonal CMT neuropathy with optic atrophy. However, the differences between CMT2A and HMSN VI with MFN2 mutations remained to be clarified. Therefore, we studied the phenotypic characteristics of CMT patients with MFN2 mutations. Mutations in MFN2 were screened in 62 unrelated axonal CMT neuropathy families. We calculated CMT neuropathy scores (CMTNSs) and functional disability scales (FDSs) to quantify disease severity. Twenty-one patients with the MFN2 mutations were studied by brain MRI. Ten pathogenic mutations were identified in 26 patients from 15 families (24.2%). Six of these mutations had not been reported, and de novo mutations were observed in five families (33.3%). The electrophysiological patterns of affected individuals with the MFN2 mutations were typical of axonal CMT; however, the clinical and electrophysiological characteristics were markedly different in early (<10 years) and late disease-onset (≥10 years) groups. All patients with an early onset had severe CMTNS (≥21) and FDS (6 or 7), whereas most patients with late onset had mild CMTNS (≤10) and FDS (≤3). We identified two HMSN VI families with the R364W mutation in the early onset group; however, two other families with the same mutation did not have optic atrophy. In addition, two early onset families with R94W mutations, previously reported for HMSN VI, did not have visual impairment. Interestingly, eight patients had periventricular and subcortical hyperintense lesions by brain MRI. In the late-onset group, three patients had sensorineural hearing loss and two had bilateral extensor plantar responses. We found that MFN2 mutations are the major cause of axonal CMT neuropathy, and that they are associated with variable CNS involvements. Phenotypes were significantly different in the early and late disease-onset groups. Our findings suggest that HMSN VI might be a variant of the early onset severe CMT2A phenotype.

Original languageEnglish
Pages (from-to)2103-2118
Number of pages16
Issue number8
StatePublished - Aug 2006

Bibliographical note

Funding Information:
We wish to thank Dr M. Shy for critical review of this manuscript. This work was supported by a grant of the Korea Health 21 R&D Project, Ministry of Health and Welfare, Korea (A05-0503-A20718-05N1-00010A), and in part by the Brain Korea 21 project, Ministry of Education.


  • CMT2A
  • Charcot-Marie-Tooth disease
  • Mitofusin 2 (MFN2)


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