Brain Advance Access originally published online on July 10, 2006
Brain 2006 129(8):2103-2118; doi:10.1093/brain/awl174
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Early onset severe and late-onset mild Charcot–Marie–Tooth disease with mitofusin 2 (MFN2) mutations
1 Department of Biological Science, Kongju National University Kongju 2 Department of Neurology, Kyung Hee University, College of Medicine, Gunpo, Korea 3 Departments of Neurology, Ewha Woman's University, College of Medicine Gunpo, Korea 4 Departments of Ophthalmology, Ewha Woman's University, College of Medicine Gunpo, Korea 5 Radiology and Ewha Medical Research Center, Ewha Woman's University, College of Medicine Gunpo, Korea 6 Division of Nanosciences, Ewha Woman's University, College of Medicine, Gunpo, Korea 7 Department of Neurology, Yonsei University College of Medicine Seoul, Korea 8 Department of Pathology, Yonsei University College of Medicine Seoul, Korea 9 Department of Neurology and INAM Neuroscience Research Center, Wonkwang University, College of Medicine Gunpo, Korea
Correspondence to: Prof. Byung-Ok Choi, MD, PhD, Department of Neurology and Ewha Medical Research Center, Ewha Woman's University, College of Medicine, Dongdaemun Hospital, 70 Jongno 6-ga, Jongno-gu, 110-783, Seoul, Korea E-mail: bochoi{at}ewha.ac.kr
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.
Key Words: Charcot–Marie–Tooth disease; CMT2A; HMSN VI; mitofusin 2 (MFN2)
Abbreviations: CMAP, compound muscle action potential; CMT, Charcot–Marie–Tooth; CMTNS, CMT neuropathy score; FDS, functional disability scale; FLAIR, fluid-attenuated inversion recovery; HMSN, hereditary motor and sensory neuropathy; MCV, motor nerve conduction velocity; MFN2, mitofusin 2; MNF, myelinated nerve fibre; MRC, Medical Research Council; PCR, polymerase chain reaction; SCV, sensory nerve conduction velocity; SNAP, sensory nerve action potential; SNHL, sensorineural hearing loss; TLIs, terminal latency indices; VEP, visual evoked potential
Received April 12, 2006. Revised May 31, 2006. Accepted June 7, 2006.
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