Early onset severe and late-onset mild CMT with mitofusin 2 (MFN2) mutations

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Brain. 2006 Jul 10

Early onset severe and late-onset mild Charcot-Marie-Tooth disease

with mitofusin 2 (MFN2) mutations.

Chung KW, Kim SB, Park KD, Choi KG, Lee JH, Eun HW, Suh JS, Hwang JH,

Kim WK, Seo BC, Kim SH, Son IH, Kim SM, Sunwoo IN, Choi BO.

Department of Biological Science, Kongju National University, Kongju,

Korea.

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.