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

Abstract

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 (> or =10 years) groups. All patients with an early onset had severe CMTNS (> or =21) and FDS (6 or 7), whereas most patients with late onset had mild CMTNS (< or =10) and FDS (< or =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.

Role of mitofusin 2 mutations in the physiopathology of Charcot–Marie–Tooth disease type 2A

“…The amino acid residue at position 94 of the Mfn2 protein displays a mutation rate much higher than any other site. Mutations in this codon have been reported 13 times in independent patients suffering from CMT2A (5 times R94W and 7 times R94Q) (Cho et al, 2007;Chung et al, 2006;Kijima et al, 2005;Neusch et al, 2007;Verhoeven et al, 2006;Zuchner et al, 2004). This position is not located in the GTPase domain but immediately upstream of it.…”

“…Typical clinical symptoms of CMT2A are progressive distal limb muscle weakness and/or atrophy, stepping gait, distal sensory loss, and mobility impairment, which can lead to wheelchair dependency. Puzzlingly, the disease onset seems to be very diverse from one case to another but seems to be tightly related to disease severity; the sooner symptoms will appear the more severe they will be (Chung et al, 2006). Accordingly, the number of peripheral axons in the sural nerve Experimental Neurology 218 (2009) [268][269][270][271][272][273] of early onset patients is dramatically reduced while it appears unchanged in late onset patients (Chung et al, 2006).…”

“…Puzzlingly, the disease onset seems to be very diverse from one case to another but seems to be tightly related to disease severity; the sooner symptoms will appear the more severe they will be (Chung et al, 2006). Accordingly, the number of peripheral axons in the sural nerve Experimental Neurology 218 (2009) [268][269][270][271][272][273] of early onset patients is dramatically reduced while it appears unchanged in late onset patients (Chung et al, 2006). This characteristic of late onset CMT2A suggests that neurodegeneration may not be the cause of the symptoms in this group of patients.…”

“…Curiously, some patients of this group experienced recovery of visual acuity several years following onset of the symptoms . A major step in the comprehension of the disease has been reached when several studies identified mutations in the Mitofusin 2 (Mfn2) gene as responsible for CMT2A (Chung et al, 2006;Kijima et al, 2005;Verhoeven et al, 2006;Zuchner et al, 2004). In other, less frequent dominant axonal CMT2s, causative mutations have also been identified in several genes including RAS-associated GTP-binding protein gene (CMT2B), glycyl-tRNA synthetase gene (CMT2D), neurofilament light chain protein gene (CMT2E), myelin protein (CMT2I and CMT2J), heat shock proteins (CMT2F and CMT2L) (for review, see Barisic et al, 2008).…”

Case Report A novel mutation of the MFN2 gene in a Chinese family with Charcot-Marie-Tooth disease

“…Some studies have reported that the phenotype is markedly different in early (<10 years) and late disease-onset (>10 years) CMT groups with MFN2 mutations, where patients with early onset usually involve severe cases and most patients with late onset show mild symptoms (Chung et al, 2006;Banchs et al, 2008). The same phenomenon occurred in this family, where 3 patients with severe disease status had early onset (the proband, χ:2 and χ:5) at 8, 6 and 11 years, respectively; they had malformation in extremities and severe muscle atrophy and were even wheelchair-bound.…”