Clinical and electrophysiologic features of CMT2A with mutations in the mitofusin 2 gene

Lawson, Victoria H.; Graham, Brad V.; Flanigan, Kevin M.

doi:10.1212/01.wnl.0000168898.76071.70

Cited by 158 publications

(120 citation statements)

References 48 publications

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“…The second pathogenic mutation, p.T105R, was detected in two sisters but not in their healthy parents with confirmed parentity, thus a gonadal mosaicism in one of the parents appears to be the most probable explanation. This mutation is not observed in EVS but another amino acid change, p.T105M, in the same codon was reported as causal and supports the current conclusion (17,18,28). Two other mutations, p.L209E and p.C281S, are assumed to be benign variants or recessive mutations since they were also identified in healthy relatives with normal findings under electrophysiological examination.…”

Section: Discussionsupporting

confidence: 77%

Spectrum and frequencies of mutations in the MFN2 gene and its phenotypical expression in Czech hereditary motor and sensory neuropathy type II patients

Brožková

Posadka

Laššuthová

et al. 2013

Molecular Medicine Reports

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Abstract. The axonal type of Charcot-Marie-Tooth (CMT) disorders is genetically heterogeneous, therefore the causal mutation is unlikely to be observed, even in clinically well characterized patients. Mitofusin-2 (MFN2) gene mutations are the most frequent cause of axonal CMT disorders in a number of populations. There are two phenotypes; early onset, which is severe and late onset, which is a milder phenotype. A cohort of 139 unrelated Czech patients with axonal neuropathy was selected for sequencing and multiplex ligation-dependent probe amplification analysis (MLPA) testing of the MFN2 gene. A total of 11 MFN2 mutations were detected, with eight pathogenic mutations and three potentially rare benign polymorphisms. MLPA testing in 64 unrelated patients did not detect any exon duplication or deletion. The frequency of the pathogenic mutations detected in Czech hereditary motor and sensory neuropathy type II (HMSN II) patients was 7.2%. Early onset was more frequent among pathogenic mutation cases. Therefore we propose to examine the MFN2 gene mainly in patients with early and severe axonal CMT.

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Section: Discussionsupporting

confidence: 77%

Spectrum and frequencies of mutations in the MFN2 gene and its phenotypical expression in Czech hereditary motor and sensory neuropathy type II patients

Brožková

Posadka

Laššuthová

et al. 2013

Molecular Medicine Reports

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“…35 Patients with early onset and severe disease and late onset mild disease have been described in the same family. 36 However, severity of the disease is typically similar in each family and the phenotype of the patients is likely associated with the genotype of the mutation. 32,37 Patients with PRX mutations presented with early onset, but slowly progressive symptoms, suggesting that the mutations may cause loss-of-function.…”

Section: Discussionmentioning

confidence: 99%

Molecular diagnosis and clinical onset of Charcot–Marie–Tooth disease in Japan

et al. 2011

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To study the genetic background of Japanese Charcot-Marie-Tooth disease (CMT) patients, we analyzed qualitative and quantitative changes in the disease-causing genes mainly by denaturing high performance liquid chromatography and multiplex ligation-dependent probe analysis in 227 patients with demyelinating CMT and 127 patients with axonal CMT. In demyelinating CMT, we identified 53 patients with PMP22 duplication, 10 patients with PMP22 mutations, 20 patients with MPZ mutations, eight patients with NEFL mutations, 19 patients with GJB1 mutations, one patient with EGR2 mutation, five patients with PRX mutations and no mutations in 111 patients. In axonal CMT, we found 14 patients with MFN2 mutations, one patient with GARS mutation, five patients with MPZ mutations, one patient with GDAP1 mutation, six patients with GJB1 mutations and no mutations in 100 patients. Most of the patients carrying PMP22, MPZ, NEFL, PRX and MFN2 mutations showed early onset, whereas half of the patients carrying PMP22 duplication and all patients with GJB1 or MPZ mutations showing axonal phenotype were adult onset. Our data showed that a low prevalence of PMP22 duplication and high frequency of an unknown cause are features of Japanese CMT. Low prevalence of PMP22 duplication is likely associated with the mild symptoms due to genetic and/or epigenetic modifying factors.

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“…Subsequently, further families presenting clinical and electrophysiological features of CMT2A have been identified with mutations in the MFN2 gene [8,11,19,20]. Clinical symptoms in the majority of MFN2 defect patients reported until now are predominantly confined to the peripheral nervous system.…”

Section: Introductionmentioning

confidence: 99%

Cerebral involvement in axonal Charcot-Marie-Tooth neuropathy caused by mitofusin2 mutations

et al. 2008

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■ Abstract Mutations in the mitofusin 2 (MFN2) gene are a major cause of primary axonal CharcotMarie-Tooth (CMT) neuropathy. This study aims at further characterization of cerebral white matter alterations observed in patients with MFN2 mutations. Molecular genetic, magnetic resonance imaging (MRI), magnetic resonance spectroscopy (MRS), and diffusion tensor imaging (DTI) investigations were performed in four unrelated patients aged 7 to 38 years with early onset axonal CMT neuropathy. Three distinct and so far undescribed MFN2 mutations were detected. Two patients had secondary macrocephaly and mild diffuse predominantly periventricular white matter alterations on MRI. In addition, one boy had symmetrical T2-hyperintensities in both thalami. Two patients had optic atrophy, one of them with normal MRI. In three patients proton MRS revealed elevated concentrations of total N-acetyl compounds (neuronal marker), total creatine (found in all cells) and myo-inositol (astrocytic marker) in cerebral white and gray matter though with regional variation. These alterations were most pronounced in the two patients with abnormal MRI. DTI of these patients revealed mild reductions of fractional anisotropy and mild increase of mean diffusivity in white matter. The present findings indicate an enhanced cellular density in cerebral white matter of MFN2 neuropathy which is primarily due to a reactive gliosis without axonal damage and possibly accompanied by mild demyelination.

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Clinical and electrophysiologic features of CMT2A with mutations in the mitofusin 2 gene

Cited by 158 publications

References 48 publications

Spectrum and frequencies of mutations in the MFN2 gene and its phenotypical expression in Czech hereditary motor and sensory neuropathy type II patients

Spectrum and frequencies of mutations in the MFN2 gene and its phenotypical expression in Czech hereditary motor and sensory neuropathy type II patients

Molecular diagnosis and clinical onset of Charcot–Marie–Tooth disease in Japan

Cerebral involvement in axonal Charcot-Marie-Tooth neuropathy caused by mitofusin2 mutations

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