Lawson Victoria H, Graham Brad V, Flanigan Kevin M
Department of Neurology, University of Utah School of Medicine, Salt Lake City, UT 84132-2305, USA.
Neurology. 2005 Jul 26;65(2):197-204. doi: 10.1212/01.wnl.0000168898.76071.70.
Axonal neuropathy linked to the CMT2A locus was originally associated with a mutation in the KIF1B gene. However, mutations in this gene have not been described associated with any other CMT2A families. Recently, mutations in the MFN2 gene, encoding the mitochondrial GTPase mitofusin 2 (Mfn2), have been identified as causative of CMT2A in seven families. The authors report three additional CMT2A families associated with novel mutations in highly conserved regions of the Mfn2 GTPase domain.
The authors performed a standardized neuromuscular and nerve conduction examination, genotyped known CMT loci, and analyzed the MFN2 gene by direct sequencing in three pedigrees and 10 additional probands affected by axonal CMT.
Sequencing of the MFN2 gene revealed a novel mutation in each family (c.818T>G, c.638T>C, and c.314C>T). The largest family demonstrated an age-independent variable expression such that approximately one quarter of individuals with the mutation presented with features mild enough as to remain occult even with electrophysiologic evaluation.
These results confirm that the majority of cases of CMT linked to the CMT2A locus are due to MFN2 mutations. The phenotype is largely indistinguishable from KIF1B-related CMT and from CMT2E and CMT2F. At least in some families, as many as 25% of individuals with MFN2 mutations may be asymptomatic and have a normal electrophysiologic examination, although a detailed neuromuscular examination may suggest the trait. Given the frequency of MFN2 mutations among CMT2 probands (3/13, or 23%), genetic testing of CMT2 patients should begin with a screen of the MFN2 gene.
与CMT2A基因座相关的轴索性神经病最初与KIF1B基因突变有关。然而，尚未有该基因突变与其他CMT2A家系相关的报道。最近，编码线粒体GTP酶线粒体融合蛋白2（Mfn2）的MFN2基因突变已被确定为7个家系中CMT2A的病因。作者报告了另外3个CMT2A家系，这些家系与Mfn2 GTP酶结构域高度保守区域的新突变相关。
作者对3个家系和另外10例受轴索性CMT影响的先证者进行了标准化的神经肌肉和神经传导检查，对已知的CMT基因座进行基因分型，并通过直接测序分析MFN2基因。
MFN2基因测序显示每个家系都有一个新突变（c.818T>G、c.638T>C和c.314C>T）。最大的家系表现出与年龄无关且可变的表型，以至于大约四分之一携带该突变的个体表现出足够轻微的特征，即使经过电生理评估也仍未被发现。
这些结果证实，与CMT2A基因座相关的大多数CMT病例是由MFN2基因突变引起的。其表型与KIF1B相关的CMT以及CMT2E和CMT2F在很大程度上难以区分。至少在一些家系中，多达25%携带MFN2基因突变的个体可能无症状且电生理检查正常，尽管详细的神经肌肉检查可能提示该特征。鉴于MFN2基因突变在CMT2先证者中的频率（3/13，即23%），CMT2患者的基因检测应首先筛查MFN2基因。
