Klein Christopher J, Kimmel Grace W, Pittock Sean J, Engelstad JaNean E, Cunningham Julie M, Wu Yanhong, Dyck Peter J
Division of Neuroimmunology, Department of Medical Genetics, Mayo Clinic, Rochester, MN 55905, USA.
Arch Neurol. 2011 Oct;68(10):1295-302. doi: 10.1001/archneurol.2011.225.
Mitofusin 2 (MFN2) is a mitochondrial membrane protein mediating mitochondrial fusion and function. Mutated MFN2 is responsible for Charcot-Marie-Tooth type 2A2. In small kindreds, specific MFN2 mutations have been reported to associate with severity of axonal neuropathy, optic atrophy, and involvement of the central nervous system. The results of the nerve biopsy specimens suggested that the mitochondria are structurally abnormal in patients with MFN2 mutations.
To study a newly identified MFN2 mutation, Leu146Phe, and the associated phenotypes in a large kindred.
An American kindred of Northern European and Cherokee American Indian descent.
Genetic analysis revealed a novel GTPase domain MFN2 mutation Leu146Phe that associated with clinical status of 15 studied persons (10 affected and 5 unaffected) and not found in 800 control persons. Clinical manifestations were markedly different. In 1 affected person, optic atrophy and brain magnetic resonance imaging abnormalities led to multiple sclerosis diagnosis and interferon β-1a treatment when neuropathy was initially unrecognized. Age of onset ranged from 1 to 45 years. In some affected family members, severe and rapid-onset motor sensory neuropathy led to early loss of ambulation, whereas other family members experienced minimal neuropathic sensory symptoms. Despite histologically significant loss of nerve fibers, the mitochondria were not distinguishable from diseased sural nerve biopsy specimens and healthy controls.
Novel MFN2 mutation Leu146Phe causes Charcot-Marie-Tooth type 2A2. Intrafamilial clinical phenotype variability is emphasized and has important implications in genetic counseling. The clinical phenotype may mimic multiple sclerosis when optic atrophy and the characteristic brain lesions of MFN2 on magnetic resonance imaging are present and neuropathy is mild or unrecognized. The predicted molecular pathogenesis may occur without evident histological abnormalities of mitochondria in nerve.
线粒体融合蛋白2（MFN2）是一种介导线粒体融合和功能的线粒体膜蛋白。MFN2突变是2A2型遗传性运动感觉神经病的病因。在一些小家系中，已报道特定的MFN2突变与轴索性神经病的严重程度、视神经萎缩及中枢神经系统受累有关。神经活检标本结果提示，MFN2突变患者的线粒体存在结构异常。
研究一个大型家系中一个新发现的MFN2突变Leu146Phe及其相关表型。
一个具有北欧和切罗基印第安人血统的美国家系。
基因分析发现一个新的GTP酶结构域MFN2突变Leu146Phe，该突变与15名被研究人员（10名患者和5名未患病者）的临床状况相关，在800名对照者中未发现。临床表现明显不同。1名患者在最初未被识别出神经病时，因视神经萎缩和脑磁共振成像异常而被诊断为多发性硬化并接受了β-1a干扰素治疗。发病年龄为1至45岁。在一些患病家庭成员中，严重且起病迅速的运动感觉神经病导致早期行走能力丧失，而其他家庭成员仅有轻微感觉神经症状。尽管在组织学上神经纤维有明显缺失，但患病腓肠神经活检标本中的线粒体与健康对照并无差异。
新的MFN2突变Leu146Phe导致2A2型遗传性运动感觉神经病。强调了家系内临床表型的变异性，这对遗传咨询具有重要意义。当存在视神经萎缩和磁共振成像上MFN2特征性脑病变且神经病症状轻微或未被识别时，临床表型可能类似多发性硬化。预测的分子发病机制可能在神经中线粒体无明显组织学异常的情况下发生。
