Charcot-Marie-Tooth disease type 2E, a disorder of the cytoskeleton
Charcot-Marie-Tooth disease type 2E, a disorder of the cytoskeleton
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DOI：
10.1093/brain/awl284
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发表时间：
2007-02-01
期刊：
影响因子：
14.5
通讯作者：
Rizzuto, Nicolo'
中科院分区：
文献类型：
--
作者：
Fabrizi, Gian Maria;Cavallaro, Tiziana;Rizzuto, Nicolo'
神经丝轻链(NF-L)是中间丝的主要组成部分，在轴突细胞骨架的组装和维持中起着举足轻重的作用。核因子-L基因突变可引起常染色体显性遗传性神经病，可归类为轴索性夏科-玛丽-牙(CMT)2E型(CMT2E)或脱髓鞘CMT 1F型(CMT1F)。这种疾病(S)的病理生理基础是难以捉摸的。对177例无髓鞘蛋白零(MPZ)、外周髓鞘蛋白22(PMP22)和连接蛋白32(GJB_1)基因突变的CMT患者进行了神经纤维营养不良基因突变分析，其中正中神经运动神经传导速度<38m/S者76例，高于38m/S者101例。我们鉴定了五个新的家系，其中包括一个新的Leu268Pro替换和一个新的del322Cys_326Asn缺失，其中包括核因子-L的头部和杆状区的四个突变。几个受检查的受影响成员在疾病严重程度和发病年龄方面表现出明显的差异。神经传导改变与轴索神经病相一致，常伴有脱髓鞘特征，如远端潜伏期延长。对先证者的腓肠神经活检病理检查发现，4例为慢性轴索神经病，以局限性堆积的神经纤维为主，伴有轴突肿胀(巨大轴突)和明显的继发性脱髓鞘；5例未见明显的神经纤维积聚，但许多有髓纤维仅由微管组成，少有或不含神经纤维。病理表型与神经传导改变的模式相关，提示NEFL突变引起细胞骨架的深刻改变，可能与NF靶向缺陷有关。
The neurofilament light chain (NF-L) is a major constituent of intermediate filaments and plays a pivotal function in the assembly and maintenance of axonal cytoskeleton. Mutations in the NF-L gene (NEFL) cause autosomal dominant neuropathies that are classified either as axonal Charcot-Marie-Tooth (CMT) type 2E (CMT2E) or demyelinating CMT type 1F (CMT1F). The pathophysiological bases of the disorder(s) are elusive. We performed a mutational analysis of NEFL in a series of 177 index cases with CMT and without mutations in the genes for peripheral myelin protein zero (MPZ), peripheral myelin protein 22 (PMP22) and connexin 32 (GJB1); the motor nerve conduction velocity (MNCV) at the median nerve was below 38 m/s in 76 cases and above 38 m/s in 101. We identified five new pedigrees with four mutations in the head and rod domains of NF-L, including a novel Leu268Pro substitution and a novel del322Cys_326Asn deletion. Several examined affected members exhibited marked variability in the severity of disease and age at onset. Nerve conduction alterations were consistent with an axonal neuropathy often associated with demyelinating features, such as prolonged distal latencies (DL). Pathological examination of sural nerve biopsies in the probands detected in four cases a chronic axonal neuropathy dominated by focal accumulations of NF with axonal swellings ( giant axons) and significant secondary demyelination; in the fifth case no NFs accumulations were evident but many myelinated fibres consisted exclusively of microtubules with few or absent NF. The pathological phenotype correlated with the pattern of nerve conduction alterations and indicated that NEFL mutations cause a profound alteration of the cytoskeleton possibly related to defective targeting of NF.