Section of Neurology, St. Christopher's Hospital for Children, Drexel University College of Medicine, Philadelphia, PA 19134, USA.
Ann Neurol. 2009 Dec;66(6):759-70. doi: 10.1002/ana.21728.
To report the first cases of a homozygous recessive mutation in NEFL, the gene that encodes the light subunit of neurofilaments.
Clinical and electrophysiologic data were evaluated, and a sural nerve biopsy from one affected child was examined by immunohistochemistry and electron microscopy. The ability of the mutant protein to form filaments was characterized in an established cell culture system.
Four of five siblings developed of a severe, progressive neuropathy beginning in early childhood. Serial nerve conduction studies showed progressively reduced amplitudes with age and pronounced slowing at all ages. Visual-evoked responses were slowed in three children, indicating that central nervous system axons were subclinically involved. All four affected children were homozygous for a nonsense mutation at glutamate 210 (E210X) in the NEFL gene; both parents were heterozygous carriers. A sural nerve biopsy from an affected patient showed markedly reduced numbers of myelinated axons; the remaining myelinated axons were small and lacked intermediate filaments. The E210X mutant protein did not form an intermediate filament network and did not interfere with the filament formation by wild-type human light subunit of neurofilaments in SW-13 vim(-) cells.
This is the first demonstration of a recessive NEFL mutation, which appears to cause a simple loss of function, resulting in a severe, early-onset axonal neuropathy with unique features. These results confirm that neurofilaments are the main determinant of axonal caliber and conduction velocity, and demonstrate for the first time that neurofilaments are required for the maintenance of myelinated peripheral nervous system axons.
报道首个神经丝轻链（NEFL）基因纯合隐性突变病例，该基因编码神经丝的轻亚基。
评估临床和电生理数据，并通过免疫组织化学和电子显微镜检查受影响儿童的腓肠神经活检。在已建立的细胞培养系统中，对突变蛋白形成纤维的能力进行了特征描述。
5 个兄弟姐妹中的 4 个在儿童早期出现严重、进行性神经病。系列神经传导研究显示，随年龄增长，振幅逐渐降低，各年龄段均有明显减慢。3 名儿童的视觉诱发电位反应减慢，表明中枢神经系统轴突受到亚临床累及。所有 4 名受影响的儿童均为 NEFL 基因中谷氨酸 210（E210X）的纯合无义突变；父母均为杂合携带者。受影响患者的腓肠神经活检显示有髓神经轴突数量明显减少；剩余的有髓神经轴突较小，缺乏中间丝。E210X 突变蛋白不能形成中间丝网络，也不会干扰 SW-13 vim(-) 细胞中野生型人类神经丝轻亚基的纤维形成。
这是首次证明 NEFL 隐性突变，该突变似乎导致单纯的功能丧失，导致严重的、早发性轴索性神经病，具有独特的特征。这些结果证实神经丝是轴突口径和传导速度的主要决定因素，并首次证明神经丝对于维持有髓周围神经系统轴突是必需的。
