Center for Neuromuscular and Neurological Rare Diseases, San Camillo Forlanini Hospital, Rome, Italy.
Neuromuscular and Rare Disease Center, Department of Neuroscience, Mental Health and Sensory Organs (NESMOS), Sapienza University, Sant'Andrea Hospital, Rome, Italy.
Eur Neurol. 2023;86(3):185-192. doi: 10.1159/000529706. Epub 2023 Feb 21.
Mutations in the neurofilament polypeptide light chain (NEFL) gene account for <1% of all forms of Charcot-Marie-Tooth (CMT) diseases and present with different phenotypes, including demyelinating, axonal and intermediate neuropathies, and with diverse pattern of transmission, with dominant and recessive inheritance being described.
Here, we present clinical and molecular data in two new unrelated Italian families, affected with CMT.
We studied fifteen subjects (11 women, 4 men), age range 23-62 year. Onset of symptoms was mainly in childhood, with running/walking difficulties; some patients were pauci-asymptomatic; almost all shared variably distributed features of absent/reduced deep tendon reflexes, impaired gait, reduced sensation, and distal weakness in the legs. Skeletal deformities were seldom documented and were of mild degree. Additional features included sensorineural hearing loss in 3 patients, underactive bladder in 2 patients, and cardiac conduction abnormalities, requiring pacemaker implantation, in one child. Central nervous system (CNS) impairment was not documented in any subject. Neurophysiological investigation disclosed feature suggestive of demyelinating sensory-motor polyneuropathy in one family and resembling an intermediate form in the other. Multigene panel analysis of all known CMT genes revealed two heterozygous variants in NEFL: p.E488K and p.P440L. While the latter change segregated with the phenotype, the p.E488K variant appeared to act as a modifier factor being associated with axonal nerve damage.
CMT related to P440L mutation in NEFL is associated with a mild, childhood-onset phenotype, showing prevalently sensory distal limbs involving and with motor impairment predominantly involving anterolateral leg muscles, in the absence of CNS involvement. Additional findings, never reported so far in patients with NEFL mutation, are cardiological and urinary dysfunctions. Our study expands the array of clinical features associated with NEFL-related CMT.
神经丝轻链（NEFL）基因突变占所有遗传性运动感觉神经病（CMT）的<1%，并表现出不同的表型，包括脱髓鞘、轴索性和中间神经元神经病，以及不同的遗传方式，包括显性和隐性遗传。
在这里，我们呈现了两个新的意大利无关家族的临床和分子数据，这些家族都受到 CMT 的影响。
我们研究了 15 名受试者（11 名女性，4 名男性），年龄在 23-62 岁之间。症状的发作主要在儿童期，表现为跑步/行走困难；一些患者为少症状型；几乎所有患者都存在分布不均的无反射/反射减弱、步态异常、感觉受损和下肢远端无力。骨骼畸形很少被记录，且程度较轻。其他特征包括 3 名患者有感觉神经性听力损失，2 名患者有膀胱功能不全，1 名儿童有心律失常需要植入起搏器。在任何患者中均未发现中枢神经系统（CNS）损害。神经生理学检查显示，一个家族中存在脱髓鞘感觉运动性多发性神经病的特征，另一个家族中则类似于中间型。对所有已知的 CMT 基因的多基因分析显示 NEFL 中有两个杂合变异：p.E488K 和 p.P440L。虽然后者变异与表型相符，但 p.E488K 变异似乎是一种修饰因子，与轴索神经损伤有关。
与 NEFL 中的 p.P440L 突变相关的 CMT 是一种轻度、儿童起病的表型，主要表现为感觉远端肢体受累，运动功能受损主要累及前外侧腿部肌肉，无中枢神经系统受累。我们的研究扩展了与 NEFL 相关的 CMT 相关的临床表现范围。
