Data_Sheet_1_Peripheral Nervous System Involvement in Late-Onset Cobalamin C Disease?.PDF

Background: Cobalamin C (cblC) has a fundamental role in both central and peripheral nervous system function at any age. Neurologic manifestations may be the earliest and often the only manifestation of hereditary or acquired cblC defect. Peripheral neuropathy remains a classical but underdiagnosed complication of cblC defect, especially in late-onset cblC disease caused by mutations in the methylmalonic aciduria type C and homocysteinemia (MMACHC) gene. So the clinical, electrophysiological, and pathological characteristics of late-onset cblC disease are not well-known.Methods: A retrospective study of patients with late-onset cblC disease was conducted at our hospital on a 3-year period. The neuropathy was confirmed by the nerve conduction study. Sural biopsies were performed in 2 patients.Results: Eight patients were identified, with a mean onset age of 16.25 ± 6.07 years. All patients had methylmalonic aciduria, homocysteinemia, compound heterozygous MMACHC gene mutations were detected in all patients, and 7/8 patients with c.482G>A mutation. One patient concomitant with homozygote c.665C>T mutation in 5,10-methylenetetrahydrofolate reductase (MTHFR) gene. All patients showed limb weakness and cognitive impairment. Five patients had possible sensorimotor axonal polyneuropathy predominantly in the distal lower limbs. Sural biopsies showed loss of myelinated and unmyelinated fibers. Electro microscopy revealed crystalline-like inclusions bodies in Schwann cells and axonal degeneration.Conclusion: Late-onset cblC disease had possible heterogeneous group of distal axonal neuropathy. c.482G>A mutation is a hot spot mutation in late-onset cblC disease.

背景：钴胺素C（cblC）在各个年龄段均对中枢和周围神经系统功能发挥着至关重要的作用。神经学表现可能是遗传性或获得性cblC缺陷的最早及最常见的症状。周围神经病变仍然是cblC缺陷的经典但常被漏诊的并发症，特别是在由甲基丙二酸尿症C型及高半胱氨酸血症（MMACHC）基因突变引起的晚发型cblC疾病中。因此，晚发型cblC疾病的临床、电生理和病理特征尚不明确。方法：对我院在三年期间收集的晚发型cblC疾病患者进行回顾性研究。通过神经传导研究证实了神经病变。对两名患者进行了腓神经活检。结果：共识别出8名患者，平均发病年龄为16.25±6.07岁。所有患者均患有甲基丙二酸尿症、高半胱氨酸血症，并在所有患者中检测到复合杂合的MMACHC基因突变，其中7/8名患者存在c.482G>A突变。一名患者同时存在5,10-亚甲基四氢叶酸还原酶（MTHFR）基因中的c.665C>T纯合突变。所有患者均表现出肢体无力及认知障碍。五名患者存在可能的远端感觉运动型轴突多神经病变，主要影响下肢远端。腓神经活检显示有髓和无髓纤维的丧失。电镜检查发现施万细胞和轴突中有结晶样包涵体。结论：晚发型cblC疾病可能存在异质性的远端轴突神经病变群体。c.482G>A突变是晚发型cblC疾病中的热点突变。