PDF(Pubmed)
Abstract：
Small-Fiber Neuropathy (SFN) is a disorder of the peripheral nervous system, characterised by neuropathic pain; approximately 11% of cases are linked to variants in Voltage-Gated Sodium Channels (VGSCs). This study aims to broaden the genetic knowledge on painful SFN by applying Whole-Exome Sequencing (WES) in Early-Onset (EO) cases. A total of 88 patients from Italy (n = 52) and the Netherlands (n = 36), with a disease onset at age ≤ 45 years old and a Pain Numerical Rating Score ≥ 4, were recruited. After variant filtering and classification, WES analysis identified 142 potentially causative variants in 93 genes; 8 are Pathogenic, 15 are Likely Pathogenic, and 119 are Variants of Uncertain Significance. Notably, an enrichment of variants in transient receptor potential genes was observed, suggesting their role in pain modulation alongside VGSCs. A pathway analysis performed by comparing EO cases with 40 Italian healthy controls found enriched mutated genes in the \"Nicotinic acetylcholine receptor signaling pathway\". Targeting this pathway with non-opioid drugs could offer novel therapeutic avenues for painful SFN. Additionally, with this study we demonstrated that employing a gene panel of reported mutated genes could serve as an initial screening tool for SFN in genetic studies, enhancing clinical diagnostics.
摘要：
小纤维神经病（SFN）是一种周围神经系统的疾病，以神经性疼痛为特征;大约11%的病例与电压门控钠通道(VGSCs)的变异有关。这项研究旨在通过在早期发病（EO）病例中应用全外显子组测序（WES）来扩大对疼痛SFN的遗传知识。共有88名患者来自意大利（n=52）和荷兰（n=36），患者发病年龄≤45岁,疼痛数值评分≥4分.经过变体过滤和分类后，WES分析确定了93个基因中的142个潜在致病变异；8个是致病的，15个可能是致病的，119是不确定意义的变体。值得注意的是,观察到瞬时受体电位基因变异的富集，提示它们与VGSCs一起在疼痛调节中的作用。通过比较EO病例与40名意大利健康对照进行的通路分析发现，“烟碱乙酰胆碱受体信号通路”中的突变基因富集。用非阿片类药物靶向该途径可以为疼痛的SFN提供新的治疗途径。此外,在这项研究中，我们证明了采用一组已报告的突变基因可以作为遗传研究中SFN的初始筛选工具，加强临床诊断。
