Familial trigeminal neuralgia - a systematic clinical study with a genomic screen of the neuronal electrogenisome
Familial trigeminal neuralgia - a systematic clinical study with a genomic screen of the neuronal electrogenisome
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DOI：
10.1177/0333102419897623
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发表时间：
2020-01-13
期刊：
影响因子：
4.9
通讯作者：
Truini, Andrea
中科院分区：
文献类型：
--
作者：
Di Stefano, Giulia;Yuan, Jun-Hui;Truini, Andrea
目的首次对三叉神经痛患者进行横断面调查，以确定家族性病例的发生情况，为家族性疾病的临床特征提供系统的描述。由于有证据表明三叉神经节神经元的过度兴奋性与三叉神经痛有关，我们还对这些患者的神经元性遗传体进行了探索性的遗传分析。方法对所有确诊为经典型或特发性三叉神经痛的患者进行系统访谈，记录其家族史。在88例入选患者中，我们发现12例有阳性家族史的三叉神经痛患者。对11例患者进行了全外显子测序。我们集中于173个基因小组中的遗传变异，包括编码钠、钾、钙、氯的通道基因、瞬时受体电位通道和缝隙连接通道。基因表达谱基于已公布的啮齿动物/人类三叉神经节组织的RNA测序数据集，重点关注与神经元兴奋性相关的基因。结果在家族性三叉神经痛患者中，疼痛多位于右侧二分部。所有患者都报告了触发因素。4名患者出现伴随的持续性疼痛。三叉神经节电基因组全外显子测序分析发现，离子通道中有41个罕见变异，包括钠通道(6个)、钾通道(10个)、氯通道(5个)、钙通道(7个)、瞬时受体电位通道(12个)和缝隙连接通道(1个)。在一名患者中，发现了先前在痛性神经病中报道的SCN10A(Nav1.8p.Ala1304Thr)的功能获得突变；该突变在未受影响的兄弟姐妹中不存在。结论我们的结果表明，三叉神经痛的家族性发生比以前认为的更常见。尽管我们的结果显示在这些患者中存在编码电压门控离子通道和瞬时受体电位通道的基因变异，但还需要进一步的研究来确定它们在三叉神经痛发病机制中的作用。
Objective This cross-sectional study examined, for the first time, a large cohort of patients with trigeminal neuralgia, to ascertain the occurrence of familial cases, providing a systematic description of clinical features of familial disease. Since there is evidence linking hyperexcitability of trigeminal ganglion neurons to trigeminal neuralgia, we also carried out an exploratory genetic analysis of the neuronal electrogenisome in these patients. Methods We recorded familial occurrence by systematically interviewing all patients with a definite diagnosis of classical or idiopathic trigeminal neuralgia. We found 12 occurrences of trigeminal neuralgia with positive family history out of 88 enrolled patients. Whole-exome sequencing was carried out in 11 patients. We concentrated on the genetic variants within a 173-gene panel, comprising channel genes encoding sodium, potassium, calcium, chloride, transient receptor potential channels, and gap junction channels. Gene expression profiles were based on published RNA sequencing datasets of rodent/human trigeminal ganglia tissues, with a focus on genes related to neuronal excitability. Results In patients with familial trigeminal neuralgia, pain was more often located in the right, second division. All patients reported triggers. Four patients experienced concomitant continuous pain. Whole-exome sequencing analysis within the trigeminal ganglion electrogenisome identified 41 rare variants in ion channels, consisting of variants in sodium channels (6), potassium channels (10), chloride channels (5), calcium channels (7), transient receptor potential channels (12), and gap junction channels (1). In one patient, a previously profiled gain-of-function mutation in SCN10A (Nav1.8 p.Ala1304Thr), previously reported in painful neuropathy, was found; this variant was not present in unaffected siblings. Conclusions Our results suggest that familial occurrence of trigeminal neuralgia is more common than previously considered. Although our results demonstrate variants in genes encoding voltage-gated ion channels and transient receptor potential channels within these patients, further study will be needed to determine their roles in the pathogenesis of trigeminal neuralgia.