一例成人起病原发性侧索硬化样综合征患者中的ATP1A3 p.Arg995His新发变异

文献信息

中文摘要

背景： ATP1A3的致病性变异经典上与儿童交替性偏瘫、CAPOS综合征和快速起病性肌张力障碍-帕金森综合征相关。然而，近年来ATP1A3相关疾病的表型谱已显著扩大，包括伴有痉挛和遗传性痉挛性截瘫样表型的不典型表现。方法：我们描述了一位43岁女性，她出现了进行性上运动神经元综合征，表现为痉挛性截瘫、全身性反射亢进、双侧Babinski征、无法耗尽的踝阵挛、痉挛性构音障碍、吞咽困难和轻度小脑受累。广泛的代谢、自身免疫、感染、神经生理、神经影像和遗传学检查未能确定替代诊断。靶向下一代测序发现了一个杂合ATP1A3 NM_152296.4:c.2984G>A, p.(Arg995His)。家系分离分析证实了经生物学亲子关系验证的新发发生。该变异影响跨膜M8结构域内一个高度保守的残基，在人群数据库中缺失，并被多种计算机预测工具预测为有害。根据ACMG/AMP标准，该变异满足PM2和PP3，目前被归类为意义未明的变异（VUS）。结果：该病例提示ATP1A3相关疾病的表型谱可能扩大，并且据我们所知，这是首例报道的与ATP1A3变异相关的成人起病原发性侧索硬化样表型。结论：这些发现提示，在不明原因的成人起病上运动神经元综合征的遗传学评估中应考虑ATP1A3。

英文摘要

Pathogenic variants in ATP1A3 are classically associated with alternating hemiplegia of childhood, CAPOS syndrome, and rapid-onset dystonia-parkinsonism. However, the phenotypic spectrum of ATP1A3-related disease has expanded considerably in recent years, including atypical presentations with spasticity and hereditary spastic paraplegia-like phenotypes. We describe a 43-year-old woman who developed a progressive upper motor neuron syndrome characterized by spastic paraparesis, generalized hyperreflexia, bilateral Babinski signs, inexhaustible ankle clonus, spastic dysarthria, dysphagia, and mild cerebellar involvement. Extensive metabolic, autoimmune, infectious, neurophysiological, neuroimaging, and genetic investigations failed to identify an alternative diagnosis. Targeted next-generation sequencing identified a heterozygous ATP1A3 NM_152296.4:c.2984G>A, p.(Arg995His). Familial segregation analysis demonstrated a confirmed de novo occurrence with biological parentage verification. The variant affects a highly conserved residue within the transmembrane M8 domain, is absent from population databases, and is predicted to be deleterious by multiple in silico tools. According to ACMG/AMP criteria, the variant fulfilled PM2 and PP3 and is currently classified as a variant of uncertain significance (VUS). This case suggests a possible expansion of the phenotypic spectrum of ATP1A3-related disease and represents, to our knowledge, the first reported adult-onset primary lateral sclerosis-like phenotype associated with an ATP1A3 variant. These findings suggest that ATP1A3 should be considered in the genetic evaluation of unexplained adult-onset upper motor neuron syndromes.