Table_1_Paroxysmal Movement Disorders.DOCX

Paroxysmal movement disorders (PxMDs) are a clinical and genetically heterogeneous group of movement disorders characterized by episodic involuntary movements (dystonia, dyskinesia, chorea and/or ataxia). Historically, PxMDs were classified clinically (triggers and characteristics of the movements) and this directed single-gene testing. With the advent of next-generation sequencing (NGS), how we classify and investigate PxMDs has been transformed. Next-generation sequencing has enabled new gene discovery (RHOBTB2, TBC1D24), expansion of phenotypes in known PxMDs genes and a better understanding of disease mechanisms. However, PxMDs exhibit phenotypic pleiotropy and genetic heterogeneity, making it challenging to predict genotype based on the clinical phenotype. For example, paroxysmal kinesigenic dyskinesia is most commonly associated with variants in PRRT2 but also variants identified in PNKD, SCN8A, and SCL2A1. There are no radiological or biochemical biomarkers to differentiate genetic causes. Even with NGS, diagnosis rates are variable, ranging from 11 to 51% depending on the cohort studied and technology employed. Thus, a large proportion of patients remain undiagnosed compared to other neurological disorders such as epilepsy, highlighting the need for further genomic research in PxMDs. Whole-genome sequencing, deep-sequencing, copy number variant analysis, detection of deep-intronic variants, mosaicism and repeat expansions, will improve diagnostic rates. Identifying the underlying genetic cause has a significant impact on patient care, modification of treatment, long-term prognostication and genetic counseling. This paper provides an update on the genetics of PxMDs, description of PxMDs classified according to causative gene rather than clinical phenotype, highlighting key clinical features and providing an algorithm for genetic testing of PxMDs.

阵发性运动障碍（Paroxysmal movement disorders, PxMDs）是一类兼具临床与遗传异质性的运动障碍疾病，以发作性不自主运动（肌张力障碍、异动症、舞蹈症和/或共济失调）为核心特征。既往PxMDs主要依据临床特征（运动触发因素与发作特点）进行分类，并以此指导单基因检测。随着下一代测序（next-generation sequencing, NGS）技术的问世，我们对PxMDs的分类与研究范式发生了革命性变革。NGS技术推动了新致病基因的发现（如RHOBTB2、TBC1D24），拓展了已知PxMDs相关致病基因的表型谱，并加深了对疾病发病机制的理解。然而，PxMDs兼具表型多效性与遗传异质性，使得基于临床表型预测基因型极具挑战。例如，阵发性运动诱发性异动症最常与PRRT2基因变异相关，但也可由PNKD、SCN8A及SCL2A1等基因的变异导致。目前尚无用于区分不同遗传病因的影像学或生物化学标志物。即便采用NGS技术，诊断率仍存在较大差异，范围为11%至51%，具体取决于研究队列与所用技术。因此，相较于癫痫等其他神经系统疾病，仍有大量患者未获得明确诊断，这凸显了开展PxMDs相关基因组研究的必要性。全基因组测序、深度测序、拷贝数变异分析、内含子深层变异检测、嵌合现象分析以及重复扩增检测等技术，有望提升PxMDs的诊断率。明确潜在遗传病因对患者诊疗、治疗方案调整、长期预后评估及遗传咨询均具有重要意义。本文对PxMDs的遗传学研究进展进行了综述，介绍了以致病基因而非临床表型为依据分类的PxMDs亚型，重点阐述了其核心临床特征，并提供了PxMDs的基因检测决策算法。