Supplementary Material for: The Expanding Phenotypic Spectrums Associated with <b><i>ATP1A3</i></b> Mutation in a Family with Rapid-Onset Dystonia Parkinsonism

<b><i>Introduction:</i></b> Rapid-onset dystonia parkinsonism (RDP), also referred to as Dystonia 12, is a rare autosomal dominant genetic disease characterized by abrupt onset of a rostrocaudal gradient of dystonia with prominent bulbar symptoms, and parkinsonian features, primarily bradykinesia and postural instability without tremor. The purpose of this study was to identify the genetic defect in a Chinese pedigree with familial RDP and to explore genotype-phenotype correlation. <b><i>Methods:</i></b> A 3-generation Chinese Han pedigree consisting of 9 members and 3 patients with RDP, and 200 unrelated ethnically matched normal subjects were recruited in this study. Exome sequencing was performed in the proband, and Sanger sequencing was then conducted in other family members and 200 normal controls. <b><i>Results:</i></b> In addition to the typical clinical manifestations of RDP, the proband and her sister presented tongue tremor which developed at the onset, and intriguingly the proband showed a “re-emergent” tongue tremor. Both the proband and her sister had a medical history of hyperthyroidism, and at the psychiatric interview they both received diagnoses of depression and anxiety. Excessive grammar errors existed in most sentences written by the proband, and this written-expression disorder occurred years before the onset of RDP. The mother of the proband presented tongue enlargement, oromandibular dystonia, and limb dystonia, which were not observed in her 2 daughters at the time of study. A missense variant, c.1838C&gt;T (p.T613M), in the <i>ATP1A3</i> gene, was identified in the 3 patients in the family and in 2 young children but was absent in family members without RDP and in the 200 normal controls. <b><i>Conclusion:</i></b> These findings may broaden the phenotypic spectrums of RDP with mutations in the <i>ATP1A3</i> gene, provide new insights into the diagnosis of RDP, and have implications for genetic counseling.

**引言：** 快速起病的肌张力障碍帕金森综合征（Rapid-onset dystonia parkinsonism, RDP），又称肌张力障碍12型（Dystonia 12），是一种罕见的常染色体显性遗传性疾病，其临床特征为突发的、呈颅尾梯度分布的肌张力障碍，伴显著延髓症状，以及以运动迟缓、姿势不稳为核心表现且无震颤的帕金森样症状。本研究旨在对一个携带家族性RDP的中国汉族家系进行致病基因鉴定，并探讨基因型与表型的关联。
**方法：** 本研究招募了一个包含9名成员、3名RDP患者的3代中国汉族家系，以及200名种族匹配的无关健康对照。对先证者（proband）进行外显子组测序（Exome sequencing），随后对其余家系成员及200名健康对照进行桑格测序（Sanger sequencing）验证。
**结果：** 除RDP典型临床表现外，先证者及其姐妹在发病初期即出现舌震颤，且值得关注的是，先证者还出现了"复现性"舌震颤。先证者及其姐妹均有甲状腺功能亢进病史，精神科访谈显示二人均被诊断为抑郁及焦虑障碍。先证者撰写的语句中存在大量语法错误，该书写表达障碍在RDP发病数年前即已出现。先证者的母亲表现为舌体增大、口下颌肌张力障碍及肢体肌张力障碍，但在研究随访时其两名女儿未出现此类表现。在该家系的3名RDP患者及2名幼儿中检出了ATP1A3基因的错义变异c.1838C>T（p.T613M），而在无RDP的家系成员及200名健康对照中未检出该变异。
**结论：** 本研究结果可拓宽ATP1A3基因突变相关RDP的表型谱，为RDP的临床诊断提供新视角，并可为遗传咨询提供参考依据。

搜集汇总

背景与挑战

背景概述

该数据集是《ATP1A3基因突变在快速发作性肌张力障碍-帕金森综合征家系中扩展表型谱》研究的补充材料，包含4个临床视频，展示与突变相关的症状如构音障碍和舌震颤。研究基于一个中国汉族家系，通过基因测序发现ATP1A3基因突变，并报告了舌震颤、甲状腺功能亢进等扩展表型，为疾病诊断和遗传咨询提供新见解。