Supplementary file 1_Beyond SGCE: expanding the clinical and molecular spectrum of KCTD17- and KCNN2-related myoclonus-dystonia.docx

Myoclonus-dystonia syndrome (MDS) is a clinically and genetically heterogeneous movement disorder characterized by myoclonus and dystonia as its core features. While mutations in the epsilon-sarcoglycan gene (SGCE) account for most familial cases, heterozygous pathogenic variants in KCTD17 and KCNN2 have recently been described as novel genetic causes of MDS. We describe three patients from two Polish families presenting with progressive movement disorder combined with other features. Exome sequencing (ES) identified a novel heterozygous KCTD17 variant c.461 T > A, p.(Met154Lys) in a five-year-old girl with abnormal gait, postural instability, myoclonus, and tongue dyskinesia. In a 38-year-old woman and her 17-year-old daughter, both showing tremor, myoclonus, dystonia, and psychiatric symptoms, ES detected a heterozygous canonical splice-site c.1780-2A > G variant in KCNN2. Neuropsychological evaluation suggested a gene-specific effect of KCNN2 on psychiatric and cognitive functioning, including significant episodic memory impairment. This study broadens the clinical and molecular spectrum of KCTD17- and KCNN2-related MDS and highlights distinctive features compared with SGCE-MDS, focusing on disease progression, treatment response, and neuropsychiatric involvement. Recognition of these patterns may guide molecular diagnosis and the management of specific MDS types.

肌阵挛-肌张力障碍综合征（Myoclonus-dystonia syndrome, MDS）是一类临床与遗传异质性的运动障碍疾病，核心特征为肌阵挛与肌张力障碍。尽管ε-肌聚糖基因（epsilon-sarcoglycan gene, SGCE）的突变是多数家族性病例的致病原因，但近期研究发现KCTD17与KCNN2的杂合致病变异可作为MDS的新型遗传病因。本研究报道了来自两个波兰家庭的3例患者，均表现为进行性运动障碍伴其他伴随临床特征。外显子组测序（Exome sequencing, ES）在1例表现为步态异常、姿势不稳、肌阵挛及舌运动障碍的5岁女童体内，检出1个新型杂合KCTD17变异c.461 T > A，p.(Met154Lys)。在1例38岁女性及其17岁女儿（二人均表现为震颤、肌阵挛、肌张力障碍及精神症状）中，ES检出KCNN2基因上的经典剪接位点杂合变异c.1780-2A > G。神经心理学评估提示，KCNN2变异对精神与认知功能存在基因特异性影响，包括显著的情景记忆受损。本研究拓展了KCTD17与KCNN2相关MDS的临床与分子谱，并对比SGCE相关MDS明确了其独特的临床特征，重点涵盖疾病进展、治疗反应及神经精神受累情况。识别此类表型特征可为特定MDS亚型的分子诊断与临床管理提供指导。