Table 1_Spinocerebellar ataxias masquerading as movement disorders: clinical and genetic characterization.docx

BackgroundSpinocerebellar ataxias (SCAs) exhibit substantial clinical and genetic heterogeneity. SCAs primarily present with progressive ataxia as the cardinal clinical feature. However, they may co-occur with non-ataxic motor symptoms, including various movement disorders. Notably, certain SCA subtypes may present with movement disorders as their primary manifestation. This phenotypic complexity poses significant diagnostic challenges, particularly in distinguishing SCAs from other neurodegenerative conditions with overlapping presentations.
MethodsThis study enrolled 35 probands initially diagnosed with movement disorders. Participants were stratified into hypokinetic movement disorders and hyperkinetic movement disorders groups. After excluding known genetic causes of movement disorders through targeted next-generation sequencing (NGS) panel, negative cases received SCA repeat expansion testing. Genetically confirmed SCA cases received comprehensive clinical-genetic characterization.
ResultsFour SCA cases were identified in the hypokinetic movement disorders group (n = 28), accounting for 14.29% (4/28). Notably, an SCA8-associated familial parkinsonism pedigree manifested a novel clinical constellation: Parkinson’s disease -like phenotype with spastic paraplegia and levodopa responsive parkinsonism with dystonia. Additionally, we observed: (i) An SCA2 pedigree demonstrating intrafamilial phenotypic heterogeneity; (ii) Two sporadic early-onset parkinsonism cases harboring pathogenic expansions in SCA8 (CTA/CTG 55 repeats) and SCA3, respectively. Two SCA cases were detected in the hyperkinetic movement disorders group (n = 7), representing 28.57% (2/7). We observed: (i) an SCA3 preataxic carrier presenting with Tourette syndrome; (ii) an SCA17 case (CAG/CAA 41 repeats) manifesting dystonia and spastic paraplegia.
ConclusionWe characterized a novel clinical constellation in an SCA8-associated familial parkinsonism pedigree: Parkinson’s disease -like phenotype with spastic paraplegia and levodopa responsive parkinsonism with dystonia. We report the first documented occurrence of Tourette syndrome in the pre-ataxic stage of SCA3, though it is more likely a coincidental comorbidity independent of SCA3 progression. Furthermore, our findings indicate that SCA subtypes presenting with movement disorder-dominant phenotypes are likely underestimated in clinical practice.

背景 脊髓小脑共济失调（Spinocerebellar ataxias, SCAs）存在显著的临床与遗传异质性。该类疾病以进行性共济失调（progressive ataxia）作为核心临床特征（cardinal clinical feature），但常可伴随各类非共济失调性运动症状（non-ataxic motor symptoms），包括多种运动障碍（movement disorders）。值得注意的是，部分SCA亚型可仅以运动障碍为首发临床表现。这种表型复杂性给临床诊断带来了极大挑战，尤其是在将SCAs与其他表型重叠的神经退行性疾病进行鉴别时。
方法 本研究纳入了35例最初被诊断为运动障碍的先证者（probands）。将受试者分为运动减退型运动障碍（hypokinetic movement disorders）组与运动亢进型运动障碍（hyperkinetic movement disorders）组。通过靶向新一代测序（targeted next-generation sequencing, NGS）面板排除已知的运动障碍遗传病因后，对检测结果阴性的病例开展SCA重复扩增检测（repeat expansion testing）。经遗传学确诊的SCA病例接受了全面的临床-遗传学特征分析（clinical-genetic characterization）。
结果 在运动减退型运动障碍组（n=28）中，共检出4例SCA病例，占比14.29%（4/28）。值得关注的是，1个与SCA8相关的家族性帕金森病（Parkinson’s disease）家系展现出全新的临床表型组合：表现为帕金森病样表型伴痉挛性截瘫（spastic paraplegia），以及对左旋多巴（levodopa）应答的帕金森综合征合并肌张力障碍（dystonia）。此外，本研究还观察到：（i）1个SCA2家系呈现出家族内表型异质性（intrafamilial phenotypic heterogeneity）；（ii）2例散发性早发性帕金森病（sporadic early-onset parkinsonism）病例分别携带SCA8（CTA/CTG 55次重复）与SCA3的致病性重复扩增（pathogenic expansions）。在运动亢进型运动障碍组（n=7）中，共检出2例SCA病例，占比28.57%（2/7）。我们观察到：（i）1例处于共济失调前期（preataxic stage）的SCA3携带者表现为抽动秽语综合征（Tourette syndrome）；（ii）1例SCA17病例（CAG/CAA 41次重复）表现为肌张力障碍与痉挛性截瘫。
结论 本研究明确了1个与SCA8相关的家族性帕金森病家系的全新临床表型组合：帕金森病样表型伴痉挛性截瘫，以及对左旋多巴应答的帕金森综合征合并肌张力障碍。本研究首次报道了SCA3共济失调前期阶段出现抽动秽语综合征的病例，不过该表现更可能是与SCA3病程无关的偶然共病。此外，本研究结果提示，以运动障碍为主要表型的SCA亚型在临床实践中很可能被低估。