Gardner Family Center for Parkinson's Disease and Movement Disorders, Department of Neurology and Rehabilitation Medicine, University of Cincinnati, Cincinnati, OH 45219, USA.
Laboratory of Transcriptional Neurobiology, Department of Cellular, Computational and Integrative Biology-CIBIO, University of Trento, 38123 Trento, Italy.
Int J Mol Sci. 2021 Jul 7;22(14):7292. doi: 10.3390/ijms22147292.
The gold standard for classification of neurodegenerative diseases is postmortem histopathology; however, the diagnostic odyssey of this case challenges such a clinicopathologic model. We evaluated a 60-year-old woman with a 7-year history of a progressive dystonia-ataxia syndrome with supranuclear gaze palsy, suspected to represent Niemann-Pick disease Type C. Postmortem evaluation unexpectedly demonstrated neurodegeneration with 4-repeat tau deposition in a distribution diagnostic of progressive supranuclear palsy (PSP). Whole-exome sequencing revealed a new heterozygous variant in , associated with spinocerebellar ataxia type 35 (SCA35). This novel variant reduced transglutaminase activity in vitro, suggesting it was pathogenic. This case could be interpreted as expanding: (1) the PSP phenotype to include a spinocerebellar variant; (2) SCA35 as a tau proteinopathy; or (3) as a novel genetic variant underlying a SCA35 phenotype with PSP pathology. None of these interpretations seem adequate. We instead hypothesize that impairment in the crosslinking of tau by the -encoded transglutaminase enzyme may compromise tau functionally and structurally, leading to its aggregation in a pattern currently classified as PSP. The lessons from this case study encourage a reassessment of our clinicopathology-based nosology.
神经退行性疾病分类的金标准是死后组织病理学;然而，这个病例的诊断探索挑战了这种临床病理模式。我们评估了一位 60 岁的女性，她有 7 年的进行性肌张力障碍-共济失调综合征伴核上性眼球运动麻痹病史，疑似尼曼-皮克病 C 型。出乎意料的是，尸检评估显示存在神经退行性变，伴有 4 重复tau 沉积，分布符合进行性核上性麻痹 (PSP)。全外显子组测序显示一种新的杂合变体在 中，与脊髓小脑性共济失调 35 型 (SCA35) 相关。这种新的 变体降低了体外的转谷氨酰胺酶活性，提示其具有致病性。这个病例可以解释为：(1) 将 PSP 表型扩展为包括脊髓小脑型；(2) 将 SCA35 解释为 tau 蛋白病；(3) 将 解释为具有 PSP 病理学的 SCA35 表型的新型遗传变异。这些解释似乎都不充分。相反，我们假设 编码的转谷氨酰胺酶对 tau 的交联的损伤可能会损害 tau 的功能和结构，导致其在目前归类为 PSP 的模式中聚集。这个病例研究的教训鼓励我们重新评估基于临床病理的分类学。
