Epilepsy Unit, Department of Child Neurology, Institut de Recerca Sant Joan de Déu, Barcelona, Spain.
Department of Neuroscience, The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology, University of Florida, Jupiter, FL, USA.
Ann Neurol. 2023 Nov;94(5):987-1004. doi: 10.1002/ana.26758. Epub 2023 Aug 31.
GNAO1-related disorders (OMIM #615473 and #617493), caused by variants in the GNAO1 gene, are characterized by developmental delay or intellectual disability, hypotonia, movement disorders, and epilepsy. Neither a genotype-phenotype correlation nor a clear severity score have been established for this disorder. The objective of this prospective and retrospective observational study was to develop a severity score for GNAO1-related disorders, and to delineate the correlation between the underlying molecular mechanisms and clinical severity.
A total of 16 individuals with GNAO1-related disorders harboring 12 distinct missense variants, including four novel variants (p.K46R, p.T48I, p.R209P, and p.L235P), were examined with repeated clinical assessments, video-electroencephalogram monitoring, and brain magnetic resonance imaging. The molecular pathology of each variant was delineated using a molecular deconvoluting platform.
The patients displayed a wide variability in the severity of their symptoms. This heterogeneity was well represented in the GNAO1-related disorders severity score, with a broad range of results. Patients with the same variant had comparable severity scores, indicating that differences in disease profiles are not due to interpatient variability, but rather, to unique disease mechanisms. Moreover, we found a significant correlation between clinical severity scores and molecular mechanisms.
The clinical score proposed here provides further insight into the correlation between pathophysiology and phenotypic severity in GNAO1-related disorders. We found that each variant has a unique profile of clinical phenotypes and pathological molecular mechanisms. These findings will contribute to better understanding GNAO1-related disorders. Additionally, the severity score will facilitate standardization of patients categorization and assessment of response to therapies in development. ANN NEUROL 2023;94:987-1004.
由 GNAO1 基因变异引起的 GNAO1 相关疾病（OMIM#615473 和#617493）的特征是发育迟缓或智力残疾、低张力、运动障碍和癫痫。尚未确定该疾病的基因型-表型相关性或明确的严重程度评分。本前瞻性和回顾性观察性研究的目的是为 GNAO1 相关疾病制定严重程度评分，并阐明潜在分子机制与临床严重程度之间的相关性。
共检查了 16 名患有 GNAO1 相关疾病的个体，他们携带 12 种不同的错义变异，包括四种新变异（p.K46R、p.T48I、p.R209P 和 p.L235P），通过重复临床评估、视频脑电图监测和脑磁共振成像进行检查。使用分子分解平台描绘了每个变异的分子病理学。
患者的症状严重程度存在广泛的可变性。在 GNAO1 相关疾病严重程度评分中，这种异质性得到了很好的体现，结果范围很广。具有相同变异的患者具有可比的严重程度评分，这表明疾病谱的差异不是由于个体间的变异性，而是由于独特的疾病机制。此外，我们发现临床严重程度评分与分子机制之间存在显著相关性。
这里提出的临床评分进一步深入了解了 GNAO1 相关疾病中病理生理学与表型严重程度之间的相关性。我们发现，每个变异都有独特的临床表型和病理分子机制特征。这些发现将有助于更好地理解 GNAO1 相关疾病。此外，严重程度评分将有助于标准化患者分类，并评估正在开发的治疗方法的反应。ANN NEUROL 2023;94:987-1004。
