2026-04-27T21:34:39Zhttps://uvadoc.uva.es/oai/request

oai:uvadoc.uva.es:10324/646502025-02-28T13:45:24Zcom_10324_1181com_10324_931com_10324_894col_10324_1387

Dominguez-Carral, Jana Ludlam, William Grant Junyent Segarra, Mar Fornaguera Marti, Montserrat Balsells, Sol Muchart, Jordi Čokolić Petrović, Dunja Espinoza, Iván Ortigoza‐Escobar, Juan Dario Martemyanov, Kirill A. Cancho Candela, Ramón 2024-01-17T11:09:39Z 2024-01-17T11:09:39Z 2023 Annals of Neurology 2023 Nov;94(5):987-1004 0364-5134 https://uvadoc.uva.es/handle/10324/64650 10.1002/ana.26758 987 5 1004 Annals of Neurology 94 1531-8249 Objective: GNAO1-related disorders (OMIM #615473 and #617493), caused by variants in the GNAO1 gene, are char acterized 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. Methods: 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. Results: The patients displayed a wide variability in the severity of their symptoms. This heterogeneity was well repre sented 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. Interpretation: 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 pheno types 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. application/pdf spa Wiley info:eu-repo/semantics/openAccess http://creativecommons.org/licenses/by-nc-nd/4.0/ Attribution-NonCommercial-NoDerivatives 4.0 Internacional Severity of GNAO1‐Related Disorder Correlates with Changes in G‐Protein Function info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion SI