RT info:eu-repo/semantics/article
T1 Severity of GNAO1‐Related Disorder Correlates with Changes in G‐Protein Function
A1 Domínguez‐Carral, Jana
A1 Ludlam, William Grant
A1 Junyent Segarra, Mar
A1 Fornaguera Marti, Montserrat
A1 Balsells, Sol
A1 Muchart, Jordi
A1 Čokolić Petrović, Dunja
A1 Espinoza, Iván
A1 Ortigoza‐Escobar, Juan Dario
A1 Martemyanov, Kirill A.
A1 Cancho-Candela, Ramon
AB 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.
PB Wiley
SN 0364-5134
YR 2023
FD 2023
LK https://uvadoc.uva.es/handle/10324/64650
UL https://uvadoc.uva.es/handle/10324/64650
LA spa
NO Annals of Neurology 2023 Nov;94(5):987-1004
DS UVaDOC
RD 06-ago-2024