Ann Neurol. 2023 Aug 7. doi: 10.1002/ana.26758. Online ahead of print.
ABSTRACT
OBJECTIVE: 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.
METHODS: Sixteen 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-EEG monitoring, and brain MRI. 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 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 inter-patient 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 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. This article is protected by copyright. All rights reserved.
PMID:37548038 | DOI:10.1002/ana.26758
