Longitudinal Phenotypic Trajectories in <scp> <i>GNAO1</i> </scp> ‐Related Disorders: Defining Disease Progression and Clinical Profiles

OBJECTIVE: Pathogenic variants in GNAO1 cause a spectrum of epilepsy, movement disorders, and developmental impairment. Clinical heterogeneity complicates prognosis and therapeutic development. We present the first longitudinal natural history study of GNAO1-related disorders (GNAO1-RD) to delineate phenotypic trajectories. METHODS: Sixty-six individuals with GNAO1-RD were included in a cross-sectional analysis. Of these, 21 were enrolled in a prospective natural history arm (March 2021-December 2024), undergoing annual standardized evaluations with validated clinical scales to monitor phenotypic progression. RESULTS: Our cohort exhibited broad phenotypic and severity variability. GNAO1-RD severity scores ranged from 0.5 to 13. Neurodevelopmental impairment varied: 45.5% lacked head control, whereas 22.7% achieved independent walking; and 65% had no expressive language. Movement disorders were nearly universal (95.5%), with dyskinetic crises in 54.5%. Epilepsy affected 51.5%, with different seizure types. Individuals carrying recurrent variants showed consistent phenotypes and severity, supporting a genotype-phenotype correlation reinforced by molecular functional data. Molecular functional analysis for 20 of 31 missense variants correlated with severity scores. Longitudinal data from 21 patients in the natural history cohort showed overall stability or mild improvement across most functional domains. No significant deterioration was observed in global severity, motor function, cognition, or quality of life. However, severe patients experienced progressive worsening of movement disorder. INTERPRETATION: This largest GNAO1-RD cohort and first longitudinal natural history study provide insights into disease progression. GNAO1-RD generally follows a non-degenerative course, showing stability or mild improvements over time in cognition, language, adaptive skills, and motor function. Importantly, although global severity scores remained stable overall, severe cases showed cumulative functional burden driven by progressive movement disorder, rather than global neurodegeneration. Mortality occurred in a subset of patients because of complications from dyskinetic crises, infections, and epilepsy-related events. Genotype-phenotype data and the GNAO1-RD severity score support early risk stratification and personalized treatment development. ANN NEUROL 2026.

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Journal
Annals of Neurology
Published
2026-04-17
DOI
https://doi.org/10.1002/ana.78213
Primary Topic
Genomics and Rare Diseases
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article
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article

Longitudinal Phenotypic Trajectories in GNAO1 ‐Related Disorders: Defining Disease Progression and Clinical Profiles

Elizabeth Jennions, Siddharth Srivastava, Wejdan Hakami, Kathryn Yang et al.
Annals of Neurology
Genomics and Rare Diseases
article

Longitudinal Phenotypic Trajectories in GNAO1 ‐Related Disorders: Defining Disease Progression and Clinical Profiles

Elizabeth Jennions, Siddharth Srivastava, Wejdan Hakami, Kathryn Yang, Divyani Garg, Beatriz De la Casa‐Fages, Manju A. Kurian, Fabian Maass, Brahim Tabarki, Salomé Nasif, Veronica Di Pisa, Iván O. Espinoza, Jana Domínguez‐Carral, Darius Ebrahimi‐Fakhari, Hirokazu Kurahashi, William G. Ludlam, Elena González Alguacil, J J Nieto-Barceló, Christoph van Riesen, Luca Soliani, Kirill A. Martemyanov, Adolfo Gallo, Husnea Ara Khan, Juan Darío Ortigoza‐Escobar, Helene Verhelst, Andreia Forno, Jobaida Parvin, Ángeles Schteinschnaider, Sol Balsells, Katerina Bernardi, Anna Duat Rodríguez, M. Troncoso, Ainara Salazar‐Villacorta, Johnny Montiel Blanco, A Lin, Dunja Čokolić Petrović, Jennifer Friedman, Jorge Luis Ramón‐Gómez, Micaela Pauni, Nuno Casanova, Micaela Chinigioli, Akihisa Okumura, Chu-Ting Chang, Daniela Muñoz‐Chesta, Ayush Agarwal, Ana María Domínguez Cobo, Luz Victoria García Ruiz, Josefina Rodríguez, María Concepción Miranda‐Herrero, Carolina Reynoso‐Osnayo, Paulo Rego Sousa, Maria del Pilar Massaro Sanchez, Anna Aguilar‐Ros
article en

Abstract

OBJECTIVE: Pathogenic variants in GNAO1 cause a spectrum of epilepsy, movement disorders, and developmental impairment. Clinical heterogeneity complicates prognosis and therapeutic development. We present the first longitudinal natural history study of GNAO1-related disorders (GNAO1-RD) to delineate phenotypic trajectories. METHODS: Sixty-six individuals with GNAO1-RD were included in a cross-sectional analysis. Of these, 21 were enrolled in a prospective natural history arm (March 2021-December 2024), undergoing annual standardized evaluations with validated clinical scales to monitor phenotypic progression. RESULTS: Our cohort exhibited broad phenotypic and severity variability. GNAO1-RD severity scores ranged from 0.5 to 13. Neurodevelopmental impairment varied: 45.5% lacked head control, whereas 22.7% achieved independent walking; and 65% had no expressive language. Movement disorders were nearly universal (95.5%), with dyskinetic crises in 54.5%. Epilepsy affected 51.5%, with different seizure types. Individuals carrying recurrent variants showed consistent phenotypes and severity, supporting a genotype-phenotype correlation reinforced by molecular functional data. Molecular functional analysis for 20 of 31 missense variants correlated with severity scores. Longitudinal data from 21 patients in the natural history cohort showed overall stability or mild improvement across most functional domains. No significant deterioration was observed in global severity, motor function, cognition, or quality of life. However, severe patients experienced progressive worsening of movement disorder. INTERPRETATION: This largest GNAO1-RD cohort and first longitudinal natural history study provide insights into disease progression. GNAO1-RD generally follows a non-degenerative course, showing stability or mild improvements over time in cognition, language, adaptive skills, and motor function. Importantly, although global severity scores remained stable overall, severe cases showed cumulative functional burden driven by progressive movement disorder, rather than global neurodegeneration. Mortality occurred in a subset of patients because of complications from dyskinetic crises, infections, and epilepsy-related events. Genotype-phenotype data and the GNAO1-RD severity score support early risk stratification and personalized treatment development. ANN NEUROL 2026.

Annals of Neurology
Scripps Research Institute (US), Boston Children's Hospital (US), Hospital Sant Joan de Déu Barcelona (ES), Riyadh Armed Forces Hospital (SA), Aichi Medical University (JP), Universidad de Los Andes, Chile (CL), Universidad Peruana Cayetano Heredia (PE), Garrahan Hospital (AR), Sahlgrenska University Hospital (SE), Ghent University Hospital (BE), Hospital Italiano de Buenos Aires (AR), Hospital Pedro de Elizalde (AR), Hospital General Universitario Gregorio Marañón (ES), Ghent University (BE), University of California San Diego (US), Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia (AR), Hospital Rafael Méndez (ES), Centre for Biomedical Network Research on Rare Diseases (ES), Hospital Infantil Universitario Niño Jesús (ES), Roosevelt Hospital (GT), Universitätsmedizin Göttingen (DE), National Institute of Neurosciences & Hospital (BD), Istituto delle Scienze Neurologiche di Bologna (IT), Sant Joan de Déu Research Foundation (ES), Klinički bolnički centar Osijek (HR), Institute of Child Health (IN), National Institute of Quality (PE), ERN GUARD-Heart (NL), Istituti di Ricovero e Cura a Carattere Scientifico (IT), Hospital San Borja Arriarán (CL), Universidad Continental (PE), Hospital Dr. Nélio Mendonça (PT), Institut de Recerca Sant Joan de Déu, University College London (GB), University of Osijek (HR), All India Institute of Medical Sciences (IN), University of Gothenburg (SE)
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