TY - JOUR
T1 - Longitudinal Phenotypic Trajectories in GNAO1-Related Disorders
T2 - Defining Disease Progression and Clinical Profiles
AU - Domínguez-Carral, Jana
AU - Domínguez Cobo, Ana María
AU - Balsells, Sol
AU - Aguilar-Ros, Anna
AU - Chang, Chu Ting
AU - Ludlam, William G.
AU - Yang, Kathryn
AU - Bernardi, Katerina
AU - Chinigioli, Micaela
AU - Salazar-Villacorta, Ainara
AU - Di Pisa, Veronica
AU - Lamagrande-Casanova, Nuria
AU - González-Alguacil, Elena
AU - De la Casa-Fages, Beatriz
AU - Okumura, Akihisa
AU - Rodríguez, Josefina
AU - Agarwal, Ayush
AU - Muñoz-Chesta, Daniela
AU - Reynoso-Osnayo, Carolina
AU - Lin, Amy
AU - Tabarki, Brahim
AU - Parvin, Jobaida
AU - Gallo, Adolfo Alberto
AU - Forno, Andreia
AU - Maass, Fabian
AU - Montiel Blanco, Johnny
AU - Nasif, Salomé
AU - Jennions, Elizabeth
AU - Ramón-Gómez, Jorge Luis
AU - Verhelst, Helene
AU - Nieto Barceló, Juan José
AU - Čokolić Petrović, Dunja
AU - García Ruiz, Luz Victoria
AU - van Riesen, Christoph
AU - Rego Sousa, Paulo
AU - Massaro Sanchez, Maria del Pilar
AU - Khan, Husnea Ara
AU - Hakami, Wejdan
AU - Friedman, Jennifer
AU - Espinoza-Quinteros, Iván
AU - Troncoso, Monica
AU - Garg, Divyani
AU - Pauni, Micaela
AU - Kurahashi, Hirokazu
AU - Miranda-Herrero, María Concepción
AU - Duat-Rodriguez, Anna
AU - Soliani, Luca
AU - Kurian, Manju A.
AU - Schteinschnaider, Angeles
AU - Srivastava, Siddharth
AU - Ebrahimi-Fakhari, Darius
AU - Martemyanov, Kirill A.
AU - Ortigoza-Escobar, Juan Darío
N1 - Publisher Copyright:
© 2026 The Author(s). Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.
PY - 2026/7
Y1 - 2026/7
N2 - 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;100:154-170.
AB - 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;100:154-170.
KW - Humans
KW - Female
KW - Male
KW - Disease Progression
KW - Phenotype
KW - Cross-Sectional Studies
KW - Child
KW - Longitudinal Studies
KW - Epilepsy/genetics
KW - GTP-Binding Protein alpha Subunits, Gi-Go/genetics
KW - Adolescent
KW - Movement Disorders/genetics
KW - Child, Preschool
KW - Adult
KW - Young Adult
KW - Severity of Illness Index
KW - Prospective Studies
UR - https://www.scopus.com/pages/publications/105036130277
UR - https://www.mendeley.com/catalogue/df3efb6e-2e4a-380b-bbdd-fec2ef5b93b5/
U2 - 10.1002/ana.78213
DO - 10.1002/ana.78213
M3 - Article
C2 - 41992961
AN - SCOPUS:105036130277
SN - 0364-5134
VL - 100
SP - 154
EP - 170
JO - Annals of Neurology
JF - Annals of Neurology
IS - 1
ER -