https://repositorio.fleni.org.ar/xmlui/handle/123456789/35 Sat, 08 Aug 2026 01:04:42 GMT 2026-08-08T01:04:42Z https://repositorio.fleni.org.ar/xmlui/handle/123456789/1563 Novel GNAO1 variant in α-helical domain reveals alternative mechanism of disease Ludlam, William Grant; Domínguez-Carral, Jana; Schteinschnaider, Ángeles; Martemyanov, Kirill A.; Ortigoza-Escobar, Juan Darío Resumen no disponible. Sun, 01 Mar 2026 00:00:00 GMT https://repositorio.fleni.org.ar/xmlui/handle/123456789/1563 2026-03-01T00:00:00Z https://repositorio.fleni.org.ar/xmlui/handle/123456789/1541 Longitudinal Phenotypic Trajectories in GNAO1-Related Disorders : Defining Disease Progression and Clinical Profiles Domínguez-Carral, Jana; Domínguez Cobo, Ana María; Balsells, Sol; Aguilar Ros, Anna; Chang, Chu-Ting; Ludlam, William Grant; Yang, Kathryn; Bernardi, Katerina; Salazar Villacorta, Ainara; Di Pisa, Veronica; Lamagrande Casanova, Nuria; González Alguacil, Elena; De la Casa Fages, Beatriz; Chinigioli, Micaela; Okumura, Akihisa; Rodríguez, Josefina; Agarwal, Ayush; Muñoz Chesta, Daniela; Reynoso Osnayo, Carolina; Lin, Amy 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. Wed, 01 Jul 2026 00:00:00 GMT https://repositorio.fleni.org.ar/xmlui/handle/123456789/1541 2026-07-01T00:00:00Z https://repositorio.fleni.org.ar/xmlui/handle/123456789/1533 Novel GNAO1 variant in α-helical domain reveals alternative mechanism of disease Ludlam, William Grant; Domínguez-Carral, Jana; Schteinschnaider, Ángeles; Martemyanov, Kirill A.; Ortigoza-Escobar, Juan Darío No abstract available. Tue, 21 Oct 2025 00:00:00 GMT https://repositorio.fleni.org.ar/xmlui/handle/123456789/1533 2025-10-21T00:00:00Z https://repositorio.fleni.org.ar/xmlui/handle/123456789/1494 Diagnostic value of genetic testing, with focus on CACNA1A, in children with episodic neurologic disorders: a single-centre retrospective study Chinigioli, Micaela; Martí-Sanchez, Laura; Yubero, Delia; Xiol, Clara; Olival, Jonathan; Alcalá San Martín, Adrián; Hernando-Davalillo, Cristina; Martorell, Loreto; Armstrong, Judith; Schteinschnaider, Ángeles; Ortigoza-Escobar, Juan Darío Background: Episodic neurologic disorders, such as paroxysmal torticollis, paroxysmal tonic upward gaze deviation, migraine, and episodic ataxia, represent a diagnostic challenge in paediatric patients. Variants in the CACNA1A and other genes such SCN8A and DEPDC5, have been implicated in episodic ataxia, hemiplegic migraine, and related conditions. However, the diagnostic yield of CACNA1A testing in paediatric populations with these symptoms remains uncertain. Methods: We conducted a retrospective study at Hospital Sant Joan de Déu, Barcelona, analysing 32 paediatric patients with episodic neurologic disorders. Clinical evaluation, neuroimaging, video EEG, and genetic testing were performed. Clinical and genetic data were correlated to identify predictors of pathogenic variants. Results: The cohort included 32 patients (21 females), with a mean age at symptom onset of 1.3 years. Paroxysmal torticollis (12/32) and paroxysmal tonic upgaze deviation (9/32) were the most frequent initial symptoms. Pathogenic variants were identified in 6/32 patients, of whom 2 carried CACNA1A variants. Positive genetic findings were significantly associated with developmental delay (p = 0.0056) and paroxysmal tonic upgaze deviation (p = 0.0185). Additional variants were identified in genes not classically linked to episodic disorders, including KAT6A, NFIX, and DEPDC5. Neuroimaging abnormalities were observed in 7/22 patients, and EEG abnormalities in 3/16. Conclusions: Genetic testing provides important insights in the evaluation of paediatric patients with episodic neurologic disorders, particularly in those with developmental delay, paroxysmal tonic upgaze, or episodic ataxia. Although the overall diagnostic yield remained low, consistent with other paroxysmal movement disorders, these findings support the integration of genetic testing into the diagnostic algorithm and underscore the need to consider broader genetic aetiologies. Larger studies are warranted to confirm these observations. Wed, 03 Dec 2025 00:00:00 GMT https://repositorio.fleni.org.ar/xmlui/handle/123456789/1494 2025-12-03T00:00:00Z