Neuropediatría.artículos

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

Wed, 01 Jul 2026 00:00:00 GMT

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.

Novel GNAO1 variant in α-helical domain reveals alternative mechanism of disease

Sun, 01 Mar 2026 00:00:00 GMT

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.

Diagnostic value of genetic testing, with focus on CACNA1A, in children with episodic neurologic disorders: a single-centre retrospective study

Wed, 03 Dec 2025 00:00:00 GMT

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.

Lactic acidosis, rhabdomyolysis, and hyperammonemia: Atypical presentation in a new patient with PDE-ALDH7A1 defect

Fri, 10 Oct 2025 00:00:00 GMT

Lactic acidosis, rhabdomyolysis, and hyperammonemia: Atypical presentation in a new patient with PDE-ALDH7A1 defect Bottino, Marina; Boyer, Monica; Steenari, Maija R.; Barrick, Rebekah; Abdenur, Jose E. Pyridoxine-Dependent Epilepsy (PDE) is an autosomal recessive disorder caused by biallelic variants in ALDH7A1. The most common presentation is intractable seizures in the neonatal/early infantile period, which respond to pyridoxine. Other manifestations include perinatal asphyxia, hypoglycemia, and neuroimaging abnormalities. Despite early treatment, patients often have neurodevelopmental abnormalities. Treatment guidelines recommend triple therapy with pyridoxine, dietary lysine restriction, and arginine supplementation. We report an individual presenting with laboratory abnormalities suggestive of mitochondrial disease. Born full-term, via NSVD, with normal Apgar scores and cord gases. At 30 min, grunting developed, and at 4 h of life, jerky movements with eye deviation were noted. Laboratory results revealed acidosis (pH 7.15) and increased lactate (11.4 mMol/L, rr <2.1). The patient was started on IV fluids, given 1 mEq/kg of sodium bicarbonate, and transferred for higher-level care. Upon arrival, the evaluation was notable for hypotonia, non-rhythmic jerking movements, rapid eye blinking, and a critically low pH (6.92), high lactate (15.3 mMol/L), hyperammonemia (153 μMol/L, rr < 75), and a creatine kinase level of 15,742 U/L (rr 35-230). A single dose of phenobarbital was given, and the baby was intubated and ventilated. Video electroencephalogram (vEEG) showed a discontinuous background with abnormal, sharply contoured bursts alternating with suppression, with no clinical correlation. The patient was treated with continuous sodium bicarbonate drip and IV fluids, restricting glucose. Abnormal movements, lactic acidosis, and hyperammonemia resolved within 24 h. An electroencephalogram (EEG) at 5 days of life (DOL) showed a mildly discontinuous background with no epileptic activity, and MRI showed a thin corpus callosum, cysts, and cerebellar hypoplasia. Creatine kinase peaked at 30,995 U/L and normalized on DOL 8. Organic acids revealed significant increases in lactate, 2-OH-butyrate, pyruvate, 3-OH-butyrate, 2-OH-isovalerate, and a mild increase in Krebs-cycle intermediates. Rapid whole genome sequence (rWGS) was available on DOL 9, disclosing two variants in ALDH7A1: c.1559C > T p.Ser520Phe, previously reported, and c.1540 A > G p.Lys514Glu, considered a VUS. Treatment with pyridoxine started at 30 mg/kg/day. Pre-treatment biomarkers were consistent with the diagnosis of PDE-ALDH7A1: urine Pipecolate 117.8 mMol/mol, RR ≤10, 6-oxo-Pipecolate 8.4 mMol/mol, RR ≤2.0 and plasma alpha-aminoadipic semialdehyde (AASA) 5.2 uMol/L, RR <0.4. Treatment with arginine was added on DOL 10 (200 mg/kg/day) and a lysine-restricted diet on DOL 12, after TPN was discontinued. Clinical exam improved, no seizures were observed, and EEG normalized. PDE biomarkers decreased, and the patient was discharged home on DOL 25. Elevated lactic acid has been reported in up to 70.3 % of PDE-ALDH7A1 patients with neonatal-onset; however, there is limited information about its severity, etiology, or pathophysiologic mechanism. We, therefore, conducted a review of published cases of neonatal-onset PDE-ALDH7A1 whose actual lactic acid values were reported. A total of 12 patients were analyzed and compared to this case. In most instances, a trigger (such as pulmonary hemorrhage, postnatal hypoxia, or status epilepticus) could be identified as the cause of elevated lactic acid; nevertheless, in many individuals, lactic acidosis remained unexplained. This case expands on the biochemical presentation of PDE-ALDH7A1 and highlights the importance of identifying increased lactic acid as another of its manifestations. We also provide evidence to support the reclassification of the c.1540 A > G (p.Lys514Glu) variant as pathogenic.