Natural History of YWHAG-Associated Neurodevelopmental Disorder

Area of Science:

• Genetics and Neurology
• Neurodevelopmental Disorders
• Epilepsy Pathophysiology

Background:

• The YWHAG gene, encoding a 14-3-3 protein, is implicated in cellular signaling and neuronal development.
• Emerging evidence links YWHAG gene variants to early-onset epilepsy, epileptic encephalopathy, and pediatric seizures.
• The natural history of YWHAG-associated Neurodevelopmental Disorders (YWHAG-NDD) remains largely undescribed.

Purpose of the Study:

• To conduct the first prospective natural history study of YWHAG-NDD in pediatric patients.
• To characterize the clinical presentation, seizure types, and developmental trajectory in children with YWHAG-NDD.
• To evaluate the epilepsy characteristics and treatment response in this cohort.

Main Methods:

• A prospective, single-site, nonrandomized, longitudinal study design.
• Inclusion of individuals with neurodevelopmental disorders and/or seizures due to pathogenic YWHAG variants.
• Data collection via standardized assessments, video visits, medical record review, neuroimaging, electroencephalograms, and Vineland-3 Adaptive Behavior Scales for the first 20 participants.

Main Results:

• Ninety-five percent of the 20 participants presented with seizures; one had isolated developmental delays.
• Common seizure types included generalized tonic-clonic, myoclonic, and absence seizures, with 60% experiencing fever-associated seizures.
• Epilepsy was frequently treatment-resistant (55%), with 40% experiencing status epilepticus; mild to moderate delays in language, cognition, social, and motor skills were observed.

Conclusions:

• This study provides initial insights into the natural history of YWHAG-NDD.
• Findings highlight the significant burden of epilepsy, including treatment resistance and status epilepticus, in YWHAG-NDD.
• Further research is warranted to identify optimal treatment strategies for YWHAG-NDD.