Natural History of YWHAG-Associated Neurodevelopmental Disorder

The YWHAG gene encodes a member of the 14-3-3 protein family important for cellular signaling and neuronal migration. Recent studies suggest its role in early-onset epilepsy, epileptic encephalopathy, and seizures in children. However, the natural history of this disorder has not been described. Here we report results of the first prospective natural history study to date in children with YWHAG-associated Neurodevelopmental Disorders (YWHAG-NDDs).

The YWHAG Natural History Study is a prospective, single site, nonrandomized, longitudinal study of individuals with neurodevelopmental disorders and/or seizures secondary to pathogenic variants in YWHAG. Participants were assessed using standardized assessments via video visits, review of medical records, neuroimaging, and electroencephalograms. Adaptive function was assessed using the Vineland-3 Adaptive Behavior Scales. This paper presents data on the first 20 participants in the study, characterizing the clinical presentation, natural history, and response to treatment of epilepsy in YWHAG-NDD.

We identified 20 participants with YWHAG-NDD. Ninety-five percent presented with seizures, while one patient presented solely with developmental delays. The most commonly reported seizure types included generalized tonic-clonic seizures, myoclonic seizures, and absence seizures. Sixty percent of participants reported seizures in the setting of fever. Fifty-five percent of participants reported treatment-resistant epilepsy and 40% reported at least one episode of status epilepticus. Other notable clinical manifestations included mild to moderate delays in language skills, cognition, social skills, and motor skills.

This study helps elucidate the natural history of YWHAG-NDD. Future research should focus on optimal treatments strategies for patients with YWHAG-NDD.