Developmental and epileptic encephalopathy 56 due to YWHAG variants: 12 new cases and review of the literature

BACKGROUND AND OBJECTIVES: Developmental and epileptic encephalopathy 56 (DEE-56) is caused by pathogenic variants in YWHAG and is characterized by early-onset epilepsy and neurodevelopmental delay. This study reports on a cohort of DEE-56 individuals, correlating antiseizure medication usage and comorbidities, to aid in understanding disease evolution.

METHODS: We analyzed data from thirty-nine individuals aged 3-40 years with YWHAG variants, including 12 previously unreported individuals (2 of these with recurrent distal 7q11.23 deletions) and 27 previously published cases (21 families, including 3 adult individuals reported in a family case). Our assessments encompassed clinical, radiological, and genetic evaluations. All procedures adhered to standardized protocols for patient approvals, registrations, and data collection.

RESULTS: Individuals with YWHAG variants exhibited variable psychomotor delay, with the majority experiencing mild intellectual disability. Early-onset seizures, particularly febrile seizures, were common, with various seizure types reported. Valproic acid has emerged as an effective antiseizure medication. Movement disorders were present in a subset of individuals, primarily manifesting as ataxia and tremor. Comorbidities such as autism spectrum disorders and attention deficit-hyperreactivity disorder were observed in a proportion of individuals. We identified a novel YWHAG variant (c.634_645del/p.Asn212_Ser215del) and expanded the genotypic spectrum of the disease.

CONCLUSIONS: We provide insights into the clinical, radiological, and genetic features of YWHAG-related epileptic encephalopathy. Despite mild clinical symptoms, affected individuals face challenges in daily functioning, underscoring the need for comprehensive care. Valproic acid has been used for seizure control with variable results.