Expanding the Phenotype of CYFIP2-Related Developmental Epileptic Encephalopathy: Case Report and Literature Review.

BACKGROUND: Pathogenic CYFIP2 variants cause developmental and epileptic encephalopathy (DEE), characterized by early-onset intractable epilepsy and developmental delay. The disease course has not been delineated. Codon Arg87 is a de novo mutational hotspot associated with a severe DEE phenotype via gain-of-function mechanisms. Currently, there are no targeted therapies for CYFIP2-related DEE. Genetic therapies initiated at early symptomatic stages have demonstrated benefit in other disorders and may be an important consideration for this patient population. METHODS: We describe a child with a de novo CYFIP2 Arg87Cys variant and a unique clinical course, along with a comprehensive literature review of reported cases. We identified 41 additional patients with pathogenic or likely pathogenic CYFIP2 variants. RESULTS: The Arg87Cys variant was present in 12/42 (29%) patients. An additional 27 variants are described across 30 patients. All individuals had global developmental delay, 32/42 (76%) developed epilepsy, and 25/42 (60%) experienced seizure onset in the first year of life. Of those with seizures, 16/32 (50%) had epileptic spasms, and 5/32 (16%), including our patient, developed other seizure types before epileptic spasm onset. Interestingly, our patient is the only report of developmental and electroencephalographic (EEG) normalization after initial seizure onset and before spasms. CONCLUSIONS: Our patient expands the phenotype of CYFIP2-related DEE by demonstrating developmental and EEG normalization after seizure onset and before onset of epileptic spasms and global developmental delay. Given the growing field of genetic therapies and other precision medicines, this period of normalization may represent a window of opportunity for future early intervention.