Abstracts

Rationale: Pathogenic CYFIP2 variants cause autosomal dominant developmental and epileptic encephalopathy (DEE) type 65, characterized by early-onset intractable epilepsy and developmental delay. There are no known targeted therapies. To improve our understanding of this rare disorder, we describe clinical features in CYFIP2-related DEE.

Methods: We present a novel case of CYFIP2-related DEE. Additionally, we conducted a literature review of clinical presentations across 37 patients with CYFIP2 variants.

Results:

A 2-month-old male presented with subclinical and clinical generalized myoclonic-tonic and tonic seizures confirmed on EEG. Epilepsy gene panel identified a de novo pathogenic CYFIP2 p.Arg87Cys variant. Following transition from levetiracetam and phenobarbital to lacosamide monotherapy, seizures were controlled, EEG normalized, and he met age-appropriate developmental milestones. At 6 months, he developed epileptic spasms and mild language/communication regression, which resolved with ACTH followed by vigabatrin. At 7 months, he developed a hyperkinetic choreoathetoid movement disorder. A second course of ACTH was given for modified hypsarrhythmia, with EEG improvement. At 11 months, he remains seizure-free with moderate global developmental delay.





Pathogenic CYFIP2 variants were first reported in 2000, associated with developmental delay, intellectual disability, seizures, and behavioral concerns. Since then, 37 additional cases were reported, further expanding the phenotype.^1-6 Of these cases, 10 patients had the Arg87Cys variant. Twenty-nine had epilepsy including absence, generalized tonic-clonic, tonic, myoclonic, focal, and febrile seizures. Most (n=21) had seizure onset within the first year of life, 12 developed epileptic spasms, and 4 had persistent spasms despite treatment with ACTH or steroids. Four patients developed seizures before epileptic spasms. However, no other patient had reported EEG normalization after seizure onset and before onset of spasms. Anti-seizure management was reported for 35 patients. Treatments varied; however, seizure freedom was reported in patients (n=10) treated with lacosamide, valproic acid, cannabidiol, vigabatrin, or zonisamide. Others (n=17) had intractable epilepsy. Most patients (n=35) had global developmental delay/intellectual disability. Only one other patient had a hyperkinetic choreoathetoid movement disorder.



Ref:

1. Nakashima, M, et al. Ann Neurol, 2018

2. Zweier, M, et al. Eur J Hum Genet, 2019

3. Begemann, A, et al. Genet Med, 2021

4. Hamaguchi, M. et al. Brain & Development, 2022

5. Veiga de Góes, F, et al. Open Neurology Journal, 2022

6. Slokivi, T, et al. Am J Med Genet, 2023








Conclusions: We report on the phenotypic landscape of CYFIP2-related DEE (DEE-65) and how our patient expands this phenotype, to improve our understanding of this rare, recently identified disorder. Patients with CYFIP2-related DEE have developmental delay, epilepsy with multiple seizure types, and a hyperkinetic movement disorder. Ours is the only reported case of substantial improvement with timely treatment following initial seizure onset and prior to epileptic spasms.

Funding: No funding was received in support of this abstract.