Abstracts

Rationale: Heterozygous loss-of-function mutations in the X-linked CASK gene cause progressive microcephaly with pontine and cerebellar hypoplasia (MICPCH) and severe intellectual disability (ID) in females. Different CASK mutations have also been reported in males. The associated phenotypes range from nonsyndromic ID to early infantile epileptic encephalopathy (EIEE) with cerebellar hypoplasia. Herein, we report on three male patients with CASK gene mutation-related epilepsy and epilepsy syndrome. Methods: Three patients, from two families, presented with epilepsy and psychomotor retardation. Patient 1 exhibited the first seizure at the age of 1 month and then multiple seizure types followed, including epileptic spasms, myoclonic seizures, focal seizures with or without evolving to bilateral tonic-clonic seizures. EEG of patient 1 showed suppression-burst pattern and the brain MRI revealed pontine and cerebellar hypoplasia. Patients 2 and 3 were siblings and both showed the first clinical seizure at the age of 6 months with the clinical feature of flexor spasms. EEG of patients 2 and 3 showed intermittent hypsarrhythmia and the brain MRIs were unremarkable. Diagnostic whole genome sequencing was performed. Results: Patient 1 had CASK c.764A (p.R255H) gene mutation. Patients 2 and 3 had hemizygous mosaic CASK c.616G>A (p.G206S) gene mutations, which were novel mutations. Patient 1 was in bed-ridden status and still had intractable epilepsy despite administration of multiple antiepileptic drugs, while patients 2 and 3 showed well seizure control under Valpropic acid and Vigabatrin. Conclusions: CASK-related EIEE with cerebellar atrophy and epileptic spasms in male patients might be underdiagnosed. Early diagnosis is important to provide genetic counseling for the patients’ families. Funding: No funding