High prevalence of genetic alterations in early-onset epileptic encephalopathies associated with infantile movement disorders

Abstract

Objective: Recent studies have elucidated causative roles for genetic abnormalities in early-onset epileptic encephalopathies (EOEE). Accompanying characteristic features, in addition to seizures, have also been suggested to provide important clues for an early and accurate genetic diagnosis of affected patients. In this study, we investigated the underlying genetic causes in patients with EOEE associated with infantile movement disorders.

Methods: We examined 11 patients with EOEE and involuntary movements (nine with West syndrome and two with nonsyndromic epileptic encephalopathy). All showed severe developmental delay, cognitive impairment, and involuntary movements such as chorea, ballism, dyskinesia or myoclonus, and hand stereotypies. We performed whole-exome sequencing of 10 patients, while the other patient underwent high-resolution melting analysis of candidate EOEE genes.

Results: We identified mutations in CDKL5, SCN2A, SETD5, ALG13, and TBL1XR1 in seven patients with West syndrome, and in SCN1A and GRIN1 in the two patients with unclassified epileptic encephalopathy. All mutations were validated as de novo events. The genetic cause was undetermined in the remaining two patients.

Conclusions: We found pathogenic mutations in seven genes, in nine of 11 patients with EOEE and involuntary movements. Although the results of our study are preliminary because of the small number of patients, they nevertheless suggest that specific accompanying phenotypes such as hyperkinetic movements or hand stereotypies could be important in narrowing the disease spectrum and identifying causative genetic abnormalities.

Keywords: Epileptic encephalopathy; Hand stereotype; Hyperkinetic movement; Involuntary movement; West syndrome; Whole-exome sequencing.