Search

Early identification of de novo variants in patients with epilepsy raises prognostic issues toward optimal management. We analyzed the clinical and genetic information from a cohort of patients with de novo pathogenic variants to dissect genotype-phenotype correlations. Patients with de novo pathogenic variants were identified from Italy, Denmark, and Belgium. Atomic resolution Kv7.2 structures were also generated using homology modeling to map the variants. We included 34 patients with a mean age of 4.7 years. Median seizure onset was 2 days, mainly with focal seizures with autonomic signs. Twenty-two patients (65%) were seizure free at the mean age of 1.2 years. More than half of the patients (17/32) displayed severe/profound intellectual disability; however, 4 (13%) of them had a normal cognitive outcome.A total of 28 de novo pathogenic variants were identified, most missense (25/28), and clustered in conserved regions of the protein; 6 variants recurred, and 7 were novel. We did not identify a relationship between variant position and seizure offset or cognitive outcome in patients harboring missense variants. Besides, recurrent variants were associated with overlapping epilepsy features but also variable evolution regarding the intellectual outcome. We highlight the complexity of variant interpretation to assess the impact of a class of de novo mutations. Genetic modifiers could be implicated, but the study paradigms to successfully address the impact of each single mutation need to be developed.

Objective: To give a comprehensive overview of the phenotypic and genetic spectrum of STXBP1 encephalopathy (STXBP1-E) by systematically reviewing newly diagnosed and previously reported patients. Methods: We recruited newly diagnosed patients with STXBP1 mutations through an international network of clinicians and geneticists. Furthermore, we performed a systematic literature search to review the phenotypes of all previously reported patients. Results: We describe the phenotypic features of 147 patients with STXBP1-E including 45 previously unreported patients with 33 novel STXBP1 mutations. All patients have intellectual disability (ID), which is mostly severe to profound (88%). Ninety-five percent of patients have epilepsy. While one-third of patients presented with Ohtahara syndrome (21%) or West syndrome (9.5%), the majority has a nonsyndromic early-onset epilepsy and encephalopathy (53%) with epileptic spasms or tonic seizures as main seizure type. We found no correlation between severity of seizures and severity of ID or between mutation type and seizure characteristics or cognitive outcome. Neurologic comorbidities including autistic features and movement disorders are frequent. We also report 2 previously unreported adult patients with prominent extrapyramidal features. Conclusion: De novo STXBP1 mutations are among the most frequent causes of epilepsy and encephalopathy. Most patients have severe to profound ID with little correlation among seizure onset, seizure severity, and the degree of ID. Accordingly, we hypothesize that seizure severity and ID present 2 independent dimensions of the STXBP1-E phenotype. STXBP1-E may be conceptualized as a complex neurodevelopmental disorder rather than a primary epileptic encephalopathy.

Neonatal-onset epilepsies are rare conditions, mostly genetically determined, that can have a benign or severe phenotype.(1,2) There is recent recognition of de novo KCNQ2 mutations in patients with severe neonatal-onset epilepsy with intractable seizures and severe psychomotor impairment, termed KCNQ2 encephalopathy.(3,4) This is a rare condition and all patients reported so far were diagnosed well after the neonatal period.(3,4) We report on 3 new cases of KCNQ2 encephalopathy diagnosed in the neonatal period and studied with continuous video-EEG recording. We describe a distinct electroclinical phenotype and report on efficacy of antiepileptic drug (AED) therapies.