Abstracts

Rationale: Many genes for X-linked Intellectual Disability (XLID) have been published recently, however in more than 50 % of XLID families the genetic causes still remain unclear. The same can be said about epilepsy syndromes, even though Next Generation Sequencing has revealed multiple novel genetic causes. The HUWE1 gene is located on chromosome Xp11.22 and encodes an E3 ubiquitin ligase. Mutations in HUWE1 have been described in several families with intellectual disability (ID). Typically males are affected, while females are asymptomatic carriers, or have a milder phenotype. Only a few patients with a HUWE1 mutation and epilepsy have been described. In this paper we describe the phenotypic spectrum of seven patients with a HUWE1 mutation and severe epilepsy.Methods: We reviewed phenotypic data of patients with HUWE1 mutations. The probands underwent detailed clinical examinations, review of the patients’ medical records, neuroimaging and EEG investigations. Seizures were diagnosed according to the International League Against Epilepsy classification.Results: We identified seven unrelated patients with a mutation in HUWE1. Three of the patients were girls. All mutations occurred de novo. The phenotypic spectrum included mild to severe intellectual disability, severe speech delay/speech difficulties and early onset epilepsy in all patients. The observed epilepsy phenotypes were broad and included focal epilepsy, Lennox-Gastaut syndrome, unspecified epileptic encephalopathy and Landau-Kleffner Syndrome. In one patient it was associated with progressive microcephaly and growth retardation. Seizures were intractable to a broad range of antiepileptic medications in the majority of the patients. The three girls all had epileptic encephalopathies, absent speech and moderate to severe ID. X-inactivation data was available for one of the females, showing a skewed X-inactivation.Conclusions: The present study shows that mutations in HUWE1 can cause severe epileptic encephalopathies, absent speech and moderate-severe ID in females. Furthermore, the study expands the phenotypic spectrum in males with HUWE1 mutations from X-linked ID with or without treatable epilepsy to include severe epileptic encephalopathies. This study defines a novel gene for epileptic encephalopathies affecting both males and females.