Mutations in two newly identified genes appear to cause Dravet syndrome in a substantial proportion of patients who do not have SCN1A gene mutations, which are known to cause the epilepsy syndrome in about 75% of affected individuals, according to a study of whole-exome sequencing in 13 patients and targeted resequencing in an additional 67 patients.
Besides four other genes that have been implicated in causing Dravet syndrome in rare cases, the genetic etiology of Dravet syndrome patients without an SCN1A mutation was previously unknown, reported lead author Gemma L. Carvill, Ph.D., of the division of genetic medicine in the department of pediatrics at the University of Washington, Seattle, and her colleagues. Now the investigators have extended the genetic causes of Dravet syndrome to mutations in the genes GABRA1 and STXBP1, as well as new SCN1A mutations that previously have not been reported and went undetected with conventional mutation detection techniques (Neurology 2014 March 12 [doi:10.1212/WNL.0000000000000291]) .
Dr. Gemma Carvill
Among four patients with novel GABRA1 mutations, three of the mutations were de novo, and the inheritance of the fourth could not be determined because parents were not available. In vitro experiments with one GABRA1 mutation indicated that it reduced sensitivity to gamma-aminobutyric acid in the brain. These four patients had a typical Dravet syndrome presentation, with the only uncommon feature being atonic drop attacks in two patients.
Three patients with Dravet syndrome onset at an age of 6-12 months had de novo STXBP1mutations. Two of the patients had both tonic and atonic seizures early in the course of the disease, which is uncommon, but tonic seizures have been reported in older Dravet syndrome patients, according to Dr. Carvill and her associates.
GABRA1 and STXBP1 mutations have been reported in other epilepsies but not previously in Dravet syndrome.
"GABRA1 and STXBP1 are significant contributors to SCN1A-negative Dravet syndrome that should be tested in patients with Dravet syndrome negative for SCN1A mutations. With identification of further cases with Dravet syndrome due to these genes, specific phenotypic patterns may emerge that distinguish these rarer causes of Dravet syndrome from those due to SCN1A mutations," the investigators wrote.
In an accompanying comment to the study, Mingxuan Xu, Ph.D., of the department of neurology at Baylor College of Medicine, Houston, wrote that the discovery provides "insights for developing new diagnostic testing and drug targets and possibly leading to individualized therapeutic strategies for [Dravet syndrome] patients with different genotypes" (Neurology 2014 March 12 [doi:10.1212/WNL.0000000000000300]).
The study was supported by a variety of governmental and nongovernmental funding sources from Australia, New Zealand, Belgium, the European Union, and the United States, including the National Institute of Neurological Disorders and Stroke. Most of the authors reported having no relevant disclosures, but some reported financial ties to companies manufacturing antiepileptic drugs and epilepsy diagnostic tests.