WASHINGTON – Recently identified genes associated with severe epilepsies have shed some light on biological pathways involved in epileptogenesis, which could eventually lead to targeted treatments, Gemma Carvill, Ph.D., said at the annual meeting of the American Epilepsy Society.
The findings from a study of over 600 patients with epilepsy, which include the identification of several genes in patients linked to epileptic encephalopathies (EEs), also have diagnostic implications, according to Dr. Carvill, a postdoctoral fellow in the department of pediatrics and genetic medicine at the University of Washington, Seattle, and the lead author of the study.
Elizabeth Mechcatie/Frontline Medical News
Dr. Gemma Carvill
EEs, the most severe types of epilepsy, primarily affect children and typically involve regression after normal development normally. They tend to be refractory to treatment.
This study is an expansion of a study she and her associates reported earlier this year (Nat. Genet. 2013;45:825-30), which involved the sequencing of 19 known EE genes and 46 candidate genes in 500 patients with EEs. They made a genetic diagnosis in 10% of these patients, identifying six new genes linked to EE, including two – CHD2 and SYNGAP1 – that accounted for about 1% of EE cases each.
Mutations in CHD2 do not directly affect the regulation of neurotransmitters at the synapse but affect the structure of DNA. "We think that changes the expression of genes downstream and affects the development of the human brain," which is a hypothesis she and her associates are researching, Dr. Carvill noted during a press briefing at the meeting.
"The vast majority of EEs are refractory to current treatment, so by identifying this new gene we’re identifying new biology, and we’re exploring new pathways and potentially new ways in which we can think about treating this disorder," she said.
This finding also may be important for the "broader spectrum of neurodevelopment disorders," Dr. Carvill said, noting that they have started screening patients with other types of neurodevelopment disorders for CHD2 mutations.
The expanded study included the addition of more patients with EE as well as patients with intellectual disabilities and genetic generalized epilepsy. Dr. Carvill and her colleagues also tested more target genes, including other genes linked to EE and genes associated with neurodevelopmental disorders.
Among the preliminary results of the expanded study are the identification of specific genes associated with "discrete phenotypes," she reported. These include mutations in the GRIN2A gene, which cause epilepsy aphasia syndromes. The investigators identified four families with mutations in the GRIN2A gene, which were associated with epilepsy aphasia, a type of epilepsy in which children tend to develop normally but then lose speech and have a certain EEG pattern during sleep, Dr. Carvill said.
This is a very specific phenotype and the finding has important diagnostic implications, she added, noting that a clinician who sees this particular phenotype in a patient can obtain a screening test for this gene.
They also identified patients with mutations in the GABRA1 (gamma-aminobutyric acid [GABA] A receptor, alpha 1) gene, which cause Dravet syndrome (also known as severe myoclonic epilepsy of infancy).
The study was funded by the National Institutes of Health. Dr. Carvill had no disclosures.