Epileptic encephalopathies in children are tied to genetic mutations

By David Douglas

NEW YORK (Reuters Health) - Genetic research has identified de novo mutations in synaptic transmission genes adding to those already associated with epileptic encephalopathies, according to researchers in the US and Europe.

"At least 12% of children with an early life epilepsy and an associated encephalopathy had an identifiable causal de novo mutation," Dr. Dennis Dlugos of The Children's Hospital of Philadelphia told Reuters Health by email.

He added, "Sending appropriate genetic testing to identify such mutations leads to a specific diagnosis with direct implications for treatment in some cases, reduces unnecessary, expensive and sometimes invasive diagnostic testing, and directly influences genetic counseling for families."

The new research, a collaboration between two consortia (EuroEPINOMICS and Epi4K/EPGP), "represents a paradigm shift in epilepsy research, giving us a new target on which to focus treatment strategies," Dr. Dlugos said in a statement. "There is tremendous potential for new drug development and personalized treatment strategies, which is our task for the years to come."

As reported September 2 online in The American Journal of Human Genetics, Dr. Dlugos and colleagues sequenced the exomes of 356 proband parent trios with what they call the "classical" epileptic encephalopathies - infantile spasms or Lennox-Gastaut syndrome - to search for additional causal de novo mutations.

They identified 429 de novo mutations. In 12% of the children, these mutations were considered unequivocally to be the cause the child's epilepsy. In addition to several known genes for childhood epilepsies, there was strong evidence for additional novel genes, many of which are involved in the function of the synapse.

Co-author Dr. Ingo Helbig, also of Children's Hospital of Philadelphia, said in a statement, "We pulled out those genes that have more mutations in patients with epilepsy than you would expect by chance. These genes will hopefully tell us a bit more about the underlying disease mechanisms and how we can address them with new treatments."

"Strikingly," say the investigators, "75% of mutations in these probands are predicted to disrupt a protein involved in regulating synaptic transmission, and there is a significant enrichment of de novo mutations in genes in this pathway in the entire cohort as well."

"Disturbance of synaptic transmission," they add, "thus seems to be a key factor in the pathogenesis of epileptic encephalopathies."

SOURCE: http://bit.ly/1rmlwwk

Am J Hum Gen 2014.

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