New Insights in Severe Childhood Epilepsies

An international group of researchers from the Epi4K - Gene Discovery in Epilepsy and Epilepsy Phenome/Genome Project (EPGP) published important findings on the development of two severe forms of epilepsy, infantile spasms (IS) and Lennox-Gastaut syndrome (LGS). These two types of epilepsy (called ‘epileptic encephalopathies') are severe brain disorders that start at a young age and include uncontrolled seizures often with many types, frequent changes in the electrical activity of the brain seen on EEG tests, and usually other cognitive, behavioral, and neurological problems. This can lead to an early death for some people with these conditions.

  • Infantile spasms begin in children usually between 3 and 7 months old, while the onset of Lennox-Gastaut syndrome may peak between 3 and 5 years old.

  • The cause of these severe childhood epilepsies is not clear and likely has many influences.

  • It has been thought that the significant electrical activity in the brain may be causing or contributing to the cognitive, behavioral, and neurological problems that can get worse over time.

  • Until now, the role of genes on the causes of infantile spasms and Lennox-Gastaut syndrome has been largely unknown.

In this week’s online Nature journal, researchers have reported new findings showing ‘de novo gene mutations’ in patients with infantile spasms or Lennox-Gastaut syndrome that offers exciting insights into how genes may lead to these conditions. The study looked at data from 264 individuals affected with one of these conditions (149 had infantile spasms and 115 had Lennox-Gastaut syndrome) and their parents who participated in the Epilepsy Phenome Genome Project (see below). The information was looked at many different ways to try and understand the complex relationships between genes, the proteins they regulate, and how they may relate to the epilepsy conditions. New techniques were used, called "exome sequencing," that demonstrated new ways of looking at the genetics of epilepsy. They also looked at whether similar changes have been found in other neurological or developmental problems.

What’s a de novo mutation?

A de novo mutation means that there’s been a change in a gene found for the first time in one family member. The genetic change comes from a change or mutation in a germ cell (for example, a sperm or egg) from one of the parents. It’s not an inherited genetic change that comes from the DNA of a parent.

What did this study find?

  • 181 people with one of the disorders had at least one de novo mutation. This means that almost 7 out of 10 people in the study group had at least one of these genetic changes found.

  • Five genes previously linked to epilepsy were seen also in many people with one of these epilepsies.

  • There was also strong evidence for two new genes being linked to these types of epilepsy in two or more patients.

  • Ten additional genes were mutated in these patients that have a role in neurodevelopment or brain function and may cause these disorders.

  • Further study showed that many of the genetic changes were found in genes called "intolerant" genes. You normally don’t see these genes change in healthy people. In other words, the DNA sequences are usually identical in all humans and often between humans and other primates and other mammals. However, even very small changes could make the genes not work right in the body. As a result, the person could be at risk for health problems associated with those gene changes.

  • The genetic changes were seen more frequently than expected in genes related to proteins (for example the "fragile X protein") that have been associated with intellectual disabilities and autism spectrum disorder.

What does all this mean?

These findings don’t change the diagnosis or treatment of a child with infantile spasms or Lennox-Gastaut syndrome now. Yet, a few lessons were learned from this study that will affect people in the future.

  • The new methods used to find the gene changes provides promising ways of learning more about other forms of epilepsy and other health conditions.

  • The genetic make-up as a whole of people affected by epilepsy should be looked at and not just single genes or small groups of genes.

  • The study offers direction to researchers who are trying to develop new drugs or other therapies to treat people with these severe forms of epilepsy. In the future, more "personalized" approaches to treatment may be possible for people with different types of epilepsy.

The Epi4K - Gene Discovery in Epilepsy and Epilepsy Phenome/Genome Project (EPGP) is a collaborative effort, funded by the National Institute of Neurological Disorders and Stroke (NINDS), whose goal is to uncover the genetic causes of epilepsy and improve the care of people with epilepsy. Many institutions from the United States, Australia, United Kingdom and Ireland contributed to this project.

In addition to grants from NINDS (NS053998, NS077364, NS077274, NS077303, NS077276), this study was funded by Finding a Cure for Epilepsy and Seizures and the Richard Thalheimer Philanthropic Fund.

For more information: NIH Funded Study - new genes for childhood epilepsy

by Patricia Osborne Shafer RN, MN
Resource Specialist, epilepsy.com
Last Reviewed: 8/12/2013

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