Researchers identify new childhood-onset epilepsy disorder and its genetic cause

Researchers from the Translational Genomics Research Institute (TGen) and the Clinic for Special Children (CSC) in Strasburg, PA, have described a new childhood-onset disorder characterized by severe epilepsy and autistic traits, and identified its genetic basis.

Epilepsies are a biologically complex group of disorders comprising many discrete genetic entities, and the majority of recurrent seizure syndromes remain unexplained. Most, if not all, epileptic disorders can be traced to abnormalities of brain structure or chemistry that alter the electrical activity of nerve cell networks. The children in this study have autistic traits, also thought to be caused by disrupted nerve cell networks.

The finding, which is published in the March 30th issue of the New England Journal of Medicine, describes the newly discovered disorder called cortical dysplasia-focal epilepsy syndrome (CDFE) in a group of closely related Old Order Amish children from Pennsylvania.

All affected children had relatively normal development until the onset of frequent intractable seizures in early childhood. Thereafter, they developed language regression and additional features of autism, possibly implicating this gene as a cause of autism in the general population. Physicians at the CSC isolated DNA from four of the affected children and their six parents and, in collaboration with TGen, identified a mutation in the gene that codes for a protein called CASPR2.

New GeneChip technologies for scanning the human genetic blueprint are powerful tools for rapidly identifying causes of disorders such as epilepsy in carefully selected families.

“The ability to rapidly decipher the genetic underpinnings of brain disorders through genetic technologies will allow the medical community to better understand disorders such as autism and epilepsy, and this understanding is the first step in developing effective treatments” said Dr. Dietrich Stephan, Director of the Neurogenomics Division at TGen, Scientific Director of the TGen/Southwest Autism Research and Resource Center’s (SARRC) autism research program, and a senior author on the study.

The protein has a well-known role in maintaining physical contacts between neurons and neighboring glial cells in the mature nervous system, but this is the first evidence that CASPR2 is also important for early human brain development.

According to Dr. Erik Puffenberger, laboratory director at the CSC, “We were able to unequivocally map the disease gene to chromosome 7 and identify a pathogenic sequence variant in the gene CNTNAP2, which codes for the CASPR2 protein. Although these patients were from an isolated population, we anticipate that CASPR2 mutations will be found in children from other populations with mental retardation, seizures, and autism.”

“Previous studies on CASPR2 in isolated cell cultures and genetic ’knockout’ mice did not predict its fundamental role in human brain development or cortical electrical activity. The present findings are compelling evidence for such roles, and open new directions for epilepsy and autism research beyond the index population,” said Dr. Kevin Strauss, a pediatrician at the CSC.

According to Dr. Holmes Morton, co-founder and medical director of the CSC, “The identification of the mutation in CASPR2 in our Amish patients has already allowed us to recognize affected newborns before they become symptomatic. Our hope is that early treatment and prevention of prolonged seizures in these infants will lessen the effects of the disorder upon the lives of children and their families.”