SAN DIEGO – Like pivotal puzzle pieces, new genetic and molecular clues to the etiology of epilepsy are bringing into focus processes that have long perplexed clinicians and researchers.
New genetic findings and the unmasking of epileptogenic molecular seizure responses were among the advances outlined by speakers at the meeting’s presidential symposium.
Photo credit: Dr. Samuel F. Berkovic
Dr. Berkovic's center's study of more than 300 twins with epilepsy has now detected a concordance rate of 0.73 for generalized epilepsy among monozygous twins.
Dr. Samuel F. Berkovic, codiscoverer of the first epilepsy gene in 1995, announced that "the impact of the new genetics is here now for clinical neurologists," bringing abundant opportunities for translational research and the possibility of unraveling causation within families burdened by epilepsy.
Population studies, twin studies, and multiplex family studies now point to a far greater impact of genetics on the development of epilepsy than ever suspected, said Dr. Berkovic, director of the Epilepsy Research Centre and laureate professor of medicine at the University of Melbourne.
"Most patients who walk into my clinic or yours don’t [speak of] a family history," he said.
Instead, "fairy stories" such as minor birth injuries or "a fall from a swing" are often cited as explanations for a family member’s seizures.
Incomplete family histories, de novo mutagenesis, and complex genetic inherence patterns all contribute to an underappreciation of the genetic underpinnings of many forms of epilepsy, not only among family members, but by clinicians as well, Dr. Berkovic explained.
His center’s study of more than 300 twins with epilepsy has now detected a concordance rate of 0.73 for generalized epilepsy among monozygous twins.
"That’s about as high as it gets in any complex disease," he said.
Monozygous concordance rates for focal epilepsy (0.34) and febrile epilepsy (0.60) were also much higher than anticipated, he said.
Epilepsy due to a single genetic mutation has proved to be rare, but "the smart money is going to be downstream, ... [with] a whole array of variants acting on common pathways."
Several unexpected findings have already surfaced in the search for genetic clues to epilepsy, including a link between mutations in the GLUT-1 gene (a glucose transporter to the brain) and paroxysmal exercise-induced dystonia and a wide spectrum of idiopathic generalized epilepsies, particularly those with absence seizures.
Unexpected deletions or duplications of gene copies have also been a fruitful avenue of study in epilepsy that includes intellectual disability or autism, Dr. Berkovic said.
Genetic investigations have become essential in such cases, producing a "hit rate on the order of 10%, somewhat of a big surprise," he said.
Studies from Dr. Berkovic’s group also revealed that the de novo mutation in the SCN1A gene found in 80% of individuals with Dravet syndrome likely occurs as early as the two-cell stage of embryonic development, since the mutation was present in a variety of tissue samples – lymphocytes, hair, buccal cells, and neuronal cells of one twin and not the other in studied pairs.
Deletion of chromosome 15q has been found to knock out seven genes and has been linked to autism, intellectual disability, and schizophrenia. Ironically, it is linked to merely a mild form of genetic generalized epilepsy.
At the opposite end of the spectrum are de novo mutations that cause profoundly severe epileptic encephalopathies in early childhood. These have now been identified as the cause of "at least a third if not half of these previously unsolved cases," he said.
"Diagnosis can be made rapidly in the clinic and one can get on with the business of counseling the families and doing the best one can with a terrible genetic burden," he said.
New technology that permits the sequencing of 20,000 genes for less than $1,000 is leading to the rapid discovery of genes underlying rare forms of epilepsy, such as the identification of the GOSR2 gene responsible for progressive myoclonic epilepsy (Am. J. Hum. Genet. 2011;88:657-63).
Genetic advances with massive parallel sequencing are "just astonishing," he said, pointing to the discovery of 50 new recessive genes for myogenic disorders.
Dr. James O. McNamara, chairman of neurobiology at Duke University Medical Center in Durham, N.C., shared Dr. Berkovic’s enthusiasm.
"This is an incredibly exciting time for the epilepsies," he marveled, embarking on a talk about a promising suspect in the search for the molecular link between complicated febrile seizures and subsequent development of mesial temporal lobe epilepsy.
Dr. McNamara reviewed a series of animal studies showing that activation of the tyrosine receptor kinase TrkB immediately following status epilepticus is both necessary and sufficient to produce temporal lobe epilepsy later in life.