News

Twin study confirmed genetic basis of several epilepsy syndromes

Publish date: August 12, 2014
By
Amy Karon

View on the News

Study illuminates genetic complexities of epilepsy

The most common epilepsy syndromes do not follow a straightforward Mendelian inheritance pattern, but instead involve combinations of large-effect and small-effect alleles and environmental factors. This twin study illuminated the genetic complexities of epilepsy and the influence of genetic variance on complex phenotypes, said Dr. Renzo Guerrini and Dr. Jeffrey Buchhalter.


Dr. Jeffrey R. Buchhalter

The study confirmed the strong genetic component of genetic epilepsy with febrile seizures plus and revealed high monozygotic concordance for the syndrome, they noted. In addition, the analysis found "compelling evidence" for a strong genetic role in generalized epilepsy, corroborating the concept of genetic epilepsy and the role of genes in some nonlesional focal epilepsies.

But it remains unclear whether current classifications for epilepsy reflect the molecular profiles of these syndromes, they said. The category of genetic epilepsy might turn out to be arbitrary, for example, "as what is presumed to be symptomatic today may be revealed as genetic after molecular screening."

The structural/metabolic epilepsy category also is heterogeneous, encompassing generalized and localized brain malformations that are determined by the time of origin of neurons with abnormal migration patterns, they said. "This suggests the need for a category that includes the genetic defect and interposed structural abnormality," they added.

The lack of concordance for monozygotic twins with benign epilepsy with centrotemporal spikes also contradicts prior reports that BECTS is primarily genetic, they noted. But perhaps the current study did not include enough BECTS twins to capture those with rare monozygotic inheritance, or perhaps postzygotic mutations led to genetic discordance in twin pairs, they said.

Dr. Guerrini is a neurologist with the University of Florence in Italy. Dr. Buchhalter is a neurologist with the Alberta Children’s Hospital and the University of Calgary (Alta.). Dr. Guerrini has received honoraria from Biocodex, UCB, and other companies. Dr. Buchhalter has been a consultant to UCB, Upsher-Smith, and Lundbeck. Their remarks were excerpted from their editorial accompanying Dr. Vadlamudi’s report (Neurology 2014 Aug. 8 [doi: 10.1212/WNL.0000000000000802]).


 

FROM NEUROLOGY

References

A study of twins with seizures confirmed the genetic basis of idiopathic generalized epilepsy, genetic epilepsy with febrile seizures plus, and focal epilepsies, investigators reported online Aug. 8 in Neurology.

The analysis did not support a genetic basis for benign epilepsy with centrotemporal spikes (BECTS), finding no concordance between monozygotic pairs of twins with the disorder, said Dr. Lata Vadlamudi of the University of Queensland in Brisbane, Australia, and her associates.

Dr. Lata Vadlamudi

The researchers calculated casewise concordance estimates for epilepsy syndromes in 558 pairs of twins with suspected epilepsy, 418 of whom had confirmed seizures. They grouped them based on the 2010 ILAE (International League Against Epilepsy) scheme, incorporating molecular data when applicable (Neurology 2014 Aug. 8 [doi: 10.1212/WNL.0000000000000790]).

The estimated concordance for monozygotic twins exceeded that for dizygotic twins for idiopathic generalized epilepsies (0.77 vs. 0.35), genetic epilepsy with febrile seizures plus (0.85 vs. 0.25), and focal epilepsies (0.40 vs. 0.03), the researchers reported.

Applying the 2010 ILAE scheme also confirmed genetic influences for syndromes classified as genetic, and 10.9% of individuals tested had large-effect mutations in known epilepsy genes or had validated susceptibility alleles, the investigators said.

Mutations most often involved the SCN1A gene, which is currently seen as the most clinically relevant gene in epilepsy, they said.

The study also found "striking monozygotic and dizygotic discordance" for BECTS, which has been presumed to have a genetic basis, the researchers said. "Our analysis of the BECTS twins ... highlighted that the etiology and genetics of BECTS are more complicated than initially conceptualized."

For epilepsy patients, the results "highlight the potential to integrate well-established clinical data with molecular genetic findings and pave the way for targeted next-generation sequencing of large cohorts, which is likely to be the next phase in diagnosis, treatment guidance, and genetic counseling," Dr. Vadlamudi and her associates wrote.

The research was supported by the National Health and Medical Research Council of Australia and fellowship funding from the Queensland Department of Health. Dr. Vadlamudi and 11 coauthors reported no disclosures. Two coauthors reported advisory or financial relationships with UCB, Janssen-Cilag EMEA, and other companies.

Next Article:

Clinical policy: critical issues in the evaluation and management of adult patients presenting to the emergency department with seizures