Literature Review

Twin Study Confirms Genetic Basis of Several Epilepsy Syndromes


 

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

The analysis did not support a genetic basis for benign epilepsy with centrotemporal spikes (BECTS) because of a lack of concordance between monozygotic pairs of twins with the disorder, said Lata Vadlamudi, PhD, Senior Lecturer at the University of Queensland in Brisbane, Australia, and her associates.

Lata Vadlamudi, PhD

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 the participants based on the 2010 International League Against Epilepsy (ILAE) scheme and incorporated molecular data when applicable.

Genetics of BECTS May Be Complex
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. Mutations most often involved the SCN1A gene, which is 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, said the researchers. “Our analysis of the BECTS twins ... highlighted that the etiology and genetics of BECTS are more complicated than initially conceptualized.”

For patients with epilepsy, 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,” said Dr. Vadlamudi.

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 Renzo Guerrini, MD, a neurologist at the University of Florence in Italy, and Jeffrey Buchhalter, MD, PhD, a neurologist at the Alberta Children’s Hospital in Calgary, Canada, in an accompanying editorial.

Jeffrey Buchhalter, MD, PhD

The study confirmed the strong genetic component of genetic epilepsy with febrile seizures plus and revealed high monozygotic concordance for the syndrome, the neurologists 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, said the coauthors. The category of genetic epilepsy might be arbitrary, for example, “as what is presumed to be symptomatic today may be revealed as genetic after molecular screening,” said Drs. Guerrini and Buchhalter.

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. “This suggests the need for a category that includes the genetic defect and interposed structural abnormality,” Drs. Guerrini and Buchhalter 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 twins with BECTS to capture those with rare monozygotic inheritance, or perhaps postzygotic mutations led to genetic discordance in twin pairs, Drs. Guerrini and Buchhalter concluded.

Amy Karon

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