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Australian-led Team Reports on New Nocturnal Epilepsy Gene

NEW YORK (GenomeWeb News) – An international team led by investigators in Australia has linked mutations in a sodium-gated potassium channel subunit gene to a subset of severe nocturnal frontal lobe epilepsy cases.

As they reported online yesterday in Nature Genetics, the researchers began by testing a family with autosomal dominant nocturnal frontal lobe epilepsy, or ADNFLE. Affected members of the family often had not only typical ADNFLE symptoms, but also intellectual and/or psychiatric features that don't usually characterize the disorder.

After narrowing in on a chromosome 9 region via linkage analyses in the family, the team identified ADNFLE-associated missense mutations in the sodium-gated potassium channel subunit gene KCNT1 by whole-exome sequencing in two affected family members. Follow-up testing on more than 100 other unrelated individuals with nocturnal frontal lobe epilepsy indicated that both inherited and de novo mutations in the gene can cause severe forms of the conditions that tend to include other co-morbidities.

"KCNT1 mutations were identified in two additional families and a sporadic case with severe ADNFLE and psychiatric features," University of South Australia researcher Leanne Dibbens and the University of Melbourne's Ingrid Scheffer, the study's co-corresponding authors, and their colleagues wrote.

"These findings implicate the sodium-gated potassium channel complex in ADNFLE, and, more broadly, in the pathogenesis of focal epilepsies," they added.

As the name suggests, ADNFLE is inherited in an autosomal dominant manner in affected families. Symptoms of the condition — including seizures that occur while individuals are asleep — generally appear in childhood, the researchers explained. And previous studies have implicated mutations to nicotinic acetylcholine receptor subunit genes in a subset of ADNFLE cases.

For the current study, the team focused on a multi-generational family with an especially severe form of ADNFLE that was accompanied by other symptoms such as intellectual disability and psychiatric disorders.

Genome-wide linkage analyses within the family led to a suspicious 2.36 million base stretch of sequence on chromosome 9, which housed almost 100 genes. Among them: two ion channel-coding genes, KCNT1 and GRIN1.

For two of the affected family members, the team turned to whole-exome sequencing to try to track down the most likely cause of ADNFLE. Indeed, missense mutations in KCNT1 that were predicted to be pathogenic turned up in one of the two exome sequences.

The mutation was not initially identified in the other family member's exome sequence data, owing to low coverage, researchers explained. But it was subsequently shown to be present in both individuals by Sanger sequencing.

Consistent with the notion that this KCNT1 mutation could be related to ADNFLE pathogenesis, the investigators did not find it when they tested 111 unaffected, ancestry-matched individuals. Nor did it turn up in the dbSNP database, they reported, or in data generated for the 1000 Genomes Project or through the National Heart, Lung, and Blood Institute's Exome Sequencing Project.

On the other hand, the team did find mutations in KCNT1 when it assessed another 108 unrelated individuals who either had ADNFLE or sporadically occurring nocturnal frontal lobe epilepsy.

That analysis helped the investigators track down two more ADNFLE-affected families with KCNT1 mutations that co-segregated with the disease, along with one case of sporadic nocturnal frontal lobe epilepsy including psychiatric features that seemed to stem from de novo mutations to KCNT1.

"[T]he phenotype associated with KNCT1 mutations is both more severe and more penetrant than that typically found with mutations affecting [nicotinic acetylcholine receptors]," the study's authors noted.

In addition to showing more pronounced ADNFLE symptoms, they explained, the disease appears to manifest itself at a younger age in the cases linked to KCNT1 mutations.

Moreover, several cases that appear to be caused by alterations to KCNT1 also included intellectual disability, psychiatric, and/or behavioral features. The severity of such symptoms varied from one individual to the next — a pattern that the researchers speculated might be due to differences in the nature and extent of the KCNT1 mutation involved.

In addition to providing clues to help classify ADNFLE cases and offer genetic counseling for families affected by it, those involved in the study say the results should also prove useful for understanding — and potentially targeting — the processes that underlie this type of epilepsy.

"[T]his finding should provide new insights into the biological mechanisms underlying the pathogenesis of ADNFLE," they concluded, "which may lead to targeted therapies addressing the serious co-morbidities as well as the debilitating seizure disorder."

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