Three studies associated with Michael Hammer’s investigation into the cause of his daughter’s epilepsy are reported in peer-reviewed journals.
• The first sought a genetic cause for Shay Hammer’s epilepsy and involved sequencing of the entire genome of Shay, her parents, Michael and Susanne Hammer, and her brother, Isaac.
It found a genetic mutation that existed only in Shay’s genome (de novo). Researchers had previously found that disrupting this gene in mice could cause seizures.
Laboratory analysis of the defect in sodium channel SCN8A showed that it resulted in “increased spontaneous firing” of neurons, which can be a cellular signature of epilepsy, said Krishna Veeramah, lead author of all three studies. The study added a fifth sodium-channel mutation to the list of known causes of such seizures.
The study was published in 2012 in the American Journal of Human Genetics.
• The second study was triggered by discovery of an inherited mutation in the gene, KCNJ8, in all four members of the Hammer family. The mutation had been identified in previous studies as the possible cause of J-Wave syndrome, an arrhythmia of the heart that can result in sudden cardiac death in patients between puberty and age 45.
The Hammers are Ashkenazi Jews by descent. When researchers looked at larger numbers of individuals from the same ethnic group, they found the gene present in about 4 percent of them. The earlier studies had not clearly identified subjects or control groups by this particular ethnicity, leading researchers to conclude that the variant is benign or that the Ashkenazi Jewish population has a “significantly increased” risk of J-Wave syndrome.
The study was published this year in the European Journal of Human Genetics.
• The third study was of 10 trios – children with severe, early-onset seizures and both their unaffected parents.
Whole-exome sequencing of the trios provided a molecular diagnosis of the cause of seizures in 7 of 10 patients. Four of the children had mutations that were already known to cause early onset seizures. Three were entirely new findings.
Researchers say the success of the study suggests that whole-exome sequencing is likely to be a powerful tool for diagnosis of the diseases in the near future, said Veeramah.
It added three mutations to the list of known causes of early-onset epilepsy.
The study was published last month in the online journal Epilepsia.