Friedman, Roberta PHDBack to top
Investigators identified mutations on the sodium channel in two families where there were cases of epilepsy and sudden unexplained death.
SAN DIEGO—Researchers in Germany and Spain have uncovered defective sodium channels on nerves that could explain instances of epilepsy and of sudden death in patients with epilepsy (SUDEP).
“The underlying mechanism of SUDEP is still unknown,” said Yunxiang Liao, PhD, a postdoctoral fellow in neurology and epileptology at the Hertie Institute of Clinical Brain Research in Tubingen, Germany, who described the findings here at the annual meeting of the Society for Neuroscience. “Now we point out that loss of function in sodium channels can be associated with SUDEP.”
The sodium channel is on GABA interneurons, and present in the brainstem and sinoatrial node pathways that dictate heart rhythm, Dr. Liao explained.
The investigators at the Hertie Institute, working with investigators in Madrid, Spain, sought mutations in which members of two families had epilepsy, with some instances of febrile seizures of early onset and SUDEP.
In the first family, there were three instances of sudden death, one person died at age 38, and two died at age 2. All of these patients bore the same mutation. In the second family, two cases of SUDEP included children, ages 6 and 7 — both of whom had a mutation in the pore region of the protein for a sodium channel.
“We observed a loss of function for both mutations,” said Dr. Liao. This is the first time the mutations have been characterized, she said, noting that three other mutations associated with SUDEP had been described previously.
“Both families showed a much higher incidence rate of sudden death” than what would be expected with epilepsy, Dr. Liao added. Usually the incidence of SUDEP is 0.1 to 2 per thousand person-years, but in these families, she said, the rate was 7.5 to 12 per thousand person-years.
DR. YUNXIANG LIAO: “The underlying mechanism of SUDEP is still unknown. Now we point out that loss of function in sodium channels can be associated with SUDEP.”
The researchers introduced each of these mutations into cells living in lab dishes and carried out patch clamp experiments — a laboratory technique that allows the study of single or multiple ion channels in cells — to see how the channels might be altered. One mutation produced a complete loss of function of the sodium channel — no current was passed. The other mutation produced a reduced current density and slowed the recovery from fast inactivation, resulting in less sodium coming into the cell.
The mutation blocks the burst activity of the GABA interneuron, and could produce a defect in the conduction at the sinoatrial pacemaker in the heart. Dr. Liao noted that the mutations might produce heart arrythmia or respiratory arrest by interrupting the control of breathing in the brainstem.
The investigators will be submitting these findings for publication.
Martin Gallagher, MD, PhD, who chaired the session, said the approach is similar to his team's efforts at the Kennedy Center and neurology department at Vanderbilt University in Nashville, TN. “Although extremely rare, monogenic autosomal dominant epilepsy syndromes provide invaluable models for the study of epilepsy because they enable the identification of single c-ausative genes which can be manipulated in vitro or in lab animals. Learning how single genes cause epilepsy will help identify therapeutic targets present in the more common polygenic forms of epilepsy,” Dr. Gallagher said.
“One goal of curing epilepsy is to understand and prevent SUDEP, a leading cause of epilepsy associated death,” he continued. Dr. Liao's research found that because this sodium channel is expressed in the sinoatrial node of the heart, a disrupted cardiac pacemaking system may contribute to the risk of SUDEP in these patients.
Some evidence in SUDEP suggests respiratory failure during seizures, or cardiac arrhythmia, Dr. Gallagher noted. “The authors of this report found two changes that disrupt the sodium channel, and presented physiological data” to show exactly how this could come about. In this way, he said a small cohort can provide crucial information that applies to large numbers of patients.
DR. MARTIN GALLAGHER: “Although extremely rare, monogenic autosomal dominant epilepsy syndromes provide invaluable models for the study of epilepsy because they enable the identification of single causative genes which can be manipulated in vitro or in lab animals. Learning how single genes cause epilepsy will help identify therapeutic targets present in the more common polygenic forms of epilepsy.”