Second Gene Implicated in Sudden Death in Epilepsy

Rosemary Frei, MSc

May 06, 2010

May 6, 2010 — A second gene has been added to a list of DNA sequences linked to sudden unexplained death in epilepsy, or SUDEP. This illuminates a new mechanism for the disorder, which affects about 1 in 150 people with epilepsy.

After extensive investigation, researchers determined that the absence of a gene coding for a particular type of potassium channel initiates neurogenic cardiac dysfunction in mice that leads to SUDEP. They report their results in a recent issue of the Journal of Neuroscience.

"We are now expanding the list of genes for 'neurocardiac' syndromes by examining simultaneous [electroencephalogram (EEG)] and [electrocardiogram (EKG)] patterns in mutant mice with different ion-channel defects," lead investigator Jeffrey Noebels, MD, PhD, director of the Blue Bird Circle Developmental Neurogenetics Laboratory at the Baylor College of Medicine, Houston, Texas, told Medscape Neurology.

"We believe this list will be invaluable for screening patients in the future to determine their risk of SUDEP," he added.

In a study published last fall, Dr. Noebels; Alicia Goldman, MD, PhD; Edward Glassock, PhD; and other researchers showed that mutations in a gene coding for a type of potassium channel called KCNQ1 — which is present in both heart and brain — are linked to SUDEP via a severe form of cardiac long QT syndrome (Sci Transl Med. 2009;1:2ra6).

The new gene implicated by Dr. Noebels, Dr. Glassock, and colleagues is Kcna1; it encodes the Kv1.1 potassium channel. The channel is widely distributed in the brain and vagus nerve — where it regulates neuronal repetitive firing — but is present at only extremely low levels in the heart.

Earlier research indicated that mice missing this channel develop epilepsy at a young age and are at high risk for sudden death. To clarify the relationship between lack of the Kv1.1 channel and SUDEP, Dr. Noebels and his team used a multipronged approach.

This included simultaneous EEG-EKG recording, EKG waveform analyses in mutant mice, cardiac magnetic resonance imaging, pharmacological blockade of the autonomic system, and immunohistochemistry to localize the channel.

The results indicated that mice that were missing both copies of the Kcna1 gene, and hence lacked the Kv1.1 channel, had a 5-fold higher rate of arterioventricular (AV) blocks than normal mice during interictal periods. Administration of selective parasympathetic blocking agents stopped the AV blocks.

The mutant mice also had a significantly wider heart rate range and were prone to bradycardia and premature ventricular contractions. Other tests did not uncover any additional functional or structural cardiac pathology.

The investigators also captured simultaneous video EEG-EKG recordings during a SUDEP event in a mutant mouse. The mouse suffered a series of 5 prolonged, severe seizures from which it did not recover.

Dr. Noebels and colleagues note this is similar to the single case of SUDEP in a human with an EEG/ECG record; this person had multiple closely spaced seizures followed by complete cessation of brain activity.

Molecular analyses revealed that the Kv1.1 channel is present in abundance in the brain but at only extremely low levels in the heart. The team concluded that the Kv1.1 channel, unlike KCNQ1, initiates lethal neurogenic cardiac dysfunction in mice by altering autonomic regulation of the heart.

"This study is exciting, as it lends further support for the hypothesis that some cases of SUDEP may be related to cardiac arrhythmias associated with clinical or subclinical seizures," commented Elizabeth Donner, MD, a pediatric neurologist at the Hospital for Sick Children in Toronto, Canada, and cofounder of SUDEP Aware, a SUDEP education, research, and support organization.

"The final endpoint of this line of research is to identify those people with epilepsy who are at higher risk of SUDEP and design surveillance mechanisms to reduce rates of death; this work moves that vision forward," she said.

Dr. Noebels and coauthors and Dr. Donner have disclosed no relevant financial relationships.

J Neurosci. 2010;30:5167-5175. Abstract