The leading cause of epilepsy-related death is a poorly understood phenomenon known as sudden unexpected death in epilepsy (SUDEP). The risk factors and causes of SUDEP remain unclear but researchers have proposed explanations ranging from irregular heart rhythm to genetic predisposition to accidental suffocation during sleep. Three studies to be presented at the American Epilepsy Society’s (AES) 69th Annual Meeting parse the contributions of genetics to SUDEP in hopes of uncovering new strategies for prevention.

Researchers from the Universities of Melbourne and Sydney report that genetic variants associated with cardiac sudden death may be to blame for SUDEP. The authors examined DNA samples from 62 people who died from SUDEP, searching for mutations in genes known to contribute to cardiac arrhythmia, respiratory function and epilepsy.

Their results reveal that nearly a quarter of people who experienced SUDEP carried mutations linked to cardiac sudden death, suggesting that irregular heart rhythms may underlie a significant number of deaths in epilepsy. Furthermore, one-quarter of the cases had genetic mutations associated with epilepsy.

‘These findings raise the possibility that SUDEP might be prevented in some cases by avoiding the use of anti-epileptic drugs known to alter the heart’s electrical activity’ says Douglas Crompton, M.D., Ph.D., a neurologist at the University of Melbourne. ‘In some cases, it may be advisable to recommend beta blockers, pacemakers or implantable defibrillators.’

In a second study, researchers from New York University’s Langone Medical Center find that genetic mutations altering the transmission of electrical impulses in the heart and brain may raise the risk of SUDEP in people.

The authors searched for genetic mutations that might explain the disproportionately high risk of SUDEP in people with poorly controlled focal epilepsy, which, by definition stems from a specific area of the brain. To identify genetic risk factors for SUDEP, the authors analysed brain tissue that had been removed during epilepsy surgery from 8 people who later experienced SUDEP and from seven living people with similar histories.

The study found mutations in 607 genes in brain tissue from patients who died from SUDEP that were not seen in the tissue from the living people. Analysis of affected genes revealed possible functional effects from 532 of the mutations. Three of people who experienced SUDEP had mutations in six genes linked to cardiac arrhythmia. The other five people who died from SUDEP had mutations in seven genes involved in GABA/Glutamate pathways.

‘Genetic testing for these mutations could potentially allow for the early identification of people with epilepsy who are at high risk of sudden death,’ notes author Daniel Friedman, M.D., an assistant professor of neurology at NYU.

A third study pinpoints a specific genetic mutation that may raise the risk of SUDEP in patients with early-infantile epileptic encephalopathy — a severe, drug-resistant disorder that manifests in the first 3 months of life. Researchers from the University of Michigan set out to explore whether genetic mutations in voltage-gated Na+ channels (VGSCs), which promote the transmission of electrical impulses in the heart and brain, increase the risk of SUDEP in patients with early-infantile epileptic encephalopathy.

The authors reproduced this disorder in mice to explore whether mutations in a particular VGSC, encoded by the SCN8A gene, increase the risk of cardiac arrhythmia, which might, in turn, influence susceptibility to SUDEP. Animal experiments revealed that mice carrying a mutated SCN8A gene had reduced heart rate compared with their healthy littermates, and that administration of caffeine produced an abnormal heart rhythm known as accelerated idioventricular rhythm. Examination of cardiac cells revealed a number of molecular changes that further altered the heart rhythm.

‘Taken together, our results suggest that SCN8A mutations in people with early-infantile epileptic encephalopathy may increase the risk of SUDEP by creating an environment in which the heart has a higher susceptibility to arrhythmias,’ explains author Chad Frasier, Ph.D., a postdoctoral researcher at the University of Michigan. American Epilepsy Society

A study by the Translational Genomics Research Institute (TGen) and other major research institutes, found a new set of genes that can indicate improved survival after surgery for patients with pancreatic cancer. The study also showed that detection of circulating tumour DNA in the blood could provide an early indication of tumour recurrence.

Using whole-exome sequencing – looking at the DNA protein-coding regions of 24 tumours – and targeted genomic analyses of 77 other tumours, the study identified mutations in chromatin-regulating genes MLL, MLL2, MLL3 and ARID1A in 20 percent of patients associated with improved survival.

In addition, using a liquid biopsy analysis, the study found that 43 percent of pancreatic cancer patients had circulating tumour DNA (ctDNA) in their bloodstream at the time of diagnosis.

Very importantly, the study also found that detection of ctDNA following surgery predicts clinical relapse of the cancer and poor outcomes for patients. In addition, using a liquid biopsy detected the recurrence of cancer 6.5 months earlier than using CT imaging.

‘These observations provide predictors of outcomes in patients with pancreatic cancer and have implications for detection of tumour recurrence, and perhaps someday for early detection of the cancer,’ said Dr. Daniel D. Von Hoff, TGen Distinguished Professor and Physician-In-Chief. TGen

A group of people with fatal H1N1 flu died after their viral infections triggered a deadly hyperinflammatory disorder in susceptible individuals with gene mutations linked to the overactive immune response, according to a study.

Researchers at Cincinnati Children’s Hospital Medical Center, the University of Alabama Birmingham and Children’s of Alabama led the study. They suggest people with other types of infections and identical gene mutations also may be prone to the disorder, known as reactive HLH (rHLH), or haemophagocytic lymphohistiocytosis.

HLH causes the immune system to essentially overwhelm the body with inflammation that attacks vital organs, often leading to death. Study authors raise the possibility of screening children for HLH genes to identify those who may be at risk during a viral infection.

“Viruses that cause robust immune responses may be more likely to trigger rHLH in genetically susceptible people,” said Randy Cron, M.D., Ph.D., a senior investigator on the study and physician in paediatric rheumatology at UAB and Children’s of Alabama. “Prenatal screening for mutations in common HLH-associated genes may find as much as 10 percent of the general population who are at risk for HLH when an inflammation threshold is reached from H1N1 or other infection triggers.”

This study is the first to identify mutations of HLH-associated genes in H1N1 cases where patients had clinical symptoms of rHLH and a related condition called macrophage activation syndrome, or MAS. An outbreak of H1N1 in 2009 turned into a global pandemic. H1N1 has since become part of the viral mix for the annual flu season and preventive vaccine, the authors note. University of Alabama Birmingham

The presence or absence of the CAP2 gene causes sudden cardiac death in mice, according to new research from the Perelman School of Medicine at the University of Pennsylvania. In particular, the absence of the gene interrupts the animal’s ability to send electrical signals to the heart to tell it to contract, a condition called cardiac conduction disease.

“This study proves that the CAP2 gene is directly responsible for cardiac conduction disease in mice,” said senior author Jeffrey Field, PhD, a professor of Systems Pharmacology and Translational Therapeutics. Heart disease is the leading cause of death among men in the United States. There are several risk factors for heart disease, many of which can be controlled with changes in behaviours and medication, but there are also hard-wired genetic factors that play a role. “Since humans have the same CAP2 gene, what we learn from the mice could advance our understanding of heart disease.”

Researchers have known that the CAP2 gene could be implicated in heart disease. However, its effect on cardiac conduction in the mouse heart was a surprise, Field said. The cardiac conduction system is a molecular network that sends electrical signals to the heart, telling it to contract in the correct rhythm to keep blood flowing smoothly.

The CAP2 gene’s class of protein, while known to regulate the structure or cytoskeleton of the heart, is not usually associated with cardiac conduction because this function is governed by a different family of proteins associated with cell communication. “Initially, saying that CAP2 is involved in cardiac conduction is like saying a person with a broken bone isn’t able to talk,” Field said. “The bone’s structural function and the ability to talk are each from entirely different systems. There’s no relationship. This finding merits further study to see how exactly CAP2 regulates conduction. While we don’t understand how, this gene definitely has a role in controlling conduction.”

Using a mouse model in which the team deleted the CAP2 gene, they found that most newborn males died suddenly, soon after weaning. The males were also prone to eye infections, and their eyes developed incorrectly and could not efficiently flush away debris. The knockout mice were also smaller in overall body size.

Though rare, some of the mice also developed hearts that were overly large. “The loss of the CAP2 gene resulted in bigger hearts because the heart had trouble contracting and to compensate, it dilated in order to get more blood flowing,” Field said.

The knockout mice also exhibited arrhythmia that worsened over four to five days. “We were able to monitor the mice as they died. Their hearts beat slower and slower, and they quickly died of heart block,” he said. Heart block happens when the heart atriums contract, but the ventricles do not get the signal to contract. As a result, the mouse hearts missed a few beats at first, and then stopped completely. This condition is called sudden cardiac death, which is distinct from a heart attack caused by clogged arteries impeding blood supply to the heart. In this experiment, there were no observable effects of a missing CAP2 gene on the female newborns.

Studies of some children with a rare developmental problem, called 6p22 syndrome, hint that this gene is associated with similar cardiac issues in people. These children have deep-set eyes and cardiac problems that are not well defined. “Almost all of these children are born with a deletion of one of their copies of the CAP2 gene,” Field noted.

Knowing this connection, the researchers generated mice that would exhibit only cardiac conduction disease (CCD). They reinstated the gene but this time engineered it so they could knock it out again, but this time only in the hearts of the mice. “It took close to five years to perfect this mouse model that exhibited only the heart knockout,” Field said. The researchers could then conduct experiments targeting only the heart problem, because all the other symptoms, such as the eye problems, were out of the picture.

The mice once again developed CCD, leading to sudden cardiac death from complete heart block, but there was an extra surprise this time. The female newborns also died of CCD. “That’s a puzzle for us. We’d be interested in studying why the gender specificity for CAP2-related sudden cardiac death goes away when we knock the gene out just in the heart,” Field said.

The team says that the study increases the understanding of how the CAP2 gene affects heart disease, but it also raises new questions that underline the need for further research heart disease and why it’s a major cause of death in humans. Perelman School of Medicine

Researchers from the University of Ottawa Heart Institute (UOHI), together with the teams of Dr. Martin Farrell at Oxford University, and Dr. Sekar Kathiresan at the Broad Institute, have found the answer to an ongoing debate in the cardiovascular scientific world. Dr. Ruth McPherson and Dr. Majid Nikpay, researchers at the UOHI’s Ruddy Canadian Cardiovascular Genetics Centre, report that the genetic basis of heart disease is largely derived from the cumulative effect of multiple common genetic variants, rather than from a few rare variants with large effects.

The study used the data from the 1000 Genomes project in order to obtain information on close to 10 million genetic variants (called SNPs). The analysis involved 60,000 heart disease patients, 120,000 healthy individuals, from a total of 48 studies around the world. Not only is the number of genetic variants much greater than the approximately 1 million previously studied, this is the first time that researchers have been able to study the link of rare genetic variants present in as few as 1 in 1000 people at risk of heart disease.
“Our analysis provides a comprehensive survey of the fine genetic architecture of coronary artery disease (CAD), showing that genetic susceptibility to this common disease is largely determined by common SNPs of small effect size rather than just a few rare variants with large effects,” say the authors of this important study.

Dr. Majid Nikpay, post-doctoral fellow at the Ottawa Heart Institute, also used an alternative statistical method of analysis to find two new risk markers that have an effect only if an individual has inherited two copies of the “bad gene”, that is one from each parent. In addition to discovering a total of 10 new risk markers, by using other statistical approaches, this research team has produced a list of 202 genetic variants in 129 gene regions that together explain approximately 23% of the heritability of coronary heart disease as compared to only 11% reported in previous studies.
“Many of these genetic variants are likely to exert their effects on the walls of arteries, making them more susceptible to the common heart disease risk factors such as cigarette smoking, diabetes and cholesterol,” added Dr Ruth McPherson, Director of the Ruddy Canadian Cardiovascular Genetics Centre at the University of Ottawa Heart Institute.

A number of preventative strategies target the vessel wall (control of blood pressure and smoking cessation), but the large majority of existing drug treatments for lowering CAD risk operate through manipulation of circulating lipid levels and few directly target vessel wall processes. Detailed investigation of new aspects of vessel wall biology that are implicated by genetic association but have not previously been explored in atherosclerosis may provide new insights into the complex etiology of disease and, hence, identify new targets. University of Ottawa Heart Institute