Study: Genetic cause for childhood epilepsy

A recent study found a new genetic cause for childhood epilepsy.

A research team led by scientists at the Scripps Translational Science Institute (STSI) has used whole genome sequencing to identify a new genetic cause of a severe, rare and complex form of epilepsy that becomes evident in early childhood and can lead to early death.

The researchers found a mutation in the KCNB1 gene after mapping the DNA of a 10-year-old girl who suffers from epileptic encephalopathy. The findings were reported in the October edition of the peer-reviewed medical journal Annals of Neurology.

The KCNB1 gene encodes the Kv2.1 voltage-gated potassium channel, which regulates the flow of potassium ions through neurons, affecting how the cells communicate with one another. The voltage-gated potassium channel also regulates potassium flow in the kidney, which affects potassium excretion and fluid balance.

The link between the KCNB1 mutation and epileptic encephalopathy has opened new treatment options for the young patient, said Robert Bjork, MD, her physician and a member of the Scripps Memorial Hospital La Jolla staff.

Earlier this year, "her prognosis was grim and appeared hopeless when she was experiencing many convulsive seizures, could barely eat or drink, and had 'drop attacks' where she would abruptly drop to the floor up to 25 times a day," he said.

Given continued close medical monitoring, an expanded medical treatment team, a uniquely designed home-school program and avoidance of dehydration, Dr. Bjork is optimistic that she can be kept out of harm's way and her status will improve over time.

Case part of IDIOM Study

The research was part of STSI's IDIOM Study, an ongoing project that uses whole genome sequencing to help determine the causes and treatments of idiopathic diseases -- those serious, rare and perplexing health conditions that defy a diagnosis and standard treatment.

"We are continuing to learn the impressive power of whole genome sequencing for making a difficult -- and heretofore impossible -- diagnosis," said Eric Topol, MD, who is the director of STSI and chief academic officer of Scripps Health.

STSI is a National Institutes of Health sponsored consortium led by Scripps Health in collaboration with The Scripps Research Institute (TSRI). Through this innovative partnership, Scripps is leading the effort to translate genetic and wireless medical technologies into high-quality, cost-effective treatments and diagnostics for patients.

To validate their findings, STSI researchers teamed with colleagues at Northwestern University Feinberg School of Medicine in Chicago, who had previously looked at similar KCNB1 mutations. The Northwestern colleagues were listed as co-authors of the journal report, along with contributors from the University of California, San Diego; Kennedy Krieger Institute; Johns Hopkins University; and Vanderbilt University.

Potential benefits of discovery

The benefits of discovering the role of KCNB1 mutations in epileptic encephalopathy reach far beyond the STSI research case, said Ali Torkamani, director of genome informatics at STSI and an assistant professor of integrative, structural and computational biology at TSRI.

"These findings can serve as a model on how to treat this particular form of epilepsy in other patients," he said. "The KCNB1 mutations also might have a role as a diagnostic biomarker for this condition, and they could help to direct the discovery and testing of new drugs to treat epilepsy."

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Medication to help children with life threatening seizures

Research has shown that an investigational medication can help treat children with potentially life threatening seizures.

In its first clinical application in pediatric patients, an investigational medication developed and manufactured at UC Davis has been found to effectively treat children with life-threatening and difficult-to-control epileptic seizures without side effects, according to a research report by scientists at UC Davis and Northwestern University.

The investigational formulation of allopregnanolone was manufactured by UC Davis Health System's Good Manufacturing Practice Laboratory. Two children were treated with the allopregnanolone formulation, one at UC Davis Children's Hospital, the other at the Ann & Robert Lurie Children's Hospital in Chicago. Both children were weaned from general anesthetics and other seizure treatments and their seizures resolved. In both instances the children are recovering.

The research is published online in Annals of Neurology, an official journal of the American Neurological Association and the Child Neurology Society.

Super-refractory status epilepticus is a condition diagnosed in patients with refractory status epilepticus being treated with infusions of general anesthetics when seizures continue for longer than 24 hours, despite anesthesia, or when seizures recur on reduction or withdrawal of the anesthesia. Super-refractory status epilepticus has high morbidity and mortality. There are no Food and Drug Administration (FDA)-approved treatments for the condition.

Allopregnanolone is a positive allosteric modulator of GABAA receptors in the brain. Research in animals has shown that allopregnanolone protects against seizures and can stop status epilepticus. Although the allopregnanolone used to manufacture the investigational treatment was produced by chemical synthesis according to procedures regulated by the FDA, it is synthesized normally in small quantities in the body from progesterone.

"Our laboratory studies have shown that allopregnanolone is effective in stopping status epilepticus that is refractory to treatment," said Michael Rogawski, professor in the UC Davis Department of Neurology and a co-author of the report.

In both of the clinical cases, the patients continued to have seizures despite weeks of intensive treatment with medications, including infusion of anesthetics. Emergency treatment with the investigational medication was approved by the FDA; the two patients received the medication over a five-day period, during which time both were weaned from anesthetics and other seizure medications. Status epilepticus did not recur after treatment. There were no adverse drug effects, the researchers said.

Mortality rates in super-refractory status epilepticus can be as high as 50 percent, and those who survive experience high rates of subsequent neurological impairment. The authors note that progesterone and ganaxolone, a chemical analog of allopregnanolone, have been studied in clinical trials for epilepsy and have shown benefit. Researchers at UC Davis, led by Rogawski, currently are investigating the use of allopregnanolone as a treatment for traumatic brain injury.

"Neurosteroids, including allopregnanolone, are a promising treatment for epilepsy and refractory status epilepticus that may overcome resistance to benzodiazepines and barbiturates and facilitate the withdrawal of these agents by preventing rebound seizures, a key problem in treatment of super-refractory status epilepticus," Rogawski said.

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Mutations and severe childhood epilepsies

An international study pinpoints a specific gene mutation that causes severe types of childhood epilepsies.

An international research team has identified gene mutations causing severe, difficult-to-treat forms of childhood epilepsy. Many of the mutations disrupt functioning in the synapse, the highly dynamic junction at which nerve cells communicate with one another.

“This research represents a paradigm shift in epilepsy research, giving us a new target on which to focus treatment strategies,” said pediatric neurologist Dennis Dlugos, M.D., director of the Pediatric Regional Epilepsy Program at The Children’s Hospital of Philadelphia, and a study co-author. “There is tremendous potential for new drug development and personalized treatment strategies, which is our task for the years to come.”

Multiple researchers from the U.S. and Europe performed the research, the largest collaborative study to date focused on the genetic roots of severe epilepsies. The scientists reported their results online today in the American Journal of Human Genetics (epub ahead of print).

Two international research consortia collaborated on the study—the Epi4K/EPGP Consortium, funded by the National Institute of Neurological Disorders and Stroke (NINDS) and the European EuroEPINOMICS consortium. The genetic analysis was performed at the NINDS-funded Epi4K Sequencing, Biostatistics, and Bioinformatics Core at Duke University, led by Drs. David Goldstein, Erin Heinzen and Andrew Allen.

The current study added to the list of gene mutations previously reported to be associated with these severe epilepsy syndromes, called epileptic encephalopathies. The researchers sequenced the exomes (those portions of DNA that code for proteins) of 356 patients with severe childhood epilepsies, as well as their parents. The scientists looked for “de novo” mutations—those that arose in affected children, but not in their parents. In all, they identified 429 such de novo mutations.

In 12 percent of the children, these mutations were considered to unequivocally cause the child’s epilepsy. In addition to several known genes for childhood epilepsies, the study team found strong evidence for additional novel genes, many of which are involved in the function of the synapse.

Epilepsies are amongst the most common disorders of the central nervous system, affecting up to 3 million patients in the U.S. Up to one third of all epilepsies are resistant to treatment with antiepileptic medication and may be associated with other disabilities such as intellectual impairment and autism. Severe epilepsies are particularly devastating in children. In many patients with severe epilepsies, no cause for the seizures can be identified, but there is increasing evidence that genetic factors may play a causal role.

The research teams used a method called family-based exome sequencing, which looks at the part of the human genome that carries the blueprints for proteins. When comparing the sequence information in children with epilepsy with that of their parents, the researchers were able to identify the de novo changes that arose in the genomes of the affected children. While de novo changes are increasingly recognized as the genetic cause for severe seizure disorders, not all de novo changes are necessarily disease-causing.

“Everybody has one or two de novo mutations and it is our task to find those changes that cause disease,” said co-author Ingo Helbig, M.D., now at The Children’s Hospital of Philadelphia. “We pulled out those genes that have more mutations in patients with epilepsy than you would expect by chance. These genes will hopefully tell us a bit more about the underlying disease mechanisms and how we can address them with new treatments.” As a member of the European EuroEPINOMICS consortium, Helbig was a co-initiator of the transatlantic collaboration that conducted the study. Helbig is also a member of the Genetics Commission of the International League Against Epilepsy (ILAE).

The most surprising finding in the study by the international research group is a gene called DNM1, which was found to be mutated in five patients. The gene carries the code for dynamin-1, a structural protein that plays a role in shuttling small vesicles between the body of the neuron and the synapse. These vesicles are structures that contain neurotransmitters, chemical signals crucial to communication between nerve cells. When the researchers looked on a network level, they found that many of the genes that were found to be mutated in patients had a clear connection with the function of the synapse.

This research finding, says Dlugos, provides important information about the functional roles of the genes that were identified. “We knew that synaptic genes were important but not to this extent,” he added.

A spokesperson for Citizens United for Research in Epilepsy (CURE), a non-profit organization dedicated to finding a cure for epilepsy and increasing awareness of the disease, applauded this study. Dr. Tracy Dixon-Salazar, Associate Research Director at CURE and mother of a child with severe genetic epilepsy, added, “It is exciting to see the big consortia put the genomic data of almost 400 patients together. This clearly highlights that by working together we can find new genes faster, helping us to explain what causes this often devastating disease in children.”

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What is the best medicine for children with seizures?

This article discusses what is the best medication for children with seizures.

A recently published clinical study in the Journal of the American Medical Association has answered an urgent question that long puzzled ER pediatricians: Is the drug lorazepam really safer and more effective than diazepam – the U.S. Food and Drug Administration-approved medication as first line therapy most often used by emergency room doctors to control major epileptic seizures in children?

The answer to that question – based on a double-blind, randomized clinical trial that compared outcomes in 273 seizure patients, about half of whom were given lorazepam – is a clear-cut "no," said Prashant V. Mahajan, M.D., M.P.H., M.B.A, one of the authors of the study.

"The results of our clinical trial were very convincing, and they showed clearly that the two medications are just about equally effective and equally safe when it comes to treating status epilepticus [major epileptic brain seizures in children]," Dr. Mahajan said. "This is an important step forward for all of us who frequently treat kids in the ER for [epilepsy-related] seizures, since it answers the question about the best medication to use in ending the convulsions and getting these patients back to normal brain functioning."

Describing the brain convulsions that were targeted by the study, its authors pointed out that status epilepticus occurs when an epilepsy-related seizure lasts more than 30 minutes. Such seizures – which occur in more than 10,000 U.S. pediatric epilepsy patients every year – can cause permanent brain damage or even death, if allowed to persist.

Published in JAMA, the study, "Lorazepam vs Diazepam for Pediatric Status Epilepticus: A Randomized Clinical Trial," was designed to test earlier assertions by many clinicians that lorazepam was more effective at controlling pediatric seizures. The study-authors wrote, "Potential advantages proposed in some studies of lorazepam include improved effectiveness in terminating convulsions, longer duration of action compared with diazepam, and lower incidence of respiratory depression. Specific pediatric data comparing diazepam with lorazepam suggest that lorazepam might be superior, but they are limited to reports from single institutions or retrospective studies with small sample sizes, thus limiting generalizability."

Based on data collected over four years at 11 different U.S. pediatric emergency departments, the new study found that "treatment with lorazepam [among pediatric patients with convulsive status epilepticus] did not result in improved efficacy or safety, compared with diazepam."

That determination led the study authors to conclude: "These findings do not support the preferential use of lorazepam for this condition."

Dr. Mahajan, a nationally recognized researcher in pediatric emergency medicine and a Wayne State University School of Medicine pediatrics professor recently appointed chair of the American Academy of Pediatrics Executive Committee of the Section on Emergency Medicine, said the JAMA study provides "a compelling example of how effective research in pediatric medicine, based on treatment of patients right in the clinical setting, can play a major role in improving outcomes."

Children's Hospital of Michigan Chief of Pediatrics Steven E. Lipshultz, M.D., said this recent breakthrough will "undoubtedly result in better care for pediatric patients who present in the emergency room with seizures related to epilepsy.

"There's no doubt that combining excellent research with excellent treatment is the key to achieving the highest-quality outcomes for patients – and Dr. Mahajan's cutting-edge study is a terrific example of how kids are benefiting from the research that goes on here at Children's every single day," said Dr. Lipshultz.

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Children with epilepsy at higher risk of injury

A study looks at epileptic children and found that they are at a significantly higher risk of injury than children without epilepsy.

Children and young adults with epilepsy are more likely to suffer broken bones, burns and poisonings compared to those without the neurological disorder, new research has found.

The study, led by academics at The University of Nottingham and funded by the National Institute for Health Research, shows that young people with the condition are at significantly greater risk of being poisoned by medication, leading the authors to call for further research into whether these poisonings are intentional.

The results, taken in tandem with previous research findings, highlight the need for further research into whether young people with the condition are at greater risk from an overdose, accidental or intentional, of their epilepsy drugs or other medication. And the researchers say that doctors and other healthcare professionals should use the results of the study to help warn epilepsy patients of the increased risk associated with their illness.

The study, published in the latest edition of the journal Pediatrics, found that young people with epilepsy were more than twice as likely to be poisoned by medication. This jumped to four times the risk in patients aged between 19 and 24 years old.

The patients, all aged between 12 months and 24 years old at the time of their diagnosis, were also almost one and a half times more likely to suffer a burn-related injury and almost 25 per cnet more at risk of breaking an arm or leg.

Dr Vibhore Prasad, of the University’s Division of Primary Care, said: “More research is needed to understand why people with epilepsy have a greater number of medicine-related poisonings and whether the poisonings are intentional or accidental. This is the first study in the UK population to estimate the risk of fractures, burns and poisonings. The risk of a poisoning in the next five years for 1,000 people with epilepsy is about 20 extra poisonings compared to people who do not have epilepsy.”

Epilepsy is a chronic condition caused by a sudden burst of electrical activity in the brain, causing a temporary interruption in the way the brain normally works and resulting in a seizure. In the UK alone there are more than 600,000 people with epilepsy.

Previous studies into the condition have suggested that these seizures — and the side effects caused by some anti-epilepsy drugs — put patients at a greater risk of accidental injuries.

However, most research may have overestimated this risk because they focused primarily on people with more severe epilepsy, such as institutionalised adults or those being treated in epilepsy clinics.

This latest study is the first to investigate the potential risk of injury exclusively in children and young people with and without epilepsy.

The research, which was carried out in association with academics at the London School of Hygiene and Tropical Medicine, used GP records from almost 12,000 patients with epilepsy to study the incidence of injury over an average of two and a half years and compared it with the records of around 47,000 non-epileptic people.

The authors say that doctors and other healthcare professionals can use the findings of the research to make children and young adults diagnosed with epilepsy, and their parents, more aware of the risk of injury and to inform existing guidelines on treatment. In particular, they cite the need for more information relating to the safe storage of medicines and the supervision of children while taking their medication to be given by doctors at the time of prescribing and by pharmacists when dispensing prescriptions.

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A gene for childhood epilepsy is identified

A study using Zebrafish was used to identify a new gene associated with childhood epilepsy.

A European consortium of epilepsy researchers has reported the discovery of a new gene involved in severe childhood epilepsy. Using a novel combination of technologies, including trio exome sequencing of patient/parental DNA and genetic studies in the tiny larvae of zebrafish, the EuroEPINOMICS RES consortium found that mutations in the gene CHD2 are responsible for a subset of epilepsy patients with symptoms similar to Dravet syndrome -- a severe form of childhood epilepsy that is in many patients resistant to currently available anti-epileptic drugs.

The discovery of CHD2's role in epilepsy offers new diagnostic tools for families and clinicians of children with Dravet syndrome and related genetic epilepsies. In addition, the creation of a zebrafish model for CHD2 encephalopathy may facilitate the discovery of new drugs that can treat patients with this form of epilepsy.

Dravet syndrome is a severe genetic epilepsy with onset during infancy, with initial seizures often triggered by fever. For most Dravet patients these seizures cannot be treated adequately with currently available anti-epileptic drugs, and therefore the syndrome is classified as pharmacoresistant. Dravet patients usually develop moderate to severe cognitive delays and some features of autism, and are at increased risk of SUDEP (sudden unexplained death in epilepsy). Approximately 80% of Dravet patients have mutations in the gene SCN1A which encodes the Nav1.1 sodium channel, however for the remaining 20% of patients the underlying genetic cause has yet to be determined.

To identify novel genes involved in Dravet Syndrome and other genetic epilepsies, epilepsy clinicians and human geneticists across Europe recently initiated the EuroEPINOMICS RES (Rare Epilepsy Syndromes) consortium. In 2011, the EuroEPINOMICS RES consortium was awarded €2,37 million in funding from the national funding agencies participating in the European Science Foundation program to systematically search for novel genes for seizure disorders.

As part of these ongoing research activities, the DNA of Dravet patients without SCN1A mutations was analyzed by trio exome sequencing, which searches across the active parts of the genome for de novo mutations that have arisen in these patients (de novo mutations are DNA copying errors that occur in the parents' gametes or in the fertilized egg or embryo, resulting in the afflicted family member being the first person in their family to have this genetic condition). In a group of 9 such patients, this analysis of their DNA (and the DNA of their parents) resulted in the identification of 2 patients with de novo mutations in CHD2, which stands for chromodomain helicase DNA binding protein 2. A third patient with a CHD2 mutation was subsequently identified as well.

To confirm that mutations in CHD2 cause the epilepsy observed in these patients, the same gene was then functionally analyzed in the tiny larvae of zebrafish, which have emerged in the last decade as a powerful animal model for the study of epilepsy. In the case of CHD2, scientists collaborating with the EuroEPINOMICS RES consortium used antisense technology to rapidly generate zebrafish larvae with a partial loss of function of this gene, and were then able to detect epileptic seizures in these animals using electrographic analysis (this method is very similar to electroencephalography, or EEG, which is used to analyze seizures in humans).

The genetic analysis was led by Peter De Jonghe, head of the Neurogenetics Group of the VIB Department of Molecular Genetics at the University of Antwerp (Antwerp, Belgium) and the epilepsy genetics group in Kiel, headed by Ingo Helbig (Dept. of Neuropediatrics, University of Kiel, Germany). Peter De Jonghe: "This research reinforces our belief that trio sequencing enables us to unravel the genetic background of syndromes which occur spontaneously. Previously, investigations into the genetic causes of syndromes such as Dravet Syndrome were not feasible. These types of investigations were only possible by screening large families and seeing how a disorder was passed along. But in disorders such as Dravet Syndrome, this did not work since the children were so seriously ill that they themselves never went on to have their own children. So this new technology also opens up new perspectives in the search for the genetic background of many disorders."

Ingo Helbig adds that "the epileptic encephalopathies pose a major clinical problem as most children have treatment-resistant epilepsy, intellectual disability and many other medical issues. We hope that identifying the underlying genetic cause will help us find better treatment options for the affected patients. In the past, we were not able to identify the reason why children have severe epilepsy. The discovery of CHD2 as the culprit gene in a subset of children with epileptic encephalopathy is a major step for us."

The zebrafish research was led by Camila Esguerra of the Laboratory for Molecular Biodiscovery of University of Leuven (Leuven, Belgium). She commented: "Our previous research to validate zebrafish as a model for epilepsy put us in a good position to be able to help the EuroEPINOMICS consortium investigate the function of CHD2. The zebrafish larva is an ideal model to study genes involved in epilepsy, and the methods necessary for such studies are now well-established in our laboratory. Looking forward, our zebrafish models of pharmacoresisant epilepsy are well-suited for large-scale pharmacological screens to find new anti-epileptic drugs."

The Dravet Syndrome Foundation EU (DSF-EU, Madrid, Spain) is a patient organization dedicated to finding a cure for Dravet Syndrome, and also works to promote awareness of the disease and to help families of Dravet patients. Julian Isla, Executive Director of DSF-EU, stated: "One of the most important things for patients with genetic disorders and their families is to be able to give a name to the gene causing their disease. When it comes to Dravet syndrome, the genes responsible for up to 20% of the cases are still unknown. The discovery that mutations in CHD2 cause a Dravet-like syndrome means some of these patients will now have access to better genetic diagnosis and therefore provide much-needed answers to these families. Importantly, the development of a new animal model for Dravet syndrome based on reduced CHD2 expression might help to find effective treatments that could improve the lives of thousands of people suffering from Dravet syndrome and perhaps other genetic epilepsies."

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