Study to sequence DNA from 4,000 people with epilepsy.

Daniel Lowenstein, UC San Francisco

To probe the genetic secrets of one of the most common neurological diseases, more than 4,000 people with various forms of epilepsy will have their DNA decoded over the next five years in a study led by researchers at the University of California, San Francisco and several collaborating institutions.

“This is the largest, most sophisticated project that has ever been attempted for identifying the genetic causes of epilepsy, and it has come about as the result of a great spirit of collaboration among scientists, clinicians, patients and their family members from throughout the world,” said Daniel Lowenstein, M.D., vice chair of the Department of Neurology and director of the UCSF Epilepsy Center.

Sorting the patients’ DNA sequences and comparing them to their histories, brain scans and other clinical data will help frame understanding of a disease that strikes tens of millions worldwide, including about 2 million people in the United States. The work may also reveal new ways to treat people with epilepsy.

UCSF has been one of the world’s leading institutions involved in epilepsy research for years and has one of the few medical centers in the world with top-ranking departments in the areas most relevant to this research: biomedical imaging, neurology and neurosurgery.

The new project, funded by a $25 million grant from the National Institute of Neurological Disorders and Stroke, follows on the heels of another study known as the Epilepsy Phenome/Genome Project and led by Lowenstein and colleagues worldwide, which is collecting detailed clinical data and DNA samples from 3,750 people with epilepsy and 1,500 of their relatives without the disease.

In addition to sequencing DNA from a larger number of people, the new project will apply cutting-edge methods for identifying disease-causing variations in the genome known as copy number variants (CNVs), and it will look for genetic clues that might explain why an apparently similar form of epilepsy can be responsive to treatment in one patient and not so in another.

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Baby Joey arrives healthy eight days after due date.

Luis Gutierrez, fiancee Eveth Martinez and their newborn son Joey, the first baby born at UC San Francisco in 2012

Joey Santino Gutierrez was supposed to be a Christmas baby, or so his parents thought. Due on December 24, his mother Eveth Martinez, 27, spent Christmas eve and Christmas day anxiously awaiting the arrival of her second son.

Instead, Joey kicked off 2012 for his parents and UC San Francisco, as the first baby born at UCSF Benioff Children’s Hospital in 2012. Born at 7:43 a.m. on Jan. 1, 2012, Joey weighed in at 7 pounds, 15 ounces, a healthy baby boy. Martinez was among seven women in labor on New Year’s Eve, but Joey was the first to make his debut at UCSF. The first baby born in San Francisco was delivered at California Pacific Medical Center at 12:02 a.m.

Martinez and fiancé Luis Gutierrez live in San Francisco’s Mission District with their seven-year-old son. And will they try for a girl? “Not for a long time!” said Martinez, just five hours after giving birth. “We’re going to space them out.”

Martinez was originally a patient at St. Luke’s Hospital, however because she suffers from epileptic seizures, she was transferred to UCSF to have access to world-renowned specialists in neurology.

Joey is the first of about 2,000 babies who will be born at UCSF Benioff Children’s Hospital this year. Starting in 2015, those babies will be born at UCSF’s new 289-bed children’s, women’s, and cancer hospital in Mission Bay – which will offer a 36-bed center for mothers and newborns, including nine deluxe labor and delivery rooms.

UCSF has not had the first San Francisco baby born in the new year since 2007, when it happened for the first time in nearly a quarter of a century.

Childhood disorder called PKD that causes epileptic seizures linked to genetic mutations.

Louis Ptacek, UC San Francisco

A large, international team of researchers led by scientists at the University of California, San Francisco, has identified the gene that causes a rare childhood neurological disorder called PKD/IC, or “paroxysmal kinesigenic dyskinesia with infantile convulsions,” a cause of epilepsy in babies and movement disorders in older children.

The study involved clinics in cities as far flung as Tokyo, New York, London and Istanbul and may improve the ability of doctors to diagnose PKD/IC, and it may shed light on other movement disorders, like Parkinson’s disease.

The culprit behind the disease turns out to be a mysterious gene found in the brain called PRRT2. Nobody knows what this gene does, and it bears little resemblance to anything else in the human genome.

“This is both exciting and a little bit scary,” said Louis Ptacek, M.D., who led the research. Ptacek is the John C. Coleman Distinguished Professor of Neurology at UCSF and a Howard Hughes Medical Institute Investigator.

Discovering the gene that causes PKD/IC will help researchers understand how the disease works. It gives doctors a potential new way of definitively diagnosing the disease by looking for genetic mutations in the gene. The work may also shed light on other conditions that are characterized by movement disorders, including possibly Parkinson’s disease.

“Understanding the underlying biology of this disease is absolutely going to help us understand movement disorders in general,” Ptacek said.

PKD/IC strikes infants with epileptic seizures that generally disappear within a year or two. However, the disease often reemerges later in childhood as a movement disorder in which children suffer sudden, startling, involuntary jerks when they start to move. Even thinking about moving is enough to cause some of these children to jerk involuntarily.

The disease is rare, and Ptacek estimates strikes about one out of every 100,000 people in the United States. At the same time, the disease is classified as “idiopathic” — which is just another way of saying we don’t really understand it, Ptacek said.

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Model lets researchers generate testable hypotheses, design highly targeted drug treatments.

Drawing on X-ray crystallography and experimental data, as well as a software suite for predicting and designing protein structures, a UC Davis School of Medicine researcher has developed an algorithm that predicts what has been impossible to generate in the laboratory: the conformational changes in voltage-gated sodium channels when they are at rest or actively transmitting a signal in muscle and nerve cells.

Structural modeling of the voltage-sensing mechanism is important because it allows researchers to generate testable hypotheses and design new, highly specific drugs to treat a wide range of disorders, from chronic pain to epilepsy. The study is published in today’s (Dec. 12) early edition of the Proceedings of the National Academy of Sciences.

Voltage-gated sodium channels are embedded in the plasma membranes of nerve and muscle cells. The channel consists of a large protein that allows sodium ions to pass when a change in voltage occurs across the cell membrane. While high-resolution structures of the voltage sensors that control ion-gate activation have been identified in an activated state, scientists need to know all of the conformational changes that occur throughout the cycle of activation and rest to develop better treatments for disease.

“Sodium channels transmit pain and are the sites of action of local anesthetics,” said Vladimir Yarov-Yarovoy, an assistant professor of physiology and membrane biology at the UC Davis School of Medicine who developed the models in collaboration with researchers from the University of Washington in Seattle. “They are critical targets for new drug development for the treatment of chronic pain, epilepsy and other conditions caused by gain or loss-of-function mutations in voltage-gated sodium channels, which hyperexcite sensory neurons or attenuate action-potential firing causing pain or seizures.”

Serious chronic pain affects at least 116 million Americans each year, and epilepsy affects nearly 3 million Americans and 50 million people worldwide. Yet, the treatment of chronic pain and epilepsy remains a major unmet medical need.

“Currently available drugs for these conditions have limited effectiveness and significant side effects,” said Yarov-Yarovoy. “While the research community has focused on identifying selective inhibitors of sodium-channel subtypes in nerve, heart and muscle cells, no new therapies have advanced to clinical trials. The algorithm is an innovative approach that fosters the design of novel subtype-selective sodium channel blocking drugs that have high efficacy and minimal side effects to treat these disorders.”

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UC Davis’ Michael Rogawski to receive American Epilepsy Society service award.

Michael Rogawski, UC Davis

Michael A. Rogawski, professor and chair of the Department of Neurology in the UC Davis School of Medicine, has been named the recipient of the American Epilepsy Society’s 2011 Service Award. The award honors Rogawski for his many contributions to the field of epilepsy and for his long record of service to the epilepsy society and its members. Among his leadership activities, Rogawski has for the past 10 years served as the co-editor of Epilepsy Currents, the society’s official journal.

Rogawski played a key role in the founding of the journal in 2001, and in the intervening years he has been instrumental in its establishment as a key educational resource for basic and clinical epilepsy researchers and clinicians. Among his other contributions to the work of the American Epilepsy Society (AES) during his more than 20 years of service, Rogawski has served on its board of directors, as chair of its technology committee and as a member of its long-range planning committee.

The AES Service Award will be presented Saturday (Dec. 3) during ceremonies at the society’s 65th Annual Meeting and Scientific Conference at the Baltimore Convention Center.

Rogawski is a leading international authority on the treatment of neurological disorders. During his career, he has investigated the mechanisms of drugs to treat epilepsy and other neurological conditions, and has advanced the development of new treatment approaches. His research encompasses cellular neurophysiological studies, animal models and clinical trials. Laboratory studies conducted in Rogawski’s laboratory on AMPA receptors and neurosteroids have been translated to new epilepsy treatment approaches.

Rogawski holds a medical degree and a doctoral degree in pharmacology from Yale University. Following a three-year residency in neurology at Johns Hopkins Hospital, he began research in the field of epilepsy as a medical staff fellow at the National Institutes of Health, where he rose to head of the Epilepsy Research Section, serving in that role from 1990 to 2006. In 2007 he joined the faculty of the UC Davis School of Medicine.

In addition to serving as editor of Epilepsy Currents, Rogawski is associate editor of Neurotherapeutics and is a member of the editorial boards of several other journals. He also has co-edited five books, including Jasper’s Basic Mechanisms of the Epilepsies, which will appear early next year.

“The friendships that I’ve made with AES colleagues have been important for me personally and professionally,” Rogawski said. “AES has provided invaluable opportunities to exchange scientific ideas and develop collaborations, which have benefited my research program. I have also made close lifelong friends. AES has been an enormously important community to be a part of all these years.”

The 3,000-member American Epilepsy Society, based in West Hartford, Conn., seeks to advance and improve the treatment of epilepsy through the promotion of research and education for healthcare professionals. Celebrating its 75th anniversary this year, it is today the nation’s leading medical society working to eliminate seizures, their fundamental causes and potential neurological effects.

The UC Davis School of Medicine is among the nation’s leading medical schools, recognized for its research and primary-care programs. The school offers fully accredited master’s degree programs in public health and in informatics, and its combined M.D.-Ph.D. program is training the next generation of physician-scientists to conduct high-impact research and translate discoveries into better clinical care. Along with being a recognized leader in medical research, the school is committed to serving underserved communities and advancing rural health. For more information, visit UC Davis School of Medicine at medschool.ucdavis.edu.

Computer models may help develop better therapuetics.

Maxim Bazhenov, UC Riverside

There are basically two main approaches to treating epilepsy — medication and surgery. About 70 percent of patients respond to current drug treatments and for those unresponsive to medication, surgery is another option. But researcher Maxim Bazhenov of the University of California, Riverside, explains that the surgery is a complicated procedure and may cause severe side effects.

“That’s why any new approach from pharmacology, which is a much easier way than surgery to deal with this, could benefit lots of patients especially considering how many people suffer from epilepsy,” Bazhenov said.

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Parents make endowment gift in memory of their late daughter, who was treated at UCLA.

Nadia and Thomas Davies (top) with Dr. Paul Crandall and Nina Davies

Thomas and Nadia Davies have committed $2 million to the UCLA Department of Neurosurgery in memory of their late daughter Alfonsina (Nina) Q. Davies and in honor of Dr. Paul Crandall, the UCLA neurosurgeon who ended her epileptic seizures.

The Davies family invested more than a decade in seeking ways to stop the uncontrollable seizures that had assailed their daughter since birth. The neurologists they met offered only temporary solutions.

When the Davieses arrived at UCLA in 1977, they consulted with Crandall. The founder of UCLA’s first epilepsy surgery research program, Crandall had been developing experimental treatments since the early 1960s. He is now retired and a professor emeritus of neurosurgery at the David Geffen School of Medicine at UCLA.

Crandall suggested an experimental surgery to control Nina’s intractable epilepsy. At the time, few surgical programs for epilepsy existed in the U.S., and doctors were often reluctant to consider a surgical approach to treating the disease.

“Dr. Crandall’s scientific knowledge and surgical skills saved our daughter’s life,” Nadia said. “We are eternally grateful for his lifelong study of surgical interventions to prevent epileptic seizures.”

After her surgery, Nina completed college and realized her dream of becoming a teacher. She went on to earn a doctoral degree in education, eventually becoming assistant superintendent for the Santa Ana Unified School District. She helped many students with disabilities, both social and physical, relating firsthand to the difficulties they faced.

Sadly, in 2011, Nina died at 52 from what is known as sudden unexplained death in epilepsy (SUDEP), a rare outcome for those who suffer from the disease.

The Davieses have established the Alfonsina Q. Davies Endowed Chair in Honor of Paul Crandall, M.D., for Epilepsy Research to recognize Crandall’s early research, which helped Nina and contributed to UCLA’s reputation as a world leader in the surgical treatment of epilepsy.

“We are extremely grateful to the Davieses for their generosity and support,” said Dr. Neil Martin, chairman of the UCLA Department of Neurosurgery. “This gift will pay tribute to Nina’s life by benefiting other patients for generations. Hundreds of children and adults with epilepsy worldwide have been cured by physicians using the techniques and technologies developed at UCLA.”

The UCLA Department of Neurosurgery is committed to providing the most comprehensive patient care through innovative clinical programs in minimally invasive brain and spinal surgery; neuroendoscopy; neuro-oncology for both adult and pediatric brain tumors; cerebrovascular surgery; stereotactic radiosurgery for brain and spinal disorders; surgery for movement disorders such as Parkinson’s disease; and epilepsy surgery. For 20 consecutive years, the department has been ranked among the top 10 neurosurgery programs in the nation by U.S. News & World Report.

Computer models study seizures at a molecular level.

Maxim Bazhenov, UC Riverside

Neuroscientists at University of California, Riverside, are using computer models to study epileptic seizures at a molecular level. Cell biologist Maxim Bazhenov explains that seizures occur when there is a buildup of sodium in neurons and current antiepileptic drugs work to slow down this buildup. But they have found that this may in fact prolong seizures.

“I’m not saying it’s completely wrong — it does some good for certain components of the seizure; however, it does slow down buildup of sodium inside the cell and, as a result, it might extend duration of the seizure,” Bazhenov said.

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Removing half the brain is the only current “cure” for neurological disease that strikes otherwise healthy children.

Gary Mathern, UCLA

The Rasmussen Encephalitis (RE) Children’s Project, a foundation that supports scientific research to find a cure for this devastating neurological disease, has donated $111,000 to researchers in the departments of neurosurgery and pathology/lab medicine (neuropathology) at Ronald Reagan UCLA Medical Center.

“We need to do more to accelerate our understanding of Rasmussen Encephalitis,” said Seth H. Wohlberg, founder of the RE Children’s Project, and whose teenage daughter suffers from the condition.  “I am hopeful that by providing extra resources to UCLA’s top notch team of talented and dedicated individuals, we can increase our knowledge of this disease and find a cure.”

Rasmussen Encephalitis is a rare neurological disease that causes intractable seizures, cognitive deficits and paralysis of half of the body.  RE typically affects previously normal children between the ages of 2 and 10 years old. The disease process typically runs its course over a one- to two-year period during which time one half of the body is rendered useless and epileptic seizures continue unabated.  An unusual feature of the disease is that it is usually confined to one hemisphere of the brain and is resistant to standard anti-seizure medicines.  The only known “cure” is a surgical hemispherectomy — the removal or disconnection of the affected side of the brain.  Recent progress in understanding of the disease, and the emergence of therapies that slow disease progression and help control symptoms, has led some researchers to believe that more targeted and effective medical treatments are potentially within reach.

The gift will be used to support the research of Dr. Gary Mathern, professor of pediatric neurosurgery and director of the UCLA Pediatric Epilepsy Program at Mattel Children’s Hospital; Dr. Carol Kruse, professor of neurosurgery; and Dr. Harry Vinters, professor of neuropathology.  The researchers’ goal is to narrow down the cause(s) of the disease by identifying whether immune cells or infectious agents such as bacteria or virus play a major role.  By developing an animal model using cells from diseased brain tissue from patients, they hope to determine what components of the human brain leads to a Rasmussen-like disease. This research involves the collaboration of experts in brain immunology and neuropathology working together to create a mouse model of RE.

In the summer of 2008, the Wohlberg’s 10-year-daughter Grace started to experience epileptic seizures.  After months of testing, her parents learned that she had the extremely rare neurological disorder.  Grace underwent an initial hemispherectomy surgery in February 2009.  However, her seizures recurred so her parents then brought Grace to UCLA to complete the hemispherectomy which was performed by Mathern in March 2010.  Today, Grace is back in school readjusting to her new life with the assistance of a full-time aid.  While the surgery has stopped the seizures, Grace faces lifelong disabilities that resulted from the surgery including partial blindness, cognitive issues and learning how to walk again.

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UCSF study finds a two-thirds success rate for neurosurgery, aided by brain mapping, used to treat severe epilepsy.

Edward Chang, UC San Francisco

Two-thirds of people with severe and otherwise untreatable epilepsy were completely cured of their frequent seizures after undergoing neurosurgery at the University of California, San Francisco Medical Center, according to a new study that examined 143 of these patients two years after their operations.

The new study not only shows the promise of this type of neurosurgery at treating severe epilepsy, it also highlights how research into brain imaging may help to further improve results for people who have such operations.

“Surgery can be a powerful way to stop this disorder in its tracks,” said UCSF neurosurgeon Edward Chang, who led study, which is published this week in the journal Annals of Neurology. “Many of these people were living 10, 15 or 20 years with very severe and dangerous seizures.”

The success of the surgery, added Chang, was directly related to the accuracy with which the medical team could map the brain, identify the exact pieces of tissue responsible for an individual’s seizures and ultimately remove them.

“We need to continue to focus on developing new methods to figure out and pinpoint where the seizures are coming from,” said Chang.

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Study identifies new approach to preventing the chronic neurologic condition.

Dr. Tallie Z. Baram

UC Irvine and French researchers have identified a central switch responsible for the transformation of healthy brain cells into epileptic ones, opening the way to both treat and prevent temporal lobe epilepsy.

Epilepsy affects 1 to 2 percent of the world’s population, and TLE is the most common form of the disorder in adults. Among adult neurologic conditions, only migraine headaches are more prevalent. TLE is resistant to treatment in 30 percent of cases.

UCI neurologist and neuroscientist Dr. Tallie Z. Baram and her colleagues found that TLE manifests after a major reorganization of the molecules governing the behavior of neurons, the cells that communicate within the brain. These alterations often stem from prolonged febrile seizures, brain infections or trauma.

“This discovery marks a dramatic change in our understanding of how TLE comes about. Previously, it was believed that neurons died after damaging events and that the remaining neurons reorganized with abnormal connections,” said Baram, the Danette Shepard Chair in Neurological Studies. “However, in both people and model animals, epilepsy can arise without the apparent death of brain cells. The neurons simply seem to behave in a very abnormal way.”

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UC Riverside scientists used computational model to study epileptic seizures at the molecular level; research could lead to novel therapeutics for seizure disorder.

Maxim Bazhenov, UC Riverside

Researchers at the University of California, Riverside, have made a discovery in the lab that could help drug manufacturers develop new antiepileptic drugs and explore novel strategies for treating seizures associated with epilepsy – a disease affecting about two million Americans.

Neurons, the basic building blocks of the nervous system, are cells that transmit information by electrical and chemical signaling. During epileptic seizures, which generally last from a few seconds to minutes and terminate spontaneously, the concentrations of ions both inside the neuron and the space outside the neuron change due to abnormal ion flow to and from neurons through ion “channels” – tiny gateways that are embedded to the surface of the neuron.

Ordinarily, intracellular (inside the cell) sodium concentration is low compared to extracellular sodium (the reverse is true of potassium). During seizure, however, there is a buildup of intracellular sodium, with sodium ions moving into neurons from the extracellular space, and potassium ions doing the opposite.

To understand exactly how neurons function during epileptic seizures, Maxim Bazhenov, an associate professor of cell biology and neuroscience, and Giri P. Krishnan, a postdoctoral researcher in his lab, developed and used realistic computer simulations in their analyses and found that while there is a progressive and slow increase in intracellular sodium during seizure, it is this accumulation of intracellular sodium that leads to the termination of the seizure.

“According to our model, sodium concentration reaches a maximum just before the seizure terminates,” Bazhenov said. “After seizure initiation, this intracellular sodium buildup is required to terminate the seizure.”

The researchers’ computational model simulates the cortical network. (The cortex is the outer layer of the cerebrum of the mammalian brain. A sheet of neural tissue, it is often referred to as gray matter.) The model simulates neurons, connections between neurons, variable extracellular and intracellular concentrations for sodium and potassium ions and variable intracellular concentrations for chloride and calcium ions.

Bazhenov explained that conventional antiepileptic drugs are commonly designed to target various sodium channels in order to reduce their activity.

“These drugs essentially slow down the intracellular build-up of sodium, but this only prolongs seizure duration,” he said. “This is because seizure duration is affected by the rate of intracellular sodium accumulation – the slower this rate, the longer the seizure duration.”

According to Bazhenov, targeting the sodium channels is not the best approach for drugs to take. He explained that even for drugs to increase the activity of the sodium channels (in order to reduce seizure duration) there is an undesirable effect: seizures become more likely.

“The drugs ought to be targeting other ion channels, such as those responsible for the buildup of intracellular chloride,” he advises. “According to our model, restricting the chloride increase would lead to a faster termination of seizure and can even make seizures impossible.”

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