Daniel Fischer remembers his daughter's first seizure with painful clarity.

Natasha and her twin sister, Nicole, were just six months old. "My wife Karina came running in one night at 4 a.m. with Natasha in her arms," he says. "We had no idea what she was doing. One arm was kind of stiff, she was making a rhythmic noise, and her head was to the side. She was completely unresponsive."

The frantic parents called Karina's father, a pediatrician in Florida, and sent him an iPhone video of their daughter's movements. The twins had been vaccinated a day or two before, and he told them it was probably just a fever-induced seizure. He suggested they cool her down with lukewarm water. He also recommended a visit to a neurologist.

Finding a Diagnosis

Over the next few months, it became clear that the seizure hadn't been an isolated reaction to a vaccination. Periodically, little Natasha's hands would start jerking; sometimes she'd turn a dusky shade of blue. She was hospitalized several times. Finally, when Natasha was around nine months old, her grandfather suggested she be tested for mutations in the SCN1A gene—a gene with many epilepsy-related mutations.

The test results pointed to a clear culprit: Natasha had Dravet syndrome, also known as severe myoclonic epilepsy of infancy. Dravet is one of a number of rare, genetically linked, catastrophic epilepsy syndromes that first appear in infancy or very early childhood; others include Doose syndrome and Lennox-Gastaut syndrome (LGS).

"It was heartbreaking," Fischer says. At first, he buried himself in his work as a management consultant, determined to support Natasha's medical needs as well as anything else his family of six, including two preteen sons, might need. "My wife was the one who was reading and doing research. She figured out the best medications for Natasha, she went to support groups and met people online, and she became like a scientist."

Through her research, Karina met Michelle Wellborn, whose eight-year-old daughter, Lilly, has Dravet syndrome. Wellborn then introduced the Fischers to Jim Jacoby, an Atlanta real estate developer whose daughter also has Dravet.

Wellborn, a pharmacist and parent advocate, is also the founder of the ICE Epilepsy Alliance. ICE stands for both Intractable Childhood Epilepsy and Ion Channel Epilepsy. SCN1A and many other genes seem to have an effect on ion channels, which regulate the activity of brain cells. When the channel is open, ions—charged atoms or molecules—can rush in and spark an electrical signal, or current, that regulates chemical signaling and the transport of proteins that help cells communicate quickly. Many diseases have now been linked to disturbances in ion channels.

Then, about three years ago, Daniel Fischer met another parent—Jeffrey Skolnick, a Georgia Tech systems biologist. Their meeting would change the lives of families coping with Dravet all over the world.

"Jeffrey told me that every drug has side effects, binding to an average of 277 genes in the body," Fischer says. "We thought, what if we came up with a systematic process to find drugs [with off-target effects, or side effects that are not what the drugs were intended for] that could be used to treat diseases like Dravet?"

Because existing drugs have already passed the toxicology and safety studies needed to win approval by the U.S. Food and Drug Administration (FDA), this time-consuming and costly step in the drug development process would be eliminated altogether—bringing potential therapies to patients sooner.

Two weeks later, out of the blue, Jim Jacoby called. He was looking for new opportunities to fund Dravet research and wondered if Daniel had any ideas.

"As a matter of fact, I do," he said.

On the Road to Discovery

Together, the two fathers founded IntelliMedix, a drug discovery company that is currently using next-generation gene sequencing and a supercomputer to screen millions of drugs in order to identify potential therapies for Dravet—and, in the future, perhaps other epilepsies as well.

"We have already screened 20 million compounds, including every single FDA-approved drug, for off-target effects that might treat Dravet," Fischer says. Their primary aim is to find drugs that might increase the expression of the copy of the SCN1A gene that works, and/or repair the copy of the gene that does not work.

So far, six drugs identified by the computer have been tested in an animal model of the disease and appear promising. In July, IntelliMedix announced a partnership with Pfizer and the Epilepsy Foundation to look for drugs that will target specific gene mutations associated with epilepsy syndromes. For their first project, they will conduct a small trial with 20 patients who have Dravet syndrome to see whether some of the drugs IntelliMedix has identified are safe and well-tolerated.

An Explosion of Research

Dravet is referred to as a "monogenic" disorder because the majority of cases—about 80 percent—can be traced to mutations in the SCN1A channel. The mysteries of Dravet may prove comparatively easier to unlock than some other genetic epilepsies of childhood, which appear to be influenced by multiple genes. Lennox-Gastaut syndrome, for example, is thought to arise from a combination of inherited mutations and random mutations that occur after birth, which are called de novo mutations.

The good news for young people with these epilepsy syndromes is that in the past five years, there has been a "relative explosion" of new discoveries linking genes to many of these conditions, says Orrin Devinsky, MD, a professor of neurology, neurosurgery, and psychiatry at New York University (NYU) Langone Medical Center and director of the NYU Comprehensive Epilepsy Center. Dr. Devinsky is also a Fellow of the American Academy of Neurology (FAAN).

Dr. Devinsky is one of many researchers participating in the Epilepsy Phenome-Genome Project (EPGP), a massive international consortium of 25 clinical epilepsy centers funded by the National Institute of Neurological Disorders and Stroke (NINDS), which is part of the National Institutes of Health. The study has enrolled more than 4,000 people with epilepsy and healthy controls, collecting blood samples and information about seizure types and effects of treatment, as well as electroencephalography and neuroimaging studies, to help identify genetic factors that influence both more common and rarer, more severe forms of epilepsy.

The Phenome-Genome Project is now part of a larger "Epilepsy Center Without Walls" for the study of epilepsy genetics, also funded by NINDS, called Epi4K. This consortium combines the separate research databases and DNA collections of a number of clinical centers across the United States, UK, Canada, and Australia. It will ultimately analyze more than 4,000 genomes.

"The EPGP-Epi4K group has identified several de novo gene mutations in children and young adults that cause two 'classical' forms of epileptic encephalopathies: infantile spasms and Lennox-Gastaut syndrome," says Dr. Devinsky. "This project is on the leading edge of genomic science," adds Katrina Gwinn, PhD, program director of the Extramural Research Program at the NINDS. "We still have a great deal to learn before we translate most of these discoveries into clinical practice, but the promise is there."

Identifying Targets for New Drugs

Many therapeutic targets for rare genetic childhood epilepsies focus on mutations in ion channels. A potassium channel modifier called ezogabine appeared promising, but in late 2013 the FDA issued a warning that the drug carries risks of abnormalities to the retina, potential vision loss, and skin discoloration, all of which may become permanent. Researchers have since turned their focus to other channel modifiers.

"There are other potassium channel modifiers in the same family that are now in early preclinical trials," says Joseph Sirven, MD, a consultant in the department of neurology at the Mayo Clinic in Phoenix, AZ, who also participated in the Epilepsy Phenome-Genome Project.

Lately, cannabinoids—compounds derived from the non-psychotropic component of the cannabis plant, or marijuana—have generated headlines for their use as a potential epilepsy treatment. The compounds are considered non-psychotropic because they don't cause changes in mood or behavior. An international, multicenter study, led by Dr. Devinsky, is now evaluating whether a purified cannabidiol is effective in treating severe forms of childhood epilepsy that do not respond to standard antiepileptic drugs. The study drug, Epidiolex, is now being tested in 150 patients between ages one and 18 who have intractable childhood epilepsies, including Dravet. An open label study—meaning patients know they are receiving the study drug—has been completed, and a new, larger phase 3 trial will begin soon.

One of the children in the study is Natasha Fischer. "For a while, she was having two tonic-clonic seizures a week," says her father. (Tonic-clonic seizures generally affect the whole body, resulting in stiff muscles, violent muscle contractions, and brief loss of consciousness.) "When she started on the cannabidiol, she went eight weeks seizure-free, and it was great. Cognitively, it helped her quite a bit, and we were able to lower the other two medications she was on to about 20 percent of the dose she'd needed before."

But then Natasha started having problems with one of her other antiseizure medications, valproic acid (Depakote). She was having severe liver complications. Her parents decided to pull her off that drug entirely, and she had a seizure while at the hospital. "She's still in the trial with the cannabidiol, and although the seizures have come back, she's only having one about every two weeks, which is better than the one or two a week she was having before. It's not a magic bullet, but we have seen overall improvement," Fischer says.

What About Lennox-Gastaut Syndrome?

Finding new therapies for Lennox-Gastaut syndrome (LGS) is a more complicated proposition, says Dr. Devinsky, since it is "more of an umbrella term, and refers to a wide variety of children and adults who meet a characteristic pattern of symptoms and behaviors. Even among the kids who have classic forms of LGS, there can be a broad set of causes—it can result from a tumor, a genetic disorder, an infection. Even the clinical features, although there's a core spectrum, can vary by age."

Still, several drugs have been specifically approved by the FDA for the treatment of LGS, including rufinamide (Banzel) and clobazam (Onfi). And there is hope that genetic screening approaches may become more applicable to children with the syndrome, says Dr. Devinsky. 

Dr. Devinsky points to a study published in the April 2014 issue of the journal Annals of Neurology involving mutations in a potassium-channel gene called KCNT1. These mutations have been linked to two other kinds of epilepsy, autosomal dominant nocturnal frontal lobe epilepsy and epilepsy of infancy with migrating focal seizures. [For more on these and other kinds of childhood epilepsies, see "Severe Epilepsies of Childhood" below.]

"The specific mechanism of action in this gene is understood, and there is already an existing heart drug called quinidine that targets that mechanism," he says. "In early studies, it's been used with very good results in a few children with these epilepsies. I think the ability to translate these in vitro studies [that look at tissue or cells in a petri dish or laboratory test tube] to individual patients is growing quickly."

"These catastrophic childhood epilepsies leave people really struggling, because there's so little out there to help," says Dr. Sirven. "Fortunately, they are rare, but despite our best efforts with multiple medications and other strategies like special diets, neurologists take care of way too many people for whom these therapies just don't work the way we'd like them to. That's why this genetic research is so important."

Daniel Fischer understands this need for research all too well. He was speaking at a conference in San Francisco recently when his wife called to tell him that Natasha had had a tonic-clonic seizure in school. "She has an issue with pattern sensitivity right now," he says. "Nothing we wear can have a pattern or it will set off a seizure. The flickering from fluorescent lights can also do it—so she can't go into a supermarket or the mall. There are constant ups and downs. Today she may be fine. Tomorrow, who knows?"

Fischer and his family are hoping that the boom in research will create greater stability—and certainty—sometime soon.

Severe Epilepsies of Childhood

Although they are rare, severe childhood epilepsy syndromes can be devastating and difficult to treat. They include:

• Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE): This very rare form of epilepsy runs in families. Onset can occur at any time from infancy to adulthood, but it usually begins in childhood and typically causes seizures while the person is asleep. Some people with ADNFLE also have daytime seizures. Sometimes these seizures are mild, but some people experience more severe episodes that can include flailing arms and legs, crying out or moaning, and getting out of bed and wandering around. ADNFLE may be mistaken for night terrors or sleepwalking. People with ADNFLE do not usually have developmental delays.
• Doose syndrome: Also known as myoclonic-astatic epilepsy (MAE), Doose syndrome usually appears between ages one and five. It involves a mixed bag of generalized seizures, but the distinguishing type is the myoclonic-astatic seizure, or "drop attack"—a sudden loss of muscle control that causes the person to fall to the ground. These abrupt attacks can often result in injury.
• Dravet syndrome: Unlike Doose and Lennox-Gastaut, Dravet syndrome almost always begins in the first year of life. The baby appears to be healthy until the first seizure. Children with Dravet develop many different types of seizures, which usually lead to developmental delays. About 80 percent of people with Dravet syndrome have a mutation in the SCN1A gene or another gene affecting ion channels; these are usually new, not inherited, mutations. A blood test can diagnose Dravet syndrome.
• Epilepsy of infancy with migrating focal seizures (EIMFS): This type of epilepsy usually begins within the first six months of life. A seemingly typical baby will develop severe, refractory (medication-resistant) focal seizures, usually in both hemispheres of the brain. These seizures can last a long time, with episodes of status epilepticus—a continued seizure of 30 minutes or more. It is considered an "epileptic encephalopathy," meaning that the seizures themselves are thought to cause further brain damage. Most children with EIMFS develop severe developmental delays and have a shortened life expectancy, although some cases may be milder than others.
• Lennox-Gastaut syndrome (LGS): LGS typically develops when a child is between ages two and six. It is thought to account for between one and four percent of childhood epilepsies and is characterized by three signs: multiple seizure types, moderate to severe cognitive impairment, and a specific type of abnormal brain-wave pattern called slow spike-wave complexes. Most children with LGS appear to be developing normally when the seizures first appear, but uncontrolled seizures can cause significant mental and behavioral regression. Lennox-Gastaut appears to have both environmental and genetic causes.

Sources: Epilepsy Foundation; ICE Alliance; International League Against Epilepsy

For More Information:

• "Epilepsy: The Basics"
• The Epilepsy Phenome/Genome Project
• AAN video, "Epilepsy: A Guide for Patients and Families"