Zebrafish help find model to treat childhood epilepsy

A study by the National Institute of Health (NIH) shows that zebrafish may help model a treatment for Dravet syndrome, a severe childhood epilepsy.

According to new research on epilepsy, zebrafish have certainly earned their stripes. Results of a study in Nature Communications suggest that zebrafish carrying a specific mutation may help researchers discover treatments for Dravet syndrome (DS), a severe form of pediatric epilepsy that results in drug-resistant seizures and developmental delays.

Scott C. Baraban, Ph.D., and his colleagues at the University of California, San Francisco (UCSF), carefully assessed whether the mutated zebrafish could serve as a model for DS, and then developed a new screening method to quickly identify potential treatments for DS using these fish. This study was supported by the National Institute of Neurological Disorders and Stroke (NINDS), part of the National Institutes of Health and builds on pioneering epilepsy zebrafish models first described by the Baraban laboratory in 2005.

Dravet syndrome is commonly caused by a mutation in the Scn1a gene, which encodes for Nav1.1, a specific sodium ion channel found in the brain. Sodium ion channels are critical for communication between brain cells and proper brain functioning.

The researchers found that the zebrafish that were engineered to have the Scn1a mutation that causes DS in humans exhibited some of the same characteristics, such as spontaneous seizures, commonly seen in children with DS. Unprovoked seizure activity in the mutant fish resulted in hyperactivity and whole-body convulsions associated with very fast swimming. These types of behaviors are not seen in normal healthy zebrafish.

“We were also surprised at how similar the mutant zebrafish drug profile was to that of Dravet patients,” said Dr. Baraban. “Antiepileptic drugs shown to have some benefits in patients (such as benzodiazepines or stiripentol) also exhibited some antiepileptic activity in these mutants. Conversely, many of the antiepileptic drugs that do not reduce seizures in these patients showed no effect in the mutant zebrafish.”

In this study, the researchers developed a fast and automated drug screen to quickly test the effectiveness of various compounds in mutant zebrafish. The researchers tracked behavior and measured brain activity in the mutant zebrafish to determine if the compounds had an impact on seizures.

“Scn1a mutants seize often, so it is relatively easy to monitor their seizure behavior at baseline and then again after a drug application,” said Dr. Baraban. “Using zebrafish placed individually in a 96-part petri dish we can accurately quantify this seizure behavior. In this way, we can test almost 100 fish at one time and quickly determine whether a drug candidate has any effect on these spontaneous seizures.”

In the first such application of this approach, UCSF researchers screened 320 compounds and found that clemizole was most effective in inhibiting seizure activity. Clemizole is approved by the U.S. Food and Drug Administration and has a safe toxicology profile. “This finding was completely unexpected. Based on what is currently known about clemizole, we did not predict that it would have antiepileptic effects,” said Dr. Baraban.

These findings suggest that Scn1a mutant zebrafish may serve as a good model of DS and that the drug screen may be effective in quickly identifying novel therapies for epilepsy.

Dr. Baraban also noted that someday these experiments can be “personalized,” by looking at mutated zebrafish that use genetic information from individual patients.

This research was funded by the Exceptional, Unconventional Research Enabling Knowledge Acceleration (EUREKA) program at NIH that supports innovative research with the potential for big impact in biomedical science.

“The goal of the EUREKA program is to provide a means to test high-risk ideas to see if they are worth pursuing further. These kinds of ideas often come from left field and are very creative. Since they are so unique, however, there may not be any existing preliminary data to support the hypothesis or demonstrate feasibility. EUREKA grants provide an opportunity to gather this information,” said Brandy Fureman, Ph.D., program director at NINDS.

This particular study was chosen in response to a request by NINDS to help spur novel research on epilepsy. “This research was selected for a EUREKA grant because it proposed a well-designed, inventive model of genetic epilepsy that could accelerate the pace of drug-screening for this devastating form of pediatric epilepsy” said Dr. Fureman.

Dr. Fureman noted that these findings not only describe a novel model of Dravet syndrome, but the positive results with an unexpected FDA-approved drug may lead to new therapeutic avenues. “There is more work to be done, but I am very pleased to see these initial results. These kinds of new directions are exactly what we hoped to stimulate with the EUREKA program,” she said.

For more information about Dravet syndrome and epilepsy, please visit:

• http://www.ninds.nih.gov/disorders/dravet_syndrome/dravet_syndrome.htm
• http://www.ninds.nih.gov/disorders/epilepsy/epilepsy.htm

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Mercury exposure during pregnancy not linked to autism

While mercury exposure while pregnant is known to cause health issues for children, a new study claims the exposure has no link to increased autism risk.

Children exposed to low levels of mercury in the womb because their mothers ate large amounts of fish during pregnancy don't appear to be at increased risk for autism, a new study suggests.

Worry that low levels of mercury might affect a child's developing brain has long been a cause for concern, and some experts have suggested that the chemical element may be responsible for behavioral disorders such as autism.

The new findings from more than 30 years of research in the Republic of Seychelles -- a group of islands in the western Indian Ocean -- found no such link, the study authors said.

"This study shows no evidence of a correlation between low level mercury exposure and autism spectrum-like behaviors among children whose mothers ate, on average, up to 12 meals of fish each week during pregnancy," study lead author Edwin van Wijngaarden, associate professor in the public health sciences department at the University of Rochester Medical Center in New York, said in a medical center news release.

"These findings contribute to the growing body of literature that suggest that exposure to the chemical does not play an important role in the onset of these behaviors," he added.

One autism expert added a note of caution, however.

"The study found no link between high mercury levels and later autism spectrum disorder behaviors. However, this should not be taken to mean that high levels of mercury are safe to ingest," said Alycia Hallday, senior director of environmental and clinical science at the advocacy group Autism Speaks.

"Other studies comparing this [Seychelles] cohort to those in other parts of the world indicate that this cohort may be spared from many adverse effects because it is consumed with nutrient-rich ocean fish," she explained.

The study, published online July 23 in the journal Epidemiology, included nearly 1,800 children, teens, young adults and their mothers.

For the study, the researchers initially determined the level of prenatal mercury exposure by analyzing the mothers' hair samples. Then the researchers used two questionnaires -- one given to parents, the other to the children's teachers -- to see if the children showed signs of autism spectrum-like behaviors. The tests included questions on language skills, communication skills and repetitive behaviors. While the tests don't give a definitive diagnosis, they are used widely in the United States as an initial screening tool and may indicate the need for additional testing, the researchers said.

Eating fish during pregnancy can present a dilemma for expectant mothers and their doctors. Fish are high in a number of beneficial nutrients, including some that are essential to brain development. However, fish can contain mercury, and high levels of mercury have been shown to lead to developmental problems in children.

Although the impact of low level exposure to mercury on children remains unknown, some organizations, including the U.S. Food and Drug Administration, recommend that pregnant women limit their consumption of fish, the study authors noted.

But is that caution necessary, the study authors wonder?

"This study shows no consistent association in children with mothers with mercury levels that were six to 10 times higher than those found in the U.S. and Europe. This is a sentinel population and if (the association between low-level mercury exposure and autism) does not exist here than it probably does not exist," Philip Davidson, principal investigator of the Seychelles Child Development Study and professor emeritus in pediatrics at the University of Rochester Medical Center, said in the news release.

The finding lends support to an emerging belief that the good may outweigh the possible bad when it comes to eating fish during pregnancy. Specifically, if the mercury did not harm brain development at the levels of exposure experienced by the children in this study, then the benefits of the nutrients in fish may counteract or surpass the potential negative effects of mercury, the study authors said.

One autism expert said changes to dietary recommendations are unlikely.

"Although fish is generally viewed as an excellent dietary choice, women have been advised to limit fish consumption when pregnant," said Dr. Andrew Adesman, chief of developmental & behavioral pediatrics at Cohen Children's Medical Center of New York in New Hyde Park, NY.

Even though the study showed no mercury-autism link, "it is unlikely that dietary recommendations will be revised in light of this study alone," he said.

Funding for the study was provided, in part, by the U.S. National Institute of Environmental Health Sciences (NIEHS), part of the U.S. National Institutes of Health.

"NIEHS has been a major supporter of research looking into the human health risks associated with mercury exposure," Cindy Lawler, acting branch chief at the National Institute of Environmental Health Sciences, said in the news release. "The studies conducted in the Seychelles Islands have provided a unique opportunity to better understand the relationship between environmental factors, such as mercury, and the role they may play in the development of diseases like autism. Although more research is needed, this study does present some good news for parents."

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Mercury Exposure in Pregnant Women Connected to ADHD in Children

A new study shows a link between low-level mercury exposure in pregnant women and ADHD risk in children.

Attention-deficit/hyperactivity disorder (ADHD) affects approximately ten percent of children worldwide, yet its causes are not well understood. Now, a study led by Susan Korrick, MD, MPH, of Brigham and Women's Hospital (BWH), and Sharon Sagiv, PhD, MPH, of Boston University School of Public Health, and published in the online version of theArchives of Pediatrics & Adolescent Medicine on October 8, 2012, links low-level prenatal mercury exposure with a greater risk of ADHD-related behaviors.

The study also finds that maternal fish consumption during pregnancy can help reduce the risk of ADHD-related behaviors in children. This duality is possible because many types of fish have low levels of mercury, so it is possible for a pregnant woman to eat nutritionally beneficial fish without being exposed to much mercury.

"These findings underscore the difficulties pregnant women face when trying to balance the nutritional benefits of fish intake with the potential detriments of low-level mercury exposure," said Dr. Korrick.

Dr. Sagiv agrees this study provides an important public health message, saying, "Women need to know that nutrients in fish are good for the brain of a developing fetus, but women need to be aware that high mercury levels in some fish pose a risk."

This analysis involved approximately 400 children born in New Bedford, Massachusetts between 1993 and 1998. Shortly after their mothers gave birth, researchers collected hair samples from the mothers and analyzed them for mercury. They also gave the mothers a questionnaire to determine their fish consumption during pregnancy. Eight years later, researchers followed up with the children and administered standardized tests to determine behaviors related to ADHD.

Researchers found an increased risk of childhood ADHD-related behaviors with increasing maternal hair mercury levels. These mercury levels were lower than levels shown to be potentially hazardous in most previous studies. Additionally, researchers found a reduced risk of ADHD-related behaviors in children whose mothers reported eating more than two servings of fish per week, which is a higher number of servings than is currently recommended by the United States Food and Drug Administration and Environmental Protection Agency.

The study did not examine what types of fish are best for a pregnant woman to eat, but previous studies have shown women should avoid fish that are high in mercury, such as shark, swordfish, king mackerel and fresh tuna. Fish that are low in mercury, such as flounder, haddock, and salmon, are safer to eat and good sources of nutrition.

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