Its news like this that keeps me going. Every day, I meet parents who have given up on neurology. Even in the last 5 years, our tools for diagnosis and treatment have changed. With advances in genetics more news will come. - JR
Researchers at UCSD found a gene that indicated autism associated with epilepsy.
A genetic cause for a rare form of epilepsy-associated autism has been identified by UC San Diego and Yale scientists.
Moreover, symptoms of the newly discovered form have been reversed in mouse models by altering diet. This gives rise to the possibility that similar treatment might help people, the researchers said. The study was published online Thursday in the journal Science.
Researchers led by Gaia Novarino and Joseph G. Gleeson of UCSD studied two families, one of Egyptian descent and another of Turkish origin. They examined the genome of patients and healthy relatives for exons, gene sequences that code for proteins. The researchers found that patients shared an exon mutation on a gene called BCKDK. The mutant gene is recessive, meaning that it must be inherited from both mother and father to manifest.
Moreover, the researchers found that the mutation caused patients to produce abnormally low levels of certain types of amino acids, the building blocks of proteins. They were able to boost levels of these amino acids to normal with a nutritional supplement from a health food store. Research is now ongoing as to whether this supplementation will reduce symptoms of epilepsy and autism in these patients.
Those who might be helped are only a small fraction of people with autism, Novarino said in an Tuesday interview. Those without the metabolic defect wouldn't benefit from the supplementation.
The study illustrates how scientists have become more sophisticated in using knowledge of the human genome to crack the puzzle of previously intractable diseases. The genome is the complete set of hereditary information encoded in DNA.
Narrowing the search
The vast majority of DNA does not code for proteins, the body's workhorse molecules. This "non-coding" DNA was ignored in the new method of DNA analysis, called "whole exome" sequencing, which looks only at the exons. An advantage of whole exome sequencing is that it focuses exclusively on proteins, which are altered or missing in genetic diseases.
Whole exome sequencing can find previously undiscovered genetic diseases, according to another study performed by some of the same UCSD researchers. They examined 118 patients diagnosed with neurological disorders who had no known genetic disease causes. In addition to the newly discovered genetic causes, in about 10 percent of cases the researchers even found a known disease-causing gene that had previously escaped detection.
That study was published in June in Science Translational Medicine, a journal devoted to getting research discoveries into the hands of doctors more quickly.
The new study is part of the same project of applying exome research to diseases, Novarino said.
Genetic knockout
In the study, the researchers produced genetically engineered "knockout mice" in which the BCKDK gene was inactivated. These mice experienced epileptic seizures, tremors, hind limb clasping and other symptoms of neurological disorders. Their brains were found to be deficient in certain chemicals called branched chain amino acids.
Seizures and hind limb clasping were "completely abolished" within a week when mice were given diets rich in these nutrients, the study said.
The researchers had previously examined neural cells of patients and unaffected family members. The neural cells were made from induced pluripotent stem cells, produced from skin cells and turned into neurons. However, the researchers couldn't find any differences in the cell cultures. That's when they turned to studying the effect of diet on whole knockout and healthy mice.
Novarino said it's too early to tell if BCAA supplementation is helping the human patients in the study.
The supplements have not caused any side effects in the patients, nor did they in the mouse, Novarino said.
The complete list of authors, including colleagues in Turkey, Egypt and Libya, can be found at the end of the press release. Funders of the study include the National Institutes of Health, the Center for Inherited Disease Research, and the Simons Foundation Research Initiative.
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