Treating autism with a supplement? New research says yes.

In Autism Spectrum Disorders, Genes, Genomic Medicine on Sunday, 7 October 2012 at 07:18

New Form of Autism May Be Treatable With Supplement

Pam Harrison

October 1, 2012 — A homozygous mutation that silences the gene involved in the metabolism of branched-chain amino acids (BCAAs) has been identified in a group of children who have autism and either epilepsy or abnormalities on electroencephalogram (EEG), an international team of investigators has reported.

Gaia Novarino, PhD, from the University of California, San Diego, and multicenter colleagues identified a mutation in the branched-chain ketoacid dehydrogenase kinase (BCKDK) gene in families among whom parents were cousins and whose children had autism, epilepsy, and intellectual disability.

“The normal role of the BCKDK gene is to shut off the metabolism of the BCAAs,” coauthor Joseph Gleeson, MD, University of California, San Diego, told Medscape Medical News. “And the end result of these mutations is hypermetabolism of the BCAAs and their depletion in patients who carry them.”

In mice, the researchers were able to show that a BCAA-enriched diet abolished the neurologic deficits within a week.

The study was published online September 6 in Science.

Related Families

As Dr. Gleeson noted, investigators set out specifically to study families in which parents were related to each other to allow them to identify recessive causes of disease.

They identified 2 consanguineous families, one of Turkish descent and a second of Egyptian ancestry, in which children had autism, intellectual disability, and either seizure or abnormal electroencephalograms (EEGs). Whole-exome sequencing was carried out in both families.

Researchers focused on the identification of homozygous variants that were predicted to result in loss of protein function, which would be consistent with the presumed mode of recessive inheritance.

“In each of these families, we identified a distinct, null, homozygous mutation in the [BCKDK] gene,” investigators write, “and no other homozygous loss-of-function mutations segregating with affected status were identified in either family.”

Investigators also studied the effect of a chow diet containing 2% BCAAs or a BCAA-enriched diet, consisting of 7% BCAAs, on Bckdk mice deficient in the same gene. These mice have reduced levels of BCAAs in various tissues.

“Mice raised on the BCAA-enriched diet were phenotypically normal,” the authors observed, “[whereas] on the 2% BCAA diet…Bckdk mice and not wildtype had clear neurological abnormalities such as seizures…that appeared within 4 days of instituting the 2% BCAA diet.”

The same neurologic deficits were completely abolished within a week of the same mice starting the BCAA-enriched diet, suggesting that Bckdk mice have an inducible yet reversible phenotype.

“What was really surprising to us is that the children [we studied] could have come into any autism clinic because they looked like any child with autism, there was no way to differentiate them clinically,” Dr. Gleeson said. “The only way we were able to make the discovery was by sequencing the DNA, which was where we found the mutation.”

Dr. Gleeson added, too, that it was “very surprising” to find mutations in a potentially treatable metabolic pathway specific for autism, namely through BCAAs supplementation in patients with this specific mutation.

Investigators would welcome any parents whose children have the same constellation of autism with accompanying epilepsy or EEG abnormalities into their screening program.

Translation Medicine

Valerie Hu, PhD, from George Washington University, Washington, DC, told Medscape Medical News that she liked how the study translated novel genetic findings from exome sequencing to a functional/biochemical phenotype, demonstrating reversibility in the mouse model through nutritional supplementation.

“I think that recent research in the field is really opening up new horizons,” she added.

Dr. Hu is herself pursuing research related to the genetic underpinnings of autism.

The study was funded in part by the National Institutes of Health. Dr. Gleeson and his co-investigators have filed for a patent on the genetic diagnosis and potential treatment of this particular form of autism. Dr. Hu has no disclosed no relevant financial relationships.

Science. Published online September 6, 2012. Abstract

Retrieved from: http://www.medscape.com/viewarticle/771886?src=nl_topic


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