Autism and epilepsy are a tough combination when brought together, but recent research conducted by groups at the Universities of California, San Diego and Yale has brought some hope to those afflicted.
Autism and Epilepsy
The research, published in the journal Science, investigated a genetic mutation which results in autism coupled with epilepsy and learning disabilities.
The team identified specific DNA mutations in a gene known as BCKDK which was present in a number of individuals with related conditions. The protein encoded by this gene, known as Branched Chain Ketoacid Dehydrogenase Kinase (BCKDK), is heavily involved in controlling one of the pathways responsible for synthesis of amino acids from products of central metabolism
BCKDK is a protein kinase (a class of enzymes responsible for adding a phosphate group to certain points on another protein molecule) which phosphorylates the E1α subunit of a protein known as Branched-Chain Ketoacid Dehydrogenase (BCKDH
); a protein which is directly involved in amino acid breakdown pathways.
Phopshorylation alters protein activity, so a mutation in the BCKDK gene results in altered activity of BCKDH, and thus, changes to the amino acid synthesis pathways vital to the cell.Laboratory mice defective in the BCKDK gene were created to provide a model with which the condition could be studied. The mice experienced a strikingly similar set of symptoms and an altered blood
amino acid level identical to that of the human patients tested in the study.
Screening the brains of these mice for the amino acid concentrations present revealed a deficiency in the branched-chain amino acids. The team concluded that phosphorylation of BCKDH by BCKDK results in its inactivation. A reduction in activity of BCKDH, therefore, removes the inhibition of BCKDK, allowing it to break down essential amino acids at a much greater rate.
The team found that giving BCKDK mutant mice extra doses of the branched-chain amino acids returned their blood amino acid levels to normal and relieved them of many of the symptoms of the disorder. Trials of this method on human patients has yielded increased branched-chain amino acid levels in the blood, but it remains to be seen whether the symptoms improve with time.
Investigation into the function of this pathway inspired the therapeutic amino acid replacement treatment for conditions resulting from this mutation, and provides an inspiring example whereby the approaches of genetics, molecular biology and biochemistry have been brought together to elucidate the pathophysiology of a condition, and provide a simple treatment to benefit its sufferers.