BCKDHA

The BCKDHA gene provides instructions for making one part, the alpha subunit, of an enzyme complex (a group of enzymes that work together). This complex is called branched-chain alpha-keto acid dehydrogenase, or BCKD. Two alpha subunits connect with two beta subunits, which are produced from the BCKDHB gene, to form a critical part of the enzyme complex called the E1 component.

The BCKD enzyme complex is responsible for one step in the normal breakdown of three protein building blocks (amino acids). These amino acids—leucine, isoleucine, and valine—are obtained from the diet. They are present in many kinds of food, particularly protein-rich foods such as milk, meat, and eggs. The BCKD enzyme complex is active in mitochondria, which are specialized structures inside cells that serve as energy-producing centers. The breakdown of leucine, isoleucine, and valine produces molecules that can be used for energy.

maple syrup urine disease - caused by mutations in the BCKDHA gene

More than 40 mutations in the BCKDHA gene have been identified in people with maple syrup urine disease, most often in individuals with the severe, classic form of the disorder. Most BCKDHA mutations change single amino acids in the alpha subunit of the BCKD enzyme complex. In the Old Order Mennonite population, where maple syrup urine disease occurs frequently, the most common mutation replaces the amino acid tyrosine with the amino acid asparagine at position 438 (written as Tyr438Asn or Y438N).

Mutations in the BCKDHA gene disrupt the normal function of the BCKD enzyme complex, preventing it from effectively breaking down leucine, isoleucine, and valine. As a result, these amino acids and their byproducts build up in the body. This accumulation is toxic to cells and tissues, particularly in the nervous system. The buildup of these substances can lead to seizures, developmental delay, and the other medical problems associated with maple syrup urine disease.