Maple Syrup Urine Disease Research Paper

Maple syrup urine disease is a rare autosomal recessive disorder of branched-chain amino acid metabolism leading to life-threatening cerebral edema, a swelling caused by excessive fluid in the brain and dysmyeination, malformed and defective myelin sheath, in affected individuals. Maple syrup urine disease is associated with a worldwide frequency of about 1 in 180,000 infants.
A higher chance in children of Amish, Mennonite, and Jewish descent. The condition gets its name from the distinctive sweet odor that smells like maple syrup or burnt sugar in the urine of affected infants.
Maple syrup urine is an inborn error of metabolism caused by a deficient in the branched-chain α-ketoacid dehydrogenase enzyme complex, which leads to elevations

of the branched-chain amino acids, also known as BCAAs (leucine, isoleucine, and valine) in plasma. Leucine, isoleucine, and valine are first converted to a-keto acids through a reaction called transamination. A-keto acids then undergo oxidative decarboxylation through the actions of the mitochondrial branched-chain α-keto acid dehydrogenase (BCKD) complex.
BCAAs make up roughly 35%-40% of our requirements for essential amino acids in skeletal muscle. BCAAs provide carbon source of oxidation as an alternative for lipid and carbohydrates as a source of energy. They are also metabolized as energy in the heart, kidneys, brain and adipose tissue.
BCKD complex is a mitochondrial enzyme formed by three catalytic subunits, referred to as E1, E2 and E3. With E1 being a thiamine pyrophosphate (TPP)-dependent decarboxylase. The E2 portion is a dihydrolipoamide branched-chain transacylase composed of 24 lipoic acid-containing polypeptides. The E3 portion is a homodimeric flavoprotein known as dihydrolipoamide dehydrogenase (DLD). E1α gene (known as BCKDHA) consists of 9 exons that generate two alternatively joined mRNAs that encode alpha subunit isoform 1 and alpha subunit isoform 2.
  The E1β gene (known as BCKDHB) is consists of 16 exons that generate two alternatively joined mRNAs that encode the same 392 amino acid protein. The E2 gene (DBT) contains 13 exons that encode a protein of 482 amino acids. The E3 gene (DLD) is located on contains 14 exons that generate several alternatively joined mRNAs. The DLD gene encodes the same dihydrolipoamide dehydrogenase subunits found in the PDHc and the 2-oxoglutarate dehydrogenase complexes.
MSUD patients can be divided into 4 different classifications:
Classic: Most severe form of MSUD. Begins with protein ingestion. With this type of MSUD, little to no enzyme activity presents. Activity of BCKD ranges less than 2% normal.
Intermediate: Infants will experience persistent elevation in BCAAs in body fluids and neurological impairment. Activity of BCKD ranges from 3%-8% normal
Intermittent: Activity of BCKD ranges from 8%-15% normal. Individuals will display normal normal early development. This doesn’t usually appear until 12-24 months of age.
Thiamine-responsive: This is due to a deficiency in E3. However, this form of MSUD is really rare. Similar to intermediate. Infants with this case are usually normal for the first few months. Persistent lactic acidosis will appear about 2 to 6 months of age.