Maple syrup urine disease (MSUD) is classified as classic or intermediate. Twelve hours after birth, untreated neonates with classic MSUD have a maple syrup odor in cerumen; by 12-24 hours, elevated plasma concentrations of branched-chain amino acids (BCAAs) (leucine, isoleucine, and valine) and allo-isoleucine, as well as a generalized disturbance of plasma amino acid concentration ratios; by age two to three days, ketonuria, irritability, and poor feeding; by age four to five days, deepening encephalopathy manifesting as lethargy, intermittent apnea, opisthotonus, and stereotyped movements such as "fencing" and "bicycling." By age seven to ten days, coma and central respiratory failure may supervene. Individuals with intermediate MSUD have partial BCKAD enzyme deficiency that only manifests intermittently or responds to dietary thiamine therapy; these individuals can experience severe metabolic intoxication and encephalopathy during sufficient catabolic stress.
MSUD is diagnosed by the presence of clinical features, elevated BCAAs and allo-isoleucine in plasma, and branched-chain hydroxyacids and ketoacids (BCKAs) in urine. Newborn screening (NBS) programs that employ tandem mass spectrometry detect MSUD by measuring the whole blood combined leucine-isoleucine concentration and its ratio to other amino acids such as alanine and phenylalanine. The three genes in which mutations are associated with MSUD are BCKDHA, encoding BCKA decarboxylase (E1) alpha subunit (MSUD type 1A); BCKDHB, encoding BCKA decarboxylase (E1) beta subunit (MSUD type 1B); and DBT, encoding dihydrolipoyl transacylase (E2) subunit (MSUD type 2). Molecular genetic testing of all three genes is available on a clinical basis.
MSUD is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being unaffected and a carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk relatives and prenatal diagnosis for pregnancies at increased risk are possible if the disease-causing mutations have been identified in an affected family member.