Maple syrup urine disease (MSUD) or branched-chain ketoaciduria is caused by a deficiency in activity of the branched-chain α-keto acid dehydrogenase (BCKD) complex. This metabolic block results in the accumulation of the branched-chain amino acids (BCAAs) leucine, isoleucine, and valine, and the corresponding branched-chain α-keto acids (BCKAs). Based on the clinical presentation and biochemical responses to thiamine administration, MSUD patients can be divided into five phenotypes: classic, intermediate, intermittent, thiamine-responsive, and dihydrolipoyl dehydrogenase (E3)-deficient. Classic MSUD has a neonatal onset of encephalopathy and is the most severe and most common form. Variant forms of MSUD generally have the initial symptoms by 2 years of age. The levels of the BCAAs, particularly leucine, are greatly increased in plasma and urine. The presence of alloisoleucine is diagnostic of MSUD. Activity of the BCKD complex in skin fibroblasts or lymphoblast cultures is reduced, and ranges from less than 2 percent of normal in the classic form to 30 percent of normal in the variant forms. The E3-deficient MSUD presents a combined deficiency of BCKD, pyruvate dehydrogenase, and α-ketoglutarate dehydrogenase complexes. This is the result of E3 being a common component of the three mitochondrial multienzymes. An animal model in Polled Hereford calves has been described.

MSUD is an autosomal recessive metabolic disorder of panethnic distribution. The worldwide frequency based on routine screening data from 26.8 million newborns is approximately 1 in 185,000. In the inbred Old Order Mennonite population of Lancaster and Lebanon Counties, Pennsylvania, MSUD occurs in approximately 1 in 176 newborns.

The BCAAs comprise about 35 percent of the indispensable amino acids in muscle, and 40 percent of the performed amino acids required by mammals. The catabolic pathways for BCAAs begin with the transport of these amino acids into cells by the system L transporter located in the cytosolic membrane. Inside the cell, BCAAs undergo reversible transamination by the cytosolic or mitochondrial isoforms of the branched-chain amino acid aminotransferase (BCAT) in the respective compartment to produce the BCKAs α-ketoisocaproate (KIC) from leucine, α-keto-β-methylvalerate (KMV) from isoleucine, and α-ketoisovalerate (KIV) from valine. BCKAs synthesized in the cytosol are translocated by the specific BCKA transporter into mitochondria, where oxidative decarboxylation of the three BCKAs is catalyzed by the single BCKD multienzyme complex. These reactions generate the respective branched-chain acyl-CoAs that are further metabolized via separate pathways. The end products of leucine catabolism are acetyl-CoA and acetoacetate. BCAAs, as a group, are both ketogenic and glucogenic. They are the precursor for fatty acids and cholesterol synthesis through acetyl-CoA. These amino acids are also substrates for energy production via succinyl-CoA and acetoacetate.

The oxidation of BCAAs occurs primarily in liver, kidney muscle, heart, brain, and adipose tissue. There is evidence that transamination is rate limiting in the catabolism of BCAAs in rat liver, where BCAT activity is low. Based on the rat model, a significant proportion of BCKAs appears to originate from skeletal muscle, and circulates to the liver where it is oxidized. However, recent studies confirm that the BCKD complex activity in human liver is markedly lower than that in rat liver. The results support the view that skeletal muscle is the major site for both BCAA transamination and oxidation in humans.

The human BCKD complex is loosely associated with the inner membrane of the mitochondria. This multienzyme complex is a macromolecule (molecular mass 4 × 106 daltons) comprising three catalytic components: a thiamine pyrophosphate (TPP)-dependent decarboxylase, or E1, with an α2β2 structure; a transacylase, or E2, that contains 24 lipoate-bearing polypeptides; and a dehydrogenase, or E3, that is flavoprotein of homodimeric structure. In addition, the BCKD complex contains two regulatory enzymes, a kinase and a phosphatase, that control activity of the complex through a reversible phosphorylation (inactive)/dephosphorylation (active) mechanism. The BCKD complex is organized around the E2 cubic core, to which E1, E3, the specific kinase, and the specific phosphatase are attached through ionic interactions. The crystal structure of human E1 has recently been determined at 2.7 Å resolution.

Full-length cDNAs encoding E1α, E1β, E2, E3, and the specific kinase of mammalian BCKD complex have been cloned. Using these probes, the human BCKD genes were assigned to different chromosomes: E1α (gene symbol BCKDHA) to chromosome 19q13.1-q13.2; E1β (gene symbol BCKDHB) to 6p21-p22; E2 (gene symbol DBT) to 1p31; and E3 (gene symbol DLD) to 7q31-q32. The genomic structure including the regulatory-promoter regions of E1α, E1β, E2, E3, and the kinase genes of the mammalian BCKD complex have been characterized. The human E1α gene (>55 kb) consists of 9 exons. The human E1β (>100 kb) and E2 (68 kb) genes and the rat kinase (6 kb) gene each contains 11 exons. The human E3 gene (approximately 20 kb) comprises 14 exons.

The genetic heterogeneity in MSUD demonstrated previously by complementation studies can now be explained by the six loci that contribute to the human BCKD complex. Four molecular phenotypes based on the affected locus of the BCKD complex are classified. Type IA (MIM 248600) refers to mutations in E1α gene; type IB (MIM 248611) refers to mutations in E1β gene; type II (MIM 248610) refers to mutations in E2 gene; and type III (MIM 246900) refers to mutations in E3 gene. Sixty-three mutations in all four phenotypes have been identified, and some have been characterized. The type IA defect in Mennonite MSUD patients is a homozygous Tyr-393 to Asn substitution in the E1α subunit that impairs the assembly with E1β. The adverse effects of type IA and type IB MSUD mutations on the catalysis and assembly of the human α2β2 heterotetramer can now be explained at the three-dimensional structure level. A strong correlation between type II mutations and the thiamine-responsive clinical phenotype has been demonstrated.

The majority of untreated classic patients die within the early months of life from recurrent metabolic crisis and neurologic deterioration. Treatment involves both long-term dietary management and aggressive intervention during acute metabolic decompensation. Advances in both aspects of treatment have considerably reduced the morbidity, mortality, and length of initial hospitalization for patients. The age of diagnosis and the subsequent metabolic control are the most important determinants of long-term outcome. Patients in whom treatment is initiated after 14 days of age rarely achieve normal intellect.

There have been five successful pregnancies in two intermediate MSUD patients. The major concerns are the stress of pregnancy on metabolic homeostasis and the rapidly changing nutritional requirements during the course of pregnancy and after delivery. These parameters require careful monitoring.