Since 1964, routine newborn screening has been performed for MSUD. Newborn Screening and Biochemical Evaluation The preferred diagnostic method is molecular analysis. Pre-implantation diagnosis requires the identification of familial pathogenic variants. Branched-chain amino acid concentrations can also be measured in amniotic fluid. Isoleucine metabolites are responsible for the maple syrup odor of the urine.Įncephalopathy and ketoacidosis with a negative newborn screening resultĭiagnosis requires the measurement of BCKAD enzyme activity in cultured chorion villus cells or amniocytes using mutational analysis. The metabolic decompensations in MSUD lead to the activation of matrix metalloproteinases, resulting in the blood-brain barrier's breakdown. In patients with classic MSUD, decreased levels of glutamate and increased cerebral lactate levels indicate inhibition of the respiratory chain by alpha-ketoisocaproic acid. Clinical evidence suggests that the neurotoxin alpha-ketoisocaproic acid contributes to the encephalopathic syndrome. In infants and children, decreased blood osmolarity can further precipitate brain herniation. This results in decreased blood osmolarity, sodium concentrations, and increased intracellular water leading to cerebral edema. Furthermore, elevated leucine concentrations impair cell volume regulation. This reversal accounts for low cerebral glutamate levels, which results in cognitive dysfunctions such as learning disabilities and memory loss. Alpha-ketoisocaproic acid levels of greater than 60 micromol/L negatively regulate transamination reactions within astrocytes. The restricted supply of the amino acids leads to decreased neurotransmitters, such as dopamine, serotonin, norepinephrine, epinephrine, GABA, and glutamate. As a consequence, brain growth and myelin synthesis are negatively impacted. As a result, the supply of tyrosine, phenylalanine, methionine, tryptophan, histidine, and valine to the brain. The transport of large neutral amino acids across the blood-brain barrier is drastically reduced due to interference from elevated leucine levels. Elevated leucine and alpha-ketoisocaproic acid levels notoriously cause neurochemical disturbances resulting in clinically apparent neurotoxicity. Accumulated BCAA and alpha-ketoacids manifests as a constellation of clinical symptoms due to dysfunction of the central nervous system, immune system, and skeletal muscle. Maple syrup urine disease occurs due to a pathogenic defect in any BCKAD subunit resulting in elevated branched-chain amino acids and their corresponding alpha keto-acids. Most BCAA transamination and oxidation occur in the skeletal muscle. The liver and kidney are responsible for the catabolism of 10% to 15% of BCAA. In the brain, BCKAD helps metabolize BCAA to facilitate cerebral GABA and glutamate synthesis. The catabolism of these amino acids is necessary to maintain various physiologic functions such as : The branched-chain amino acids are essential amino acids with hydrophobic side chains and are found in protein-rich food. These intermediates are then converted into succinyl-CoA, acetoacetate, and acetyl-CoA. Consequently, alpha-ketoacids are further metabolized into intermediates such as isovaleryl-coenzyme A, alpha-methylbutyryl-CoA, and isobutyrl-CoA. Alpha-ketoacids are then oxidatively decarboxylated by the branched-chain ketoacid dehydrogenase complex. Their respective yielded alpha-ketoacids include alpha-ketoisocaproic acid, alpha-keto-beta-methyl valeric acid, and alpha-ketoisovaleric acid. Therefore, within the mitochondria, branched-chain amino acids are first converted into their respective alpha-ketoacids by the enzyme branched-chain amino acid transaminase. The activity of branched-chain ketoacid dehydrogenase is further regulated by BCKAD phosphatase and BCKAD kinase. The E3 subunit helps reoxidize the lipoic acid residue in E2. The lipoic acid residue in E2 transfers the acyl group from E1 to CoA. In the presence of thiamin pyrophosphate, E1 decarboxylates the alpha ketoacids. Together with branched-chain amino acid transaminase, it helps mediate catabolism of branched-chain amino acids (BCAA). It is composed of three catalytic subunits (E1, E2, and E3). Branched-chain ketoacid dehydrogenase (BCKAD) is located within the inner mitochondrial membrane of various tissues such as skeletal muscle, liver, kidney, and the brain.
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