Chapter 87

### Abstract

1. 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.

2. 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.

3. 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.

4. 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 ...

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