Branched-chain amino acids accumulation

Decreased brain 5HT and DA in rats on a high dietary leucine intake is probably due to inhibition of amine precursor transport to the brain [411, 412]. Similar biochemical changes might be responsible for the mental retardation associated with maple syrup disease in which keto acids derived from leucine and other branched chain amino acids accumulate [413]. Decreased brain 5HT might also be involved in the mental... 

Cultured fibroblasts or amniocytes can be probed with FAO substrates and carnitine. Cell cultures deficient of an FAO enzyme will accumulate specific acylcarni-tine species when incubated with substrates such as palmitate, allowing for the diagnosis of FAO disorders [28-37]. Modifications of this assay system have also been developed for the diagnosis of defects affecting the metabolism of branched-chain amino acids [20, 31, 34]. Recently, this approach was also adapted for the study of peripheral blood mononuclear cells [38]. 

When Rinaldo analyzed Ryan s blood serum, he found high concentrations of methylmalonic acid, a breakdown product of the branched-chain amino acids isoleucine and valine, which accumulates in MMA patients because the enzyme that should convert it to the next product in the metabolic pathway is defective. And particularly telling, he says, the child s blood and urine contained massive amounts of ketones, another metabolic consequence of the disease. Like Shoemaker, he did not find any ethylene glycol in a sample of the baby s bodily fluids. The bottle couldn t be tested, since it had mysteriously disappeared. Ri-naldo s analyses convinced him that Ryan had died from MMA, but how to account for the results from two labs, indicating that the boy had ethylene glycol in his blood Could they both be wrong ... 

In a rare autosomal recessive condition (discovered in 1954) the urine and perspiration has a maple syrup odor/ High concentrations of the branched-chain 2-oxoacids formed by transamination of valine, leucine, and isoleucine are present, and the odor arises from decomposition products of these acids. The branched-chain amino acids as well as the related alcohols also accumulate in the blood and are found in the urine. The biochemical defect lies in the enzyme catalyzing oxidative decarboxylation of the oxoacids, as is indicated in Fig. 24-18. Insertions, deletions, and substitutions may be present in any of the subunits (Figs. 15-14,15-15). The disease which may affect one person in 200,000, is usually fatal in early childhood if untreated. Children suffer seizures, mental retardation, and coma. They may survive on a low-protein (gelatin) diet supplemented with essential amino acids, but treatment is difficult and a sudden relapse is apt to prove fatal. Some patients respond to administration of thiamin at 20 times the normal daily requirement. The branched-chain oxoacid dehydrogenase from some of these children shows a reduced affinity for the essential coenzyme thiamin diphosphate.d... 

In maple syrup urine disease, the enzyme complex that decarboxy-lates the transamination products of the branched-chain amino acids is defective (see Figure 7-11). Valine, isoleucine, and leucine accumulate. Urine has the odor of maple syrup. Mental retardation occurs. 

In this disease, the a-keto derivatives for all three branched-chain amino acids are found in the urine. The transamination of the amino acids is normal, but the enzyme related to the oxidation of the a-keto acid derivatives (branched-chain a-keto acid dehydrogenase) is genetically defective or missing. Thus, there is an accumulation of the branched-chain amino acids and keto... 

In maple syrup urine disease, the branched-chain a-keto acid dehydrogenase that oxidatively decar-bo xylates the branched-chain amino acids is defective. As a result, the branched-chain amino acids and their a-keto analogs (produced by transamination) accumulate. They appear in the urine, giving it the odor of maple syrup or burnt sugar. The accumulation of a-keto analogs leads to neurologic complications. This condition is difficult to treat by dietary restriction, because abnormalities in the metabolism of three essential amino acids contribute to the disease. 

Maple syrup urine disease is a rare genetic disorder affecting the metabohsm of leucine, isoleucine and valine. Accumulation of these branched-chain amino acids results in severe neurological damage and death. The aim of dietary management is to prevent the accumulation of these amino acids, by the use of a low-protein diet and leucine-, isoleucine-and vahne-free amino acid preparations. Natural protein supplies the necessary leucine, isoleucine and valine, based on a leucine exchange system with additional isoleucine and/ or valine available as single amino acid supplements. 

Branched chain amino acids prevent SM-medlated Inhibition of bacterial ( 1, 30 ), yeast (31), and pea (32) growth. This suggests that the mode of Inhibition Is similar In each organism. Accumulation of -ketobutyrate Is observed upon treatment of... 

MSUD is an autosomal recessive disorder caused by deficiency of branched-chain a-ketoacid dehydrogenase (Pig. 47.1). The a-ketoadds derived from isoleucine, valine and leucine (branched-chain amino adds) accumulate and are excreted in the urine, giving it the peculiar odour of maple syrup. The branched-chain amino acids and the branched-chain a-ketoacids that accumulate in the blood are neurotoxic, causing severe neurological symptoms, cerebral oedema and mental retardation. A diet low in branched-chain amino acids is an effective treafinenL... 

Branched-chain keto aciduria or maple syrup urine disease (McKusick 24 860) is an autosomal recessive disease first described by Menkes et al. (1954) in which, because of the reversible nature of the preceding transamination step, a characteristic branched-chain amino aciduria also occurs (Westall etal, 1957). In the classical form of the disease, the metabolism of all three branched-chain amino acids is affected, leading to accumulation of the three corresponding keto acids (Menkes, 1959 MacKenzie and Woolf, 1959 Dancis etaL, 1959), with the keto acid of isoleucine, 2-keto-3-methylvalerate, apparently being responsible for the characteristic maple syrup smell in the patients urine (Snyderman ra/., 1964). 

This chapter describes the case reports of these enzyme deficiencies and the underlying biochemistry of the disorders and their associations. It is not the intention to discuss keto acidosis associated with other diseases, for example juvenile diabetes, or ketogenesis and its control which are reviewed elsewhere (Wildenhoff, 1975, 1977 McGarry and Foster, 1976 Halperin, 1977). In addition to the common occurrence of 3-hydroxybutyrate and acetoacetate in body fluids of patients with keto acidosis, secondary organic acids have been observed in urine, including adipic and suberic acids (Pettersen et aL, 1972), 3-hydroxyisovaleric acid (Landaas, 1974), 3-hydroxyisobutyric acid and 2-methyl-3-hydroxybutyric acid (Landaas, 1975). The dicarboxylic acids occur as a result of initial co-oxidation of accumulating long-chain fatty acids followed by )8-oxidation (Pettersen, 1972), and metabolites of the branched-chain amino acids occur because of inhibition of their metabolic pathways by 3-hydroxybutyrate and acetoacetate (Landaas and Jakobs, 1977). 

Organic acidemias are disorders of branched-chain amino metabolism in which non-amino organic acids accumulate in serum and urine. 

T There is a relatively rare genetic disease in which the three branched-chain a-lceto acids (as well as their precursor amino acids, especially leucine) accumulate in the blood and spill over into the urine. This condition, called maple syrup urine disease because of the characteristic odor imparted to the urine by the a-lceto acids, results from a defective branched-chain a-lceto acid dehydrogenase complex. Untreated, the disease results in abnormal development of the brain, mental retardation, and death in early infancy. Treatment entails rigid control of the diet, limiting the intake of valine, isoleucine, and leucine to the minimum required to permit normal growth. ... 

Maple syrup urine disease (MSUD) is a recessive disorder in which there is a partial or complete deficiency in branched-chain o-ketoacid dehydrogenase, an enzyme that decarboxylates leucine, isoleucine, and valine (see Figure 20.10). These amino acids and their corre sponding a-keto acids accumulate in the blood, causing a toxic effect that interferes with brain functions. The disease is characterized by feeding problems, vomiting, dehydration, severe metabolic acidosis, and a characteristic maple syrup odor to the urine. If untreated, the disease leads to mental retardation, physical disabilities, and death. 

The large accumulation in the urine of the a-keto acid compared to the amino acid occurs because the kidney is adapted to effectively reabsorb amino acids, but not to reabsorb the branched-chain a-keto acids as effectively. Therefore, there is a greater spillage of the a-keto acids than the amino acids. We will see the same occurrence of large amounts of a-keto acid compared to amino acid in the urine when we look at another metabolic disease associated with aromatic amino-acid metabolism. 

---