Branched-chain amino aciduria

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). 

The catabolism of leucine, valine, and isoleucine presents many analogies to fatty acid catabolism. Metabolic disorders of branched-chain amino acid catabolism include hypervalinemia, maple syrup urine disease, intermittent branched-chain ketonuria, isovaleric acidemia, and methylmalonic aciduria. 

Many organic acidurias originate in the breakdown of the three branched-chain amino acids, leucine, isoleucine and valine (Fig. 40-1). Metabolism of the organic acids requires the presence of specific enzymes, congenital... 

Figure 20.20 Pathways of branched-chain amino acid metabolism. A, B, C, D, E, and F indicate defects in valinemia, maple syrup urine disease, isovaleric acidemia, /3-hydroxyisovaleric aciduria, a-methyl-j3-hydroxybutyric aciduria, and methylmalonic aciduria, respectively.

The inborn errors of L-leucine catabolism present biochemically with branched-chain amino and/or organic aciduria [1]. These disorders include maple syrup disease (MSD branched-chain a-ketoacid dehydrogenase (BCKD) deficiency), isovaleric acidemia (isovaleryl-coenzyme A (CoA) dehydrogenase deficiency), isolated 3-methylcrotonyl-CoA carboxylase deficiency, the 3-methylglutaconic acidurias (3-methylglutaconyl-CoA hydratase deficiency, Barth syndrome, and other disorders in which the primary defect has not been demonstrated), and 3-hydroxy-3-methylglutaric aciduria (3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) lyase deficiency). 

Amino acid determination in blood and urine may be helpful. Alanine is increased in many patients with a mitochondrial disorder (see above). Deficiency of E3 complex leads to branched-chain amino acid elevation. Severe generalised amino aciduria associated with DeToni-Fanconi-Debrd tubulopathy may indicate a respiratory chain defect. 

Further reading Dancis, J. and Levitz, M. (1978). Abnormalities of branched-chain amino acid metabolism (hyper-valinaemia, maple syrup urine disease, isovaleric acidaemia and -methylcrotonic aciduria). In Stanbury, J.B., Wyngaarden, J.B. and Fredrickson, D.S. (eds.) The Metabolic Basis of Inherited Disease. 4th Ed., p. 397. (New York McGraw-Hill)... 

This chapter is concerned with the known disorders in the metabolism of the branched-chain amino acids after the initial transamination step, that lead to abnormal organic aciduria. Disorders of propionate and methylmalonate metabolism are discussed separately in Chapter 11. 

Disorders affecting all three branched-chain amino acids Branched-chain keto aciduria (maple syrup urine disease)... 

The patient with the classical form of the disease (Dancis and Levitz, 1978) appears normal at birth, but shows symptoms by the end of the first week, with poor feeding, vomiting and lethargy. Muscular hypertonicity and convulsions may appear. Death usually occurs as a result of intercurrent infections within the first year of life, and children surviving into their first and second years suffer severe brain damage. Abnormal amino acidaemia and amino aciduria with abnormal keto aciduria are apparent within the first week of life. Treatment by dietary protein restriction and the use of artificial amino acid mixtures has been attempted but is much more difficult and less successful in practise than treatment of phenylketonuria (Chapter 16), since most foods have a high content of branched-chain amino acids (Dancis and Levitz, 1978). Careful laboratory supervision is essential, there is a continued risk of recurrent infections, and it is unclear how long therapy will be required. 

Oast house urine disease (methionine malabsorption syndrome, 2-hydroxybutyric aciduria) Methionine, 2-hydroxybutyric, phenylpyruvic and the branched-chain keto acids especiaUy 2-oxoisovaleric Methionine malabsorption (amino acid-transport defect) (Chapter 16)... 

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