Keto aciduria

Dancis, J., Levitz, M., Westall, R. (1960) Maple syrup urine disease branched-chain keto-aciduria. Pediatrics 25, 72-79. Menkes, J.H. (1959) Maple syrup disease isolation and identification of organic acids in the urine. Pediatrics 23, 348-353. 

The concentration and associated ratio of the ketone bodies, aceto-acetate and 3-hydroxybutyrate, may also be helpful [15, 18, 19]. Ketosis and keto-aciduria are observed in certain patients with a mitochondrial disorder. A non-physiological increase of ketone bodies postprandially may be another indicator of a mitochondrial defect (Saudubray et al). Increased 3-hydroxybutyrate/acetoacetate ratio may suggest a defect in the respiratory chain in liver tissue. 

Another inherited error of valine, isoleucine and leucine metabolism is branched-chain a-keto aciduria, also known as maple syrup urine disease because the odour of urine of these patients resembles that of maple syrup. Branched-chain a-keto acid dehydrogenase, the enzyme complex that is used to oxidatively decarboxylate 2-ketoisovaleric, 2-keto-3-methylvaleric and 2-ketoisocaproic acids to the corresponding branched-chain CoA esters is defective, and very high concentrations of these keto acids accumulate in the blood and urine of these... 

Fig. 3.3 Chromatogram of organic acids extracted from urine of a patient with branched-chain keto aciduria, separated as their methyl esters on 4 per cent QF-1 coated on Chromosorb G (HP, 100-120 mesh) at 79°C (isothermal). Peak identifications are 1, methyl 2-hydroxyisovalerate 2, methyl 2-ketO isovalerate 3, methyl 2-keto-3-methylvalerate 4, methyl 2-keto-isocaproate 5, methyl benzoate (internal standard). (Redrawn with modifications from Greer and Williams, 1967)...

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

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 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. 

Fig. 10.1 Metabolites in the urine of an untreated patient with branched-chain keto aciduria (maple syrup urine disease). Extracted using ethyl acetate and separated as their trimethylsilyl-oxime derivatives on a 25 m SE-30 capillary column, using temperature programming from 80°C to 110°C at 0.5°C min and an injection split ratio 1 12 at a temperature of 250°C. The peaks marked R are due to solvent and reagents. Peak identifications are 1, lactic 2, 2-hydroxyisobutyric 3, 2-hydroxybutyric 4, pyruvic 5, 3-hydroxybutyric 6, 2-hydroxyisovaleric 7, 2-oxobutyric 8, 2-methyl-3-hydroxy-isovaleric 10, a and b, 2-oxoisovaleric 11, acetoacetic 12, 2-hydroxyisocaproic 13, 2-hydroxy-3-methyl- -valeric 14, 2-oxo-3-methyl-/i-valeric (14a L- 14b D-) 15, 2-oxoisocaproic acids. The internal standard was malonic acid. (Redrawn with modifications from Jellum etal., 1976)...

Langenbeck et al. (1977) reported the use of O-trimethylsilylquinoxalinol derivatives in studies on branched-chain keto aciduria, including the use of single-ion monitoring with a mass spectrometer, but did not report the concentrations of organic acids observed. A typical chromatogram of these derivatives is given in Fig. 10.6. 

Thus, although relatively few studies have been reported in the literature on the organic acids in branched-chain keto aciduria, particularly by use of gas chromatography and mass spectrometry, the potential of these techniques in... 

Fig. 10.3 Chromatogram of organic acids extracted from the urine of an untreated patient with branched-chain keto aciduria (maple syrup urine disease), extracted and separated as described in the legend to Fig. 10.2. The chromatogram illustrates the overlapping peaks in the regions occupied by 3-hydroxybutyric, 2-hydroxyisovaleric and 2-oxoisovaleric acids (peak 1) and 2-oxo-3-methyl-valeric, 2-hydroxyisocaprioic and 2-oxoisocaproic acids (peak 2) and phosphate (peak 3). Other peaks of interest are (4) citric, (5) 4-hydroxyphenyl-lactic, (6) 4-hydroxyphenylpyruvic, (7) n-tetracosane (standard) and (8) -hexacosane (standard). (Compare with Fig. 10.4.)...

Duran, M., Tielens, A.G.M., Wadman, S.K., Stigter, J.C.M. and Kleijer, W.J. (1978b), Effect of thiamine in a patient with a variant form of branched-chain keto aciduria. Acta Paediatr. Scand., 67,367. 

Gompertz, D. and Draffan, G.H. (1972a), The gas chromatographic diagnosis of intermittent maple syrup urine disease (branch-chain keto aciduria). Clin. Chim. Acta, 40, 5. 

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