Isovaleric aciduria

Methylmalonic aciduria Propionic aciduria Isovaleric aciduria... 

In propionic and methylmalonic aciduria, metronidazole, given orally, inhibits the production of propionic acid by gut bacteria. In isovaleric aciduria and methylcrotonyl-CoA carboxylase deficiency, glycine accompanied by carnitine supplementation inCTeases the elimination of toxic metabolites. In many severe conditions, empiric administration of substances that act as cofactors proves to be helpful, and this treatment option should not be neglected (Table 5.3) [19]. 

Dionisi-Vici C, et al. Classical organic acidurias, propionic aciduria, methylmalonic aciduria and isovaleric aciduria long-term outcome and effects of expanded newborn screening using tandem mass spectrometry. J Inherit Metab Dis. 2006 29(2-3) 383-9. 

Eldjam, L., Jellum, E., Stokke, O., Pande, H. and Waaler, P.E. (1970), )8-Hydroxy-isovaleric aciduria and )8-methylcrotonylglycinuria A new inborn error of metabolism. Lancet, ii, 521. 

Tanaka, K. and Isselbacher, K.J. (1967), The isolation and identification of N-iso-valerylglycine from urine of patients with isovaleric aciduria. J. Biol. Chem., 242, 2966. 

Tanaka, K., Mandell, R. and Shih, V.E. (1976), Metabolism of [l-C-14] and [2-C-14] leucine in cultured skin fibroblasts from patients with isovaleric aciduria - characterisation of metabolic defects. J. Clin. Invest., 58,164. 

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. 

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.

Individuals who are deficient in HMG-CoA lyase are unable to complete the metabolism of leucine. The increased urinary excretion of 3-hydroxy-3-methylglutaric acids is the primary biochemical criterion that distinguishes this particular enzymatic defect from other defects in enzymes of leucine catabolism that also result in metabolic acidosis and abnormal organic aciduria. There is also substantial urinary excretion of intermediates of leucine catabolism, such as 3-methylglutaconic acid, and their metabolites, including 3-hydroxy-isovaleric acid produced from isovaleric acid. 

Isovaleric acidemia Glutaric acidemia type II 3-Hydroxy-3-methylglutaric aciduria... 

Sweaty feet Isovaleric acid Isovaleric acidemia 3-Hydroxy-3-methylglutaric aciduria MAD... 

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). 

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)... 

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)...

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)...

It is of interest that one of the cases of Sidbury et al (1967), who were described as having hexanoic and butanoic aciduria due to a proposed defect in short-chain fatty acid metabolism located at green acyl-CoA (butyryl-CoA) dehydrogenase, was subsequently shown to have isovaleric acidaemia (Ando et al, 1973) (Case 4, Family II of Sidbury etal, 1967). It is possible that the other three cases of Sidbury et al (1967) (Cases 1-3, Family I) also had isovaleric... 

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