2- Hydroxyisovaleric acid deficiency

Holocarboxylase synthetase deficiency can be diagnosed prenatally by assessing the response of carboxylase activity in cultured amniocytes (obtained by amniocentesis) to the addition of biotin, or by the detection of methylcitric and hydroxyisovaleric acids in the amniotic fluid. Prenatal therapy, by giving the mother 10 mg of biotin per day, results in sufficiently elevated fetal blood concentrations of biotin to prevent the development of organic acidemia at birth. 

Mock NI, Malik MI, Stumbo PJ, Bishop WP, and Mock DM (1997) Increased urinary excretion of 3-hydroxyisovaleric acid and decreased urinary excretion of biotin are sensitive early indicators of decreased biotin status in experimental biotin deficiency. American Journal of Clinical Nutrition 65, 951-8. 

An example of a search for unusual metabolites related to a human disorder is well illustrated with the case of hereditary progressive deafness in a large Norwegian family, studied by Jellum et al. [164]. While no other obvious clinical symptoms were associated with the deafness cases, capillary GC/MS demonstrated the presence of two unusual metabolites, 3-hydroxyisovaleric acid and 3-methylcrotonylglycine. Both compounds appear to be intermediates in the metabolism of leucine, and as Fig. 3.13 demonstrates, a metabolic loading experiment with leucine revealed an enzymatic deficiency in patients with hereditary progressive deafness. 

IVA was initially described in 1966 and became the first organic acidemia described. IVA is caused by a deficiency of the enzyme isovaleryl-CoA dehydrogenase, an enzyme important in leucine catabolism and also important in the transfer of electrons to the respiratory chain [7, 13]. The consequent accumulating metabolites include isovaleric add, isovalerylglydne, 3-hydroxyisovaleric acid, and isovalerylcamitine (C5) [7, 13] (Fig. 17.3). These are easily identified on urine organic acid analysis and acylcamitine profile. The excretion of isovalerylglydne and 3-hydroxyisovaleric acid is diagnostic. 

Reduced activities of carboxylase enzymes can cause a metabolic block of certain substrates and a use of alternative pathways for catabolism. Therefore, 3-hydroxyisovaleric acid and 3-methylcrotonyl glycine are formed consequently to a shunt of 3-methylcrotonyl carboxylase counterbalancing its activity decrease. Marginal biotin deficiency experimentally induced by 20 days of free biotin diets in human increased 3-hydroxyisovaleric acid excretion in urine above the upper limit of normal. The normal urinary excretion of 3-hydroxyisovaleric acid in healthy adults is 112 38 pmol per 24 hours (Mock et al. 1997). This suggests that 3-hydroxyisovaleric acid urinary excretion is a good indicator of marginal biotin deficiency. 

Cat urine 3-Hydroxyisovaleric acid 3-Methylcrotonylglycinuria Multiple carboxylase deficiency... 

Mock DM, Henrich CL, Camell N, Mock Nf. Indicators of marginal biotin deficiency and repletion in humans validation of 3-hydroxyisovaleric acid excretion and a leucine challenge. Am J Clin Nutr 2002 76 1061—1068. 

Odd-chain fatty acid accumulation is also a marker of biotin deficiency. The accumulation of odd-chain fatty acid is thought to result from PCC deficiency (Figure 3) the accumulation of propionyl-CoA likely leads to the substitution of a propionyl-CoA moiety for acetyl-CoA in the ACC reaction and to the incorporation of a three- (rather than two-) carbon moiety during fatty acid elongation. However, in comparison to lymphocyte PCC activity and urinary excretion of 3-hydroxyisovaleric acid, odd-chain fatty acids accumulate in blood lipids more slowly during biotin deficiency and return to normal more gradually after biotin repletion. 

These brief reports have been confirmed by a more detailed description of a similar case (Truscott et al, 1979), a girl who died at 5 days of age with hyperammonaemia, and raised plasma glutamine, alanine and lysine. Increased excretion of 3-methylglutaric, 3-methylglutaconic and 3-hydroxy-3-methylglutaric acids (but not of 3-hydroxyisovaleric acid) was observed but at much lower concentrations than those in patients with authentic 3-hydroxy-3-methylglutaryl-CoA lyase deficiency, being 170,463 and 181 mmol mol of creatinine respectively or 20 per cent, 6 per cent and 1 per cent of the concentrations in an authentic patient. Measurement of enzyme activities in cultured fibroblasts showed these to be normal and a primary defect in the urea cycle was suspected ... 

Finnic, M.D.A., Cottrall, K., Seakins, J.W.T. and Snedden, W. (1976), Massive excretion of 2-oxoglutaric acid and 3-hydroxyisovaleric acid in a patient with a deficiency of 3-methylcrotonyl Co A carboxylase. Clin. Chim. Acta, 73,513. 

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). 

Urinary organic acid analysis is useful for differentiating isolated carboxylase deficiencies from the biotin-responsive multiple carboxylase deficiencies. P-Hydroxyisovalerate is the most common urinary metabolite observed in isolated P-methylcrotonyl-CoA carboxylase deficiency, biotinidase deficiency, biotin holo-carboxylase synthetase deficiency, and acquired biotin deficiency. In addition to P-hydroxy-isovalerate, elevated concentrations of urinary lactate, methylcitrate, and P-hydroxypropionate are indicative of multiple carboxylase deficiency. 

In leucine catabolism (Scheme 62c), the first steps leading to isovaleryl-CoA 233, X = CoA, are similar to those in the catabolism of valine 179 and isoleucine 212. When samples of (2R)- and (2S)-[2- H Jisovaleric acid 233, X = OH, were fed to biotin-deficient rats, / -hydroxyisovalerate 235 was isolated and shown to have lost the 2-pro-R hydrogen (212), thus indicating that the dehydrogenation step 233 234 had occurred with loss of this hydrogen. The hydration step 234 235 proved to be nonstereospecific for... 

Analysis of organic acids of the urine reveals the picture of multiple carboxylase deficiency characterized by pronounced excretion of lactate and 3-hydroxyisovalerate, 3-methylcrotonylglycine, 3-hydroxypropionate and methylcitrate. 

Multic2irboxylase deficiency Lactic, propionic, 3-hydroxypropionic, 3-hydroxyisovaleric, 3-hydroxy-w-valeric and methylcitric acids and 3-methylcrotonylglycine Holocarboxylase synthetase (probable) 10.3.2... 

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