3-Hydroxyisovaleric acid, biotin deficiency

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. 

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. 

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... 

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. 

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. 

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