Isovaleric acid deficiency

Allyl isovalerate has low irritancy potential. It is deduced that one of its metabolites, isovaleric acid, is toxic, based upon the effects of an inborn error of leucine metabolism caused by isovaleiy l-coenzynie A dehydrogenase deficiency. This is a sx ndrome of neonatal vomiting and lethargy progressing to coma, pancytopenia and ketoacidosis that can be alleviated by glycine treatment, which enhances the synthesis and excretion of iso-valerylglycine (Cohn et al., 1978 lARC, 1985). 

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. 

Biotin deficiency in experimental animals is teratogenic, and a number of the resultant birth defects resemble human birth defects. Up to half of pregnant women have elevated excretion of 3-hydroxy-isovaleric acid (Section 11.4), which responds to supplements of biotin, in the first trimester, suggesting that marginal stams may be common in early pregnancy and may be a factor in the etiology of some birth defects. This may be the result of increased catabolism of biotin as a result of steroid induction of biotin catabolic enzymes there is increased excretion of bisnorbiotin and biotin sulfoxide (Zempleni and Mock, 2000a Mock et al., 2002). 

Animal and human studies have shown that an elevated concentration of ammonia (hyperammonemia) exerts toxic effects on the central nervous system. There are several causes, both inherited and acquired, of hyperammonemia. The inherited deficiencies of urea cycle enzymes are the major cause of hyperammonemia in infants. The two major inherited disorders are those involving the metabolism of the dibasic amino acids lysine and ornithine and those involving the metabolism of organic acids, such as propionic acid, methylmalonic acid, isovaleric acid, and others (see Chapter 55). 

To allow estimation of human biotin requirements and evaluation of potential deleterious efiects of marginal degrees of biotin deficiency, indicators of biotin status need to be determined and validated. Several explored directions include serum concentrations and urinary excretion rates of biotin and biotin metabolites, activities of the biotin-dependent decarboxylases in peripheral blood mononuclear cells, and urinary excretion rates of 3-hydroxy-isovaleric acid 3-methylcrotonyl glycine and 2-methylcitric acid. 

Further enzymological studies on the condition have been provided by Bartlett et al. (1980), who described a 4-year-old girl with mild metabolic acidosis and who excreted grossly increased concentrations of 3-hydroxy-isovaleric acid and 3-methylcrotonylglycine in her urine. She was responsive to biotin therapy (oral, 5 mg day ) and studies on her cultured skin fibroblasts showed deficient activities of propionyl-CoA carboxylase and of 3-methyl-crotonyl-CoA carboxylase. Studies in vivo showed that the latter enzyme was stimulated by biotin supplementation of the medium to a much greater degree than the other mitochondrial carboxylase enzymes. 

Chalmers and Spellacy (1980) studied cultured skin fibroblasts from this child and were unable to demonstrate deficient activity of 3-methylcrotonyl-CoA carboxylase, or of propionyl-CoA carboxylase measured as a control, in disrupted confluent fibroblasts. However, using a newly developed assay that measures incorporation of [l- C]isovaleric acid into protein, with incorporation of [l- C]acetyl-CoA as control, in intact subconfluent dividing fibroblasts grown in monolayer (Chalmers and Spellacy, 1979), which effectively screens for disorders in the metabolism of L-leucine between isovaleryl-CoA and acetyl-CoA, these workers were able to demonstrate a grossly reduced incorporation of isovalerate into protein (21 and 23 pmol of... 

Diabetes - insulin dependent Methyl malonic, propionic or isovaleric acidaemias Pyruvate carboxylase and multiple carboxylase deficiency Gluconeogenesis enzyme deficiency glucose-6-phosphatase, fructose-1,6-diphosphatase or abnormality of glycogen synthesis (glycogen synthase) Ketolysis defects Succinyl coenzyme A 3-keto acid transferase ACAC coenzyme A thiolase... 

Fig. 3.2.5 Profiles of acylcarnitines as their butyl esters in plasma (precursor of m/z 85 scan) of a normal control (a) and patients with various organic acidemias. Propionylcarnitine (C> m/z 274 peak 3) is the primary marker for both propionic acidemia (b) and methylmalonic acidemias (c). Note that an elevation of methylmalonylcarnitine (C4-UC m/z 374) is not typically found in patients with methylmalonic acidemias. In the three cases of ethylmalonic encephalopathy (d) analyzed in our laboratory, elevations of ,- (m/z 288 peak 4) and C5-acylcarnitine (m/z 302 peak 5) species were noted. Isolated C5-acylcarnitine elevations are encountered in patients with isovaleric acidemia (e), where it represents isovalerylcarnitine. Cs-Acylcarnitine is also elevated in patients with short/branched chain acyl-CoA dehydrogenase deficiency, where it represents 2-methylbutyrylcarnitine (see Fig. 3.2.4), and in patients treated with antibiotics that contain pivalic acid, where it represents pivaloylcarnitine [20, 59, 60]. Patients with /3-ketothio-lase deficiency (f) present with elevations of tiglylcarnitine (C5 i m/z 300 peak 6) and C5-OH acylcarnitine (m/z 318 peak 7). In most cases of 3-methylcrotonyl-CoA carboxylase deficiency (g) Cs-OH acylcarnitine is the only abnormal acylcarnitine species present. The differential diagnosis of C5-OH acylcarnitine elevations includes eight different conditions (Table 3.2.1). Also note that C5-OH acylcarnitine represents 3-hydroxy isovalerylcarnitine in 3-methylcrotonyl-CoA carboxylase deficiency (g), and 2-methyl 3-hydroxy butyrylcarnitine in / -ketothiolase 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. 

Isovaleric acidemia is a rare disorder of leucine metabolism caused by the deficiency of isovaleryl-CoA dehydrogenase this leads to mild neurological impairment and, at its severest, to coma and death. Dietary management aims to hmit leucine intake by means of a low-protein diet, and by supplementing the diet with a leucine-free amino acid mixture if necessary. 

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]. 

They are defects in the degradation pathways of leucine, isoleucine, and valine. These conditions are usually diagnosed by examining organic acids in urine with abnormal metabolites also notable on acylcamitine profile. Organic acidemias comprise a variety of disorders and include methylmalonic acidemia (MMA), propionic acidemia (PROP), isovaleric acidemia (IVA), glutaric acidemia type 1 (GA-1), 3-methylcrotonyl carboxylase deficiency (3-MCC), 3-methylglutaconic acidemia (3-MGA), and vitamin B12 uptake, transport, and synthesis defects. 

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. 

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