Isoleucine metabolism disorders

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. 

Fig. 6.1. The L-leucine degradative pathway. Reactions for which inherited metabolic disorders have not been conclusively identified include A, leucine-isoleucine aminotransferase and the majority of the 3-methylglutaconic acidurias (6.6-6.7). 6.1, Branched-chain a-ketoacid dehydrogenase (BCKD) complex, a reaction also occurring in the initial steps of L-isoleucine and L-valine degradation 6.2, isovaleryl-CoA dehydrogenase 6.3, 3-methylcrotonyl-CoA carboxylase 6.4, 3-methylglutaconyl-CoA hydra-tase 6.8, HMG-CoA lyase. Pathologic urinary metabolites used as specific markers in the differential diagnosis are presented in squares. Abbreviation Co A, coenzyme A...

The disorders of valine and isoleucine metabolism comprise quite distinct diseases. 

The 0X0 acids have been discussed in part in the section on the Krebs cycle acids, however, the importance of branched-chain aliphatic 2-oxo acids in valine, leucine and isoleucine metabolism and of oxo acids in other disorders prompts further comment of their chromatographic analysis. 

In the metabolism of L-leucine, the isovaleryl-CoA produced by the oxidative decarboxylation step is further metabolized by a series of enzyme-catalysed steps to acetoacetate and acetyl-CoA and thence into the tricarboxylic acid cycle. Specific enzyme deficiencies at every stage of this metabolic pathway are known and are described in Section 10.3. In contrast, only one disorder of L-isoleucine metabolism subsequent to the oxidative decarboxylation step has been recognized (Section 10.4), and no disorders of the L-valine pathway from isobutyryl-CoA have been described. This may be due to their relative rarity but possibly also to greater difficulty in their detection. The metabolism of valine and leucine is, however, of particular interest in the organic acidurias, since both are major precursors of propionyl-CoA and methylmalonyl-CoA, defects in the metabolism of which lead to propionic acidaemia and methylmalonic aciduria (Chapter 11). 

Maple syrup urine disease (MSUD) is a recessive disorder in which there is a partial or complete deficiency in branched-chain o-ketoacid dehydrogenase, an enzyme that decarboxylates leucine, isoleucine, and valine (see Figure 20.10). These amino acids and their corre sponding a-keto acids accumulate in the blood, causing a toxic effect that interferes with brain functions. The disease is characterized by feeding problems, vomiting, dehydration, severe metabolic acidosis, and a characteristic maple syrup odor to the urine. If untreated, the disease leads to mental retardation, physical disabilities, and death. 

In known metabolic states and disorders, the nature of metabolites excreted at abnormal levels has been identified by GC-MS. Examples of this are adipic and suberic acids found in urine from ketotic patients [347], 2-hydroxybutyric acid from patients with lactic acidosis [348], and methylcitric acid (2-hydroxybutan-l,2,3-tricarboxylic acid) [349] in a case of propionic acidemia [350,351]. In the latter instance, the methylcitric acid is thought to be due to the condensation of accumulated propionyl CoA with oxaloacetate [349]. Increased amounts of odd-numbered fatty acids present in the tissues of these patients due to the involvement of the propionyl CoA in fatty acid synthesis, have also been characterised [278]. A deficiency in a-methylacetoacetyl CoA thiolase enzyme in the isoleucine pathway prevents the conversion of a-methylacetoacetyl CoA to propionyl CoA and acetyl CoA [352,353]. The resultant urinary excretion of large amounts of 2-hydroxy-3-methylbutanoic acid (a-methyl-/3-hydroxybutyric acid) and an excess of a-methylacetoacetate and often tiglyl glycine are readily detected and identified by GC-MS. 

Knerr I, Vockley J, Gibson KM. Disorders of leucine, isoleucine and valine metabolism. In Physician s guide to the diagnosis, treatment and follow-up of... 

Propionic acidemia (PROP) and methylmalonic acidemia (MMA) are inherited disorders of the metabolism of the propiogenic amino acids valine, isoleucine, threonine, and methionine and odd-chain fatty acids (Figs. 20.1 and 20.2,... 

The disorders of isoleucine and valine metabolism are detected in a sequential process that begins with the evaluation of the symptoms and signs displayed by the patient. Clinical chemistry is helpful in the assessment of ketogenesis by urinary tests for ketones or quantification of 3-hydroxybuty-rate and acetoacetate in the blood. The electrolytes and pH may provide evidence of acidosis and it is important to assess the presence or absence of hyperammonemia. Amino acid analysis of the plasma and urine may be helpful. In virtually all instances the definitive diagnosis will come from organic acid analysis of the urine. 

Daum, R.S., Scriver, C.R., Mamer, O.A., Delvin, E., Lamm, P. and Goldman, H. (1973), An inherited disorder of isoleucine catabolism causing accumulation of a-methylacetoacetate and a-methyl-j8-hydroxybutyrate, and intermittent metabolic acidosis. Pediatr. Res., 7,149. 

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