Abstract

1. Metabolism of the Branched Chain Organic Acids. The essential branched chain amino acids, leucine, isoleucine, and valine, are transaminated to the 2-oxo branched chain organic acids and oxidatively decarboxylated to form branched chain acyl coenzyme A (CoA) products. The branched chain amino acid and organic acid disorder maple syrup urine disease, caused by a deficiency of branched chain α-ketoacid dehydrogenase, is described in Chap. 87. Isovaleryl-CoA, derived from leucine; 2-methylbutyryl-CoA, derived from isoleucine; and isobutyryl-CoA, derived from valine, are metabolized by separate pathways to intermediates, which enter the general metabolism. Defects in these pathways cause 10 known metabolic disorders, called branched chain organic acidurias (see Table 93-1).

   
   

   Propionic acidemia and methylmalonic acidemia are disorders of propionic acid degradation derived in part from the catabolism of isoleucine and valine, but they are described separately in Chap. 94. Inherited deficiencies of all four enzymes of the catabolism of isovaleryl-CoA derived from leucine are known: isovaleric acidemia (isovaleryl-CoA dehydrogenase deficiency), isolated biotin-unresponsive 3-methylcrotonyl-CoA carboxylase deficiency, 3-methylglutaconic aciduria (3-methylglutaconyl-CoA hydratase deficiency), and 3-hydroxy-3-methylglutaryl-CoA lyase deficiency. Mevalonic aciduria, due to a defect in the biosynthesis of cholesterol and isoprenoids from 3-hydroxy-3-methylglutaryl-CoA, is also considered a branched chain organic aciduria in this chapter. One inherited disorder of the catabolism of 2-methylbutyryl-CoA derived from isoleucine is known: mitochondrial acetoacetyl-CoA thiolase deficiency. Five disorders of the catabolism of isobutyryl-CoA derived from valine are known: isobutyryl-CoA dehydrogenase deficiency; 3-hydroxyisobutyryl-CoA deacylase deficiency; 3-hydroxyisobutyric aciduria; methylmalonic semialdehyde dehydrogenase deficiency with combined 3-hydroxyisobutyric, 3-aminoisobutyric, 3-hydroxypropionic, β-alanine, and 2-ethyl-3-hydroxybutyric aciduria; and a new form of mild methylmalonic aciduria related to methylmalonic semialdehyde metabolism. A new disorder, ethylmalonic encephalopathy, with increased excretion of ethylmalonic acid, isobutyrylglycine, and 2-methylbutyrylglycine, may be due to a deficiency or inhibition of short-branched chain acyl-CoA dehydrogenase affecting the catabolism of both valine and isoleucine. Although not a branched chain organic aciduria, malonic aciduria due to malonyl-CoA decarboxylase deficiency is described in this chapter.

   
   

2. Isovaleric Acidemia (Isovaleryl-CoA Dehydrogenase Deficiency, MIM 243500). Isovaleryl-CoA dehydrogenase deficiency may present either in the neonatal period as an acute episode of severe metabolic acidosis and moderate ketosis with vomiting, which may lead to coma and death, or as a chronic intermittent form with episodes of metabolic acidosis. Infants who survive an acute neonatal episode go on to exhibit the chronic form. Neutropenia, thrombocytopenia, or, rarely, pancytopenia often occurs with acidotic episodes. The “odor of sweaty feet” due to isovaleric acid is usually present during acute episodes. The major abnormal metabolite findings are large elevations of isovalerylglycine in urine and of isovalerylcarnitine in plasma. Treatment with leucine restriction and carnitine and/or glycine generally results in normal development if no permanent neurologic damage has occurred during the initial presentation.

   
   

3. Isolated 3-Methylcrotonyl-CoA Carboxylase Deficiency (MIM 210200). The isolated deficiency of 3-methylcrotonyl-CoA carboxylase is not responsive to biotin and is distinct from the biotin-responsive multiple carboxylase deficiencies that are due to a deficiency of biotinidase or holocarboxylase synthetase described in Chap. 156. Patients typically present with acute metabolic acidosis, hypoglycemia, and carnitine deficiency. The major abnormal metabolites are 3-hydroxyisovaleric acid in urine and 3-hydroxyisovalerylcarnitine in plasma. Treatment with carnitine and restriction of leucine usually results in normal development.

   
   

4. 3-Methylglutaconic Aciduria. At least four types of this disorder are known. Type I (MIM 250950), with a deficiency of 3-methylglutaconyl-CoA hydratase, has diverse and nonspecific clinical symptoms. The major urinary metabolites are 3-methylglutaconic and 3-hydroxyisovaleric acids. Dietary treatment has not proven to be of definite benefit, but carnitine supplementation and modest leucine restriction may be mildly beneficial.

   
   

   Type II (Barth syndrome, MIM 302060), or X-linked, 3-methylglutaconic aciduria is associated with dilated cardiomyopathy, neutropenia, and growth retardation, with normal activity of 3-methylglutaconyl-CoA hydratase. Excretion rates of 3-methylglutaconic acid and 3-methylglutaric acid are only moderately increased, and that of 3-hydroxyisovaleric acid is normal. The basic biochemical abnormality is unknown, and the clinical outcome is variable. Specific dietary restriction has not been effective.

   
   

   Type III (Costeff optic atrophy syndrome, MIM 258501) includes optic atrophy, choreoathetosis, spastic paraparesis, cerebellar ataxia, and nystagmus, with mild 3-methylglutaconic aciduria (normal 3-hydroxyisovaleric acid) and normal activity of 3-methylglutaconyl-CoA hydratase.

   
   

   Type IV (MIM 250951), or the “unclassified” form, with mild 3-methylglutaconic aciduria and normal activity of 3-methylglutaconyl-CoA hydratase, is a clinically heterogeneous group of disorders with variable psychomotor retardation, hypertonicity, hypotonia, optic atrophy, dysmorphic features, seizures, cardiomyopathy, and hepatic dysfunction. Some patients have elevated lactic or citric acid cycle intermediates, and some have abnormalities of the mitochondrial electron transport chain. The basic biochemical defect(s) is unknown, and no effective treatment has been found.

   
   

5. 3-Hydroxy-3-methylglutaryl-CoA Lyase Deficiency (MIM 246450). One-third of patients present in the neonatal period, and two-thirds present between 3 and 11 months of age with severe hypoglycemia and metabolic acidosis (but with little or no ketosis), hyperammonemia, vomiting, and hypotonia, which may progress to coma and death. The symptoms resemble those of Reye syndrome. Treatment by restriction of leucine and fat, avoidance of fasting, and carnitine supplementation generally leads to normal development. 3-Hydroxy-3-methylglutaryl-CoA lyase deficiency is a disorder of branched chain amino acid (leucine) metabolism; its diagnosis from the major abnormal metabolites in urine, 3-hydroxy-3-methylglutaric, 3-methylglutaconic, and 3-hydroxyisovaleric acids, is described in this chapter. But this disorder is also one of ketone body metabolism, and therefore its clinical, biochemical, and molecular aspects are described in detail in Chap. 102.

   
   

6. Mevalonic Aciduria (Mevalonate Kinase Deficiency, MIM 251170). Patients with the severe form of mevalonic aciduria present in the neonatal period with dysmorphic features, anemia, hepatosplenomegaly, gastroenteropathy, failure to thrive, and severe developmental delay. Patients with a milder form show poor muscle development, hypotonia, ataxia, and elevated creatine kinase. There is no metabolic acidosis, and although the defect is in cholesterol biosynthesis, blood cholesterol may be normal. The only abnormal metabolite finding is an extremely elevated amount of mevalonic acid in urine and plasma. No effective therapy is yet available.

   
   

7. Mitochondrial Acetoacetyl-CoA Thiolase Deficiency (MIM 203750). In patients with mitochondrial acetoacetyl-CoA thiolase deficiency, intermittent episodes of severe metabolic acidosis and ketosis begin during the first 2 years of life. These are accompanied by vomiting (often with hematemesis), diarrhea, and coma, which may progress to death. Deficiency of this thiolase is a disorder of branched chain amino acid (isoleucine) metabolism, and diagnosis from detection in urine of the major abnormal metabolites, 2-methyl-3-hydroxybutyric acid, 2-methylacetoacetic acid, and tiglylglycine, is described in this chapter. But this disorder is also one of ketone body metabolism, and therefore clinical, biochemical, and molecular aspects are described in detail in Chap. 102.

   
   

8. Isobutyryl-CoA Dehydrogenase Deficiency? A patient presenting with anemia and dilated cardiomyopathy at 11 months of age had low carnitine levels and an elevation of a four-carbon (butyryl/isobutyryl)acylcarnitine. When fibroblasts were incubated with [¹³C]valine, [¹³C]isobutyrylcarnitine accumulated, suggesting an isolated deficiency of isobutyryl-CoA dehydrogenase. Treatment with carnitine reversed the cardiomyopathy.

   
   

9. 3-Hydroxyisobutyryl-CoA Deacylase Deficiency (MIM 250620). In a single patient with a deficiency of 3-hydroxyisobutyryl-CoA deacylase, there were congenital malformations and a lack of neurologic development without acidosis. The major abnormal urinary metabolites are not organic acids but the amino acids S-(2-carboxypropyl)-cysteine and S-(2-carboxypropyl)-cysteamine, which are formed by addition of cysteine to methacrylyl-CoA, the precursor of 3-hydroxyisobutyryl-CoA. No treatment is known.

   
   

10. 3-Hydroxyisobutyric Aciduria (MIM 236795). A number of patients have presented with 3-hydroxyisobutyric aciduria, which may be due to a deficiency of 3-hydroxyisobutyrate dehydrogenase or to a secondary inhibition of this enzyme. Symptoms can include repeated episodes of ketoacidosis and lactic acidemia, failure to thrive, dysmorphic features, brain dysgenesis, malformations, and hypotonia. There is a high rate of excretion of 3-hydroxyisobutyric acid. Treatment with carnitine and valine restriction may be beneficial.

    
    

11. Methylmalonic Semialdehyde Dehydrogenase Deficiency with Combined 3-Hydroxypropionic, β-Alanine, 3-Hydroxyisobutyric, and 3-Aminoisobutyric Aciduria. In one individual with no clinical symptoms and another with mild symptoms, a deficiency of an uncharacterized semialdehyde dehydrogenase acting on both methylmalonic semialdehyde and malonic semialdehyde led to elevated excretion levels of 3-hydroxyisobutyric, 3-aminoisobutyric, 2-ethyl-3-hydroxybutyric, and 3-hydroxypropionic acids, together with β-alanine.

    
    

12. Methylmalonic Aciduria Related to Methylmalonic Semialdehyde Dehydrogenase Deficiency. A patient with developmental delay and no episodes of metabolic acidosis excreted moderate amounts of methylmalonic acid. Methylmalonyl-CoA mutase was normal, and there was no indication of a cobalamin disorder. Patients with deficient activity of methylmalonyl-CoA metabolism have elevated propionylcarnitine levels, which this patient did not, suggesting that the elevated methylmalonic acid levels were derived not from methylmalonyl-CoA but rather from methylmalonic semialdehyde. In vivo studies of the metabolism of labeled valine and thymine to isomers of 3-hydroxyisobutyric acid and 3-aminoisobutyric acid suggest a defect in methylmalonic semialdehyde dehydrogenase.

    
    

13. Ethylmalonic Aciduria Encephalopathy (MIM 602473). This disorder may be due to a deficiency or a secondary inhibition of a short-branched chain acyl-CoA dehydrogenase affecting both valine and isoleucine catabolism. Patients present with neonatal hypotonia, severe progressive pyramidal dysfunction and spastic diplegia, orthostatic acrocyanosis with distal swelling, chronic diarrhea, and diffuse petechiae. The outcome has been severe mental retardation or death. Biochemical abnormalities include lactic acidemia and increased excretion of ethylmalonic acid, 2-methylbutyrylglycine, and isobutyrylglycine. Therapeutic intervention has been unsuccessful.

    
    

14. Malonic Aciduria (Malonyl-CoA Decarboxylase Deficiency, MIM 248360). Fifteen patients have been reported with malonic aciduria, generally accompanied by lesser excretions of methylmalonic acid. Most have had developmental delay, many are hypotonic, and some have had hypoglycemia, metabolic acidosis, cardiomyopathy, or gastrointestinal distress. Eight of the patients have been documented to have a deficiency of malonyl-CoA decarboxylase, two had normal activity, and in the others, enzyme activity was not determined. Treatment with carnitine and a high-carbohydrate diet low in long chain fatty acids with medium chain triglyceride supplementation has had some success.

    
    

Purchase Chapter PDF

Access All of OMMBID

Already a user? Sign in here

Username:

Password:

Forgot your Username/Password?