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Siegel GJ, Agranoff BW, Albers RW, et al., editors. Basic Neurochemistry: Molecular, Cellular and Medical Aspects. 6th edition. Philadelphia: Lippincott-Raven; 1999.

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Basic Neurochemistry: Molecular, Cellular and Medical Aspects. 6th edition.

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Disorders of Organic Acid Metabolism


Correspondence to Marc Yudkoff, Children's Hospital of Philadelphia, 1 Children's Center, Philadelphia, Pennsylvania 19104.

The cause of isovaleric acidemia is a congenital deficiency of isovaleryl-CoA dehydrogenase, which mediates formation of 3-methylcrotonate

The dehydrogenase (Fig. 44-1, reaction 3) is a mitochondrial enzyme of approximately 175 kDa composed of four identical subunits that are coded on human chromosome 15. The enzyme first transfers electrons from isovaleryl-CoA to FAD and then to electron-transferring flavoprotein (ETF). A specific ETF dehydrogenase then shifts the electrons to coenzyme Q in the electron-transport chain.

Affected patients usually have <5% of control capacity to oxidize isovaleric acid. The clinical presentation includes both a fulminant syndrome of neonatal onset and an intermittent disorder that usually becomes manifest in the first year or two of life. In the former instance, the baby develops irritability, vomiting, convulsions and progressive loss of consciousness during the first week. The rancid odor of isovaleric acid, which often is apparent from the urine, saliva and ear cerumen, accounts for the unusual name, “sweaty socks syndrome.” Patients frequently exhibit hyperammonemia, ketoaciduria, metabolic acidosis, pancytopenia and hypocalcemia.

Youngsters with intermittent disease usually present with the characteristic odor, lethargy, ataxia and vomiting in association with an intercurrent infection or the administration of a relatively large amount of protein. Hyperammonemia is common. A family may have children with both the neonatal and intermittent forms of the disease, suggesting that several phenotypes may be related to one genotype.

Glycine-N-acylase, a hepatic enzyme that mediates formation of hippuric acid from benzoyl-CoA and glycine, also catalyzes the synthesis of isovalerylglycine from glycine and isovaleryl-CoA, which has a Km of approximately 0.6 mM (Fig. 44-1, reaction 4). Patients excrete isovalerylglycine even when clinically compensated, thereby facilitating diagnosis. Formation of isovalerylglycine also detoxifies isovaleric acid during periods of stress since the conjugate is hydrophilic and excreted into urine more efficiently than isovaleric acid itself. Indeed, supplementation of the diet with glycine is beneficial, especially during a crisis [10].

Patients usually fare well with a low-protein, that is, low-leucine, diet. Some suffer no relapses at all. The blood carnitine concentration usually is low, reflecting excessive excretion of isovalerylcarnitine. Carnitine therapy therefore has been suggested, but the utility of this approach still is uncertain.

3-Methylcrotonic aciduria is caused by defects in a biotin-dependent reaction that forms 3-methylglutaconic acid

Isolated carboxylase deficiencies (Fig. 44-1, reaction 5) are rare and should be distinguished from the syndrome of 3-methylcrotonic aciduria, which occurs secondarily to defects of biotin metabolism (see below). Some patients present in early infancy with vomiting, metabolic acidosis, hyperlactatemia, convulsions and coma. Others remain well for 2 to 5 years, when they develop recurrent vomiting, metabolic acidosis, hypoglycemia and progressive lethargy leading to coma.

The urine usually contains marked elevations of 3-hydroxyisovaleric acid, which is formed from 3-methylcrotonyl-CoA via crotonase (Fig. 44-1, reaction 6). It should be emphasized that 3-hydroxyisovaleric aciduria can be a nonspecific finding in ketotic patients. Excretion of 3-methylcrotonylglycine is elevated.

3-Methylglutaconic aciduria is caused by deficiencies of 3-methylglutaconyl-CoA hydratase, which mediates formation of 3-hydroxy-3-methylglutaryl-CoA

Defects in this enzyme (Fig. 44-1, reaction 7) are extremely rare. Patients may present only with delayed speech development or with relatively mild psychomotor retardation. The urine contains increased amounts of 3-methylglutaconate, 3-hydroxyisovalerate and 3-methylglutarate, the latter presumably being formed from hydrogenation of 3-methylglutaconic acid.

Several patients now have been described with an autosomal recessive disorder involving 3-methylglutaconic aciduria but with normal hydratase activity. Loading with oral leucine does not increase urinary excretion of 3-methylglutaconate. Most of these children have had a progressive course characterized by neurodegeneration, often beginning in the first few months of life, and death after a few months or years. These patients, unlike those with hydratase deficiency, do not excrete excessive amounts of 3-hydroxyisovaleric acid. The underlying biochemical defect is not yet known.

3-Hydroxy-3-methylglutaric aciduria is caused by a lack of 3-hydroxy-3-methylglutaryl-CoA lyase, which catalyzes conversion of 3-hydroxy-3-methylglutarate to acetoacetate and acetyl-CoA

Many patients with deficiency in this enzyme (Fig. 44-1, reaction 8) become ill as neonates. In others, the symptoms are inapparent until 6 to 12 months. The most prominent findings are vomiting, lethargy, coma, convulsions and metabolic acidosis. An important finding is hypoglycemia without significant ketoaciduria, reflecting the significance of 3-hydroxy-3-methylglutaryl-CoA lyase to the synthesis of ketone bodies. The hypoglycemia may be referable to excessive consumption of glucose in the absence of the capacity to utilize an alternate fuel such as acetoacetate. Hepatomegaly with increased serum transaminases and hyperammonemia can occur and may lead to confusion with Reye's syndrome.

The urine organic acid profile shows increased 3-hydroxy-3-methylglutarate even when patients are stable. Excretion of 3-methylglutaconic acid also is high because the hydratase reaction is reversible (Fig. 44-1, reaction 7).

Patients must avoid fasting, which predisposes them both to developing hypoglycemia and, by favoring the synthesis of ketones from fatty acids, to the accumulation of 3-hydroxy-3-methylglutaric acid. Restriction of dietary protein and fat also may have a therapeutic role.

β-Ketothiolase deficiency syndrome is caused by defects in 2-methylacetoacetyl-CoA thiolase, which mediates the conversion of 2-methylacetoacetyl-CoA to acetyl-CoA and propionyl-CoA

This thiolase (Fig. 44-1, reaction 9) is one of several 3-oxothiolases that catalyze formation of acetyl-CoA and the corresponding acyl-CoA. The reactions usually are reversible, and one such enzyme is a cytoplasmic protein that mediates the condensation of 2 mol of acetyl-CoA to form acetoacetyl-CoA, which then reacts with another mol of acetyl-CoA to generate 3-hydroxy-3-methylglutaryl-CoA in the pathway of cholesterol synthesis.

The mitochondrial thiolase is specific for 2-methylacetoacetyl-CoA. In the liver, this enzyme also abets ketogenesis by catalyzing synthesis of 3-hydroxy-3-methylglutaryl-CoA from acetoacetyl-CoA and acetyl-CoA. It is a tetramer of approximately 170 kDa and is stimulated by potassium, unlike the cytosolic enzyme.

The inherited disorder, sometimes termed β-ketothiolase deficiency, causes recurrent acidosis, ketosis, vomiting and even death. Patients respond to intravenous glucose and bicarbonate. Mental retardation is not unprecedented, but it is exceptional.

Patients commonly excrete large amounts of 2-methyl-3-hydroxybutyric acid, formed via enzymatic reduction of 2-methylacetoacetyl-CoA. Tiglyl-CoA, a precursor to 2-methylacetoacetyl-CoA in the pathway of isoleucine catabolism (Fig. 44-1), also accumulates and usually is excreted as tiglylglycine. The ketosis is referable to inhibition of acetoacetyl-CoA metabolism by 2-methylaceto-acetyl-CoA. Excretion of these metabolites is variable when patients are not acutely ill.

3-Hydroxyisobutyryl-CoA deacylase deficiency causes a block in valine catabolism by preventing the conversion of 3-hydroxybutyryl-CoA to 3-hydroxyisobutyric acid

Methylacrylyl-CoA, a valine metabolite proximal to the site of the metabolic block (Fig. 44-1, reaction 13), accumulates and forms ninhydrin-positive conjugates with cysteine and cysteamine, which can be detected with amino acid analysis. The urine organic acids are otherwise unremarkable. A single patient had multiple congenital anomalies, including tetralogy of Fallot, facial dysmorphism and dysgenesis of the brain. The infant died at 3 months of age. There is no treatment.

Image ch44f1

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Copyright © 1999, American Society for Neurochemistry.
Bookshelf ID: NBK27945