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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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Branched-Chain Amino Acid Metabolism


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Maple syrup urine disease was the first congenital defect of branched-chain amino acid catabolism to be described

Maple syrup urine disease (MSUD) is a deficiency of branched-chain ketoacid dehydrogenase (Fig. 44-1, reaction 2), a mitochondrial enzyme. Decarboxylation of the branched-chain ketoacids, derived from transamination of branched-chain amino acids (BCAA), proceeds via a reaction for which the cofactors are thiamine pyrophosphate, lipoic acid, NAD, FAD and coenzyme A. The ketoacids are freely reaminated to the parent amino acids, the latter being readily measured in the blood and urine. Ketoacids impart to the urine a distinct odor that sometimes is compared with maple syrup or burnt sugar.

The decarboxylase is composed of four subunits: E1-α, E1-β, E2 and E3. A specific kinase and phosphatase activate and deactivate, respectively, the enzyme complex. Most MSUD patients have mutations involving the E1-α subunit, which catalyzes the actual decarboxylation of the ketoacid, although defects of the E1-β protein have been described [7]. The E1-α mutation usually causes faulty assembly of the heterotetrameric (α2β2) E1 protein. Lesions of either the E2 or E3 moiety are extremely rare. The E3 subunit is common to other decarboxylating systems, including pyruvate dehydrogenase and 2-oxyglutarate dehydrogenase. Hence, mutations in this protein can cause lactic acidosis and deranged TCA activity, as well as an accumulation of BCAA.

Infants are protected during gestation because the placenta clears most potential toxins. The classical form of the disease, therefore, does not become clinically manifest until a few days after birth. Initial periods of alternating irritability and lethargy progress over a period of days to coma and respiratory embarrassment. Irreversible brain damage is common in babies who survive, particularly those whose treatment is delayed until after the first week of life.

Survivors may suffer a metabolic relapse at any time. The most common cause of relapse is intercurrent infection, which often favors endogenous protein catabolism. As a consequence, the patient's limited capacity to oxidize BCAA is overwhelmed and these compounds, together with their cognate ketoacids, accumulate to a toxic level. Relapse also can occur in association with surgery, trauma and emotional upset.

Patients with partial enzymatic deficiencies may present later in life with intermittent ketoacidosis, prostration and recurrent ataxia. Plasma concentrations of BCAA are elevated during these episodes, but they may be normal or near normal during the periods when patients are metabolically compensated.

Rare patients respond to the administration of thiamine in large doses, 10 to 30 mg per day. In these patients, the clinical course is even more mild than in patients with intermittent disease. Thiamine is a cofactor for the branched-chain ketoacid dehydrogenase, and the presumed mutation in these patients involves faulty binding of the vitamin to the apoprotein.

In many localities, newborn screening has become standard for this disorder, which in the general population has an approximate incidence of 1 in 250,000 live births. Carrier detection is possible, either by measurement of enzymatic activity in cultured fibroblasts or by study of restriction endonuclease fragments of DNA via Southern blotting. Antenatal testing is possible.

Treatment entails continuous dietary restriction of the BCAA. This is accomplished by administration of a special formula from which these amino acids are removed. The outlook for intellectual development is favorable in youngsters whose diagnosis is made early and who do not suffer recurrent, severe episodes of metabolic decompensation [8].

Gene therapy for this metabolic defect may become available within the next few years. In vitro studies have demonstrated the feasibility of retrovirus-mediated gene transfer of both the E1-α and E2 subunits of the branched-chain decarboxylase complex [7,9].

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Copyright © 1999, American Society for Neurochemistry.
Bookshelf ID: NBK28225


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