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INTRODUCTION

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Sulfur-containing amino acids have various important roles: They mediate the transfer of methyl groups for virtually all transmethylation reactions; they provide reactive thiol groups that are needed for detoxification of endogenous and exogenous substances; they help maintain the intracellular redox potential; and they are a source of sulfate. More than 20 disorders of sulfur-containing amino acid metabolism have been described.

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Severe hyperhomocysteinemia, defined when plasma total homocysteine (tHcy) concentration is above 100 μmol/L, is generally caused by single-enzyme deficiencies of homocysteine metabolism. When concentrations of free homocysteine exceed the plasma protein binding capacity, the disulfide homocysteine forms nonenzymatically and is excreted in urine, hence causing homocystinuria. The term homocystinuria is sometimes used to indicate the most common form of the disease, which is caused by defective activity of the enzyme cystathionine β-synthase (CBS). Homocystinuria, however, also results from defects in the folate- and cobalamin-dependent remethylation cycle (see Chapter 144), of which 5,10-methylenetetrahydrofolate reductase (MTHFR) deficiency and the cobalamin C defect are by far the most common. Severe nutritional deficiency of cobalamin or folate can also cause hyperhomocysteinemia and homocystinuria and should always be ruled out first.

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CLASSICAL HOMOCYSTINURIA (CBS DEFICIENCY)

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PATHOGENESIS, EPIDEMIOLOGY, AND GENETICS

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The disturbance in metabolism resulting in homocystinuria is shown in Figure 133-1. CBS initiates the first step of homocysteine elimination. As a consequence of CBS deficiency, homocysteine, S-adenosylhomocysteine (SAH), S-adenosylmethionine (SAM), and methionine accumulate when methionine intake exceeds the residual transsulfuration and total remethylation activity. Moreover, high SAH inhibits many transmethylases, which increases accumulation of SAM and methionine. Increased homocysteine facilitates remethylation, which leads to further accumulation of methionine. The intermediate metabolites cystathionine and cysteine are decreased. The pathophysiology of CBS deficiency is not completely understood, but accumulation of homocysteine plays a major role in the development of vascular damage and thromboembolic complications. Classic tests of clotting function are normal, but elevated homocysteine causes increased platelet adhesiveness, damage to endothelial cells, and proliferation of smooth muscle and fibrous tissue within the vessel wall. Defective cross-linking of collagen fibrils contributes to the connective tissue dysplasia, and structural alterations of fibrillin structures in zonular fibers cause lens dislocation.

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Figure 133-1

Pathways of sulfur amino acids and methyl group metabolism in man. Methionine adenosyltransferase (MAT) activates methionine to S-adenosylmethionine (SAM), the universal methyl group donor for numerous methylation reactions. These “transmethylation” reactions yield a methylated product and demethylated S-adenosylhomocysteine (SAH), which is readily hydrolyzed to homocysteine by SAH-hydrolase (SAHH). Excessive homocysteine is removed by condensation with serine, catalyzed by cystathionine beta synthase (CBS), an enzyme requiring pyridoxal phosphate (vitamin B6) as cofactor. Cystathionine is catabolized to cysteine by cystathionase (CTH), another B6-dependent enzyme, and eventually to sulfite. Highly reactive sulfite is oxidized to sulfate by sulfite oxidase (SOX). Cysteine is a precursor for the synthesis of glutathione via gamma-glutamylcysteine synthetase (gGCS) and glutathione synthetase (GSS). ...

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