Introduction

Homocystinuria due to cystathionine β-synthase (CBS) deficiency (MIM # 236200) is the most common inborn error of sulfur amino acid metabolism. It is inherited as an autosomal recessive trait. The frequency of the disease has been estimated between 1 in 200 000 and 1 in 335 000 (Mudd et al., 1989), though several lines of evidence indicate that this frequency might be higher (Mudd et al., 1995).

Sulfur-containing amino acids, homocysteine, methionine and cysteine are linked by the remethylation cycle and the trans-sulfuration pathway (Fig. 26.1). CBS (shape l-serine hydrolyase; EC 4.2.1.22) catalyzes the condensation of homocysteine with serine to form the thioether cystathionine, a reaction requiring pyridoxal-phosphate as cofactor (Fig. 26.1, enzyme 2). Cystathionine is cleaved to cysteine and α-ketobutyrate by another pyridoxal-phosphate-dependent enzyme, γ-cystathionase (enzyme 3). The trans-sulfuration pathway ends converting sulfite to sulfate and is catalyzed by sulfite oxidase (enzyme 4), requiring a molybdenum cofactor. Conversion of methionine into homocysteine proceeds via methionine adenosyltransferase (enzyme 1) yielding S-adenosylmethionine, a methyl-group donor used in several transmethylation reactions, and S-adenosylhomocystein e, which is cleaved to adenosine and homocysteine. About 50% of homocysteine, not entering the trans-sulfuration pathway, is recycled into methionine. This step involves methyl transfer either from 5-methyl-tetrahydrofolate (THF), catalyzed by cobalamin-requiring 5-methyl THF-homocystei ne methyltransferase (methionine synthase, MS, enzyme 5), or from betaine, catalyzed by betaine-homocysteine methyltransferase (enzyme 6).