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Sulfur-containing amino acids have various 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 sulphate. Thirteen disorders of sulphur amino acid metabolism have been consistently described, 11 of them potentially leading to disease.

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Severe hyperhomocysteinemia, defined as plasma total homocysteine (tHcy) concentrations 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 homocystine 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).1 Homocystinuria, however, results from a defect in CBS and from defects in the folate- and cobalamin-dependent remethylation cycle (see Chapter 147). Severe deficiency of cobalamin or folate can also cause homocystinuria and should always be ruled out.

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Homocystinuria should not be confused with mild (tHcy 15 to 30 μmol/l) or moderate (tHcy 30 to 100 μmol/l) hyperhomocysteinemia, which is much more common and is usually caused by nutritional deficiency of folates or cobalamin. It can also occur secondary to systemic or liver and kidney disease, or from medication, often in combination with homozygosity for a common polymorphism in the enzyme.

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Clinical Presentation

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Classical homocystinuria presents as multisystemic disease with a dysplasia of connective tissue, with a predisposition to arterial and venous thromboembolism, and with mental retardation. Clinical variability is wide,2but presentation is usually in the first decade with the exception of embolism, which occurs later. Homocystinuria is one of the few disorders of amino acid metabolism in which clinical manifestations tend to be progressive in adulthood, because many clinical manifestations result from arteriosclerosis and thrombotic complications.

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The most characteristic feature of this disorder is subluxation of the ocular lens, which occurs in almost all untreated individuals until adulthood. Most patients have osteoporosis and skeletal abnormalities similar to those seen in Marfan syndrome, such as tall stature, scoliosis, genu valgum, pes cavus, arachnodactyly, and pectus carinatum or excavatum.3 In homocystinuria, however, the joints tend to be limited in mobility rather than hypermobile. Mental retardation is common, although it is often mild, and many individuals have psychiatric disturbances.4

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Metabolic Derangement, Pathophysiology

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The disturbance in metabolism resulting in homocystinuria is shown in Figure 138-1. CBS initiates the first step of homocysteine elimination. As a consequence of CBS deficiency, homocysteine, SAH, 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 ...

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