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21 Disorders of Sulfur Amino Acid Metabolism

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21 Disorders of Sulfur Amino Acid Metabolism 21 Disorders of Sulfur Amino Acid Metabolism Generoso Andria, Brian Fowler, Gianfranco Sebastio 21.1 Homocystinuria due to Cystathione β-Synthase Deficiency – 275 21.1.1 Clinical Presentation – 275 21.1.2 Metabolic Derangement – 276 21.1.3 Genetics – 276 21.1.4 Diagnostic Tests – 277 21.1.5 Treatment and Prognosis – 277 21.2 Methionine S-Adenosyltransferase Deficiency – 278 21.2.1 Clinical Presentation – 278 21.2.2 Metabolic Derangement – 278 21.2.3 Genetics – 279 21.2.4 Diagnostic Tests – 279 21.2.5 Treatment and Prognosis – 279 21.3 Glycine N-Methyltransferase Deficiency – 279 21.3.1 Clinical Presentation – 279 21.3.2 Metabolic Derangement – 279 21.3.3 Genetics – 279 21.3.4 Diagnostic Tests – 279 21.3.5 Treatment and Prognosis – 279 21.4 S-Adenosylhomocysteine Hydrolase Deficiency – 279 21.4.1 Clinical Presentation – 279 21.4.2 Metabolic Derangement – 279 21.4.3 Genetics – 280 21.4.4 Diagnostic Tests – 280 21.4.5 Treatment and Prognosis – 280 21.5 γ-Cystathionase Deficiency – 280 21.5.1 Clinical Presentation – 280 21.5.2 Metabolic Derangement – 280 21.5.3 Genetics – 280 21.5.4 Diagnostic Tests – 280 21.5.5 Treatment and Prognosis – 280 21.6 Isolated Sulfite Oxidase Deficiency – 280 21.6.1 Clinical Presentation – 280 21.6.2 Metabolic Derangement – 280 21.6.3 Genetics – 281 21.6.4 Diagnostic Tests – 281 21.6.5 Treatment and Prognosis – 281 References – 281 274 Chapter 21 · Disorders of Sulfur Amino Acid Metabolism Metabolism of the Sulfur-Containing Amino Acids Methionine, homocysteine and cysteine are linked by 5-methyl-tetrahydrofolate (THF), catalyzed by cobal- the methylation cycle (. Fig. 21.1, left part) and the amin-requiring 5-methyl THF-homocysteine methyl- trans-sulfuration pathway (. Fig. 21.1, right part). Con- transferase (enzyme 2), or betaine, catalyzed by betaine- version of methionine into homocysteine proceeds homocysteine methyltransferase (enzyme 3). Homo- via methionine S-adenosyltransferase (enzyme 4). This cysteine can also be condensed with serine to form yields S-adenosylmethionine, the methyl-group donor cystathionine via a reaction catalyzed by pyridoxal- in a wide range of transmethylation reactions, a quanti- phosphate-requiring cystathionine E-synthase (enzy- IV tatively important one of which is glycine N-methyl- me 1). Cystathionine is cleaved to cysteine and D-keto- transferase (enzyme 5). These reactions also produce butyrate by another pyridoxal-phosphate-dependent S-adenosylhomocysteine, which is cleaved to adenosine enzyme, J-cystathionase (enzyme 7). The last step of and homocysteine by S-adenosylhomocysteine hydro- the trans-sulfuration pathway converts sulfite to sulfate lase (enzyme 6). Depending on a number of factors, and is catalyzed by sulfite oxidase (enzyme 8), which about 50% of available homocysteine is recycled into requires a molybdenum cofactor. methionine. This involves methyl transfer from either . Fig. 21.1. Metabolism of the sulfur-containing amino acids. ferase; 4, methionine S-adenosyltransferase; 5, glycine N-methyl- 1, cystathionine E-synthase; 2, 5-methyltetrahydrofolate-homo- transferase; 6, S-adenosylhomocysteine hydrolase; 7, J-cystathio- cysteine methyltransferase; 3, betaine-homocysteine methyltrans- nase; 8, sulfite oxidase 275 21 21.1 · Homocystinuria due to Cystathione E-Synthase Deficiency As in Marfan syndrome, homocystinuric patients tend to Several inherited defects are known in the conversion of be tall, with thinning and elongation (dolichostenomelia) the sulfur-containing amino acid methionine to cys teine of long bones near puberty, enlarged metaphyses and epi- and the ultimate oxidation of cysteine to inorganic sul- physes, especially at the knees, and arachnodactyly, present fate (. Fig. 21.1). Cystathionine E-synthase (CBS) defi- in about half the patients. Other bone deformities include ciency is the most important. It is associated with severe genu valgum with knobbly knees, pes cavus, and pectus abnormalities of four organs or organ systems: the eye carinatum or excavatum. Restricted joint mobility, partic- (dislocation of the lens), the skeleton (dolichosteno- ularly at the extremities, contrasts with the joint laxity melia and arachnodactyly), the vascular system (throm- observed in Marfan syndrome. Abnormal X-ray findings boembolism), and the central nervous system (mental include biconcavity and flattening of the intervertebral retardation, cerebro-vascular accidents). A low-methio- discs, growth arrest lines in the distal tibia, metaphyseal nine, high-cystine diet, pyridoxine, folate, and betaine spicules in the hands and feet, enlarged carpal bones, re- in various combinations, and antithrombotic treatment tarded lunate development, and shortening of the fourth may halt the otherwise unfavourable course of the di- metacarpal. sease. Methionine S-adenosyltransferase deficiency and J-cystathionase deficiency usually do not require Central Nervous System treatment. Isolated sulfite oxidase deficiency leads (in Developmental delay and mental retardation affect about its severe form) to refractory convulsions, lens disloca- 60% of patients to a variable degree of severity. Seizures, tion, and early death. No effective treatment exists. electroencephalogram abnormalities, and psychiatric dis- Combined deficiency of sulfite oxidase and xanthine turbances have also been reported in approximately half oxidase is discussed in Chap. 35. Deficiencies of glycine of cases. Focal neurologic signs may be a consequence of N-methyltransferase and S-adenosylhomocysteine cerebro-vascular accidents. hydrolase have been described in a few patients. Vascular System Thromboembolic complications, occurring in arteries and veins of all parts of the body, constitute the major cause of 21.1 Homocystinuria due to Cysta- morbidity and mortality. The prognosis is influenced by thione β-Synthase Deficiency the site and extent of the vascular occlusion. Thrombophle- bitis and pulmonary embolism are the most common vas- 21.1.1 Clinical Presentation cular accidents. Thrombosis of large- and medium-sized arteries, particularly carotid and renal arteries, is a frequent The eye, skeleton, central nervous system, and vascular sys- cause of death. Ischemic heart disease is a less prominent tem are all involved in the typical presentation. The patient feature of homocystinuria. Association with other geno- is normal at birth and, if not treated, progressively develops types linked to increased risk of vascular disease, such as the full clinical picture. the factor V Leiden R506Q mutation or the 677CoT muta- tion of the MTHFR gene, were reported to increase the risk Eye of thrombosis in homocystinuric patients [1]. Dislocation of the ocular lens (ectopia lentis), myopia, and glaucoma are frequent, severe and characteristic complica- Other Features tions. Retinal detachment and degeneration, optical atrophy, Spontaneous pneumothorax and pancreatitis were reported and cataracts may eventually appear. Myopia may precede to be rare findings in homocystinuric patients [2]. lens dislocation, and worsens afterwards. Ectopia lentis is detected in most untreated patients from 5–10 years of age Clinical Variability and Natural History and in nearly all untreated patients by the end of the fourth The spectrum of clinical abnormalities is wide, and mild decade and is often the clue to diagnosis. The dislocation cases may only be recognized by late complications, such as is generally downwards, whereas it is usually upwards in thromboembolic accidents. Time-to-event curves based on Marfan syndrome, a phenocopy of homocystinuria caused detailed information on 629 patients were calculated by by mutations of the fibrillin-1 gene. Once ectopia lentis Mudd et al. [3] for the main clinical manifestations and has occurred, a peculiar trembling of the iris (iridodonesis) mortality. Each abnormality occurred significantly earlier following eye or head movement may be evident. and at a higher rate in untreated pyridoxine-nonresponsive individuals than in untreated pyridoxine-responsive ones. Skeleton The risk of thromboembolic accidents in patients under- Osteoporosis is almost invariably detected, at least after going surgery was relatively small, complications, six of childhood. Frequent consequences are scoliosis and a ten- which were lethal, being recorded in only 25 patients fol- dency towards pathological fractures and vertebral collapse. lowing 586 operations. 276 Chapter 21 · Disorders of Sulfur Amino Acid Metabolism An Italian multicenter survey [2] revealed a strong cor- vascular damage and thromboembolic complications. respondence of ectopia lentis, mental retardation, seizures, Thromboembolism has been suggested to be the end-point dolichostenomelia, and thrombotic accidents among af- of homocysteine-induced abnormalities of platelets, endo- fected sib-pairs, supporting a prominent role of genetic thelial cells, and coagulation factors. Many underlying me- factors in determining the phenotype. Nevertheless, rare chanisms have been investigated with, so far, no unifying cases of intrafamilial variability have been reported. Prob- theory proven. For example, a recent study in homocystin- ably, both early diagnosis and strict compliance to treat- uric patients points to enhanced peroxidation of arachid- ment will change the natural history of cardiovascular and onic acid as an important mechanism linking hyperhomo- mental efficiency even in pyridoxine-nonresponsive indi- cysteinemia and platelet activation in CBS patients suggest- IV viduals. ing the possible value of vitamin E treatment
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