Advertisement

Disorders of Sulfur Amino Acid Metabolism

  • Generoso Andria
  • Brian Fowler
  • Gianfranco Sebastio

Abstract

Several defects can exist in the conversion of the sulfur-containing amino acid methionine to cysteine and the ultimate oxidation of cysteine to inorganic sulfate (Fig. 18.1). Cystathionine-β-synthase (CBS) deficiency is the most important. It is associated with severe abnormalities of four organs or organ systems: the eye (dislocation of the lens), the skeleton (dolichostenomelia and arachnodactyly), the vascular system (thromboembolism), and the central nervous system (mental retardation, cerebrovascular accidents). A low-methionine, highcystine diet, pyridoxine, folate, and betaine in various combinations, and antithrombotic treatment may halt the otherwise unfavorable course of the disease. Methionine adenosyltransferase deficiency and γ-cystathionase deficiency usually do not require treatment. Isolated sulfite oxidase deficiency leads (in its severe form) to refractory convulsions, lens dislocation, and early death. No effective treatment exists.

Keywords

Sulfite Oxidase Methionine Adenosyltransferase Methionine Concentration Lens Dislocation Sulfur Amino Acid Metabolism 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Rubba P, Faccenda F, Pauciullo P, Carbone L, Mancini M, Strisciuglio P, Carrozzo R, Sartorio R, Del Giudice E, Andria G (1990) Early signs of vascular disease in homocystinuria: a noninvasive study by ultrasound methods in eight families with cystathionine ß-synthase deficiency. Metabolism 39: 1191–1195PubMedCrossRefGoogle Scholar
  2. 2.
    Kang S-S, Wong PWK, Malinow MR (1992) Hyperhomocyst(e)inemia as a risk factor for occlusive vascular disease. Annu Rev Nutr 12: 279–288PubMedCrossRefGoogle Scholar
  3. 3.
    Boushey CJ, Beresford SA, Omenn GS, Motulsky AG (1995) A quantitative assessment of plasma homocysteine as a risk factor for vascular disease. Probable benefits of increasing folic acid intakes. JAMA 274: 1049–1057Google Scholar
  4. 4.
    Mudd SH, Skovby F, Levy HL, Pettigrew KD, Wilcken B, Pyeritz RE, Andria G, Boers GHJ, Bromberg IL, Cerone R, Fowler B, Grobe H, Schmidt H, Schweitzer L (1985) The natural history of homocystinuria due to cystathionine (3-synthase deficiency. Am J Hum Genet 37: 1–31PubMedGoogle Scholar
  5. 5.
    de Franchis R, Sperandeo MP, Sebastio G, Andria G. The Italian Collaborative Study Group on Homocystinuria (1998) Clinical aspects of cystathionine ß-synthase deficiency: how wide is the spectrum? Eur J Pediatr 157: S67–7oGoogle Scholar
  6. 6.
    Kraus JP (1994) Molecular basis of phenotype expression in homocystinuria. J Inherited Metab Dis 17: 383–390PubMedCrossRefGoogle Scholar
  7. 7.
    Uhlendorf BW, Mudd SH (1968) Cystathionine ß-synthase in tissue culture derived from human skin: enzyme defect in homocystinuria. Science 160: 1007–1009PubMedCrossRefGoogle Scholar
  8. 8.
    Fowler B, Kraus J, Packman S, Rosenberg LE (1978) Homocystinuria: evidence for three distinct classes of cystathionine ß-synthase mutants in cultured fibroblasts. J Clin Invest 61: 645–653PubMedCrossRefGoogle Scholar
  9. 9.
    Baumgartner R, Wick H, Ohnacker H, Probst A, Maurer R (1980) Vascular lesions in two patients with congenital homocystinuria due to different defects of remethylation. J Inherited Metab Dis 3: 101–103PubMedCrossRefGoogle Scholar
  10. 10.
    Fowler B, Jakobs C (1998) Post-and prenatal diagnostic methods for the homocystinurias. Eur J Pediatr 157: 588–93Google Scholar
  11. 11.
    ASHG/ACMG Statement (1998) Measurement and use of total plasma homocysteine. Am J Hum Genet 63: 1541–1543CrossRefGoogle Scholar
  12. 12.
    Goldstein JL, Campbell BK, Gartler SM (1972) Cystathionine ß-synthase activity in human lymphocytes: induction by phytohemagglutinin. J Clin Invest 51: 1034–1037PubMedCrossRefGoogle Scholar
  13. 13.
    Finkelstein JD, Mudd SH, Irreverre F, Laster L (1964) Homocystinuria due to cystathionine ß-synthase deficiency: the mode of inheritance. Science 146: 785–787PubMedCrossRefGoogle Scholar
  14. 14.
    Naughten ER, Yap S, Mayne PD (1998) Newborn screening for homocystinuria: Irish and world experience. Eur J Pediatr 157: S84–87PubMedCrossRefGoogle Scholar
  15. 15.
    Fowler B, Borresen AL, Boman N (1982) Prenatal diagnosis of homocystinuria. Lancet 2: 875PubMedCrossRefGoogle Scholar
  16. 16.
    Poenaru L (1987) First trimester prenatal diagnosis of metabolic diseases: a survey in countries from the European Community. Prenat Diagn 7: 333–342PubMedCrossRefGoogle Scholar
  17. 17.
    Sardharwalla IB, Fowler B, Robins AJ, Komrower GM (1974) Detection of heterozygotes for homocystinuria: study of sulfur-containing amino acids in plasma and urine after L-methionine loading. Arch Dis Child 49: 553–559PubMedCrossRefGoogle Scholar
  18. 18.
    McGill JJ, Mettler G, Rosenblatt DS, Scriver CR (1990) Detection of heterozygotes for recessive alleles. Homocyst(e)inemia: paradigm of pitfalls in phenotypes. Am J Med Genet 36: 45–52PubMedCrossRefGoogle Scholar
  19. 19.
    Boers GHJ, Smals AGH, Trijbels FJM, Fowler B, Bakkeren JAJM, Schoonderwaldt HC, Kleijer WJ, Kloppenborg PWC (1985) Heterozygosity for homocystinuria in premature peripheral and cerebral occlusive arterial disease? N Engl J Med 313: 709–715PubMedCrossRefGoogle Scholar
  20. 20.
    Clarke R, Daly L, Obinson K, Naughten E, Cahalane S, Fowler B, Graham I (1991) Homocysteinemia: a risk factor for vascular disease. N Engl J Med 324: 1149–1155PubMedCrossRefGoogle Scholar
  21. 21.
    Kozich V, Kraus E, de Franchis R, Fowler B, Boers GH, GrahamGoogle Scholar
  22. I, Kraus JP (1995) Hyperhomocysteinemia in premature arterial disease: examination of cystathionine beta-synthase alleles at the molecular level. Hum Mol Genet 4: 623–629CrossRefGoogle Scholar
  23. 22.
    Kluijtmans LAJ, van der Heuvel LPWJ, Boers GHJ, Frosst P, Stevens EMB, van Oost BA, den Heijer M, Trijbels FJ, Rozen R, Blom HJ (1996) Molecular genetic analysis in mild hyperhomocysteinemia: a common mutation in the methylenetetrahydrofolate reductase gene is a genetic risk factor for cardiovascular disease. Am J Hum Genet 58: 35–41PubMedGoogle Scholar
  24. 23.
    Wilcken B, Turner B (1973) Homocystinuria: reduced folate levels during pyridoxine treatment. Arch Dis Child 48: 58–62PubMedCrossRefGoogle Scholar
  25. 24.
    The Ross Metabolic Formula System (1997) Nutrition Support Protocols. Ross Products Division, ColumbusGoogle Scholar
  26. 25.
    Wilcken DE, Wilcken B, Dudman NPB, Tyrrell PA (1983) Homocystinuria–the effect of betaine in the treatment of patients not responsive to pyridoxine. N Engl J Med 309: 448–453PubMedCrossRefGoogle Scholar
  27. 26.
    Di Minno G, Davi G, Margaglione M, Cirillo F, Grandone E, Ciabattoni G, Catalano I, Strisciuglio P, Andria G, Patrono C, Mancini M (1993) Abnormally high thromboxane biosynthesis in homozygous homocystinuria. Evidence for platelet involvement and probucol-sensitive mechanism. J Clin Invest 92: 1400–1406Google Scholar
  28. 27.
    Wilcken DE, Wilcken B (1997) The natural history of vascular disease in homocystinuria and the effects of treatment. J Inherit Metab Dis 20: 295–300PubMedCrossRefGoogle Scholar
  29. 28.
    Kraus JP, Le K, Swaroop M, Ohura T, Tahara T, Rosenberg LE, Roper MD, Kozich V (1993) Human cystathionine ß-synthase cDNA: sequence, alternative splicing and expression in cultured cells. Hum Mol Genet 2: 1633–1638PubMedCrossRefGoogle Scholar
  30. 29.
    Kraus JP, Oliveriusova J, Sokolova J, Kraus E, Vlcek C, de Franchis R, Maclean KN, Bao L, Bukovska G, Patterson D, Paces V, Ansorge W, Kozich V (1998) The human cystathionine ß-synthase (CBS) gene: complete sequence, alternative splicing and polymorphism. Genomics 52: 312–324PubMedCrossRefGoogle Scholar
  31. 30.
    Kraus JP, Janosik M, Kozich V, Mandell R, Shih V, Sperandeo MP, Sebastio G, de Franchis R, Andria G, Kluijtmans AJ, Blom H, Boers GHJ, Gordon RB, Kamoun P, Tsai MY, Kruger WD, Koch HG, Ohura T, Gaustadnes (1999) M Cystathionine ß-synthase mutations in homocystinuria. Hum Mutat 13: 368–375Google Scholar
  32. 31.
    Sebastio G, Sperandeo MP, Panico M, de Franchis R, Kraus JP, Andria G (1995) The molecular basis of homocystinuria due to cystathionine ß-synthase deficiency in Italian families and report of four novel mutations. Am J Hum Genet 56: 1324–1333PubMedGoogle Scholar
  33. 32.
    Sperandeo MP, de Franchis R, Andria G, Sebastio G (1996) A 68 bp insertion found in a homocystinuric patient is a common variant and is skipped by alternative splicing of the cystathionine ß-synthase mRNA. Am J Hum Genet 5913911393Google Scholar
  34. 33.
    Mudd SH, Levy HL, Tangerman A, Boujet C, Buist N, Davidson-Mundt A, Hudgins L, Oyanagi K, Nagao M, Wilson WG (1995b) Isolated persistent hypermethioninemia. Am J Hum Genet 57: 882–892PubMedGoogle Scholar
  35. 34.
    Chamberlin ME, Ubagai T, Mudd SH, Wilson WG, Leonard JV, Chou JY (1996) Demyelination of the brain is associated with methionine adenosyltransferase I/III deficiency. J Clin Invest 98: 1021–1027PubMedCrossRefGoogle Scholar
  36. 35.
    Hazelwood S, Barnardini I, Shotelersuk V, Tangerman A, Guo J, Mudd H, Gahl WA (1998) Normal brain myelination in a patient homozygous for a mutation that encodes a severely truncated methionine adenosyltransferase I/III. Am J Med Genet 75: 395–400PubMedCrossRefGoogle Scholar
  37. 36.
    Ubagai T, Lei K-J, Huang S, Mudd SH, Levy HL, Chou JY (1995) Molecular mechanisms of an inborn error of methionine pathway: methionine adenosyltransferase deficiency. J Clin Invest 96: 1943–1947PubMedCrossRefGoogle Scholar
  38. 37.
    Chamberlin ME, Ubagai T, Mudd SH, Levy HL, Chou JY (1997) Dominant inheritance of isolated hypermethioninemia is associated with a mutation in the human methionine adenosyltransferase 1 A gene. Am J Hum Genet 60: 540–546PubMedGoogle Scholar
  39. 38.
    Fowler B (1982) Transsulphuration and methylation of homocysteine in control and mutant human fibroblasts. Biochim Biophys Acta 721: 201–207PubMedCrossRefGoogle Scholar
  40. 39.
    Lu Y, Odowd BF, Orrego H, Israel Y (1992) Cloning and nucleotide sequence of human liver cDNA encoding for cystathionine gamma-lyase. Biochem Biophys Res Commun 189: 749–758PubMedCrossRefGoogle Scholar
  41. 40.
    Rupar CA, Gillett J, Gordon BA et al. (1996) Isolated sulfite oxidase deficiency. Neurpediatrics 27: 299–304CrossRefGoogle Scholar
  42. 41.
    Tardy P, Parvy P, Charpentier C, Bonnefont JP, Saudubray JM, Kamoun P (1989) Attempt at therapy in sulphite oxidase deficiency. J Inherit Metab Dis 12: 94–95PubMedCrossRefGoogle Scholar
  43. 42.
    Garrett RM, Johnson JL, Graf TN, Feigenbaum A, Rajagopalan KV (1998) Human sulfite oxidase R16oQ: identification of the mutation in a sulfite oxidase-deficient patient and expression of the mutant enzyme. Proc Natl Acad Sci USA 95: 6394–6398PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2000

Authors and Affiliations

  • Generoso Andria
  • Brian Fowler
  • Gianfranco Sebastio

There are no affiliations available

Personalised recommendations