Advertisement

Metabolic Profiling of Total Homocysteine and Related Compounds in Hyperhomocysteinemia: Utility and Limitations in Diagnosing the Cause of Puzzling Thrombophilia in a Family

  • Sally P. Stabler
  • Mark Korson
  • Reena Jethva
  • Robert H. Allen
  • Jan P. Kraus
  • Elaine B. Spector
  • Conrad Wagner
  • S. Harvey Mudd
Research Report
Part of the JIMD Reports book series (JIMD, volume 11)

Abstract

We describe a family illustrating the diagnostic difficulties occurring when pyridoxine-responsive cystathionine beta-synthase (CBS) deficiency presents with thrombotic disease without associated ocular, skeletal, or CNS abnormalities, a situation increasingly recognized. This family had several thromboembolic episodes in two generations with apparently inconstant elevations of plasma total homocysteine (tHcy). When taking (sometimes even low amounts) of pyridoxine, the affected family members had low-normal tHcy and normal values for cystathionine, methionine, and cysteine. Withdrawal of vitamin therapy was necessary before lower cystathionine, elevated methionine, and decreased cysteine became apparent, a pattern suggestive of CBS deficiency, leading to the finding that the affected members were each compound heterozygotes for CBS p.G307S and p.P49L. To assist more accurate diagnosis of adults presenting with thrombophilia found to have elevated tHcy, the patterns of methionine-related metabolites in CBS-deficient patients are compared in this article to those in patients with homocysteine remethylation defects, including inborn errors of folate or cobalamin metabolism, and untreated severe cobalamin or folate deficiency. Usually serum cystathionine is low in subjects with CBS deficiency and elevated in those with remethylation defects. S-Adenosylmethionine and S-adenosylhomocysteine are often markedly elevated in CBS deficiency when tHcy is above 100 umol/L. We conclude that there are likely other undiagnosed, highly B6-responsive adult patients with CBS deficiency, and that additional testing of cystathionine, total cysteine, methionine, and S-adenosylmethionine will be helpful in diagnosing them correctly and distinguishing CBS deficiency from remethylation defects.

Keywords

Compound Heterozygote Pyridoxal Phosphate Methylmalonic Acid Case Family Cobalamin Deficiency 
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.

Abbreviations

5-MTHF

5-methyltetrahydrofolate

AdoHcy

S-adenosylhomocysteine

AdoMet

S-adenosylmethionine

B6

Pyridoxine

Cbl

Cobalamin

CBS

Cystathionine B-synthase

CGL

Cystathionine gamma-lyase

Cysta

Cystathionine

MAT

Methionine adenosyltransferase

Me-Cbl

Methyl-cobalamin

Met

Methionine

MS

Methionine synthase

MTHFR

Methylenetetrahydrofolate reductase

PLP

Pyridoxal phosphate

SAHH

S-adenosylhomocysteine hydrolase

tCys

Total Cysteine

tHcy

Total homocysteine

Notes

Acknowledgments

We would like to acknowledge the expert technical assistance of Carla Ray, Linda Farb, and Bev Raab. Preparation of the manuscript was assisted by Theresa M. Martinez.

References

  1. Allen RH, Stabler SP, Lindenbaum J (1993) Serum betaine, N, N-dimethylglycine and N-methylglycine levels in patients with cobalamin and folate deficiency and related inborn errors of metabolism. Metabolism 42:1448–1460PubMedCrossRefGoogle Scholar
  2. Bermúndez M, Frank N, Bernal J, Urreizti R, Briceño I, Begoña M, Perez-Cerdá C, Ugarte M, Grinberg D, Balcells S, Kraus JP (2006) High prevalence of CBS p.T191M mutation in homocystinuric patients from Columbia. Hum Mutat 27:296–302CrossRefGoogle Scholar
  3. Capdevila A, Wagner C (1998) Measurement of plasma S-adenosylmethionine and S-adenosylhomocysteine as their fluorescent isoindoles. Anal Biochem 264:180–184PubMedCrossRefGoogle Scholar
  4. Chauveheid M-P, Lidove O, Papo T, Laissy J-P (2008) Adult-inset homocystinuria arteriography mimics fibromuscular dysplasia. Am J Med 121:e5–e6PubMedCrossRefGoogle Scholar
  5. Cochran FB, Sweetman L, Schmidt K, Barsh G, Kraus J, Packman S (1990) Pyridoxine-unresponsive homocystinuria with an unusual clinical course. Am J Med Genet 35:519–522PubMedCrossRefGoogle Scholar
  6. Cozar M, Urreizti R, Vilarinho L, Grosso C, Dodelson de Kremer R, Asteggiano CG, Dalmau J, Garcia AM, Vilaseca MA, Grinberg D, Balcells S (2011) Identification and functional analyses of CBS alleles in Spanish and Argentinian homocystinuric patients. Hum Mutat 32:835–842PubMedCrossRefGoogle Scholar
  7. de Franchis R, Sperandeo MP, Sebastio G, Andria G, The Italian Collaborative Study Group on Homocystinuria (1998) Clinical aspects of cystathionine β-synthase deficiency: how wide is the spectrum? Eur J Pediatr 157(Suppl 2):S67–S70PubMedCrossRefGoogle Scholar
  8. Ducros V, Rousset J, Garambois K, Boujet C, Rolland MO, Valenti K, Bouillet L, Jaillard A, Favier A (2006) Severe hypermethioninemia revealing homocystinuria in two young adults with mild phenotype. Revue de Medécine Interne 27:140–143PubMedCrossRefGoogle Scholar
  9. Favre JP, Becker F, Lorcerie B, Dumas R, David M (1992) Vascular manifestations in homocystinuria. Ann Vasc Surg 6:294–297PubMedCrossRefGoogle Scholar
  10. Gan-Schreier H, Kebbewar M, Fang-Hoffman J, Wilrich J, Abdoh G, Ben-Omran T, Shahbek N, Bener A, Al Rifai H, Al Khal AL, Lindner M, Zschocke J, Hoffman GF (2010) Newborn population screening for classic homocystinuria by determination of total homocysteine from Guthrie cards. J Pediatr 156:427–432PubMedCrossRefGoogle Scholar
  11. Gaustadnes M, Ingerslev J, Rütiger N (1999) Prevalence of congenital homocystinuria in Denmark. N Engl J Med 340:1513PubMedCrossRefGoogle Scholar
  12. Gaustadnes M, Rüdiger N, Rasmussen K, Ingerslev J (2000a) Intermediate and severe hyperhomocysteinemia with thrombosis: a study of genetic determinants. Thromb Haemost 83:554–558PubMedGoogle Scholar
  13. Gaustadnes M, Rüdiger N, Rasmussen K, Ingerslev J (2000b) Familial thrombophilia associated with homozygosity for the cystathionine beta-synthase 833T - C mutation. Arterioscler Thromb Vasc Biol 20:1392–1395PubMedCrossRefGoogle Scholar
  14. Gaustadnes M, Wilcken B, Oliveriusova J, McGill J, Fletcher J, Kraus JP, Wilcken DEL (2002) The molecular basis of cystathionine β-synthase deficiency in Australian patients: genotype-phenotype correlations and response to treatment. Hum Mutation 20:117–126CrossRefGoogle Scholar
  15. Guerra-Shinohara EM, Morita OE, Pagliusi RA, Blaia-d'Avila VL, Allen RH, Stabler SP (2007) Elevated serum S-adenosylhomocysteine in cobalamin-deficient megaloblastic anemia. Metabolism 56:339–347PubMedCrossRefGoogle Scholar
  16. Janosík M, Sokolová J, Janosíková B, Krijt J, Klatovská V, Kozich V (2009) Birth prevalence of homocystinuria in Central Europe: frequency and pathogenicity of mutation c.1105C>T (p.R369C) in the cystathionine beta-synthase gene. J Pediatr 154:431–437PubMedCrossRefGoogle Scholar
  17. Kanzelmeyer N, Tsikas D, Chobanyan-Jürgens K, Beckmann B, Vaske B, Illsinger S, Das AM, Lücke T (2011) Asymmetric dimethyhlarginine in children with homocystinuria or phenylketonuria. Amino Acids. doi: DOI 10.1007/s00726-011-0892-4 Google Scholar
  18. Keating AK, Freehauf C, Jiang H, Brodsky GL, Stabler SP, Allen RH, Graham DK, Thomas JA, Van Hove JLK, Maclean KN (2011) Constitutive induction of pro-inflammatory and chemotactic cytokines in cystathionine beta-synthase deficient homocystinuria. Mol Genet Metab 103:330–337PubMedCrossRefGoogle Scholar
  19. Kelly PJ, Furie KL, Kistler JP, Barron M, Picard EH, Mandell R, Shih VE (2003) Stroke in young patients with hyperhomocysteinemia due to cystathionine beta-synthase deficiency. Neurology 60:275–279PubMedCrossRefGoogle Scholar
  20. Kluijtmans LAJ, Boers GHJ, Kraus JP, van den Heuvel LPWJ, Cruysberg JRM, Trijbels FJM, Blom HJ (1999) The molecular basis of cystathionine β-synthase deficiency in Dutch patients with homocystinuria: effect of CBS genotype on biochemical and clinical phenotype, and on response to treatment. Am J Hum Genet 65:59–67PubMedCrossRefGoogle Scholar
  21. Linnebank M, Junker R, Nabavi DG, Linnebank A, Koch HG (2003) Isolated thrombosis due to the cystathionine β-synthase mutation c.833T>C (I278T). J Inherit Metab Dis 26:509–511PubMedCrossRefGoogle Scholar
  22. Lu C-Y, Hou J-W, Wang P-J, Chiu H-H, Wang T-R (1996) Homocystinuria presenting as fatal common carotid artery occlusion. Pediatr Neurol 15:159–162PubMedCrossRefGoogle Scholar
  23. Maclean KN, Gaustadnes M, Oliveriusova J, Janosik M, Kraus E, Kozich V, Kery V, Skovby F, Rüdiger N, Ingerslev J, Stabler SP, Allen RH, Kraus JP (2002) High homocysteine and thrombosis without connective tissue disorders are associated with a novel class of cystathionine β-synthase (CBS) mutations. Hum Mutation 19:641–655CrossRefGoogle Scholar
  24. Magner M, Krupková L, Honzik T, Zeman J, Hyánek J, Kozich V (2011) Vascular presentation of cystathionine beta-synthase deficiency in adulthood. J Inherit Metab Dis 34:33–37PubMedCrossRefGoogle Scholar
  25. Majtan T, Liu L, Carpenter JF, Kraus JP (2010) Rescue of cystathionine beta-synthase (CBS) mutants with chemical chaperones: purification and characterization of eight CBS mutant enzymes. J Biol Chem 285:15866–15873PubMedCrossRefGoogle Scholar
  26. Marchal G, Giroud M, Nivelon A, Saudubray JM, Becker F, Martin F, Dumas R (1989) Révélation tardive d’une homocystinurie par une aphasie et un spasme des artères iliaques externes. Ann Med Interne 140:520–522Google Scholar
  27. Mudd SH (2011) Hypermethioninemias of genetic and non-genetic origin: a review. Am J Med Genet Part C 157:3–32PubMedCrossRefGoogle Scholar
  28. 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 β-synthase deficiency. Am J Hum Genet 37:1–31PubMedGoogle Scholar
  29. Mudd SH, Cerone R, Schiaffino MC et al (2001) Glycine N-methyltransferase deficiency: a novel inborn error causing persistent isolated hypermethioninemia. J Inherit Metab Dis 24:448–464PubMedCrossRefGoogle Scholar
  30. Newman G, Mitchell JRA (1984) Homocystinuria presenting as multiple arterial occlusions. Q J Med 210:251–258Google Scholar
  31. Novy J, Ballhausen D, Bonafé L, Cairoli A, Angelillo-Scherrer A, Bachmann C, Michel P (2010) Recurrent postpartum cerebral sinus vein thrombosis as a presentation of cystathionine beta-synthase deficiency. Thromb Haemost 103:871–873PubMedCrossRefGoogle Scholar
  32. Orendäc M, Zeman J, Stabler SP, Allen RH, Kraus JP, Bodamer O, Stöckler-Ipsiroglu S, Kvasnicka J, Kožich V (2003) Homocystinuria due to cystathionine β-synthase deficiency: novel biochemical findings and treatment efficacy. J Inherit Metab Dis 26:761–773PubMedCrossRefGoogle Scholar
  33. Peterschmitt MJ, Simmons JR, Levy HL (1999) Reduction of false negative results in screening of newborns for homocystinuria. N Engl J Med 341:1572–1576PubMedCrossRefGoogle Scholar
  34. Refsum H, Fredriksen A, Meyer K, Ueland PM, Kase BF (2004) Birth prevalence of homocystinuria. J Pediatr 144:830–832PubMedGoogle Scholar
  35. Savage D, Gangaidzo I, Lindenbaum J, Kiire C, Mukiibi JM, Moyo A, Gwanzura C, Mudenge B, Bennie A, Sitima J, Stabler SP, Allen RH (1994) Vitamin B12 deficiency is the primary cause of megaloblastic anaemia in Zimbabwe. Br J Haematol 86:844–850PubMedCrossRefGoogle Scholar
  36. Skovby F, Gaustadnes M, Mudd SH (2010) A revisit to the natural history of homocystinuria due to cystathionine β-synthase deficiency. Mol Genet Metab 99:1–3PubMedCrossRefGoogle Scholar
  37. Sokolova J, Janosikova B, Terwilliger JD, Freiberger T, Kraus JP, Kozich V (2001) Cystathionine beta-synthase deficiency in Central Europe: discrepancy between biochemical and molecular genetic screening for homocystinuric alleles. Hum Mutation 18:548–549CrossRefGoogle Scholar
  38. Stabler SP, Allen RH (2004) Quantification of serum and urinary S-adenosylmethionine and S-adenosylhomocysteine by stable-isotope-dilution liquid chromatography-mass spectrometry. Clin Chem 50:365–372PubMedCrossRefGoogle Scholar
  39. Stabler SP, Marcell PD, Podell ER, Allen RH, Savage DG, Lindenbaum J (1988) Elevation of total homocysteine in the serum of patients with cobalamin or folate deficiency detected by capillary gas chromatography–mass spectrometry. J Clin Invest 81:466–474PubMedCrossRefGoogle Scholar
  40. Stabler SP, Lindenbaum J, Savage DG, Allen RH (1993) Elevation of serum cystathionine levels in patients with cobalamin and folate deficiency. Blood 81:3404–3413PubMedGoogle Scholar
  41. Stabler SP, Steegborn C, Wahl MC, Oliveriusova J, Kraus JP, Allen RH, Wagner C, Mudd SH (2002) Elevated plasma total homocysteine in severe MAT I/III deficiency. Metabolism 51:981–988PubMedCrossRefGoogle Scholar
  42. Strauss KA, Morton DH, Puffenberger EG, Hendrickson C, Robinson DL, Wagner C, Stabler SP, Allen RH, Chwatko G, Jakubowski H, Niculescu MD, Mudd SH (2007) Prevention of brain disease from severe 5,10-methylenetetrahydrofolate reductase deficiency. Mol Genet Metab 91:165–175PubMedCrossRefGoogle Scholar
  43. Sueyoshi E, Sakamoto I, Ashizawa K, Hayashi K (2004) Pulmonary and lower extremity vascular lesions in a patient with homocystinuria: radiologic findings. Am J Radiology 182:830–831Google Scholar
  44. Tangerman A, Mudd SH, Wilcken B, Boers GHJ, Levy HL (2000) Methionine transamination metabolites in patients with homocystinuria due to cystathionine β-synthase deficiency. Metabolism 49:1071–1077PubMedCrossRefGoogle Scholar
  45. Varlibas F, Cobanoglu O, Ergin B, Tireli H (2009) Different phenotypy in three siblings with homocystinuria. Neurologist 15:144–146PubMedCrossRefGoogle Scholar
  46. Weiss N, Demeret S, Sonneville R, Guillevin R, Bolgert F, Pierrot-Deseilligny C (2006) Bilateral internal carotid artery dissection in cystathionine beta-synthase deficiency. Eur Neurol 55:177–178PubMedCrossRefGoogle Scholar
  47. Wilcken DEL, Wang J, Sim AS, Green K, Wilcken B (2006) Asymmetric dimethylarginine in homocystinuria due to cystathionine β-synthase deficiency: Relevance of renal function. J Inherit Metab Dis 29:30–37PubMedCrossRefGoogle Scholar
  48. Yaghmai R, Kashani AH, Geraghty MT, Okoh J, Pomper M, Tangerman A, Wagner C, Stabler SP, Allen RH, Mudd SH, Braverman N (2002) Progressive cerebral edema associated with high methionine levels and betaine therapy in a patient with cystathionine β-synthase (CBS) deficiency. Am J Med Genet 108:57–63PubMedCrossRefGoogle Scholar
  49. Yap S, Boers GHJ, Wilcken B, Wilcken DEL, Brenton DP, Lee PJ, Walter JH, Howard PM, Naughten ER (2001) Vascular outcome in patients with homocystinuria due to cystathionine β-synthase deficiency treated chronically. A multicenter observational study. Arterioscler Thromb Vasc Biol 21:2080–2085PubMedCrossRefGoogle Scholar

Copyright information

© SSIEM and Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • Sally P. Stabler
    • 1
  • Mark Korson
    • 2
  • Reena Jethva
    • 3
  • Robert H. Allen
    • 1
  • Jan P. Kraus
    • 4
  • Elaine B. Spector
    • 4
  • Conrad Wagner
    • 5
  • S. Harvey Mudd
    • 6
  1. 1.Division of Hematology, Department of MedicineUniversity of Colorado School of MedicineAuroraUSA
  2. 2.Division of Genetics and Metabolism, Department of PediatricsTufts Medical CenterBostonUSA
  3. 3.Section of Neurology, Department of PediatricsSt. Christopher’s Hospital for ChildrenPhiladelphiaUSA
  4. 4.Department of PediatricsUniversity of Colorado School of MedicineAuroraUSA
  5. 5.Department of BiochemistryVanderbilt UniversityNashvilleUSA
  6. 6.Laboratory of Molecular BiologyNational Institute of Mental HealthBethesdaUSA

Personalised recommendations