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.
Competing interests: S.P. Stabler and R.H. Allen
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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
References
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 42:1448–1460
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 27:296–302
Capdevila A, Wagner C (1998) Measurement of plasma S-adenosylmethionine and S-adenosylhomocysteine as their fluorescent isoindoles. Anal Biochem 264:180–184
Chauveheid M-P, Lidove O, Papo T, Laissy J-P (2008) Adult-inset homocystinuria arteriography mimics fibromuscular dysplasia. Am J Med 121:e5–e6
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 35:519–522
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 32:835–842
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–S70
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 27:140–143
Favre JP, Becker F, Lorcerie B, Dumas R, David M (1992) Vascular manifestations in homocystinuria. Ann Vasc Surg 6:294–297
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 156:427–432
Gaustadnes M, Ingerslev J, Rütiger N (1999) Prevalence of congenital homocystinuria in Denmark. N Engl J Med 340:1513
Gaustadnes M, Rüdiger N, Rasmussen K, Ingerslev J (2000a) Intermediate and severe hyperhomocysteinemia with thrombosis: a study of genetic determinants. Thromb Haemost 83:554–558
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 20:1392–1395
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 20:117–126
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 56:339–347
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 154:431–437
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
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 103:330–337
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 60:275–279
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 65:59–67
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 26:509–511
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 15:159–162
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 19:641–655
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 34:33–37
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 285:15866–15873
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 140:520–522
Mudd SH (2011) Hypermethioninemias of genetic and non-genetic origin: a review. Am J Med Genet Part C 157:3–32
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 37:1–31
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 24:448–464
Newman G, Mitchell JRA (1984) Homocystinuria presenting as multiple arterial occlusions. Q J Med 210:251–258
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 103:871–873
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 26:761–773
Peterschmitt MJ, Simmons JR, Levy HL (1999) Reduction of false negative results in screening of newborns for homocystinuria. N Engl J Med 341:1572–1576
Refsum H, Fredriksen A, Meyer K, Ueland PM, Kase BF (2004) Birth prevalence of homocystinuria. J Pediatr 144:830–832
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 86:844–850
Skovby F, Gaustadnes M, Mudd SH (2010) A revisit to the natural history of homocystinuria due to cystathionine β-synthase deficiency. Mol Genet Metab 99:1–3
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 18:548–549
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 50:365–372
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 81:466–474
Stabler SP, Lindenbaum J, Savage DG, Allen RH (1993) Elevation of serum cystathionine levels in patients with cobalamin and folate deficiency. Blood 81:3404–3413
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 51:981–988
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 91:165–175
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 182:830–831
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 49:1071–1077
Varlibas F, Cobanoglu O, Ergin B, Tireli H (2009) Different phenotypy in three siblings with homocystinuria. Neurologist 15:144–146
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 55:177–178
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 29:30–37
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 108:57–63
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 21:2080–2085
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.
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Communicated by: Ivo Bari
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Take-Home Message
In connection with the puzzling history of a family with B6-responsive cystathionine B-synthase deficiency without decreased cystathionines, and usually with normal methionines, extensive data are presented on values of relevant metabolites that may facilitate the differential diagnosis of elevated total homocysteine.
Contributions of Authors
SPS, RHA, and SHM were responsible for planning the details in the manuscript. SPS, MK, RJ, RHA, JPK, EBS, CW, and SHM were all involved in the conduct of obtaining the clinical and laboratory measures described in the manuscript. SPS, JPK, CW, and SHM wrote the bulk of the manuscript with contributions from the other authors.
Guarantor for Article
Sally P. Stabler serves as the guarantor for this article, accepting full responsibility for the work. She had access to all the data and controlled the decision to publish.
Competing Interest Statement
Two of the authors, Sally P. Stabler and Robert H. Allen and the University of Colorado have competing interests. A patent on the use of homocysteine, methylmalonic acid, and cystathionine had been obtained by the University of Colorado and the two authors, which is now expired. A company has been formed at the University of Colorado to assay homocysteine, methylmalonic acid, and cystathionine. The other authors do not have competing interests.
Funding for Research
JPK was supported by the American Heart Association Grant NA09GRNT2110159. The authors confirm independence from the sponsors; the content of this article has not been influenced by the sponsors.
Ethics Approval
The compiled data came from studies previously reported which were under the purview of Institutional Review Boards as listed in the References. In addition, Protocol # 00–664 – “Methionine Metabolites in Inborn Errors” – was approved by the Colorado Multiple Institutional Review Board. Personal patient information for the case family is not included in the manuscript.
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Stabler, S.P. et al. (2013). Metabolic Profiling of Total Homocysteine and Related Compounds in Hyperhomocysteinemia: Utility and Limitations in Diagnosing the Cause of Puzzling Thrombophilia in a Family. In: Zschocke, J., Gibson, K., Brown, G., Morava, E., Peters, V. (eds) JIMD Reports - Volume 11. JIMD Reports, vol 11. Springer, Berlin, Heidelberg. https://doi.org/10.1007/8904_2013_235
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DOI: https://doi.org/10.1007/8904_2013_235
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