Metabolic Profiling of Total Homocysteine and Related Compounds in Hyperhomocysteinemia: Utility and Limitations in Diagnosing the Cause of Puzzling Thrombophilia in a Family
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.
KeywordsCompound Heterozygote Pyridoxal Phosphate Methylmalonic Acid Case Family Cobalamin Deficiency
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.
- 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
- 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
- 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
- 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
- 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
- Newman G, Mitchell JRA (1984) Homocystinuria presenting as multiple arterial occlusions. Q J Med 210:251–258Google Scholar
- 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
- 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
- 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
- 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