Summary
Previous data on tentative identification of the carrier state for homocystinuria due to cystathionine synthase deficiency using methionine loading or measurement of cystathionine synthase activity in tissue extracts are conflicting. We studied the results of standardized oral methionine loading in 20 obligate heterozygotes and compared them with those of determination of cystathionine synthase activity in cultured fibroblasts. Special attention was devoted to our recently reported observation on the small but striking differences in methionine metabolism between healthy pre- and postmenopausal women and men. Fasting and after load peak levels of methionine in serum did not discriminate the carriers from the control subjects. The mean fasting level of total homocysteine was only significantly higher in the group of premenopausal heterozygotes than in the corresponding control group. Nevertheless, the individual values overlapped with the normal range in 4 of 12 premenopausal heterozygotes. After loading peak levels of total homocysteine in 18 out of the 20 obligate heterozygotes exceeded the upper limit of the ranges in the three control groups. Thus, this parameter discriminated 90% of the obligate carriers. Measurement of cystathionine synthase activity in cultured fibroblasts from a skin biopsy identified the obligate heterozygotes to a similar degree (85%). No significant correlation between the measurements of cystathionine synthase activity and the after load peak levels of total homocysteine in the individual heterozygotes was established. Combination of both methionine loading and determination of cystathionine synthase activity in cultured fibroblasts identified all of these carriers.
Similar content being viewed by others
References
Bittles AH, Carson NAJ (1981a) Homocystinuria: studies on cystathionine β-synthase, S-adenosylmethionine synthetase and cystathionase activities in skin fibroblasts. J Inherited Metab Dis 4:3–6
Bittles AH, Carson NAJ (1981b) Homocystinuria: the effect of pyridoxine supplementation on cultured skin fibroblasts. J Inherited Metab Dis 4:7–9
Boers GHJ, Smals AGH, Drayer JIM, Trijbels FJM, Leermakers AI, Kloppenborg PWC (1983a) Pyridoxine treatment does not prevent homocystinemia after methionine loading in adult homocystinuria patients. Metabolism 32:390–397
Boers GHJ, Smals AG, Trijbels FJ, Leermakers AI, Kloppenborg PW (1983b) Unique efficiency of methionine metabolism in premenopausal women may protect against vascular disease in the reproductive years. J Clin Invest 72:1971–1976
Boers GHJ, Trijbels JM, Smals AG, Kloppenborg PW (1983c) Methionine-loading can lead to the erroneous conclusion of heterozygosity for homocystinuria in normal postmenopausal women. Clin Genet 24:289–290
Boers GHJ, Polder TW, Cruysberg JRM, Schoonderwaldt HC, Peetoom JJ, van Ruyven TWJ, Smals AGH, Kloppenborg PWC (1984) Homocystinuria versus Marfan's syndrome: the therapeutical relevance of the differential diagnosis. Neth J Med 27:206–212
Brenton DP, Cusworth DC, Gaull GE (1965) Homocystinuria: metabolic studies on three patients. J Pediatr 67:58–68
Chase HP, Goodman SI, O'Brien D (1967) Treatment of homocystinuria. Arch Dis Child 42:514–520
Dunn HG, Perry TL, Dolman CL (1966) Homocystinuria. Neurology 16:407–420
Finkelstein JD, Mudd SH, Irreverre F, Laster L (1964) Homocystinuria due to cystathionine synthetase deficiency: the mode of inheritance. Science 146:785–787
Fleisher LD, Tallan HH, Beratis NG, Hirschhorn K, Gaull GE (1973) Cystathionine synthase deficiency: heterozygote detection using cultured skin fibroblasts. Biochem Biophys Res Commun 55:38–44
Fowler B, Kraus J, Packman S, Rosenberg LE (1978) Homocystinuria. Evidence of three distinct classes of cystathionine β-synthase mutants in cultured fibroblasts. J Clin Invest 61:645–653
Gaull G, Sturman JA, Schaffner F (1974) Homocystinuria due to cystathionine synthase deficiency: enzymatic and ultrastructural studies. J Pediatr 84:381–390
Kennedy C, Shih VE, Rowland LP (1965) Homocystinuria: a report in two siblings. Pediatrics 36:736–741
Laster L, Mudd SH, Finkelstein JD, Irreverre F (1965a) Homocystinuria due to cystathionine synthase deficiency: the metabolism of L-methionine. J Clin Invest 44:1708–1719
Laster L, Spaeth GL, Mudd SH, Finkelstein JD (1965b) Homocystinuria due to cystathionine synthase deficiency. Ann Intern Med 63:1117–1142
Longhi RC, Fleisher LD, Tallan HH, Gaull GE (1977) Cystathionine β-synthase deficiency: a qualitative abnormality of the deficient enzyme modified by vitamin B6-therapy. Pediatr Res 11:100–103
Mudd SH, Levy HL (1982) Disorders of transsulphuration. In: Stanbury JB, Wijngaarden JB, Frederickson DS (eds) The metabolic basis of inherited disease. McGraw-Hill, New York, pp 522–559
Sardhawalla IB, Fowler B, Robins AJ, Komrower GM (1974) Detection of heterozygotes for homocystinuria. Arch Dis Child 49:553–559
Uhlendorf BW, Conerly EB, Mudd SH (1973) Homocystinuria: studies in tissue culture. Pediatr Res 7:645–658
White HH, Thompson HL, Rowland LP, Cohen D, Araki S (1964) Homocystinuria. Trans Am Neurol Assoc 89:24–27
Wilcken DEL, Reddy SG, Gupta VJ (1983) Homocysteinemia, ischemic heart disease, and the carrier state of homocystinuria. Metabolism 32:363–370
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Boers, G.H.J., Fowler, B., Smals, A.G.H. et al. Improved identification of heterozygotes for homocystinuria due to cystathionine synthase deficiency by the combination of methionine loading and enzyme determination in cultured fibroblasts. Hum Genet 69, 164–169 (1985). https://doi.org/10.1007/BF00293290
Received:
Issue Date:
DOI: https://doi.org/10.1007/BF00293290