Detection of heterozygotes for homocystinuria by oral loading with L-methionine

Sardharwalla, I. B.; Fowler, Brian; Robins, Alexander

doi:10.1136/adc.46.249.738-a

Cited by 8 publications

(11 citation statements)

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“…Our findings finally indicate that a standardized methionine load can lead to overt homocystinemia in normal men and normal postmenopausal women and that an increase in the mixed disulphide levels even up to those found in obligate heterozygotes (18) in normal postmenopausal women could give rise to the erroneous conclusion of the presence of heterozygous classical homocystinuria.…”

mentioning

confidence: 93%

Unique efficiency of methionine metabolism in premenopausal women may protect against vascular disease in the reproductive years.

Boers¹,

Smals²,

Trijbels³

et al. 1983

J. Clin. Invest.

142

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A B S T R A C T Premenopausal women develop occlusive artery disease less frequently than postmenopausal women. In coronary heart disease, higher blood levels of homocysteine-cysteine mixed disulphide have been reported. Therefore, in healthy subjects, we studied the role of menopausal status in the transsulphuration of methionine in 10 premenopausal and 10 postmenopausal women. To exclude the role of aging, we compared these results with those in 10 younger and 10 older men of comparable age groups. An oral methionine load (0.1 g/kg of body weight) was administered after overnight fasting. Before and during 8 h, thereafter, serum levels of methionine, homocystine, and homocysteine-cysteine mixed disulphide were measured. In the fasting state, serum methionine levels were similar in the premenopausal women and both groups of men. Postmenopausal women had significantly lower fasting levels. Peak levels and clearances of methionine after loading did not differ between the groups. In the fasting state, homocystine was never detectable; yet, after methionine loading, slight homocystinemia was present in 12 out of 20 men, and was more pronounced in all postmenopausal women. However, homocystinemia did not occur in any of the premenopausal women after loading. Fasting serum homocysteine-cysteine mixed disulphide levels did not differ between both groups of men and postmenopausal women. In premenopausal women, both fasting and postloading disulphide levels were significantly lower than in any other group. We conclude that premenopausal women have a unique efficiency of methionine Address reprint requests to Dr. Boers,

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mentioning

confidence: 93%

Unique efficiency of methionine metabolism in premenopausal women may protect against vascular disease in the reproductive years.

Boers¹,

Smals²,

Trijbels³

et al. 1983

J. Clin. Invest.

142

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“…Some reports in the literature indicated that heterozygosity for homocystinuria might be identified by means of an oral me thionine loading test, but the data on the sen sitivity of such tests are contradictory [7,8] and, therefore, we had to reevaluate this cri terion of heterozygosity. We first performed a strictly standardized methionine loading test in 40 normal control subjects catego rized as young and older men and women.…”

Section: Heterozygosity For Homocystinuria and Premature Arteriosclermentioning

confidence: 99%

Carriership for Homocystinuria in Juvenile Vascular Disease

Boers¹

1989

Pathophysiol Haemos Thromb

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The frequency of pathological homocysteine accumulation after standardized methionine loading was investigated in 75 patients with clinical signs of ischemic disease before age 50: 25 with occlusive peripheral arterial disease, 25 with occlusive cerebrovascular disease, and 25 with myocardial infarction. On the basis of abnormally high homocysteinemia after methionine loading and cystathionine synthase deficiency in fibroblast cultures, carriership for homocystinuria could be established in 7 patients in each of the first two groups, however in none of the patients in the third group. This high frequency of heterozygosity compared with the frequency of 1 in 70 at the most in the normal population leads to the conclusion that such carriership predisposes to the development of premature occlusive arterial disease.

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“…Eleven articles [Carson et al, 1963;Brenton et al, 1965;Dunn et al, 1966;Sardharwalla et al, 1974;Kanget al, 1979;Wilcken et al, 1983;Boers et al, 1985a;Murphy-Chutorian et al, 1985;Sartorio et al, 1986;Brattstrom et al, 1988;Wiley et al, 19881 provided plasma values in overnight fasted subjects (n = 94).…”

Section: Plasma Metabolitesmentioning

confidence: 99%

“…Eight articles [Chase et al, 1967;Sardharwalla et al, 1974;Wilcken et al, 1983;Boers et al, 1985a;Murphy-Chutorian et al, 1985;Sartorio et al, 1986;Brattstrom et al, 1988;Wiley et al, 19881 provided data on plasma values after methionine loading at a standard dose of 100 mg/kg orally (n = 67). The postload interval selected for analysis of the loading response was that at which the greatest difference between the means for control individuals and heterozygotes was reported in the article.…”

Section: Plasma Metabolitesmentioning

confidence: 99%

“…Some investigators found a difference between the 2 groups but only for some metabolites (Table I). Measurement of protein-bound homocyst(e)ine initially appeared to yield significant differences between these 2 groups, but the clear discrimination reported by Kang et al [19791 has not been corroborated by subsequent and larger studies [Sartorio et al, 1986;Brattstrom et al, 1988;Wiley et al, 19881. Metabolites other than homocysteine have been measured, notably methionine [Carson et al, 1963;Brenton et al, 1965;Dunn et al, 1966;Sardharwalla et al, 1974;Wilcken et al, 1983;Murphy-Chutorian et al, 1985;Brattstrom et al, 19881, mixed disulfide [Wilcken and Wilcken, 1976;Murphy-Chutorian et al, 19851, non-protein-bound cysteine [Wiley et al, 19881, total cysteine [Brattstrom et al, 19881, and protein-bound cysteine [Wiley et al, 19881. Heterozygous and normal subjects were not differentiated by any plasma metabolite value in the fasted state and the variation within specific sets of values was considerable.…”

Section: Plasma Metabolite Valuesmentioning

confidence: 99%

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Detection of heterozygotes for recessive alleles. Homocyst(e)inemia: Paradigm of Pitfalls in phenotypes

et al. 1990

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Excess homocysteine in body fluids has been implicated as a factor in the pathogenesis of occlusive vascular disease (peripheral and cerebrovascular arterial disease, and perhaps coronary artery disease). Heterozygotes for inborn errors of homocysteine metabolism (transsulfuration or remethylation pathways) are much more frequent than are homozygotes/compounds. If heterozygotes are at increased risk (a question not addressed here), it is of interest to know whether they can be identified consistently by a "screening" measurement of blood homocyst(e)ine. We used hyperhomocyst(e)inemia (cystathioninemia beta-synthase deficiency) as a test case. From reviews of metabolite values in blood samples either fasting (11 articles) or after a methionine load (8 articles), and of measures of enzyme activity (12 articles), it is apparent that (1) The heterozygous phenotype cannot be identified consistently by any single measure (there is overlap with normal values); and (2) the exaggerated gene dosage effect (negative allelic complementation) present in most heterozygotes does not assist their classification. The failure of enzyme assay to distinguish heterozygotes consistently (relative to normal values) may reflect allelic heterogeneity. The failure of metabolic values to identify heterozygotes consistently reflects the local and global properties of the homeostatic system controlling the homocysteine pool size. The problem described here is a particular example of a general one in physiological and medical genetics, namely detection of heterozygotes for recessive alleles, affecting metabolic homeostasis, for purposes of medical intervention and for genetic counselling.

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Detection of heterozygotes for homocystinuria by oral loading with L-methionine

Cited by 8 publications

References 0 publications

Unique efficiency of methionine metabolism in premenopausal women may protect against vascular disease in the reproductive years.

Unique efficiency of methionine metabolism in premenopausal women may protect against vascular disease in the reproductive years.

Carriership for Homocystinuria in Juvenile Vascular Disease

Detection of heterozygotes for recessive alleles. Homocyst(e)inemia: Paradigm of Pitfalls in phenotypes

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