McGill J J, Mettler G, Rosenblatt D S, Scriver C R
deBelle Laboratory for Biochemical Genetics, McGill University-Montreal Children's Hospital Research Institute, Quebec, Canada.
Am J Med Genet. 1990 May;36(1):45-52. doi: 10.1002/ajmg.1320360111.
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.
体液中同型半胱氨酸过多被认为是闭塞性血管疾病（外周和脑血管动脉疾病，或许还有冠状动脉疾病）发病机制中的一个因素。同型半胱氨酸代谢先天性缺陷（转硫或再甲基化途径）的杂合子比纯合子/复合杂合子更为常见。如果杂合子有更高的风险（本文未探讨此问题），那么了解是否可以通过血液同型半胱氨酸的“筛查”测量来持续识别他们就很有意义。我们将高同型半胱氨酸血症（胱硫醚β-合酶缺乏症）作为一个测试案例。从对空腹（11篇文章）或蛋氨酸负荷后（8篇文章）血样中的代谢物值以及酶活性测量（12篇文章）的综述来看，很明显：（1）无法通过任何单一测量来持续识别杂合子表型（其与正常值有重叠）；（2）大多数杂合子中存在的夸张基因剂量效应（负等位基因互补）无助于对其进行分类。酶测定无法持续区分杂合子（相对于正常值）可能反映了等位基因异质性。代谢值无法持续识别杂合子反映了控制同型半胱氨酸池大小的稳态系统的局部和全局特性。这里描述的问题是生理和医学遗传学中一个普遍问题的具体例子，即检测影响代谢稳态的隐性等位基因的杂合子，以便进行医学干预和遗传咨询。
