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Homozygous familial hypercholesterolemia: specificity of the biochemical defect in cultured cells and feasibility of prenatal detection.

Familial hypercholesterolemia is an autosomal dominant disorder [1-4] in which heterozygotes manifest hypercholesterolemia, tendinous xanthomas, and, in the third to sixth decade of life, signs of coronary heart disease [3, 4]. Homozygotes manifest a much more severe clinical syndrome characterized by a profound hypercholesterolemia often exceeding 800 mg/dl, cutaneous planar xanthomas appearing within the first 4 years of life, and rapidly progressive coronary heart disease developing in childhood and eventuating in death from myocardial infarction, often before age 20 [3, 5, 6]. Recent investigations in our laboratory have established that the cultured fibroblasts from subjects with familial hypercholesterolemia overproduce cholesterol because of a genetically determined abnormality in the regulation of the enzyme 3-hydroxy-3-methylglutaryl Coenzyme A reductase (HMG CoA reductase), the rate-controlling enzyme in the cholesterol biosynthetic pathway [7]. Our original studies indicated that, when fibroblasts were cultured in the presence of serum, the activity of HMG CoA reductase in cells of three homozygotes with familial hypercholesterolemia was about 40-fold higher than in cells of seven control subjects. The enhanced enzyme activity in the mutant cells resulted from a nearly complete absence of normal feedback suppression of the enzyme by the low-density lipoproteins of the serum in which the cells were grown [7-9]. The fibroblasts of two obligate heterozygotes showed a degree of enzyme inhibition by low-density lipoproteins intermediate between that of controls and homozygotes [7]. These studies raised the following questions. (1) Is the defect in regulation of HMG CoA reductase activity in homozygotes a specific genetic marker for familial hypercholesterolemia or is it merely a reflection of severe hypercholesterolemia and