FAMILIAL DEFECTIVE APOLIPOPROTEIN B-100 IS CLINICALLY INDISTINGUISHABLE FROM FAMILIAL HYPERCHOLESTEROLEMIA

Background: Familial defective apolipoprotein B-100 is caused by a sub stitution of adenine for guanine in exon 26 of the gene coding for apo lipoprotein B, which results in the substitution of glutamine for argi nine in the putative low-density lipoprotein-receptor binding domain o f the mature protein. This amino acid substitution diminishes the bind ing capacity of the low-density lipiprotein particle for the low-densi ty lipoprotein receptor, which in turn leads to an increase in levels of plasma total and low-density lipoprotein cholesterol.Methods: To id entify carriers of this mutation by means of molecular biology techniq ues in a large cohort of Dutch patients living in the Netherlands and in Canada with primary hypercholesterolemia, to establish the frequenc y of the disorder, and to investigate its clinical signs and symptoms and the response to cholesterol-lowering therapy. Results: A total of 1248 patients were screened, and the mutation was found in 18 patients who were initially all diagnosed as having familial hypercholesterole mia. Ten of 18 patients had tendon xanthomas or an arcus cornealis or both, and eight of 18 patients had angina or other evidence of coronar y artery disease. Conclusions: The disorder was clinically indistingui shable from familial hypercholesterolemia in terms of physical charact eristics and lipoprotein measures. Response to lipid-lowering therapy with beta-hydroxy-beta-methylglutaryl coenzyme A reductase inhibitors was similar to that reported in patients with familial hypercholestero lemia. The mutation was associated with a similar haplotype, which was also reported in other patients of Western European descent with fami lial defective apolipoprotein B100. This strongly suggests that the mu tation has a common chromosomal background that originated in Western Europe.