DELAYED LOW-DENSITY-LIPOPROTEIN (LDL) CATABOLISM DESPITE A FUNCTIONALINTACT LDL-APOLIPOPROTEIN-B PARTICLE AND LDL-RECEPTOR IN A SUBJECT WITH CLINICAL HOMOZYGOUS FAMILIAL HYPERCHOLESTEROLEMIA

We identified a 38-yr-old male patient with the clinical expression of homozygous familial hypercholesterolemia presenting as severe coronar y artery disease, tendon and skin xanthomas, arcus lipoides, and joint pain. The genetic trait seems to be autosomal recessive. Interestingl y, serum concentrations of cholesterol responded well to diet and stat ins. We had no evidence of an abnormal low density Lipoprotein (LDL)-a polipoprotein B (apoB) particle, which was isolated from the patient u sing the U937 proliferation assay as a functional test of the LDL-bind ing capacity. The apoB 3500 and apoB 3531 defects were ruled out by PC R. In addition, we found no evidence for a defect within the LDL-recep tor by skin fibroblast analysis, linkage analysis, single-strand confo rmational polymorphism and Southern blot screening across the entire L DL-receptor gene. The in vivo kinetics of radioiodinated LDL-apoB were evaluated in the proband and three normal controls, subsequently. The LDL-apoB isolated from the patient showed a normal catabolism, confir ming an intact LDL particle. In contrast the fractional catabolic rate (d(-1)) of autologous LDL in the subject and the normal controls reve aled a remarkable delayed catabolism of the patient's LDL (0.15 us. 0. 33-0.43 d(-1)). In addition, the elevation of LDL-cholesterol in the p atient resulted from an increased production rate with 22.8 mg/kg per day us. 12.7-15.7 mg/kg per day. These data indicate that there is ano ther catabolic defect beyond the apoB and LDL-receptor gene causing fa milial hypercholesterolemia.