We previously described a Sardinian family in which the probands had a severe form of
hypercholesterolemia, suggestive of
familial hypercholesterolemia (FH). However,
low density lipoprotein (
LDL) receptor activity in fibroblasts from these subjects and
LDL binding ability were normal. The characteristics of the pedigree were consistent with an autosomal recessive trait.
Sitosterolemia and pseudohomozygous
hyperlipidemia were ruled out. A second Sardinian kindred with similar characteristics was identified. Probands showed severe
hypercholesterolemia, whereas their parents and grandparents were normolipidemic. FH, familial defective
apoprotein (
apo) B,
sitosterolemia, and
cholesteryl ester storage disease were excluded by in vitro studies. We addressed the metabolic basis of this inherited disorder by studying the in vivo metabolism of
LDL in 3 probands from these 2 families. 125I-LDL turnover studies disclosed a marked reduction in the fractional catabolic rate (0.19+/-0.01 versus 0.36+/-0.03 pools per day, respectively; P<0.001) and a significant increase in the production rate [20.7+/-4.4 versus 14. 0+/-2.4 mg. kg-1. d-1, respectively; P<0.01] of
LDL apoB in the probands compared with normolipidemic controls. We then studied the in vivo biodistribution and tissue uptake of 99mtechnetium-labeled
LDL in the probands and compared them with those in normal controls and 1 FH homozygote. The probands showed a significant reduction in hepatic
LDL uptake, similar to that observed in the FH homozygote. A reduced uptake of
LDL by the kidney and spleen was also observed in all patients. Our findings suggest that this recessive form of
hypercholesterolemia is due to a marked reduction of in vivo
LDL catabolism. This appears to be caused by a selective reduction in hepatic
LDL uptake. We propose that in this new
lipid disorder, a recessive defect causes a selective impairment of
LDL receptor function in the liver.