CHOLESTEROL-LOWERING DRUG-THERAPY IN A PATIENT WITH RECEPTOR-NEGATIVEHOMOZYGOUS FAMILIAL HYPERCHOLESTEROLEMIA

Familial hypercholesterolaemia (FH) is caused by mutations in the gene for the low density lipoprotein (LDL) receptor. It is generally belie ved that homozygous FH patients do not respond well to lipid-lowering drug therapy with inhibitors of 3-hydroxy-3-methylglutaryl CoA reducta se because they cannot respond to an increased demand for hepatic chol esterol by up-regulation of LDL-receptor activity. In this paper we sh ow that serum cholesterol in a homozygous FH patient with a receptor-n egative LDL-receptor phenotype was reduced by 30% after treatment with simvastatin alone and by a further 11% with simvastatin in combinatio n with probucol and nicotinic acid. The patient was a true homozygote, with two identical alleles of the LDL receptor gene in which a previo usly undescribed point mutation in exon 11 introduces a premature term ination codon at residue 540 in the protein; the mutant protein is pre dicted to be truncated in the domain with homology to the epidermal gr owth factor precursor. Cultured cells from the patient were unable to bind, internalise or degrade LDL by the receptor pathway and there was no immunodetectable LDL receptor protein in the cells. Thus the lipid lowering effect of simvastatin in this individual must involve mechan isms other than stimulation of LDL receptors.