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Cholesterol-lowering drug therapy in a patient with receptor-negative homozygous familial hypercholesterolaemia
M D Feher1, J C Webb, D D Patel
1Department of Academic Therapeutics, Chelsea and Westminster Hospital, London, UK.
Insights
Familial hypercholesterolaemia (FH) patients with no LDL receptor function can still lower cholesterol with statins. This study shows simvastatin effectively reduced serum cholesterol in a homozygous FH patient lacking LDL receptors.
Area of Science:
- Biochemistry
- Genetics
- Pharmacology
Background:
- Familial hypercholesterolaemia (FH) is a genetic disorder characterized by high LDL cholesterol levels.
- It is typically caused by mutations in the LDL receptor gene.
- Homozygous FH patients often show limited response to statin therapy due to impaired LDL receptor function.
Abstract:
Familial hypercholesterolaemia (FH) is caused by mutations in the gene for the low density lipoprotein (LDL) receptor. It is generally believed that homozygous FH patients do not respond well to lipid-lowering drug therapy with inhibitors of 3-hydroxy-3-methylglutaryl CoA reductase because they cannot respond to an increased demand for hepatic cholesterol by up-regulation of LDL-receptor activity. In this paper we show that serum cholesterol in a homozygous FH patient with a receptor-negative LDL-receptor phenotype was reduced by 30% after treatment with simvastatin alone and by a further 11% with simvastatin in combination with probucol and nicotinic acid. The patient was a true homozygote, with two identical alleles of the LDL receptor gene in which a previously undescribed point mutation in exon 11 introduces a premature termination codon at residue 540 in the protein; the mutant protein is predicted to be truncated in the domain with homology to the epidermal growth 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 mechanisms other than stimulation of LDL receptors.