Monogenic hypercholesterolemia: new insights in pathogenesis and treatment
Authors: Daniel J. Rader, Jonathan Cohen, Helen H. Hobbs
Journal: Journal of Clinical Investigation (2003)

The careful clinical characterization of patients with genetic forms of severe hypercholesterolemia has played a critical role in the historic linkage of hypercholesterolemia to atherosclerosis. Elucidation of gene defects that cause severe hypercholesterolemia has provided molecular entrees into the biosynthetic and regulatory pathways that produce and eliminate cholesterol and has led to the development of potent pharmacological agents that dramatically reduce circulating levels of cholesterol. The last decade of the twentieth century culminated in the demonstration that pharmacological reductions in plasma cholesterol levels result in fewer cardiovascular events and reduce total mortality.

This review will summarize recent developments in our understanding of the molecular pathogenesis and treatment of monogenic forms of severe hypercholesterolemia, and some implications that these findings have for the management of common forms of hypercholesterolemia.

General overview of LDL metabolism.
Cholesterol is a rigid, hydrophobic molecule that confers structural integrity to plasma membranes of vertebrate cells. Excess cellular cholesterol is esterified with fatty acids to form cholesteryl esters, which are either stored as lipid droplets in cells or packaged with other apolipoproteins to form VLDL in the liver and and chylomicrons in the intestine (Figure ​(Figure1).1). The two major cholesterol-carrying lipoproteins in humans are LDL and HDL. Approximately 70% of circulating cholesterol is transported as LDL.



Figure 1

Overview of LDL metabolism in humans. Dietary cholesterol and triglycerides are packaged with apolipoproteins in the enterocytes of the small intestine, secreted into the lymphatic system as chylomicrons (CM). As chylomicrons circulate, the core triglycerides ...



LDL is formed in the circulation from VLDL (Figure ​(Figure1).1). The triglycerides and phospholipids of circulating VLDL are hydrolyzed by lipases anchored to vascular endothelial surfaces, forming cholesterol-enriched VLDL remnant particles. Approximately half of the VLDL remnants are cleared from the circulation by LDL receptor–mediated (LDLR-mediated) endocytosis in the liver, and the remainder undergoes further processing to produce LDL. Most LDL is removed from the circulation after binding to the hepatic LDLR via apoB-100.

Plasma levels of LDL-cholesterol (LDL-C) are directly related to the incidence of coronary events and cardiovascular deaths. Approximately 50% of the interindividual variation in plasma levels of LDL-C is attributable to genetic variation (1). The major portion of this genetic variation is polygenic, reflecting the cumulative effects of multiple sequence variants in any given individual. A subset of patients with very high plasma LDL-C levels have monogenic forms of hyper-cholesterolemia, which are associated with the deposition of cholesterol in tissues, producing xanthomas and coronary atherosclerosis.

The clinical features, diagnosis, and pathophysiology of the known mendelian disorders of severe hypercholesterolemia will be serially reviewed (Table ​(Table1).1). This will be followed by a discussion of how insights gleaned from the study of these disorders may be extended to the treatment of hypercholesterolemia in the general population.



Table 1

Major monogenic diseases that cause severe hypercholesterolemia





Familial hypercholesterolemia


Historical perspective. 
Familial hypercholesterolemia (FH), the most common and most severe form of monogenic hypercholesterolemia, was the first genetic disease of lipid metabolism to be clinically and molecularly characterized (2). The disease has an autosomal codominant pattern of inheritance and is caused by mutations in the LDLR gene; individuals with two mutated LDLR alleles (FH homozygotes) are much more severely affected than those with one mutant allele (FH heterozygotes). The plasma levels of LDL-C are uniformly very high in FH homozygotes, irrespective of diet, medications, or lifestyle. For example, FH homozygotes living in China, where the dietary intake of cholesterol and saturated fat is low, have plasma LDL-C levels similar to those of FH homozygotes living in Western countries (3).

FH homozygotes develop cutaneous (planar) xanthomas and coronary atherosclerosis in childhood (2). Atherosclerosis develops initially in the aortic root, causing supravalvular aortic stenosis, and then extends into the coronary ostia. The severity of atherosclerosis is proportional to the extent and duration of elevated plasma LDL-C levels (calculated as the cholesterol-year score) (4). If the LDL-C level is not effectively reduced, FH homozygotes die prematurely of atherosclerotic cardiovascular disease. Optimization of other cardiovascular risk factors has little impact on the clinical course of the disease.

Patients with homozygous FH are classified into one of two major groups based on the amount of LDLR activity measured in their skin fibroblasts: patients with less than 2% of normal LDLR activity (receptor-negative), and patients with 2–25% of normal LDLR activity (receptor-defective) (2). In general, plasma levels of LDL-C are inversely related to the level of residual LDLR activity. Untreated, receptor-negative patients with homozygous FH rarely survive beyond the second decade; receptor-defective patients have a better prognosis but, with few exceptions, develop clinically significant atherosclerotic vascular disease by age 30, and often sooner (2).

The plasma levels of LDL-C in FH heterozygotes are lower (elevated two- to threefold) and much more dependent on other genetic and environmental factors than are those in FH homozygotes. Although the nature of the molecular defect has some impact on the severity of hypercholesterolemia, FH heterozygotes with the same LDLR mutation can have widely different plasma levels of LDL-C (2). The clinical prognosis of FH heterozygotes is related not only to the magnitude of the elevation in plasma LDL-C but also to the presence of other coronary risk factors (5).