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1. INTRODUCTION
Primary hypercholesterolaemia (i.e., elevation of plasma low density lipoprotein-cholesterol (LDL-cholesterol) which is not secondary to environmental, dietary, or other underlying diseases) is a relatively common condition that has been associated with the development of atherosclerosis and premature cardiovascular disease. More than half of all deaths in Western society are related to atherosclerotic cardiovascular diseases [1]. The pathogenesis of atherosclerosis results from a combination of heritable and environmental factors. Inherited disturbances in the low density-lipoprotein (LDL) receptor and similar lipid-related defects account for the majority of these deaths [2]. Three recent studies indicate that heart attacks can be reduced by one third, and deaths related to heart attacks by nearly 40%, with drug treatment in high-risk individuals [3-5]. The definition of high risk is important, because serum cholesterol levels included in this category overlap the normal range.
Since cholesterol-lowering is possible in almost all individuals, cost-effectiveness is entirely dependent on risk. Consequently, treatment decisions should be based on proper risk assessment. Primary prevention is important since at least thirty percent of individuals with coronary artery disease never get any chance for intervention or secondary prevention; they die prior to receiving medical attention. Currently, testing procedures for risk assessment rely on total cholesterol, LDL-cholesterol, high-density-lipoprotein- (HDL) cholesterol, triglyceride determinations, and other cardiovascular risk factors [6]. Such factors are hypertension, diabetes, and left ventricular hypertrophy. However, cardiovascular disease has a strong genetic component. Sibling pair and twin studies show beyond any doubt the importance of heredity in terms of cardiovascular risk [7]. Thus, genetic diagnostic screening will be of major importance in the future. To this end, familial hypercholesterolaemia (FH) presents a new challenge for those interested in applying genetic principles to prevent disease consequences.
The World Health Organization invited experts to present state-of-the-art information regarding what can be done to best help 10 million FH heterozygotes and 5,000 FH homozygotes world-wide avoid preventable early heart attack death. Following an in-depth discussion on the challenges and opportunities in the diagnosis and management of FH held at a WHO Consultation in October 1997, the group also developed a series of recommendations.
2. MOLECULAR BASIS OF FH
Primary hypercholesterolaemia is a broad term which includes both monogenic disorders (caused by mutations of a single gene with a large effect) and polygenic conditions (involving multiple genes, each with a relative small effect).
Monogenic disorders
Familial hypercholesterolaemia (FH) is a classical monogenic disorder associated with primary hypercholesterolaemia. FH is characterized by autosomal co-dominant inheritance with strikingly elevated LDL-cholesterol, the presence of xanthoma and premature atherosclerosis. FH is due to a lack of functional receptors for LDL on the cell surface, whereby LDL cannot be taken up and catabolized by the cells, especially by the hepatocytes. In heterozygous FH, a defective gene for the LDL-receptor is inherited from one parent and a normal gene from the other. Since two normal genes are needed to maintain the "normal" plasma level of LDL-cholesterol, the absence of one functional gene causes the LDL-cholesterol level to rise to approximately twice the normal level early in childhood. FH-homozygotes inherit two abnormal LDL-receptor genes, and consequently, have no functioning LDL-receptors. In these patients plasma LDL-cholesterol levels increase by approximately 4-5 fold and generalized atherosclerosis usually develops during childhood. The heterozygote frequency is estimated to be 1:500 in most populations (European, North American and Japanese) and the
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