Extreme phenotypes in hypercholesterolemia From genotype to therapy

Familial hypercholesterolemia (FH) is an inherited disorder of cholesterol metabolism, resulting in increased LDL-cholesterol levels and, as a consequence, an increased risk for coronary heart disease. Recently, many causal FH mutations in different genes have been identified and advances in genetic diagnostics have provided more insight into the relation between different FH genotypes (e.g. type of mutation) and their phenotypic expression (e.g. LDL-C level, coronary heart disease), and vice versa. Part I (chapter 2 to 10) of this thesis describes recent studies on genotype-phenotype relations in familial forms of hypercholesterolemia. The author describes that the prevalence of FH is much higher as compared with the historical prevalence described in 1973 (~1:250 instead of 1:500 individuals). Moreover, the author shows that the phenotype of patients with FH mutations is very variable and, among others, overlaps with a lysosomal storage disease, called cholesteryl-ester storage disease. Part II (chapter 11 to 18) focuses on the management for patients with FH, and describes both current as well as future treatment perspectives for this patient population.