2.1. Familial hypercholesterolemia

Familial hypercholesterolemia is one of the most common monogenic inherited diseases, the frequency of the heterozygous form being about 1:500 in most populations (Goldstein & Brown 1983). FH is caused by a diminished number of functional LDL receptors on the cell membranes (Brown & Goldstein 1986). Five different classes of mutations have been described, each of which includes several different gene defects. Class 1 mutations disrupt the synthesis of LDL receptors, resulting in a complete absence of detectable receptors, in class 2 mutations the transport of the receptor to the cell surface is blocked or obstructed, class 3 receptors bind LDL defectively, class 4 receptors are unable to cluster in the coated pits, and class 5 mutated receptors fail to recycle to the cell surface or deliver LDL to the endosomes (Hobbs et al. 1990). More than 150 different mutations causing FH have been described (Hobbs et al. 1992). The FH-Helsinki mutation belongs to class 4, and it is caused by a large 9500-bp deletion extending from intron 15 to exon 18 (Aalto-Setälä et al. 1989a). The FH North Karelia mutation results in a receptor-negative or binding-defective LDL receptor due to a 7 nucleotide deletion in exon 6 (Koivisto et al. 1992). Approximately one-third of the FH patients in Finland have the FH-Helsinki (Aalto-Setälä et al. 1988a), and one-third the FH-North Karelia (Koivisto et al. 1992) mutation. The other FH-mutations described in Finland include the FH Espoo (Koivisto et al. 1993), FH Jalasjärvi (Koivisto & Kontula 1996), FH Turku (Koivisto et al. 1995) and FH Pori (Koivisto et al. 1995).

The clinical diagnostic criteria for FH are a serum cholesterol concentration above 9 mmol/l after adequate dietary intervention, when secondary hypercholesterolemia has been excluded, and FH or early onset coronary artery disease in at least one first-degree relative (males < 45 years, females < 55 years) or tendon xanthomata. Tendon xanthomata is an age-related phenomenon, with only 7% of FH heterozygotes below the age of 19 years exhibiting xanthomata compared to >80% of patients older than 30 years (Thompson et al. 1989).