FAMILIAL HYPERCHOLESTEROLEMIA - MOLECULAR, BIOCHEMICAL, AND CLINICAL CHARACTERIZATION OF A FRENCH-CANADIAN PEDIATRIC POPULATION

Background. Familial hypercholesterolemia (FH) is a dominantly-inherit ed disorder attributable to a defect in the low-density lipoprotein (L DL) receptor gene. Five mutations at this locus have been identified i n French-Canadians. In children, it may be difficult to clinically dis tinguish FH from other forms of polygenic or monogenic hyperlipidemia. Therefore, our objectives were to define the molecular basis of our s ubjects' hypercholesterolemia, to characterize their biochemical pheno type in relation to the underlying molecular defect, and to assess the ir response to chronic dietary therapy. Methods. We studied 88 unrelat ed French-Canadian children with a persistent increase in LDL choleste rol and a parental history of hyperlipidemia. Baseline and end-of-diet lipid and apolipoprotein levels were measured. Mutational analysis at the LDL receptor gene locus was performed. Results. Heterozygosity fo r the common French-Canadian LDL receptor gene > 10-kb deletion was fo und in 57% of subjects (group 1), 14% carried one of the other four pr eviously characterized LDL receptor gene mutations (group 2), and none of the five molecular defects tested was detected in 29% (group 3). T otal cholesterol, LDL cholesterol, and apolipoprotein B baseline level s were similar among these three groups but significantly higher than in control subjects. However, there was wide interindividual variabili ty even among those carrying the same mutation. Significantly lower ba seline levels of high-density lipoprotein cholesterol and apolipoprote in Al were found in group 1 compared with group 3 and the controls. Th e response to diet was similar among the three groups with an average reduction in the mean level of total cholesterol of 4.4%. Conclusions. The frequency of proven FH heterozygotes (71%) was remarkable in the pediatric population studied. Our data suggest that, in children, a pe rsistent primary increase in LDL cholesterol associated with a parenta l history of hyperlipidemia is a good predictor of an underlying monog enic disorder as opposed to a polygenic disorder, at least in French-C anadians. Only molecular analysis allowed us to unequivocally define t he cause of our patients' hypercholesterolemia. Most children with fam ilial hyperlipidemia did not reach desirable plasma lipid levels solel y under diet therapy.