Correlation between Genotype and Phenotype in Heterozygous Familial Hypercholesterolaemia in Children: Out First Experience from the Metabolic Out-patient Department

Overview

From a group of 166 children and adolescents (1992 - 1999) on the basis of biochemical criteria and a positive family-history familial hypercholesterolaemia (dFH) was diagnosed. 36 patients were selected with a high risk of cardiovascular complications in later age. In this group DNA analysis was performed with the objective to detect mutations R3500Q or R3500W in the gene for apoB 100 synthesis which are the cause of a familial defect of the ligand (FDB) for the bond with the LDL receptor. Concurrently also their closest relatives - so far 42 - from risk families were examined. In 18.6% of the children the mutation was found in the mentioned triplet 3500. Analysis of the gene for synthesis of the LDL receptor, which is more demanding, is implemented successively. So far in 16.6% children with dFH the presence of various mutations was found in different parts of the LDL receptor gene, suggesting a reduced functional glycoprotein activity.In both groups of children with deficient receptors the metabolic finding and genetic risk in the family was always more marked than in the group of children without receptor deficiency. In both groups of children by diet of medicamentous treatment a significant reduction of the total cholesterol was achieved but only in exceptional instances to normal reference values. The mean drop of total cholesterol as a result of a low-cholesterol diet was in children with a mutation in the LDL receptor gene only 0.8 mmol/l, as a result of medicamentous treatment 2.0 mmol/l. In mutations of the gene for synthesis of the apoB 100 receptor diet caused a drop of 1.0 mmol/l and medication a drop of 1.1 mmol/l. In all instances however great individual differences of cholesterol tolerance were found frequently even between siblings with the same mutation.A positive finding of different mutations in the mentioned two genes of receptors helps us nevertheless to decide responsibly on the introduction of medicamentous treatment.

Key words:
familial hypercholesterolaemia in children, mutations in genes for LDL receptor, synthesis and apoB 100 ligand, dietetic and medicamentous treatment