P0171 PP CLINICAL AND BIOLOGICAL PREDICTORS FOR DOMINANTLY INHERITED HYPERCHOLESTEROLEMIA IN CHILDREN. VALIDATION BY MOLECULAR GENETICS.

Abstract

Introduction: Hypercholesterolemia (HC) with autosomal dominant inheritance [Familial HC (FH) and familial deficiency in apolipoprotein B100 (FDB)] are frequent in childhood. Although possibly confused in clinical practice with more common forms of hyperlipidemia, they represent a group at much higher risk for cardiovascular disease. Case finding during childhood may allow timely treatment in order to prevent premature coronary disease or sudden death in adults. The aim of the study was to use genetic testing to define the most predictive clinical and biological characteristics for severe dominantly inherited forms of disease in children with HC. Methods: Inclusion criteria were: total cholesterol (TC) > 200mg/dl with LDL-C > 130mg/dl and age <12 years at diagnosis. In all children, direct sequencing of the LDL receptor (LDLR) gene and of the LDLR binding domain of APOB gene was performed on genomic DNA. Lipid measurements [12h fasting plasma TC, HDL-C and triglycerides] were performed before and after 6 months under adapted diet. In addition, family history for cardiovascular disease was documented together with fasting plasma lipids measurements in first degree relatives. Results: 82 children (40 girls) were studied [median age: 5 years (1–12 y), mean 5,5 „b 2,8 years]. Forty nine children heterozygous for a LDLR (n=43) or APOB (n=6) mutation, were compared with 33 non mutation carrier HC children. Significantly higher plasma TC and LDL-C were found in mutation carriers (328 „b 61 vs 254 „b 37 mg/dl and 255 „b 51 vs 181 „b 37 mg/dl respectively; p<0,0001) with a lower LDL-C decrease under diet (−12 „b 16 vs −22 „b 14%; p=0,027). A higher frequency of lipid lowering drugs regularly taken by parents (79% vs 33%; p<0,0001) and of premature cardiovascular disease in grandparents (44% vs 17%; p=0,014) was found in mutation carrier children. Biological criteria for dominantly inherited HC were 1) TC > 300 mg/dl (specificity = 93%, PPV = 92%, p< 0,0001) and LDL-C > 220 mg/dl (specificity = 91%, PPV = 92%, p< 0,0001) at diagnosis; 2) persistent LDL-C > 190 mg/dl after 6 months under diet (specificity=96%, PPV=97%, p<0,0001). Conclusion: The precise analysis of family history and biological characteristics in children with HC before and after a test diet, may readily identify those children with inherited HC whom will mostly benefit from early and adapted prevention of cardiovascular disease.