Background: One major problem of using hypercholesterolaemia alone as a primary criterion for diagnosing familial hypercholesterolaemia (FH) is that 15-40% of relatives may be misdiagnosed because plasma lipid levels in FH heterozygotes overlap with those in the general population.
Setting: General Hospital/University of Vienna, Department of Pediatrics, Outpatient lipid clinic.
Methods: As a part of the MED-PED (make early diagnosis-prevent early death) project we are currently investigating children, adolescents and their relatives who are suspected to be affected with FH in our out-patient clinic for metabolic diseases using MED-PED inclusion criteria and confirming the diagnosis by means of DNA analysis.
Patients: 263 patients with premature atherosclerosis and/or hypercholesterolaemia: 116 children (mean age 11.6 +/- 4.1 years; 57 girls and 59 boys) and 147 adults (64 women, mean age 41.5 +/- 13.7 years; 83 men, mean age 42.8 +/- 10.8 years).
Results: 119 patients with mutations have been detected; 56 children with either low density lipoprotein receptor (LDLR) and/or ApoB mutations (27 girls and 29 boys; mean total cholesterol (TC) 275 +/- 71 mg/dl, triglycerides (TG) 101 +/- 57 mg/dl, high-density lipoprotein cholesterol (HDL-C) 49 +/- 12 mg/dl, low-density lipoprotein cholesterol (LDL-C) 198 +/- 67 mg/dl) and one boy with a homozygous. LDLR mutation. A further 62 adults with LDLR and/or ApoB mutations were documented; 33 women (mean age 36.9 +/- 11.1 years; mean TC 283 +/- 76 mg/dl, TG 137 +/- 78 mg/dl, HDL-C 55 +/- 17 mg/dl, LDL-C 210 +/- 67 mg/dl) and 29 men (mean age 45.0 +/- 10.6 years; mean TC 301 +/- 87 mg/dl, TG 163 +/- 112 mg/dl, HDL-C 42 +/- 12 mg/dl, LDL-C 233 +/- 83 mg/dl). In 32 of these subjects (11 children (21%), 21 adults (42%)), serum lipid levels were lower than the diagnostic MED-PED limits adopted, so that they might have been misclassified without an additional DNA analysis.
Conclusion: In our study, diagnosis of FH and related disorders (ApoB-100 defect) by means of conventional laboratory methods missed at least 21% in children and 42% in adults affected with LDLR and/or ApoB gene mutations. Genetic FH diagnosis provides a tool for specific diagnosis of mutation carrier status.