Evaluation of a newly discovered LDL-receptor-mutation (exon 10, GAC > AAC, D471N, "FH graz-1") in familial hypercholesterolemia - a family study

Heterozygous familial hypercholesterolemia (FH? prevalence 1:500) is a majo r cause of early atherosclerotic disease. Little is known about possible co -factors:influencing individual patient's risk. We investigated this questi on in a large family carrying a new LDL-receptor-mutation. Genetic analysis of all exons of the LDL-receptor gene in the index case us ing polymerase chain reaction (PCR) and Denaturing Gradient Gel Electrophor esis (DGGE) revealed a previously unknown mutation in exon:10 (GAC>AAC, D47 1N, "FH Graz-1"). Investigation of 21 family members (15 females, 6 males), aged 17 to 86 years, revealed 9 female and 4 male carriers of the mutation . 7 female carriers aged 17 to 58 years show no clinical signs of macrovascul ar disease. An 86-year old female patient, who was asymptomatic until 85, r ecently suffered a transient cerebral ischemic attack. All these females we re normotensive. The only hypertensive 76-year old,patient (ex-smoker with a history Of 15 pack years) suffers from angina pectoris. 2 male carriers of the mutation (32 and 38 years old) are asymptomatic. A 6 5-year old patient suffers from cardiovascular disease. A 49-year old patie nt had a coronary artery bypass graft after a myocardial infarction at the age of 37. Additionally he has a history of bilateral thrombendarterectomy of the carotid arteries and suffers from bilateral peripheral artery diseas e. This patient also carries the apoE-genotype 4/3, which might be responsi ble for his poor response to statin therapy, and needs extracorporal lipid elimination (LDL-C > 200 mg/dl under drug therapy). Both of his daughters a re homozygous for the apoE-allele 3 and responded well to statin therapy. G enetic analysis in patients with FH assures diagnosis, but is not sufficien t to determine the individual patient's risk. A precise clinical examinatio n remains the gold standard for individual risk evaluation.