Familial Deficiency of Apolipoproteins A-I and C-III and Precocious Coronary-Artery Disease

We studied two sisters 29 and 31 years old who had skin and tendon xanthomas, corneal clouding, and severe coronary atherosclerosis. Histologic examination showed collections of lipid-laden histiocytes in the skin. The patients' plasma cholesterol concentrations were 177 and 135 mg per deciliter (4.58 and 3.49 mmol per liter). Levels of high-density-lipoprotein cholesterol were 4 and 7 mg per deciliter (0.1 and 0.2 mmol per liter). Only traces of apolipoprotein A-I were detected in whole plasma. The plasma density fraction from 1.06 to 1.21 g per milliliter contained no high-density lipoprotein on high-pressure liquid chromatography, no apolipoprotein A-I on sodium dodecyl sulfate electrophoresis, and only traces of apolipoprotein A-I on radioimmunoassay. Apolipoprotein C-III was also not detectable. The activity of lecithin-cholesterol acyltransferase was 40 per cent of normal. The half-life of infused normal high-density lipoprotein was three days (normal, 5.8 days). The parents and children of these two patients had low levels of high-density-lipoprotein cholesterol and apolipoprotein A-I. These cases support the hypothesis that low concentrations of high-density lipoprotein promote atherosclerosis. (N Engl J Med. 1982; 306:1513–9.) THE inverse relation between coronary-artery disease and the concentration of high-density-lipoprotein (HDL) cholesterol in blood suggests that this lipoprotein is an important factor in the pathogenesis of atherosclerosis. 1 2 3 Low levels of HDL cholesterol have been associated with an increased frequency of coronary heart disease, even at an HDL level no less than 50 per cent of normal. Yet in Tangier disease, an inherited disorder of cholesterol metabolism in which HDL cholesterol is about 8 per cent of normal, the frequency of atherosclerosis is not increased. 4 We have studied two sisters with a severe deficiency in HDL who had severe and . .