Abstract
Atherosclerosis and xanthomatosis are frequently associated with familial hyperbetalipoproteinemia. In this report, we present three kindreds (SS, YS and N) with familial hypercholesterolemia and xanthomatosis. Two probands (S. S. and Y. S.) were born to consanguineous marriages. S. S., 17-yr-old female, and Y. S., 2-yr-old female, had an extremely high serum cholesterol level, 1003 and 903mg/dl respectively, being affected with severe cutaneous xanthomatosis. All of the probands' parents and many other relatives had moderate hypercholesterolemia (more than 300mg/dl). But, the inheritance of xanthomatosis and atherosclerosis was not so severe among members of the SS and YS families. Only one of them (father of proband Y. S.) had xanthomatosis and another one (an uncle of proband S. S.) had coronary insufficiency.
The synthesis of cholesterol and the HMG CoA reductase activity were estimated on cultured skin fibroblasts from the probands S. S. and Y. S. Both of the incorporation of 14C-acetate into cholesterol and the activity of HMG CoA reductase were elevated by approximately 10-fold. In contrast to normal fibroblasts which received a feedback control by LDL, the HMG CoA reductase activity of the fibroblasts from the probands did not show any change even after the fibroblasts were cultured in lipoprotein-free medium. According to the results of Goldstein and Brown, these probands were identified with homozygotes with familial hypercholesterolemia. The HMG CoA reductase activity of fibroblasts from Y. S.' father and the regulation of this enzyme activity by lipoproteins were just intermediate between homozygous and normal subjects, showing that he was heterozygotic with familial hypercholesterolemia.
In both of families, hypercholesterolemia was transmitted as dominant inheritance, with many family members being affected with this disorder as heterozygote. Consanguineous marriage of heterozygotics gave rize to a homozygote with severe cutaneous xanthomatosis.
On the other hand, the N family was characterized by dominant inheritance of tendon xanthomas and also had a tendency of atherosclerosis. Though hypercholesterolemic subjects in this family were not homozygous but heterozygous, all of them had tendon xanthomas. Furthermore, some of the other members, even if normolipidemic, had distinct tendon xanthomas. It was assumed that, in the members of the N family, the formation of xanthomas was dependent on the presence of macrophages with a strong activity of incorporating cholesterol, while in S. S. and Y. S. the deposition of cholesterol depended on the excessively high cholesterol level.
