Hypercholesteremia with predisposition to atherosclerosis: An inborn error of lipid metabolism

In the field of disturbances of lipid metabolism certain inborn errors have long been known. The genetic mechanisms involved in these disorders are summarized, with special emphasis on primary cholesterol lipidosis (xanthomatosis). Genetic analysis supports the concept that this disturbance of cholesterol metabolism is inherited as an (incomplete) dominant trait. The abnormalities most frequently encountered in members of xanthomatous families are hypercholesteremia and coronary atherosclerosis; xanthoma, from which the name of the disorder was derived, is found least often, while xanthelasma and corneal arcus are more frequently noted. The term “cholesterol lipidosis” appears therefore to be more appropriate than “xanthomatosis” to describe this disorder. Studies of patients with coronary atherosclerosis below the age of fifty, and their families, reveal that their disease exhibits a pattern similar to that encountered in xanthomatous families. The majority of these patients show abnormally high serum cholesterol levels. Approximately onethird to one-half of their siblings exhibit hypercholesteremia and many have, in addition, corneal arcus and xanthelasma, and a few develop xanthoma. Genetic analysis reveals that the number of persons in these sibships presenting hypercholesteremia fits a 1:1 Mendelian ratio and that hereditary transmission occurs probably as a dominant trait. The common denominator for most patients with early coronary atherosclerosis may be a hereditary disturbance of lipid (or lipoprotein) metabolism manifested by elevated serum cholesterol levels. Familial xanthomatosis is the most severe form of this inborn metabolic fault and coronary atherosclerosis is very frequent in such persons. They carry, we assume, two genes responsible for disturbed lipid metabolism, i.e., they are homozygotes. Uncomplicated coronary artery disease apparently represents a milder form of this same general disturbance. These persons probably carry one gene responsible for faulty lipid metabolism, i.e., they are heterozygotes. A study of the families of 500 consecutive unselected admissions, 250 males and 250 females, to a medical ward of a large general hospital reveals an incidence of hereditary hypercholesteremia of 4 to 5 per cent. This incidence was higher than suspected. Hereditary hypercholesteremia was not encountered in the non-white segment of the hospital population although 10 per cent of the studied families belonged in this category. There is a