Severe hypercholesterolaemia: unusual inheritance in an Italian pedigree

A family presenting several cases of severe primary hypercholesterolaemia and/or premature sudden death was studied. This family is characterized by consanguinity, absence of vertical transmission, bimodal distribution of plasma cholesterol values, and reduction of reproductive fitness in affected individuals. The probands have clinical traits of homozygous familial hypercholesterolaemia, including hypercholesterolaemia, xanthomas and early coronary atherosclerosis, while the parents and grandparents are clinically normal. Eight relatives on the mother's side experienced premature sudden death, and in four cases hypercholesterolaemia was diagnosed. Haplotype segregation analysis of the inheritance of the LDL receptor and apo B genes in the probands' family excluded the involvement of these two genes in the pathogenesis of the disease. LDL receptor activity, as well as the ability of LDL to bind to the LDL receptor, and plasma vegetal sterols were within normal limits both in probands and in their relatives. The study of this pedigree suggests that hypercholesterolaemia is not produced by defects in the LDL receptor or LDL particles, and disease inheritance is consistent with an autosomal recessive trait.