Individuals with genetic disorders of lipoproteins offer a unique means by which lipoprotein metabolism can be investigated. Specific defects in apolipoproteins, enzymes and lipoprotein receptors afford a way to quantitate pathways of lipid metabolism. Low density lipoproteins (LDL) are strongly correlated with the onset of premature cardiovascular disease. Patients with absent or markedly decreased LDL receptors have a genetic disorder called familial hypercholesterolemia (FH). Patients with partial defects (heterozygous FH) are common cause of cardiovascular disease occurring in 1 out of 500 Americans. Patients with FH have tendinous xanthomas and develop premature cardiovascular disease. Patients with FH have a strong family history of cardiovascular disease. FH is characterized by the decreased or absent LDL receptors on hepatocytes. LDL is unable to be removed from the plasma in FH and plasma LDL cholesterol becomes markedly elevated. We have identified a patient with markedly elevated LDL cholesterol, xanthomas and premature cardiovascular disease typical of familial hypercholesterolemia (FH). Despite clinical similarities to FH the patient has no family history of cardiovascular disease and normal in vitro LDL receptor activity. In vivo metabolic studies of LDL showed a marked delay in the catabolism of the proband compared to controls. The FCR was identical to that of patients with familial hypercholesterolemia and the production rate was not increased. Further studies showed that the proband~s LDL composition was normal but markedly elevated. This suggests that the patient has an intracellular defect in cholesterol metabolism that is currently being investigated.
