Genetic Disorders of Lipoprotein Metabolism

Disorders of lipoprotein metabolism lead to atherosclerotic cardiovascular disease (ASCVD) and its clinical manifestations as well as other disorders such as pancreatitis. Blood lipid concentrations, including low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides (TG), have been shown to be highly heritable. It is estimated that at least half of the variation in serum lipids between individuals can be explained by genetic variation. While some genetic lipid disorders are associated with increased risk of ASCVD, others result in reduced ASCVD risk. This chapter summarizes the prevalence, genetics, pathophysiology, clinical presentation, diagnosis, and treatments for diseases that primarily affect LDL (familial hypercholesterolemia, autosomal recessive hypercholesterolemia, and hereditary sitosterolemia), diseases that lead to elevated TG (familial combined hyperlipidemia, familial hypertriglyceridemia, familial dysbetalipoproteinemia, and familial chylomicronemia syndrome), diseases that lead to low HDL (familial hypoalphalipoproteinemia, complete and partial familial lecithin:cholesterol acyltransferase deficiency, and ApoA1 Milano), and diseases causing low LDL (abetalipoproteinemia, familial hypobetalipoproteinemia, loss-of-function proprotein convertase subtilisin kexin type 9 mutations, and chylomicron retention disease). The genetics, structure, and function of lipoprotein (a), and its association with ASCVD are also covered. The reader should keep in mind that in patients with underlying genetic lipid disorders, the phenotype can appear atypical if other superimposed disorders are present such as diabetes, metabolic syndrome, or use of medications that can affect lipids. Consideration of these factors can help with diagnosis when the presentation of a genetic dyslipidemia appears to be atypical.