Hyperlipidemia describes the phenotype of elevated blood lipids, predisposing a patient to atherosclerotic vascular disease. The overall heritability of blood lipids is often due to the interaction of a variety of alleles.
Classic Mendelian monogenic lipoprotein disorders, while rare, have provided profound insight into lipoprotein metabolism and atherosclerotic vascular disease.
Originally characterized by Fredrickson and Levy by the type of lipoprotein that accumulated in the circulation, the modern approach to classic Mendelian monogenic disorders emphasizes the molecular basis of the disease and the defect in cholesterol metabolism.
Within the population, blood lipid variation is typically the consequence of variation at multiple loci, in addition to significant effect from the environment.
The vast majority of cases of hyperlipidemia are discovered on routine screening and are infrequently due to a monogenic lipoprotein disorder. However, the presence of markedly elevated lipids or lipoproteins, xanthomas, accelerated atherosclerosis, or other clinical manifestations of hyperlipoproteinemia are suggestive of a monogenic disorder. It is important to screen for secondary causes such as nephrotic syndrome, obstructive liver disease, and hypothyroidism before making a diagnosis of a monogenic disorder and before initiating therapy.
Genetic Differential Diagnosis
Diagnostic Criteria and Clinical Characteristics of Disorders of Elevated LDL-C and Normal TGs
Often accompanied by one or more of the following:
Table 13-1Mendelian Disorders Causing Elevated LDL-C Levels and Normal TGs |Favorite Table|Download (.pdf) Table 13-1 Mendelian Disorders Causing Elevated LDL-C Levels and Normal TGs
|Syndrome ||Gene Symbol ||Pathogenesis |
|Familial hypercholesterolemia ||LDLR ||Loss of function mutation in the LDL receptor (LDLR), reducing clearance of LDL |
|Familial defective apolipoprotein B-100 ||APOB ||Mutation in the region of ApoB-100 that binds the LDLR, hindering clearance of LDL |
|Autosomal dominant hypercholesterolemia ||PCSK9 ||Gain of function mutation in proprotein convertase subtilisin/kexin type 9, which causes degradation of the LDLR, thus reducing LDL clearance |