Clinical Information

Autosomal dominant hypercholesterolemia (ADH) is characterized by high levels of LDL cholesterol and associated with premature cardiovascular disease and myocardial infarction. The majority of ADH is caused by genetic variants that lead to decreased intracellular uptake of cholesterol. Approximately 1 in 500 individuals worldwide are affected by ADH and 15% of individuals with ADH have familial defective apolipoprotein B-100 (FDB) due to variants in the LDL receptor-binding domain of the APOB gene, which maps to chromosome 2p and encodes for apolipoprotein B-100. FDB can occur in either the heterozygous or homozygous state, with the latter expressing more severe disease. Approximately 40% of males and 20% of females with an APOB mutation will develop coronary artery disease.

The vast majority of FDB cases are caused by a single APBO variant at residue 3500, resulting in a glutamine substitution for the arginine residue (R3500Q). This common FDB variant occurs at an estimated frequency of 1:500 individuals of European descent. Another, less frequently occurring variant at that same codon results in a tryptophan substitution, R3500W, and is more prevalent in individuals of Chinese and Malay descent, but has been identified in the Scottish population as well. The R3500W variant is estimated to occur in approximately 2% of ADH cases. Residue 3500 interacts with other apolipoprotein B-100 residues to induce conformational changes necessary for apolipoprotein B-100 binding to the LDL receptor. Thus, variants at residue 3500 lead to a reduced binding affinity of LDL for its receptor.

There is a high degree of phenotypic overlap between FDB and familial hypercholesterolemia (FH), the latter due to variants in LDLR, which encodes for the LDL receptor (LDLR). In general, individuals with FDB have less severe hypercholesterolemia, fewer occurrences of tendinous xanthomas, and a lower incidence of coronary artery disease, compared with FH. Plasma LDL cholesterol levels in patients with homozygous FDB are similar to levels found in patients with heterozygous (rather than homozygous) FH.

Identification of APOB variants in individuals suspected of having ADH helps to obtain a definitive diagnosis of the disease as well as determine appropriate treatment. Therapy for FDB is aimed at lowering the plasma levels of LDL, and both heterozygotes and homozygotes generally respond well to statins. Screening of at-risk family members allows for effective primary prevention by instituting statin therapy and dietary modifications at an early stage.