Familial defective apolipoprotein b 100 E78.0

Vega and Grundy 1986

Rare autosomal dominant inherited lipid metabolic disorder
based onfunctionally important mutations in the gene
of the LDL (low-density lipoprotein) receptor ligand (APOB, cytogenetic localization on chromosome 2p24.1). Clinically significant are the two mutations in the LDL receptor ligand gene ApoB R3500Q and ApoB R3531C.

The incidence of familial ApoB-100 deficiency is similar to familial hypercholesterolemia due to LDL receptor deficiency with 1:500 to 1:700 (in Europe and North America).

Apolipoprotein B (ApoB) is the only protein of LDL (low density lipoprotein) and serves as a ligand of the LDL receptor. LDL predominantly transports cholesterol in the bloodstream. The high-affinity interaction between LDL and its LDL receptor is crucially mediated by the ligand function of ApoB. ApoB is thus an important component for the regulation of LDL levels (Andersen LH et al. 2016).

In the lipid metabolic disorder known as "familial defective apolipoprotein B 100", mutations in the LDL receptor ligand gene lead to a conformational change in the ApoB protein and thus in the LDL. This leads clinically to a type IIa hyperlipoproteinaemia (see Fredrickson classification). The conformational change in the ApoB protein disrupts the interaction between the LDL ligand and its LDL receptor. This causes a significant reduction in the affinity between the ligand and its receptor. This leads to an impairment of the removal of the atherogenic LDL from the blood. The consequence is an increased concentration of LDL and a premature manifestation of coronary heart disease and the development of xanthomas.

Due to the dominant inheritance, the presence of one of the two mutations in the LDL receptor ligand gene causes a significantly increased serum cholesterol level (hypercholesterolemia type IIa according to Frederickson).

The increase in the Apo B-R3500Q mutation compared to the normal value is about 700-950 mg/l and in the Apo B-R3531C mutation about 450-650 mg/l. Clinically, there is a premature manifestation of coronary heart disease and the development of xanthomas (Ferrières J 2019).

Xanghelasmas are found in 10% of patients, anArcus lipoides corneae in up to 15%. In heterozygous coronary artery disease, up to 60%, depending on age.

Disturbances in LDL level regulation can be on the side of the ligand as well as on the side of the receptor. The phenotype of hereditary (familial) hypercholesterolemia can be triggered by mutations in the gene for the LDL receptor, of which more than 200 different mutations have now been identified and which are inherited codominantly (familial hypercholesterolemia). Patients with familial hypercholesterolemia show even greater increases in serum cholesterol levels. In heterozygous carriers, the serum cholesterol level increases by 2000-4500 mg/l compared to the normal range and by more than 4500 mg/l in homozygous patients.

Therapeutically, the administration of HMG-CoA reductase inhibitors (statins) is indicated. In extreme cases of hxpercholesterolemia, selective removal of LDL by lipid apheresis is also indicated.11

There are two main mutations of importance, which are summarized under the clinical name "Familial Defective Apolipoprotein B-100 (FDB)".

The phenotype of the "Familial Defective Apolipoprotein B-100" is clinically indistinguishable from the LDL receptor defect with its increased LDL concentration, despite different genotypes and pathomechanisms. From the age of 50 onwards, heterozygotes have developed coronary heart disease in 40% (men) and 20% (women).

1. Andersen LH et al (2016) Familial defective apolipoprotein B-100: A review. J Clin Lipidol 10:1297-1302.
2. Ferrières J (2019) Hypercholesterolaemia and coronary artery disease: A silent killer with several faces. Arch Cardiovasc Dis 112:75-78.
3. Hansen PS (1998): Familial defective apolipoprotein B-100. Dan Med Bull 45, 370-382