Autosomal dominant hypercholesterolemia with pcsk9 mutation E78.0

Haddad et al. 1999

Rare; only a few families have been described worldwide.

PCSK9 (Proproteinconvertase subtilisin-like kexin type 9) is a serine protease that mediates the proteasomal degradation of LDL receptors. PCSK9 binds to the LDL-receptor (LDL-R) and is taken up by liver cells in increased amounts. Binding to PCSK9 promotes endocytosis and the degradation of the LDL receptor in endosomes. Thus, fewer LDL-receptors are available for recirculation to the cell surface. As a result, the binding of LDL cholesterol decreases.

Mutations in the PCSK9 gene lead to a pathologically increased PCSK9 activity and to an increased degradation of LDL receptors (LDL=low density lipoproteins) and thus to an increase of LDL in plasma.

The humanized antibody Evolocumab specifically binds serum PCSK9, thereby preventing the formation of LDL-receptor-PCSK9 complexes and the intracellular degradation of the LDL receptor. Thus, increased LDL cholesterol can be absorbed by the LDL receptors and then degraded intracellularly.

The clinical course corresponds to the autosomal dominant familial hypercholesterolemia with LDL-receptor defects (see there).

PCSK9 inhibitors such as evolocumab