Familial hypercholesterolemia (FH, type IIa according to the Fredrickson classification) is one of the most common monogenic diseases with a frequency of 1:200 to 1:500. The classical form of FH follows an autosomal dominant inheritance pattern and is characterized by an increase in serum LDL-cholesterol (LDL-C) (in heterozygotes LDL-C ranges from 190-450 mg/dl and in homozygotes it is >400 mg/dl). Pathogenic variants in three genes that influence the function of the LDL receptor are described as the cause of autosomal dominant FH. The most common cause (74% of cases) is pathogenic variants in the LDLR gene, but genetic defects of the apolipoprotein B-100 (APOB gene, 2-7%) or the protease PCSK9 gene (<3%) can also be causative.
The LDL-C concentration in the blood is regulated by the interaction of LDL with the LDL receptor (Apo B/E- or LDLR). The proprotein convertase subtilisin/kexin type 9 (pcsk9) is involved in the degradation of the LDL receptor and thus also influences the LDL-C concentration. The FH phenotype includes skin and tendon xanthomas as well as arcus lipoides, which can occur in childhood in homozygous carriers of the autosomal dominant form. If left untreated, homozygous FH often leads to death before the age of 30 due to myocardial infarction; in heterozygous patients, symptomatic coronary artery disease is likely before the age of 50. The detection of variants in the causative genes may justify more intensive therapeutic measures (e.g., lipid apheresis) if drug treatment is not sufficient.
If a so-called gain-of-function variant in the PCSK9 gene is detected in a patient, treatment with alirocumab and evolocumab, which were approved in Europe in 2015, may be considered as a therapy. These are monoclonal antibodies that reduce the number of pcsk9 molecules; this leads to an increased availability of LDL receptors on the surface of hepatocytes and a significant reduction in LDL cholesterol in plasma.
In rare cases, familial hypercholesterolemia has an autosomal recessive inheritance pattern. Pathogenic variants in the LDLRAP1 gene (LDL adaptor protein) have been identified that are associated with the autosomal recessive form of FH. The treatment of homozygous carriers of LDLRAP1 variants corresponds to that of LDLR variants. Pathogenic APOB gene variants (FLDB) can also cause clinical symptoms of FH.
Lee et al. 2019, Lipids in Health and Disease 18:95 / Ramasamy 2016, Clin Chim Acta 454:143 / Schulze-Bahr et al. 2015, Dtsch Med Wochenschr 140:1538 / Hopkins et al. 2015, Circ Cardiovasc Genetic 8:823 / Gabcova-Balaziova et al. 2015, Endocr Regul 49:164 / Goldstein et al. in Scriver et al. 2001 (eds): The Metabolic and Molecular Bases of Inherited Disease, 8th Ed, Chapter 120