Center for Human Genetics and Laboratory Diagnostics, Dr. Klein, Dr. Rost and Colleagues

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Hypercholesterolemia, familial (FH) [E78.0]

OMIM numbers: 143890, 107730 (APOB), 606945 (LDLR), 603813, 605747 (LDLRAP1)

Dr. med. Hanns-Georg Klein

Scientific Background

With a frequency of 1 in 5,000, familial hypercholesterolemia (FH) is one of the most common monogenic diseases. The classic form of FH follows an autosomal dominant pattern of inheritance and is characterized by an increase mainly of the LDL cholesterol (LDL-C) in the serum (LDL-C in heterozygous carriers 250-400 mg/dl, in homozygous carriers >600 mg/dl). In addition, mutations that have been associated with an autosomal recessive form of FH (ARH, autosomal recessive hypercholesterolemia) were identified in an LDL adaptor protein (LDLRAP1). It is estimated that approx. 15% of all clinically diagnosed FH cases are due to mutations in the LDLRAP1 gene.

The LDL-C concentration in the blood is regulated by interaction of LDL and the LDL receptor (Apo B/E or LDLR). The phenotype of FH displays skin and tendon xanthomas as well as arcus lipoides which in homozygous carries of the autosomal dominant form may already manifest during childhood. If not treated, homozygous FH leads to death prior to 30 years of age due to myocardial infarction; in heterozygous patients, symptomatic coronary vascular disease occurring prior to age 50 is likely. More than 400 mutations in the LDLR gene are thought to cause the autosomal dominant form FH. An LDLR mutation detection can justify intensive therapeutic measures (e.g. lipid apheresis) if drug treatment does not suffice. The treatment of homozygous carriers of LDLRAP1 mutations is the same as in cases of LDLR mutations. Mutations in APOB (FLDB, familial ligand-defective Apo B) may also cause the clinical picture of FH.