Familial hypercholesterolaemia: history, diagnosis, screening, management and challenges

Abstract

### Learning objectives Clinical familial hypercholesterolaemia (FH) was systematically described for the first time in 1937. In 17 families and in four generations, xanthomatosis, hypercholesterolaemia and cardiovascular disease (CVD) followed a pattern of an inborn error of metabolism and monogenetic autosomal dominant inheritance.1–3 However, single-patient cases of xanthomatosis and CVD had been reported as early as in 1873 by Fagge, by Lebzen and Knauss in 1889, by Torok in 1893 and by Raeder in 1936.4 ### Genetics In 1964, the clinical heterozygous and homozygous forms of the disease were described3 and in 1973 Brown and Goldstein showed that FH was caused by defects in the gene coding for the low-density lipoprotein (LDL) receptor (LDLr) resulting in decreased removal of LDL-cholesterol (LDL-C) from the circulation.4 Brown and Goldstein were in 1985 awarded the Nobel Prize for their work. Several genes are known to cause FH, although mutations in the LDLr gene coding for defective LDLr are by far (>90%) the most common. More than 1700 mutations in the LDLr gene have now been described, and of those more than 12005 are believed to be expressed as a severe hypercholesterolaemic phenotype.6 7 Mutation in the apolipoprotein B (apoB) gene may inhibit the receptor-mediated uptake of atherogenic apoB containing particles and thereby cause FH. Gain of function mutations in proprotein convertase subtilisin/kexin type 9 ( PCSK9 ) cause FH by degrading the LDLr, while LDL adaptor protein 1 (LDLRAP1) may cause FH by inhibiting the LDLr function.8 All, except the recessive LDLRAP1 mutation, cause FH in an autosomal dominant pattern.7 9 In this …

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