Familial hypercholesterolaemia
Authors: Thompson Gilbert R. 
Published: July 2011

Familial hypercholesterolaemia (OMIM 143890) is characterized by hypercholesterolaemia from birth, with the subsequent development of cutaneous and tendon xanthomas and premature onset of atherosclerosis, as first described by Müller over 70 years ago (1). Myant (2) noted that the monogenically determined increase in plasma cholesterol was largely confined to low-density lipoprotein (LDL) cholesterol and Goldstein and Brown (3) showed that the increase in LDL was due to mutations of the gene encoding the formation of LDL receptors, leading to defective catabolism of LDL.

Over 1000 variations in the LDL receptor gene have now been described, most of which can cause familial hypercholesterolaemia (4). Usually only one mutant gene is inherited, which gives rise to the heterozygous form of the disease. Rarely, inheritance of two identical mutant alleles occurs, giving rise to homozygous familial hypercholesterolaemia. Inheritance of two mutations results in compound heterozygosity, which is clinically indistinguishable from genetically homozygous familial hypercholesterolaemia.

The frequency of familial hypercholesterolaemia in the populations of Europe and North America averages 0.2%, but in some parts of the world it is much higher. Regions with an increased prevalence of familial hypercholesterolaemia include Lebanon, South Africa, and the Canadian province of Quebec. In each instance this is attributable to an unusually high frequency of one or two mutations within the population, such as the Lebanese allele, the Afrikaner 1 and 2 mutations, and the French Canadian allele. In South Africa and Canada the increased prevalence of familial hypercholesterolaemia represents a founder gene effect traceable to immigrant settlers from Europe, whereas in Muslim communities it reflects the frequency of first-cousin marriages. In notable contrast is the multiplicity of mutations found among familial hypercholesterolaemia patients in the UK, as shown in Fig. 12.2.2.1.

An identical clinical syndrome to familial hypercholesterolaemia can occur as a result of inheritance of a mutation at the apoB locus, which results in a functionally defective form of LDL (5). This disorder, familial defective apoB-100 or FDB (OMIM 144010), has a frequency of 0.1% in people of European descent but has never been described in Japan. Rarely, familial hypercholesterolaemia is caused by dominantly inherited gain of function mutations of a gene encoding proprotein convertase subtilisin/kexin type 9 (PCSK9) (OMIM 603776), which results in increased degradation of LDL receptors and an unusually severe clinical phenotype (6). It can also be caused by recessively inherited loss of function mutations of a gene encoding a protein involved in the clathrin-mediated internalization of the LDL receptor (6), which results in a milder phenotype than dominantly inherited forms of the condition and is known as autosomal recessive hypercholesterolaemia (OMIM 603813).

A recent survey detected mutations of the LDL receptor, apoB, and PCSK9 genes in only 62% of patients with clinically definite familial hypercholesterolaemia (7), raising the likelihood that mutations of genes encoding other proteins involved in LDL metabolism remain to be discovered.