HYPERCHOLESTEROLEMIC XANTHOMATOSIS, FAMILIAL
HYPER-LOW-DENSITY-LIPOPROTEINEMIA
HYPERLIPOPROTEINEMIA, TYPE IIA
HYPERLIPOPROTEINEMIA, TYPE II
LDLCQ2, INCLUDED
LDL RECEPTOR DISORDER LOW DENSITY LIPOPROTEIN CHOLESTEROL LEVEL QUANTITATIVE TRAIT LOCUS 2, INCLUDED
FHC
FH
Familial hypercholesterolemia is an autosomal dominant disorder characterized by elevation of serum cholesterol bound to low density lipoprotein (LDL).
Heterozygotes develop tendinous xanthomas, corneal arcus, and coronary artery disease; the last usually becomes evident in the fourth or fifth decade (Hobbs et al., 1992). Homozygotes develop these features at an accelerated rate in addition to planar xanthomas, ... Heterozygotes develop tendinous xanthomas, corneal arcus, and coronary artery disease; the last usually becomes evident in the fourth or fifth decade (Hobbs et al., 1992). Homozygotes develop these features at an accelerated rate in addition to planar xanthomas, which may be evident at birth in the web between the first 2 digits. The ranges of serum cholesterol and LDL-cholesterol are, in mg per dl, 250-450 and 200-400 in heterozygotes, greater than 500 and greater than 450 in homozygous affecteds, and 150-250 and 75-175 in homozygous unaffecteds, with some positive correlation with age (Khachadurian, 1964; Kwiterovich et al., 1974). In homozygous familial hypercholesterolemia, the aortic root is prone to develop atherosclerotic plaque at an early age. Such plaques can accumulate in unusual sites, such as the ascending aorta and around the coronary ostia. Summers et al. (1998) evaluated the aortic root using MRI imaging in a blinded, prospective study of 17 homozygous FH patients and 12 healthy controls. When patient age and body mass index were taken into account, 53% of patients with homozygous FH had increased aortic wall thickness compared to controls; this was thought to result from a combination of medial hyperplasia and plaque formation. Supravalvular aortic stenosis was seen in 41% of patients. Houlston et al. (1988) studied the relationship of lipoprotein(a) (152200) levels and coronary heart disease in patients with familial hypercholesterolemia. Individuals with coronary artery disease had a significantly higher mean lipoprotein(a) concentration than those without coronary heart disease, suggesting that lipoprotein(a) measurements may help predict the risk of coronary heart disease in individuals with familial hypercholesterolemia. Deramo et al. (2003) investigated the relationship between nonarteritic ischemic optic neuropathy (NAION; 258660) and serum lipid levels in 37 consecutive patients diagnosed with NAION at or below age 50 years and 74 age- and gender-matched controls. They found that hypercholesterolemia was a risk factor in these patients and suggested that NAION might be the first manifestation of a previously unrecognized lipid disorder. The patients had experienced a focal, microvascular central nervous system ischemic event at a relatively young age. Deramo et al. (2003) suggested that aggressive treatment of lipid abnormalities might be warranted in these patients.
Goldstein et al. (1977) found that both receptor-absent and receptor-defective mutants occur and they concluded that some of the 'homozygotes' are in fact genetic compounds. An internalization mutant of the LDL receptor binds LDL but is unable to ... Goldstein et al. (1977) found that both receptor-absent and receptor-defective mutants occur and they concluded that some of the 'homozygotes' are in fact genetic compounds. An internalization mutant of the LDL receptor binds LDL but is unable to facilitate passage of LDL to the inside of the cell. A patient was found to be a genetic compound, having inherited the internalization mutant from the father and the binding mutant from the mother. From the fact that an individual was shown by family studies to be a genetic compound and that complementation did not occur, Goldstein et al. (1977) concluded that the gene for binding of LDL and the gene for internalization of LDL are allelic mutations at the structural locus for the LDL receptor. Miyake et al. (1981) found homozygosity for the internalization defect. The LDL receptor is synthesized as a 120-kD glycoprotein precursor that undergoes change to a 160-kD mature glycoprotein through the covalent addition of a 40-kD protein. Tolleshaug et al. (1982) reported a heterozygous child who inherited one allele from his mother which produced an abnormal 120-kD protein that could not be further processed, and one allele from his father which produced an elongated 170-kD precursor that underwent an increase in molecular weight to form an abnormally large receptor of 210 kD. Levy et al. (1986) reported 2 brothers with a unique genetic compound form of 'homozygous' hypercholesterolemia in which the mother had typical FHC and the father and 3 of his close relatives had what they termed the HMWR (high molecular weight receptor) trait. In these persons 2 types of functional LDL receptors were found in cultured skin fibroblasts: one with molecular weight of 140,000 and one with molecular weight of 176,000. Curiously and puzzlingly, the compound heterozygotes and the regular heterozygotes for the HMWR showed increased cholesterol synthesis, which the authors suggested may play a significant role in the pathology of the disease. Funahashi et al. (1988) studied 16 Japanese kindreds with homozygous FHC. Ten had a receptor-negative form of the disease; 5 had a receptor-defective form; and 1 represented an internalization defect. The receptor-defective group, in which residual amounts of functional receptors were produced, showed a lower tendency to coronary artery disease than the receptor-negative group. - Modifiers Feussner et al. (1996) described a 20-year-old man with a combination of heterozygous FH caused by splice mutation (606945.0054) and type III hyperlipoproteinemia (107741). He presented with multiple xanthomas of the elbows, interphalangeal joints and interdigital webs of the hands. Active lipid-lowering therapy caused regression of the xanthomas and significant decrease of cholesterol and triglycerides. Flat xanthomas of the interdigital webs were described in 3 of 4 formerly reported patients with a combination of these disorders of lipoprotein metabolism. Feussner et al. (1996) proposed that the presence of these xanthomas should suggest compound heterozygosity (actually double heterozygosity) for FH and type III hyperlipoproteinemia. Sass et al. (1995) described a 4-generation French-Canadian kindred with familial hypercholesterolemia in which 2 of the 8 heterozygotes for a 5-kb deletion (exons 2 and 3) in the LDLR gene were found to have normal LDL-cholesterol levels. Analyses showed that it was unlikely that variation in the genes encoding apolipoprotein B (107730), HMG-CoA reductase (HMGCR; 142910), apoAI-CIII-AIV (see APOA1; 107680), or lipoprotein lipase was responsible for the cholesterol-lowering effect. Expression of the LDL receptor, as assessed in vitro with measurements of activity and mRNA levels, was similar in normolipidemic and hyperlipidemic subjects carrying the deletion. Analysis of the apoE isoforms (107741), on the other hand, revealed that most of the E2 allele carriers in this family, including the 2 normolipidemic 5-kb deletion carriers, had LDL cholesterol levels substantially lower than subjects with the other apoE isoforms. Thus, this kindred provided evidence for the existence of a gene or genes, including the apoE2 allele, with profound effects on LDL-cholesterol levels. Vergopoulos et al. (1997) presented findings suggesting the existence of a xanthomatosis susceptibility gene in a consanguineous Syrian kindred containing 6 individuals with homozygous FH (see 602247). Half of the homozygotes had giant xanthomas, while half did not, even though their LDL-cholesterol concentrations were elevated to similar degrees (more than 14 mmol/l). Heterozygous FH individuals in this family were also clearly distinguishable with respect to xanthoma size. By DNA analysis they identified a hitherto undescribed mutation in the LDLR gene in this family: a T-to-C transition at nucleotide 1999 in codon 646 of exon 14, resulting in an arginine for cysteine substitution. Segregation analysis suggested that a separate susceptibility gene may explain the formation of giant xanthomas. In a 13-year-old girl with severe hypercholesterolemia, Ekstrom et al. (1999) demonstrated compound heterozygosity for a cys240-to-phe mutation (606945.0059) and a tyr167-to-ter mutation (606945.0045) in the LDLR gene. Her 2 heterozygous sibs also carried the C240F mutation, but only one of them was hypercholesterolemic. The authors concluded that there may be cholesterol-lowering mechanisms that are activated by mutations in other genes. Knoblauch et al. (2000) studied an Arab family that carried the tyr807-to-cys substitution (606945.0019). In this family, some heterozygous persons had normal LDL levels, while some homozygous individuals had LDL levels similar to those persons with heterozygous FH. The authors presented evidence for the existence of a cholesterol-lowering gene on 13q (604595). Takada et al. (2002) demonstrated that a SNP of the promoter of the APOA2 gene, -265T-C (107670.0002), influenced the level of total cholesterol and low density lipoprotein (LDL) cholesterol in members with the IVS14+1G-A mutation (606945.0063) in the LDLR gene causing hypercholesterolemia. Strikingly lower total cholesterol and LDL cholesterol values were observed among most of the LDLR mutation carriers who were simultaneously homozygous for the -265C allele of the APOA2 gene. In the same large family reported by Takada et al. (2002), Takada et al. (2003) found that a SNP in the GHR gene, resulting in a L526I (600946.0028) substitution, influenced plasma levels of high density lipoprotein (HDL) cholesterol in affected family members with the IVS14+1G-A mutation. The lowest levels of plasma HDL were observed among leu/leu homozygotes, highest levels among ile/ile homozygotes, and intermediate levels among leu/ile heterozygotes. No such effect was observed among noncarriers of the LDLR mutation. In the pedigree reported by Takada et al. (2002), Sato et al. (2004) demonstrated a significant modification of the phenotype of familial hypercholesterolemia resulting from the IVS14+1G-A mutation by the arg287 variation in the EPHX2 gene (132811.0001).
Horsthemke et al. (1987) analyzed DNA from 70 patients in the UK with heterozygous familial hypercholesterolemia. In most, the restriction fragment pattern of the LDLR gene was indistinguishable from the normal; however, 3 patients were found to have ... Horsthemke et al. (1987) analyzed DNA from 70 patients in the UK with heterozygous familial hypercholesterolemia. In most, the restriction fragment pattern of the LDLR gene was indistinguishable from the normal; however, 3 patients were found to have a deletion of about 1 kb in the central portion of the gene. In 2 patients, the deletion included all or part of exon 5 (606945.0027); in the third, the deletion included exon 7 (606945.0033). Including a previously described patient with a deletion in the 3-prime part of the gene, these results indicated that 4 of 70 patients, or 6%, have deletions. Hobbs et al. (1990) reviewed the many mutations found in the LDLR gene as the cause of familial hypercholesterolemia. Varret et al. (2008) reviewed 17 published studies of autosomal dominant hypercholesterolemia and evaluated the contribution of mutations in the LDLR, APOB, and PCSK9 genes. They noted that the proportion of subjects without an identified mutation ranged from 12% to 72%, suggesting the existence of further genetic heterogeneity. In a patient diagnosed with probable heterozygous FH, Bourbon et al. (2007) analyzed the LDLR gene and identified a novel variant initially assumed to be a silent polymorphism (R385R; 606945.0065); however, analysis of mRNA from the patient's cells showed that the mutation introduces a new splice site predicted to cause premature truncation of the protein. The R385R mutation was also found in a Chinese homozygous FH patient. Defesche et al. (2008) analyzed the LDLR gene in 1,350 patients clinically diagnosed with familial hypercholesterolemia who were negative for functional DNA variation in the LDLR, APOB (107730), and PCSK9 (607786) genes. The authors examined the effects of 128 seemingly neutral exonic and intronic DNA variants and identified 2 synonymous variants in LDLR, R385R and G186G (606945.0066), that clearly affected splice sites and segregated with hypercholesterolemia in all families examined. The R385R variant was found in 2 probands of Chinese origin, whereas G186G was found in 35 Dutch probands, 2 of whom were homozygous for the variant and had a more severe phenotype, with myocardial infarction occurring in both before the age of 20 years. Kulseth et al. (2010) performed RNA analysis in 30 unrelated patients with clinically defined hypercholesterolemia but without any LDLR mutations detected by standard DNA analysis; sequencing of RT-PCR products from an index patient revealed an insertion of 81 bp from the 5-prime end of intron 14 of LDLR, and DNA sequencing of exons 13 and 14 detected an splice site mutation in intron 14 (606945.0067). Twelve of 23 family members tested were heterozygous for the mutation, and carriers had significantly increased total cholesterol levels compared to noncarriers. Kulseth et al. (2010) analyzed an additional 550 index patients and identified the same splice site mutation in 3 more probands. In 1 proband's family, the mutation was found in 6 of 7 tested family members, who all had LDL cholesterol levels above the 97th percentile.
In most populations the frequency of the homozygote is 1 in a million (probably a minimal estimate, being a prevalence figure rather than incidence at birth) and the frequency of heterozygotes not less than 1 in 500. Thus, ... In most populations the frequency of the homozygote is 1 in a million (probably a minimal estimate, being a prevalence figure rather than incidence at birth) and the frequency of heterozygotes not less than 1 in 500. Thus, heterozygous familial hypercholesterolemia is the most frequent mendelian disorder, being more frequent than either cystic fibrosis or sickle cell anemia which, in different populations, are often given that distinction. Among survivors of myocardial infarction, the frequency of heterozygotes is about 1 in 20. Seftel et al. (1980) pointed to a high frequency of hypercholesterolemic homozygotes in South Africa. In a 7-year period, 34 homozygotes were seen in one clinic in Johannesburg. All were Afrikaners and most lived in Transvaal Province. The authors calculated the frequency of heterozygotes and homozygotes to be 1 in 100 and 1 in 30,000, respectively. The oldest of their patients was a 46-year-old woman. Of the 34, six were age 30 or older. The authors concluded that the high frequency of the gene is attributable to founder effect, as in the case of porphyria variegata (176200), lipoid proteinosis (247100), and sclerosteosis (269500). Torrington and Botha (1981) found that 20 of 26 families with FHC (77%) belonged to the Gereformeerde Kerk, whereas according to the 1970 census only 5% of the Afrikaans-speaking white population of South Africa belonged to this religious group. Again, the data were consistent with a founder effect. Using the LDLR activity of lymphocytes, Steyn et al. (1989) calculated the prevalence of heterozygous FHC in the permanent residents of a predominantly Afrikaans-speaking community in South Africa to be 1 in 71--the highest prevalence reported to date. In the Saguenay-Lac-Saint-Jean region of Quebec Province, De Braekeleer (1991) estimated the prevalence of familial hypercholesterolemia as 1/122, compared to the usually used frequency of 1/500 for European populations. Defesche and Kastelein (1998) stated that more than 350 different mutations had been found in patients with familial hypercholesterolemia. They tabulated the preferential geographic distribution that has been demonstrated for some of the LDL receptor mutations. For example, in the West of Scotland about half of the index cases of FH were found to have the cys163-to-tyr mutation (606945.0058). Defesche and Kastelein (1998) commented on the geographic associations of LDL receptor mutations within the Netherlands. Deletion of gly197 (606945.0005) is the most prevalent LDL receptor mutation causing familial hypercholesterolemia in Ashkenazi Jewish individuals. Studying index cases from Israel, South Africa, Russia, the Netherlands, and the United States, Durst et al. (2001) found that all traced their ancestry to Lithuania. A highly conserved haplotype was identified in chromosomes carrying this deletion, suggesting a common founder. When 2 methods were used for analysis of linkage disequilibrium between flanking polymorphic markers and the disease locus and for the study of the decay of LD over time, the estimated age of the deletion was found to be 20 +/- 7 generations, so that the most recent common ancestor of the mutation-bearing chromosomes would date to the 14th century. This corresponds with the founding of the Jewish community of Lithuania (1338 A.D.), as well as with the great demographic expansion of Ashkenazi Jewish individuals in eastern Europe, which followed this settlement. Durst et al. (2001) could find no evidence supporting a selective evolutionary metabolic advantage. Therefore, the founder effect in a rapidly expanding population from a limited number of families remains a simple, parsimonious hypothesis explaining the spread of this mutation in Ashkenazi Jewish individuals.