Alternative titles; symbols
SNOMEDCT: 238040008, 238081000; ICD10CM: E78.2; ORPHA: 391665;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 2p24.1 | Hypercholesterolemia, familial, 2 | 144010 | Autosomal dominant | 3 | APOB | 107730 |
A number sign (#) is used with this entry because of evidence that autosomal dominant familial hypercholesterolemia-2 (FHCL2) is caused by heterozygous mutation in the APOB gene (107730) on chromosome 2p24.
Higgins et al. (1975) described father and daughter with hypercholesterolemia which appeared to be due to an abnormality in LDL such that it did not interact properly with the receptor. The proband's leukocytes showed normal suppression of HMG CoA reductase activity when exposed to lipoprotein from sources other than the 2 patients.
Vega and Grundy (1986) showed that some patients with hypercholesterolemia have reduced clearance of LDL not because of decreased activity of LDL receptors but because of a defect in the structure (or composition) of LDL that reduces its affinity for receptors. In 5 of 15 patients, turnover rates indicated that clearance of autologous LDL was significantly lower than for homologous normal LDL. In these 5 patients, autologous LDL appeared to be a poor ligand for LDL receptors. The authors did not carry the investigations far enough to determine whether abnormality in the primary structure of apoB100 accounted for the poor binding to receptors.
Innerarity et al. (1987) found that moderate hypercholesterolemia could be attributed to defective receptor binding of a genetically altered apoB100 to the LDL receptor; they designated the disorder 'familial defective apolipoprotein B100.' The proband of the family studied by Innerarity et al. (1987) was described earlier by Vega and Grundy (1986). A finding of the same abnormality in several of the proband's first-degree relatives indicated the inherited nature of the defect.
Weisgraber et al. (1988) found an antibody with an isotope between residues 3350 and 3506 of apoB that distinguished abnormal LDL from normal LDL in this disorder; the antibody MB47 bound with a higher affinity to abnormal LDL. Thus, an assay was provided for screening large populations for this disorder.
Goldstein (1987) stated that an abnormality in LDL was not confirmed in his or in a second laboratory. The putatively abnormal LDL tested normal in all of their culture systems and also tested normal when injected into animals. Myant et al. (1976) found that the putatively abnormal LDL behaved in a normal fashion in various in vivo and in vitro assays. Goldstein (1987) stated further that although no documented cases of hypercholesterolemia due to mutations in the apoB gene were known, he 'would not be surprised if such cases were discovered any time--now that cDNA probes for the apoB of LDL are widely available.' The prophecy was fulfilled by the demonstration of familial hypercholesterolemia due to defective apoB-100.
Illingworth et al. (1992) found that LDL cholesterol was reduced after administration of lovastatin in 12 hypercholesterolemic patients from 10 unrelated families with familial defective apoB100.
Hansen et al. (1997) attempted to identify determinants of phenotypic variation in patients heterozygous for familial defective apolipoprotein B in 205 patients: 73 from Germany, 87 from the Netherlands, and 45 from Denmark. In addition, they attempted to assess whether the clinical phenotype of familial defective apoB differs from that of familial hypercholesterolemia. Besides age, sex, and geographic origin, variation in the LDLR gene was found to be the most powerful determinant of variation in total cholesterol and LDL cholesterol levels. Polymorphic variation in the LDLR gene was associated with total cholesterol and LDL variation in women. The expected association of APOE genotypes with cholesterol concentrations was also seen. With regard to clinical expression, familial defective APOB patients had lower total cholesterol and LDL cholesterol levels and a lower prevalence of cardiovascular disease than did 101 Danish patients with familial hypercholesterolemia.
Statins
Luirink et al. (2019) reported a 20-year follow-up study of statin therapy in children with familial hypercholesterolemia. A total of 214 patients with familial hypercholesterolemia, genetically confirmed in 98% as due to mutations in either LDLR (see FHCL1, 143890) or APOB, who were previously participants in a placebo-controlled trial evaluating the 2-year efficacy and safety of pravastatin, were invited for follow-up, together with their 95 unaffected sibs. The incidence of cardiovascular disease among the patients with familial hypercholesterolemia was compared with that among their 156 affected parents. The mean LDL cholesterol level in the patients had decreased from 237.3 to 160.7 mg per deciliter, a decrease of 32% from the baseline level; treatment goal of LDL cholesterol less than 100 mg per deciliter was achieved in 37 patients (20%). Mean progression of carotid intima-media thickness over the entire follow-up period was 0.0056 mm per year in patients with familial hypercholesterolemia and 0.0057 mm per year in sibs (mean difference adjusted for sex, -0.0001 mm per year). The cumulative incidence of cardiovascular events and of death from cardiovascular causes at 39 years of age was lower among the patients with familial hypercholesterolemia than among their affected parents (1% vs 26% and 0% vs 7%, respectively). Luirink et al. (2019) concluded that initiation of statin therapy during childhood in patients with familial hypercholesterolemia slowed the progression of carotid intima-media thickness and reduced the risk of cardiovascular disease in adulthood.
Inclisiran
Ray et al. (2020) reported the results of 2 phase 3 trials of inclisiran, a small interfering RNA that reduces hepatic synthesis of PCSK9 (607786). Ray et al. (2020) enrolled patients with atherosclerotic cardiovascular disease (ORION-10 trial) and patients with atherosclerotic cardiovascular disease or an atherosclerotic cardiovascular disease risk equivalent (ORION-11 trial) who had elevated LDL cholesterol levels despite receiving statin therapy at the maximum tolerated dose. Patients were randomly assigned in a 1:1 ratio to receive either inclisiran (284 mg) or placebo, administered by subcutaneous injection on day 1, day 90, and every 6 months thereafter over a period of 540 days. The coprimary end points in each trial were the placebo-corrected percentage change in LDL cholesterol level from baseline to day 510 and the time-adjusted percentage change in LDL cholesterol level from baseline after day 90 and up to day 540. A total of 1,561 and 1,617 patients underwent randomization in the ORION-10 and ORION-11 trials, respectively. Mean (+/- SD) LDL cholesterol levels at baseline were 104.7 +/- 38.3 mg per deciliter and 105.5 +/- 39.1 mg per deciliter, respectively. At day 510, inclisiran reduced LDL cholesterol levels by 52.3% in the ORION-10 trial and by 49.9% in the ORION-11 trial, with corresponding time-adjusted reductions of 53.8% and 49.2% (p less than 0.001 for all comparisons vs placebo). Adverse events were generally similar in the inclisiran and placebo groups in each trial, although injection-site adverse events were more frequent with inclisiran than with placebo. Nevertheless such reactions were generally mild, and none were severe or persistent.
Raal et al. (2020) performed a phase 3, double-blind clinical trial of inclisiran in which 482 adults with heterozygous familial hypercholesterolemia were randomly assigned in a 1:1 ratio to receive either subcutaneous injections of inclisiran sodium (at a dose of 300 mg) or matching placebo on days 1, 90, 270, and 450. The median age of the patients was 56 years, and 47% were men; the mean baseline level of LDL cholesterol was 153 mg per deciliter. The patients included 15 LDLR (606945) homozygotes, 131 patients with LDLR variants, 11 patients with APOB (107730) variants, and 91 patients who either did not have detectable variants or had no genetic testing done. The 2 primary end points were the percent change from baseline in the LDL cholesterol level on day 510 and the time-adjusted percent change from baseline in the LDL cholesterol level between day 90 and day 540. At day 510, the percent change in the LDL cholesterol level was a reduction of 39.7% in the inclisiran group and an increase of 8.2% in the placebo group, for a between-group difference of minus 47.9 percentage points. The time-averaged percent change in the LDL cholesterol level between day 90 and day 540 was a reduction of 38.1% in the inclisiran group and an increase of 6.2% in the placebo group. There were robust reductions in LDL cholesterol levels in all genotypes of familial hypercholesterolemia.
Goldstein and Brown (1974) showed that the classic form of familial hypercholesterolemia (143890) results from defects in the cell surface receptor that removes LDL particles from plasma (LDLR; 606945). Innerarity et al. (1987) demonstrated the genetic heterogeneity of autosomal dominant hypercholesterolemia by reporting hypercholesterolemic patients with normal LDLR activity and defective apolipoprotein B-100 (APOB; 107730) that displayed low affinity for its receptor. This novel form of the disorder was called familial ligand-defective apolipoprotein B-100, or type B familial hypercholesterolemia, because mutations were identified in the APOB gene (e.g., R3500Q; 107730.0009). Classic FH and the ligand-defective form (type B) map to chromosomes 19 and 2, respectively.
In a 46-year-old woman of Celtic and Native American ancestry with primary hypercholesterolemia and pronounced peripheral vascular disease, Pullinger et al. (1995) identified heterozygosity for a missense mutation in the APOB gene (R3531C; 107730.0017). Screening of 1,560 individuals revealed an unrelated man of Italian ancestry with coronary heart disease and elevated triglyceride and LDL cholesterol levels who carried the same R3531C mutation; the mutation was also detected in 8 other members of the families of the 2 patients. LDL from R3531C-positive individuals had an affinity for the LDL receptor that was 63% of that of control LDL, compared to 91% for unaffected family members and 36% for patients heterozygous for the R3500Q mutation (107730.0009).
Goldstein, J. L., Brown, M. S. Binding and degradation of low density lipoproteins by cultured human fibroblasts: comparison of cells from a normal subject and from a patient with homozygous familial hypercholesterolemia. J. Biol. Chem. 249: 5153-5162, 1974. [PubMed: 4368448]
Goldstein, J. L. Personal Communication. Dallas, Tex. 3/9/1987.
Hansen, P. S., Defesche, J. C., Kastelein, J. J. P., Gerdes, L. U., Fraza, L., Gerdes, C., Tato, F., Jensen, H. K., Jensen, L. G., Klausen, I. C., Faergeman, O., Schuster, H. Phenotypic variation in patients heterozygous for familial defective apolipoprotein B (FDB) in three European countries. Arterioscler. Thromb. Vasc. Biol. 17: 741-747, 1997. [PubMed: 9108789] [Full Text: https://doi.org/10.1161/01.atv.17.4.741]
Higgins, M. J. P., Lecamwasam, D. S., Galton, D. J. A new type of familial hypercholesterolemia. Lancet 306: 737-740, 1975. Note: Originally Volume II. [PubMed: 52771] [Full Text: https://doi.org/10.1016/s0140-6736(75)90723-0]
Illingworth, D. R., Vakar, F., Mahley, R. W., Weisgraber, K. H. Hypocholesterolaemic effects of lovastatin in familial defective apolipoprotein B-100. Lancet 339: 598-600, 1992. [PubMed: 1347103] [Full Text: https://doi.org/10.1016/0140-6736(92)90875-4]
Innerarity, T. L., Weisgraber, K. H., Arnold, K. S., Mahley, R. W., Krauss, R. M., Vega, G. L., Grundy, S. M. Familial defective apolipoprotein B-100: low density lipoproteins with abnormal receptor binding. Proc. Nat. Acad. Sci. 84: 6919-6923, 1987. [PubMed: 3477815] [Full Text: https://doi.org/10.1073/pnas.84.19.6919]
Luirink, I. K., Wiegman, A., Kusters, D. M., Hof, M. H., Groothoff, J. W., de Groot, E., Kastelein, J. J. P., Hutten, B. A. 20-year follow-up of statins in children with familial hypercholesterolemia. New Eng. J. Med. 381: 1547-1556, 2019. [PubMed: 31618540] [Full Text: https://doi.org/10.1056/NEJMoa1816454]
Myant, N. B., Reichl, D., Thompson, G. R., Higgins, M. J., Galton, D. J. The metabolism in vivo and in vitro of plasma low-density lipoprotein from a subject with inherited hypercholesterolaemia. Clin. Sci. Molec. Med. 51: 463-465, 1976. [PubMed: 186227] [Full Text: https://doi.org/10.1042/cs0510463]
Pullinger, C. R., Hennessy, L. K., Chatterton, J. E., Liu, W., Love, J. A., Mendel, C. M., Frost, P. H., Malloy, M. J., Schumaker, V. N., Kane, J. P. Familial ligand-defective apolipoprotein B: identification of a new mutation that decreases LDL receptor binding affinity. J. Clin. Invest. 95: 1225-1234, 1995. [PubMed: 7883971] [Full Text: https://doi.org/10.1172/JCI117772]
Raal, F. J., Kallend, D., Ray, K. K., Turner, T., Koenig, W., Wright, R. S., Wijngaard, P. L. J., Curcio, D., Jaros, M. J., Leiter, L. A., Kastelein, J. J. P. Inclisiran for the treatment of heterozygous familial hypercholesterolemia. New Eng. J. Med. 382: 1520-1530, 2020. [PubMed: 32197277] [Full Text: https://doi.org/10.1056/NEJMoa1913805]
Ray, K. K., Wright, R. S., Kallend, D., Koenig, W., Leiter, L. A., Raal, F. J., Bisch, J. A., Richardson, T., Jaros, M., Wijngaard, P. L. J., Kastelein, J. J. P. Two phase 3 trials of inclisiran in patients with elevated LDL cholesterol. New Eng. J. Med. 382: 1507-1519, 2020. [PubMed: 32187462] [Full Text: https://doi.org/10.1056/NEJMoa1912387]
Vega, G. L., Grundy, S. M. In vivo evidence for reduced binding of low density lipoproteins to receptors as a cause of primary moderate hypercholesterolemia. J. Clin. Invest. 78: 1410-1414, 1986. [PubMed: 3771801] [Full Text: https://doi.org/10.1172/JCI112729]
Weisgraber, K. H., Innerarity, T. L., Newhouse, Y. M., Young, S. G., Arnold, K. S., Krauss, R. M., Vega, G. L., Grundy, S. M., Mahley, R. W. Familial defective apolipoprotein B-100: enhanced binding of monoclonal antibody MB47 to abnormal low density lipoproteins. Proc. Nat. Acad. Sci. 85: 9758-9762, 1988. [PubMed: 3200853] [Full Text: https://doi.org/10.1073/pnas.85.24.9758]