Abstract
Familial Hypercholesterolemia (FH) is one of the most common inherited lipid disorders, with recent studies estimating a prevalence as high as 1 in 200 people [1–3]. Inherited in an autosomal-dominant fashion, it is associated with lifelong, severe elevations in low-density lipoprotein-cholesterol (LDL-c) levels. Individuals with FH have a markedly elevated risk of premature ischemic heart disease, 5–20-fold higher than the general population [4–6]. Mutations in the genes for the LDL receptor (LDLR), apolipoprotein B-100 (APOB), as well as gain of function mutations in the proprotein convertase subtulisin/kexin type 9 protein (PCSK9) have all been associated with the pathogenesis of FH [6]. Appropriate management can dramatically improve the life expectancy of those with FH [6]; however, many patients experience delayed diagnosis and inadequate cholesterol lowering [1], underscoring the need for increased awareness, recognition, and timely treatment of this disorder in the general community.
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References
deGoma EM, et al. Treatment gaps in adults with heterozygous familial hypercholesterolemia in the United States: data from the CASCADE-FH registry. Circ Cardiovasc Genet. 2016;9(3):240–9.
Benn M, et al. Familial hypercholesterolemia in the Danish general population: prevalence, coronary artery disease, and cholesterol-lowering medication. J Clin Endocrinol Metab. 2012;97(11):3956–64.
Nordestgaard BG, et al. Familial hypercholesterolaemia is underdiagnosed and undertreated in the general population: guidance for clinicians to prevent coronary heart disease: consensus statement of the European Atherosclerosis Society. Eur Heart J. 2013;34(45):3478–90a.
Parizo J, Sarraju A, Knowles JW. Novel therapies for familial hypercholesterolemia. Curr Treat Options Cardiovasc Med. 2016;18(11):64.
Ahmad ZS, et al. US physician practices for diagnosing familial hypercholesterolemia: data from the CASCADE-FH registry. J Clin Lipidol. 2016;10(5):1223–9.
Gidding SS, et al. The agenda for familial hypercholesterolemia: a scientific statement From the American Heart Association. Circulation. 2015;132(22):2167–92.
Youngblom E, Pariani M, Knowles JW. Familial hypercholesterolemia. In: Pagon RA, et al., editors. GeneReviews(R). Seattle, WA: University of Washington; 2016.
Talmud PJ, et al. Use of low-density lipoprotein cholesterol gene score to distinguish patients with polygenic and monogenic familial hypercholesterolaemia: a case-control study. Lancet. 2013;381(9874):1293–301.
Langsted A, et al. High lipoprotein(a) as a possible cause of clinical familial hypercholesterolaemia: a prospective cohort study. Lancet Diabetes Endocrinol. 2016;4(7):577–87.
Nordestgaard BG, et al. Lipoprotein(a) as a cardiovascular risk factor: current status. Eur Heart J. 2010;31(23):2844–53.
Soutar AK, Naoumova RP. Mechanisms of disease: genetic causes of familial hypercholesterolemia. Nat Clin Pract Cardiovasc Med. 2007;4(4):214–25.
Expert Panel on Integrated Guidelines for Cardiovascular, H, et al. Expert panel on integrated guidelines for cardiovascular health and risk reduction in children and adolescents: summary report. Pediatrics. 2011;128(Suppl 5):S213–56.
US Preventive Services Task Force. Screening for lipid disorders in children and adolescents: US preventive services task force recommendation statement. JAMA. 2016;316(6):625–33.
Helfand M, Carson S. Screening for lipid disorders in adults: selective update of 2001 US preventive services task force review. Rockville (MD): Agency for Healthcare Research and Quality; 2008.
Goldstein JL, Brown MS. The LDL receptor. Arterioscler Thromb Vasc Biol. 2009;29(4):431–8.
De Castro-Orós I, Pocoví M, Civeira F. The genetic basis of familial hypercholesterolemia: inheritance, linkage, and mutations. Appl Clin Genet. 2010;3:53–64.
Mabuchi H, et al. Genotypic and phenotypic features in homozygous familial hypercholesterolemia caused by proprotein convertase subtilisin/kexin type 9 (PCSK9) gain-of-function mutation. Atherosclerosis. 2014;236(1):54–61.
Usifo E, et al. Low-density lipoprotein receptor gene familial hypercholesterolemia variant database: update and pathological assessment. Ann Hum Genet. 2012;76(5):387–401.
Hobbs HH, Brown MS, Goldstein JL. Molecular genetics of the LDL receptor gene in familial hypercholesterolemia. Hum Mutat. 1992;1(6):445–66.
Koivisto UM, Hubbard AL, Mellman I. A novel cellular phenotype for familial hypercholesterolemia due to a defect in polarized targeting of LDL receptor. Cell. 2001;105(5):575–85.
Khera AV, et al. Diagnostic yield and clinical utility of sequencing familial hypercholesterolemia genes in patients with severe hypercholesterolemia. J Am Coll Cardiol. 2016;67(22):2578–89.
Borén J, et al. The molecular mechanism for the genetic disorder familial defective apolipoprotein B100. J Biol Chem. 2001;276(12):9214–8.
Thomas ER, et al. Identification and biochemical analysis of a novel APOB mutation that causes autosomal dominant hypercholesterolemia. Mol Genet Genomic Med. 2013;1(3):155–61.
Shen H, et al. Familial defective apolipoprotein B-100 and increased low-density lipoprotein cholesterol and coronary artery calcification in the old order Amish. Arch Intern Med. 2010;170(20):1850–5.
Arnold KS, et al. Isolation of allele-specific, receptor-binding-defective low density lipoproteins from familial defective apolipoprotein B-100 subjects. J Lipid Res. 1994;35(8):1469–76.
Soria LF, et al. Association between a specific apolipoprotein B mutation and familial defective apolipoprotein B-100. Proc Natl Acad Sci USA. 1989;86(2):587–91.
Musunuru K, et al. Exome sequencing, ANGPTL3 mutations, and familial combined hypolipidemia. N Engl J Med. 2010;363(23):2220–7.
Abifadel M, et al. Mutations in PCSK9 cause autosomal dominant hypercholesterolemia. Nat Genet. 2003;34(2):154–6.
Cohen JC, et al. Sequence variations in PCSK9, low LDL, and protection against coronary heart disease. N Engl J Med. 2006;354(12):1264–72.
Risk of fatal coronary heart disease in familial hypercholesterolaemia. Scientific Steering Committee on behalf of the Simon Broome Register Group. BMJ. 1991;303(6807):893–6.
Watts GF, et al. Integrated guidance on the care of familial hypercholesterolemia from the International FH Foundation. J Clin Lipidol. 2014;8(2):148–72.
Raal FJ, Santos RD. Homozygous familial hypercholesterolemia: current perspectives on diagnosis and treatment. Atherosclerosis. 2012;223(2):262–8.
Williams RR, et al. Diagnosing heterozygous familial hypercholesterolemia using new practical criteria validated by molecular genetics. Am J Cardiol. 1993;72(2):171–6.
Civeira F, I.P.o.M.o.F. Hypercholesterolemia. Guidelines for the diagnosis and management of heterozygous familial hypercholesterolemia. Atherosclerosis. 2004;173(1):55–68.
Foody JM. Familial hypercholesterolemia: an under-recognized but significant concern in cardiology practice. Clin Cardiol. 2014;37(2):119–25.
Kindt I, Mata P, Knowles JW. The role of registries and genetic databases in familial hypercholesterolemia. Curr Opin Lipidol. 2017;28(2):152–60.
Mata N, et al. Clinical characteristics and evaluation of LDL-cholesterol treatment of the Spanish Familial Hypercholesterolemia Longitudinal Cohort Study (SAFEHEART). Lipids Health Dis. 2011;10:94.
Perez de Isla L, et al. Coronary heart disease, peripheral arterial disease, and stroke in familial hypercholesterolaemia: insights from the SAFEHEART registry (Spanish familial hypercholesterolaemia cohort study). Arterioscler Thromb Vasc Biol. 2016;36(9):2004–10.
Wiegman A, et al. Familial hypercholesterolaemia in children and adolescents: gaining decades of life by optimizing detection and treatment. Eur Heart J. 2015;36(36):2425–37.
Neil A, et al. Reductions in all-cause, cancer, and coronary mortality in statin-treated patients with heterozygous familial hypercholesterolaemia: a prospective registry study. Eur Heart J. 2008;29(21):2625–33.
Versmissen J, et al. Efficacy of statins in familial hypercholesterolaemia: a long term cohort study. BMJ. 2008;337:a2423.
Knowles JW. Statins in familial hypercholesterolemia: translating evidence to action. J Am Coll Cardiol. 2016;68(3):261–4.
Vuorio A, et al. Statins for children with familial hypercholesterolemia. Cochrane Database Syst Rev. 2014;7:CD006401.
Kusters DM, et al. Ten-year follow-up after initiation of statin therapy in children with familial hypercholesterolemia. JAMA. 2014;312(10):1055–7.
Cuchel M, et al. Homozygous familial hypercholesterolaemia: new insights and guidance for clinicians to improve detection and clinical management. A position paper from the consensus panel on familial hypercholesterolaemia of the European Atherosclerosis Society. Eur Heart J. 2014;35(32):2146–57.
Raal FJ, et al. Reduction in mortality in subjects with homozygous familial hypercholesterolemia associated with advances in lipid-lowering therapy. Circulation. 2011;124(20):2202–7.
Raal FJ, et al. Inhibition of PCSK9 with evolocumab in homozygous familial hypercholesterolaemia (TESLA Part B): a randomised, double-blind, placebo-controlled trial. Lancet. 2015;385(9965):341–50.
Cuchel M, et al. Efficacy and safety of a microsomal triglyceride transfer protein inhibitor in patients with homozygous familial hypercholesterolaemia: a single-arm, open-label, phase 3 study. Lancet. 2013;381(9860):40–6.
Rader DJ, Kastelein JJ. Lomitapide and mipomersen: two first-in-class drugs for reducing low-density lipoprotein cholesterol in patients with homozygous familial hypercholesterolemia. Circulation. 2014;129(9):1022–32.
Stein EA, et al. Apolipoprotein B synthesis inhibition with mipomersen in heterozygous familial hypercholesterolemia: results of a randomized, double-blind, placebo-controlled trial to assess efficacy and safety as add-on therapy in patients with coronary artery disease. Circulation. 2012;126(19):2283–92.
McGowan MP, et al. Randomized, placebo-controlled trial of mipomersen in patients with severe hypercholesterolemia receiving maximally tolerated lipid-lowering therapy. PLoS One. 2012;7(11):e49006.
Maiorana A, et al. Preemptive liver transplantation in a child with familial hypercholesterolemia. Pediatr Transplant. 2011;15(2):E25–9.
Moyle M, Tate B. Homozygous familial hypercholesterolaemia presenting with cutaneous xanthomas: response to liver transplantation. Australas J Dermatol. 2004;45(4):226–8.
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Sarraju, A., Knowles, J.W. (2019). Familial Hypercholesterolemia. In: Erdmann, J., Moretti, A. (eds) Genetic Causes of Cardiac Disease. Cardiac and Vascular Biology, vol 7. Springer, Cham. https://doi.org/10.1007/978-3-030-27371-2_6
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DOI: https://doi.org/10.1007/978-3-030-27371-2_6
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