Genetische Erkrankungen des Lipidstoffwechsels

An angeborene Störungen des Fettstoffwechsels ist zu denken, wenn bei jungen Individuen die Konzentrationen des LDL-C über 190 mg/dl (4,9 mmol/l) und/oder der Triglyzeride über 200 mg/dl (2,3 mmol/l) liegen, eine sekundäre Hyperlipoproteinämie (HLP) ausgeschlossen ist oder sich bei Angehörigen ebenfalls erhöhte Lipidkonzentrationen oder frühzeitige Herzinfarkte finden. Für eine primäre HLP spricht auch das Auftreten von Xanthelasmen, Arcus lipoides, Xanthomen und abdominellen Beschwerden. Diese Übersicht fasst den Stand der Kenntnisse zur Ätiologie und Pathogenese dieser primären HLP zusammen.

Abstract

Congenital disorders of lipid metabolism are characterised by LDL-C concentrations > 190 mg/dl (4.9 mM) and/or triglycerides > 200 mg/dl (2.3 mM) in young individuals after having excluded a secondary hyperlipoproteinemia. Further characteristics of this primary hyperlipoproteinemia are elevated lipid values or premature myocardial infarctions within families or xantelasms, arcus lipoides, xanthomas and abdominal pain. This overview summarises our current knowledge of etiology and pathogenesis of primary hyperlipoproteinemia.

Schlüsselwörter

genetisch verursachte Störungen des Lipidstoffwechsels - familiäre Hypercholesterinämie - familiäre kombinierte Hyperlipoproteinämie - polygene Hypercholesterinämie - genetische Diagnostik - Atherosklerose

Key words

genetic disorders of lipoprotein metabolism - familial hypercholesterolemia - familial combined hypolipoproteinemia - polygenic hypercholesterolemia - genetic diagnosis - atherosclerosis

• Literatur

• 1 Goldstein JL, Brown MS. A century of cholesterol and coronaries: from plaques to genes to statins. Cell 2015; 161: 161-172
• 2 Kuivenhoven JA, Hegele RA. Mining the genome for lipid genes. Biochim Biophys Acta 2014; 1842: 1993-2009
• 3 Willer CJ, Schmidt EM, Sengupta S. et al. Discovery and refinement of loci associated with lipid levels. Nat Genet 2013; 45: 1274-1283
• 4 Klose G, Laufs U, März W. et al. Familial hypercholesterolemia: developments in diagnosis and treatment. Dtsch Ärztebl Int 2014; 111: 523-529
• 5 Nauck MS, Scharnagl H, Nissen H. et al. FH-Freiburg: a novel missense mutation (C317Y) in growth factor repeat A of the low density lipoprotein receptor gene in a German patient with homozygous familial hypercholesterolemia. Atherosclerosis 2000; 151: 525-534
• 6 Nauck MS, Koster W, Dorfer K. et al. Identification of recurrent and novel mutations in the LDL receptor gene in German patients with familial hypercholesterolemia. Hum Mutat 2001; 18: 165-166
• 7 Grenkowitz T, Kassner U, Wuhle-Demuth M. et al. Clinical characterization and mutation spectrum of German patients with familial hypercholesterolemia. Atherosclerosis 2016; 253: 88-93
• 8 März W, Ruzicka V, Pohl T. et al. Familial defective apolipoprotein B-100: mild hypercholesterolemia without atherosclerosis in a homozygous patient. Lancet 1992; 340: 1362
• 9 März W, Baumstark MW, Scharnagl H. et al. Accumulation of 'small dense' low density lipoproteins in a homozygous patient with familial defective apolipoprotein B-100 results from heterogenous interaction of LDL-subfractions with the LDL receptor. J Clin Invest 1993; 92: 2922-2933
• 10 Abifadel M, Varret M, Rabes JP. et al. Mutations in PCSK9 cause autosomal dominant hypercholesterolemia. Nat Genet 2003; 34: 154-156
• 11 Soutar AK, Naoumova RP. Mechanisms of disease: genetic causes of familial hypercholesterolemia. Nat Clin Pract Cardiovasc Med 2007; 4: 214-225
• 12 Taylor A, Wang D, Patel K. et al. Mutation detection rate and spectrum in familial hypercholesterolaemia patients in the UK pilot cascade project. Clin Genet 2010; 77: 572-580
• 13 Talmud PJ, Shah S, Whittall R. et al. Use of low-density lipoprotein cholesterol gene score to distinguish patients with polygenic and monogenic familial hypercholesterolaemia: a case-control study. The Lancet 2013; 381: 1293-1301
• 14 Talmud PJ, Futema M, Humphries SE. The genetic architecture of the familial hyperlipidaemia syndromes: rare mutations and common variants in multiple genes. Curr Opin Lipidol 2014; 25: 274-281
• 15 Khera AV, Won HH, Peloso GM. et al. Diagnostic Yield and Clinical Utility of Sequencing Familial Hypercholesterolemia Genes in Patients With Severe Hypercholesterolemia. J Am Coll Cardiol 2016; 67: 2578-2589
• 16 Braenne I, Kleinecke M, Reiz B. et al. Systematic analysis of variants related to familial hypercholesterolemia in families with premature myocardial infarction. Eur J Hum Genet 2016; 24: 191-197
• 17 Iacocca MA, Chora JR, Carrie A. et al. ClinVar database of global familial hypercholesterolemia-associated DNA variants. Hum Mutat 2018; 39: 1631-1640
• 18 Versmissen J, Oosterveer DM, Yazdanpanah M. et al. Efficacy of statins in familial hypercholesterolaemia: a long term cohort study. BMJ 2008; 337: a2423
• 19 Benn M, Watts GF, Tybjaerg-Hansen A. et al. Familial hypercholesterolemia in the danish general population: prevalence, coronary artery disease, and cholesterol-lowering medication. J Clin Endocrinol Metab 2012; 97: 3956-3964
• 20 Marks D, Thorogood M, Neil HA. et al. A review on the diagnosis, natural history, and treatment of familial hypercholesterolaemia. Atherosclerosis 2003; 168: 1-14
• 21 Walma EP, Wiersma TJ. NHG-Standpunt Diagnostiek en behandeling van familiaire hypercholesterolemie. Huisarts Wet 2006; 49: 202-204
• 22 Garcia CK, Wilund K, Arca M. et al. Autosomal recessive hypercholesterolemia caused by mutations in a putative LDL receptor adaptor protein. Science 2001; 292: 1394-1398
• 23 Humphries SE, Whittall RA, Hubbart CS. et al. Genetic causes of familial hypercholesterolaemia in patients in the UK: relation to plasma lipid levels and coronary heart disease risk. J Med Genet 2006; 43: 943-949
• 24 Bjornsson E, Thorgeirsson G, Helgadottir A. et al. Large-Scale Screening for Monogenic and Clinically Defined Familial Hypercholesterolemia in Iceland. Arterioscler Thromb Vasc Biol 2021; 41: 2616-2628
• 25 Umans-Eckenhausen MA, Defesche JC, van Dam MJ. et al. Long-term compliance with lipid-lowering medication after genetic screening for familial hypercholesterolemia. Arch Intern Med 2003; 163: 65-68
• 26 Futema M, Shah S, Cooper JA. et al. Refinement of variant selection for the LDL cholesterol genetic risk score in the diagnosis of the polygenic form of clinical familial hypercholesterolemia and replication in samples from 6 countries. Clin Chem 2015; 61: 231-238
• 27 Catapano AL, Graham I, De Backer G. et al. 2016 ESC/EAS Guidelines for the Management of Dyslipidaemias: The Task Force for the Management of Dyslipidaemias of the European Society of Cardiology (ESC) and European Atherosclerosis Society (EAS) Developed with the special contribution of the European Assocciation for Cardiovascular Prevention & Rehabilitation (EACPR). Atherosclerosis 2016; 253: 281-344
• 28 Piepoli MF, Hoes AW, Agewall S. et al. 2016 European Guidelines on cardiovascular disease prevention in clinical practice: The Sixth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice (constituted by representatives of 10 societies and by invited experts)Developed with the special contribution of the European Association for Cardiovascular Prevention & Rehabilitation (EACPR). Eur Heart J 2016; 37: 2315-2381
• 29 Collaboration EASFHS. Global perspective of familial hypercholesterolaemia: a cross-sectional study from the EAS Familial Hypercholesterolaemia Studies Collaboration (FHSC). Lancet 2021; 398: 1713-1725
• 30 Damgaard D, Larsen ML, Nissen PH. et al. The relationship of molecular genetic to clinical diagnosis of familial hypercholesterolemia in a Danish population. Atherosclerosis 2005; 180: 155-160
• 31 Civeira F, Ros E, Jarauta E. et al. Comparison of genetic versus clinical diagnosis in familial hypercholesterolemia. Am J Cardiol 2008; 102: 1187-1193
• 32 Leren TP, Finborud TH, Manshaus TE. et al. Diagnosis of familial hypercholesterolemia in general practice using clinical diagnostic criteria or genetic testing as part of cascade genetic screening. Community Genet 2008; 11: 26-35
• 33 Futema M, Whittall RA, Kiley A. et al. Analysis of the frequency and spectrum of mutations recognised to cause familial hypercholesterolaemia in routine clinical practice in a UK specialist hospital lipid clinic. Atherosclerosis 2013; 229: 161-168
• 34 Futema M, Plagnol V, Li K. et al. Whole exome sequencing of familial hypercholesterolaemia patients negative for LDLR/APOB/PCSK9 mutations. J Med Genet 2014; 51: 537-544
• 35 Leal LG, Hoggart C, Jarvelin MR. et al. A polygenic biomarker to identify patients with severe hypercholesterolemia of polygenic origin. Mol Genet Genomic Med 2020; 8: e1248
• 36 Hegele RA, Ban MR, Hsueh N. et al. A polygenic basis for four classical Fredrickson hyperlipoproteinemia phenotypes that are characterized by hypertriglyceridemia. Hum Mol Genet 2009; 18: 4189-4194
• 37 Johansen CT, Hegele RA. Genetic bases of hypertriglyceridemic phenotypes. Curr Opin Lipidol 2011; 22: 247-253
• 38 Lewis GF, Xiao C, Hegele RA. Hypertriglyceridemia in the genomic era: a new paradigm. Endocr Rev 2015; 36: 131-147
• 39 Brahm AJ, Hegele RA. Combined hyperlipidemia: familial but not (usually) monogenic. Curr Opin Lipidol 2016; 27: 131-140
• 40 Welty FK. Hypobetalipoproteinemia and abetalipoproteinemia. Curr Opin Lipidol 2014; 25: 161-168
• 41 Putz-Bankuti C, Datz C, März W. et al. Clinical-pathological conference series from the Medical University of Graz: case no. 131: elevated transaminases in a 30-year-old male. Wien Klin Wochenschr 2006; 118: 769-775
• 42 Cohen JC, Boerwinkle E, Mosley TH. et al. Sequence Variations in PCSK9, Low LDL, and Protection against Coronary Heart Disease. New Engl J Med 2006; 354: 1264-1272
• 43 Zhao Z, Tuakli-Wosornu Y, Lagace TA. et al. Molecular characterization of loss-of-function mutations in PCSK9 and identification of a compound heterozygote. Am J Hum Genet 2006; 79: 514-523
• 44 Musunuru K, Pirruccello JP, Do R. et al. Exome sequencing, ANGPTL3 mutations, and familial combined hypolipidemia. N Engl J Med 2010; 363: 2220-2227
• 45 Jones B, Jones EL, Bonney SA. et al. Mutations in a Sar1 GTPase of COPII vesicles are associated with lipid absorption disorders. Nat Genet 2003; 34: 29-31
• 46 Beaty TH, Kwiterovich Jr PO, Khoury MJ. et al. Genetic analysis of plasma sitosterol, apoprotein B, and lipoproteins in a large Amish pedigree with sitosterolemia. Am J Hum Genet 1986; 38: 492-504
• 47 Berge KE, Tian H, Graf GA. et al. Accumulation of dietary cholesterol in sitosterolemia caused by mutations in adjacent ABC transporters. Science 2000; 290: 1771-1775
• 48 Gallus GN, Dotti MT, Federico A. Clinical and molecular diagnosis of cerebrotendinous xanthomatosis with a review of the mutations in the CYP27A1 gene. Neurol Sci 2006; 27: 143-149
• 49 Mignarri A, Magni A, Del Puppo M. et al. Evaluation of cholesterol metabolism in cerebrotendinous xanthomatosis. J Inherit Metab Dis 2016; 39: 75-83
• 50 Schaaf CP, Koster J, Katsonis P. et al. Desmosterolosis-phenotypic and molecular characterization of a third case and review of the literature. Am J Med Genet A 2011; 155A: 1597-1604
• 51 Bjorkhem I, Leoni V, Meaney S. Genetic connections between neurological disorders and cholesterol metabolism. J Lipid Res 2010; 51: 2489-2503
• 52 Wierzbicka-Rucinska A, Janczyk W, Lugowska A. et al. Diagnostic and therapeutic management of children with lysosomal acid lipase deficiency (LAL-D). Review of the literature and own experience. Dev Period Med 2016; 20: 212-215
• 53 Reiner Z, Guardamagna O, Nair D. et al. Lysosomal acid lipase deficiency--an under-recognized cause of dyslipidaemia and liver dysfunction. Atherosclerosis 2014; 235: 21-30
• 54 Kostner KM, März W, Kostner GM. When should we measure lipoprotein (a)?. Eur Heart J 2013; 34: 3268-3276
• 55 Utermann G. The mysteries of lipoprotein(a). Science 1989; 246: 904-910
• 56 Utermann G, Menzel HJ, Kraft HG. et al. Lp(a) glycoprotein phenotypes. Inheritance and relation to Lp(a)-lipoprotein concentrations in plasma. J Clin Invest 1987; 80: 458-465
• 57 Kronenberg F, Utermann G. Lipoprotein(a): resurrected by genetics. J Intern Med 2013; 273: 6-30
• 58 Nordestgaard BG, Chapman MJ, Ray K. et al. Lipoprotein(a) as a cardiovascular risk factor: current status. Eur Heart J 2010; 31: 2844-2853
• 59 Utermann G. Lipoprotein(a): A genetic risk factor for premature coronary heart disease. Curr Opin Lipidol 1990; 1: 404-410
• 60 Nordestgaard BG, Chapman MJ, Ray K. et al. Lipoprotein(a) as a cardiovascular risk factor: current status. Eur Heart J 2010; 31: 2844-2853
• 61 Viney NJ, van Capelleveen JC, Geary RS. et al. Antisense oligonucleotides targeting apolipoprotein(a) in people with raised lipoprotein(a): two randomised, double-blind, placebo-controlled, dose-ranging trials. Lancet 2016; 388: 2239-2253
• 62 Feussner G, Feussner V, Hoffmann MM. et al. Molecular basis of type III hyperlipoproteinemia in Germany. Hum Mutat 1998; 11: 417-423
• 63 Nauck MS, Nissen H, Hoffmann MM. et al. Detection of mutations in the apolipoprotein CII gene by denaturing gradient gel electrophoresis. Identification of the splice site variant apolipoprotein CII-Hamburg in a patient with severe hypertriglyceridemia. Clin Chem 1998; 44: 1388-1396
• 64 Young SG, Davies BS, Voss CV. et al. GPIHBP1, an endothelial cell transporter for lipoprotein lipase. J Lipid Res 2011; 52: 1869-1884
• 65 Hegele RA, Ginsberg HN, Chapman MJ. et al. The polygenic nature of hypertriglyceridaemia: implications for definition, diagnosis, and management. Lancet Diabetes Endocrinol 2014; 2: 655-666
• 66 Brown RJ, Araujo-Vilar D, Cheung PT. et al. The Diagnosis and Management of Lipodystrophy Syndromes: A Multi-Society Practice Guideline. J Clin Endocrinol Metab 2016; 101: 4500-4511
• 67 März W, Kleber ME, Scharnagl H. et al. [Clinical importance of HDL cholesterol]. Herz 2017; 42: 58-66
• 68 Calabresi L, Baldassarre D, Castelnuovo S. et al. Functional lecithin: cholesterol acyltransferase is not required for efficient atheroprotection in humans. Circulation 2009; 120: 628-635
• 69 Bodzioch M, Orso E, Klucken J. et al. The gene encoding ATP-binding cassette transporter 1 is mutated in Tangier disease. Nat Genet 1999; 22: 347-351
• 70 Rust S, Rosier M, Funke H. et al. Tangier disease is caused by mutations in the gene encoding ATP-binding cassette transporter 1. Nat Genet 1999; 22: 352-355
• 71 Schaefer EJ, Santos RD, Asztalos BF. Marked HDL deficiency and premature coronary heart disease. Curr Opin Lipidol 2010; 21: 289-297
• 72 Modesto KM, Dispenzieri A, Gertz M. et al. Vascular abnormalities in primary amyloidosis. Eur Heart J 2007; 28: 1019-1024
• 73 Hovingh GK, Brownlie A, Bisoendial RJ. et al. A novel apoA-I mutation (L178P) leads to endothelial dysfunction, increased arterial wall thickness, and premature coronary artery disease. J Am Coll Cardiol 2004; 44: 1429-1435
• 74 Ritsch A, Scharnagl H, Eller P. et al. Cholesteryl ester transfer protein and mortality in patients undergoing coronary angiography: the Ludwigshafen Risk and Cardiovascular Health study. Circulation 2010; 121: 366-374
• 75 Vergeer M, Korporaal SJ, Franssen R. et al. Genetic variant of the scavenger receptor BI in humans. N Engl J Med 2011; 364: 136-145
• 76 Ljunggren SA, Levels JH, Hovingh K. et al. Lipoprotein profiles in human heterozygote carriers of a functional mutation P297S in scavenger receptor class B1. Biochim Biophys Acta 2015; 1851: 1587-1595
• 77 Zanoni P, Khetarpal SA, Larach DB. et al. Rare variant in scavenger receptor BI raises HDL cholesterol and increases risk of coronary heart disease. Science 2016; 351: 1166-1171