Angeborene Störungen im Lipoproteinstoffwechsel

Herz - Tập 42 - Trang 449-458 - 2017
W. März1,2,3, T. B. Grammer4, G. Delgado1, M. E. Kleber1
1Medizinische Klinik V (Nephrologie, Hypertensiologie, Rheumatologie, Endokrinologie, Diabetologie), Medizinische Fakultät Mannheim der Universität Heidelberg, Mannheim, Deutschland
2Klinisches Institut für medizinische und Chemische Labordiagnostik, Medizinische Universität Graz, Graz, Österreich
3Synlab Akademie, synlab Holding Deutschland GmbH, Mannheim, Deutschland
4Institut für Public Health, Medizinische Fakultät Mannheim der Universität Heidelberg, Mannheim, Deutschland

Tóm tắt

Die angeborenen Störungen des Fettstoffwechsels werden durch eine breite Palette von Varianten in Genen für Rezeptoren, Apolipoproteine, Enzyme, Transferfaktoren und zelluläre Cholesterintransporter verursacht. Klinisch die größte Bedeutung haben die autosomal-dominante familiäre Hypercholesterinämie (FH) und die familiäre kombinierte Hyperlipoproteinämie (FKHL). Die FH hat eine Prävalenz von 1:250. Sie ist auf Mutationen des LDL(„low-density lipoprotein“)-Rezeptors (LDLR), seltener auf Mutationen von Apolipoprotein B (APOB), PCSK9 („proprotein convertase subtilisin/kexin type 9“) oder STAP-1 („signal transducing adaptor family member 1“) zurückzuführen. Die FH führt meist zu frühzeitiger Atherosklerose. Die Diagnose kann nur molekulargenetisch sicher gestellt werden. Der Nachweis von Mutationen an LDLR, APOB oder PCSK9 ist unabhängig vom Serumwert für LDL-Cholesterin ein Indikator für extrem hohes kardiovaskuläres Risiko. Die FKHL ist ebenfalls häufig (1:100) und kommt bei etwa 10 % der Patienten mit frühem Myokardinfarkt vor. Sie entsteht durch Kombinationen von häufigen genetischen Varianten mit Wirkungen auf Triglyzeride und LDL-Cholesterin. Weitere monogene Hyperlipoproteinämien (HLP) betreffen den Abbau der Chylomikronen (familiäre Chylomikronämie) oder der „remnants“ triglyzeridreicher Lipoproteine (Typ-III-Hyperlipoproteinämie). Im Stoffwechsel der HDL sind viele erbliche Störungen bekannt. Die atherogene Wirkung dieser Defekte ist unterschiedlich. Aktuell werden Sequenzierungsmethoden der zweiten Generation angewendet, um die relevanten Gene simultan zu sequenzieren. Diese Vorgehensweise liefert kostenneutral auch weitere Informationen wie genetisches Atheroskleroserisiko und Prädisposition zur Statinunverträglichkeit.

Tài liệu tham khảo

Abifadel M, Varret M, Rabes JP et al (2003) Mutations in PCSK9 cause autosomal dominant hypercholesterolemia. Nat Genet 34:154–156 Beaty TH, Kwiterovich PO Jr., Khoury MJ et al (1986) Genetic analysis of plasma sitosterol, apoprotein B, and lipoproteins in a large Amish pedigree with sitosterolemia. Am J Hum Genet 38:492–504 Benn M, Watts GF, Tybjaerg-Hansen A et al (2012) Familial hypercholesterolemia in the danish general population: prevalence, coronary artery disease, and cholesterol-lowering medication. J Clin Endocrinol Metab 97:3956–3964 Berge KE, Tian H, Graf GA et al (2000) Accumulation of dietary cholesterol in sitosterolemia caused by mutations in adjacent ABC transporters. Science 290:1771–1775 Bjorkhem I, Leoni V, Meaney S (2010) Genetic connections between neurological disorders and cholesterol metabolism. J Lipid Res 51:2489–2503 Bodzioch M, Orso E, Klucken J et al (1999) The gene encoding ATP-binding cassette transporter 1 is mutated in Tangier disease. Nat Genet 22:347–351 Braenne I, Kleinecke M, Reiz B et al (2016) Systematic analysis of variants related to familial hypercholesterolemia in families with premature myocardial infarction. Eur J Hum Genet 24:191–197 Brahm AJ, Hegele RA (2016) Combined hyperlipidemia: familial but not (usually) monogenic. Curr Opin Lipidol 27:131–140 Brown RJ, Araujo-Vilar D, Cheung PT et al (2016) The diagnosis and management of lipodystrophy syndromes: a multi-society practice guideline. J Clin Endocrinol Metab 101:4500–4511 Bundesausschuss G (2016) Beschluss des Gemeinsamen Bundesausschusses über eine Änderung der Arzneimittel-Richtlinie (AM-RL): Anlage III – Übersicht über Verordnungseinschränkungen und -ausschlüsse Alirocumab. 4. August 2016 Bundesausschuss G (2016) Beschluss des Gemeinsamen Bundesausschusses über eine Änderung der Arzneimittel-Richtlinie (AM-RL): Anlage III – Übersicht über Verordnungseinschränkungen und -ausschlüsse Evolocumab. BAnz AT 12. Aug. 2016 B1 Calabresi L, Baldassarre D, Castelnuovo S et al (2009) Functional lecithin: cholesterol acyltransferase is not required for efficient atheroprotection in humans. Circulation 120:628–635 Catapano AL, Graham I, De Backer G et al (2016) 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 253:281–344 Civeira F, Ros E, Jarauta E et al (2008) Comparison of genetic versus clinical diagnosis in familial hypercholesterolemia. Am J Cardiol 102:1187–1193.e1 Clarke R, Peden JF, Hopewell JC et al (2009) Genetic variants associated with Lp(a) lipoprotein level and coronary disease. N Engl J Med 361:2518–2528 Cohen JC, Boerwinkle E, Mosley TH et al (2006) Sequence variations in PCSK9, low LDL, and protection against coronary heart disease. N Engl J Med 354:1264–1272 Damgaard D, Larsen ML, Nissen PH et al (2005) The relationship of molecular genetic to clinical diagnosis of familial hypercholesterolemia in a Danish population. Atherosclerosis 180:155–160 Erqou S, Kaptoge S, Perry PL et al (2009) Lipoprotein(a) concentration and the risk of coronary heart disease, stroke, and nonvascular mortality. JAMA 302:412–423 Feussner G, Feussner V, Hoffmann MM et al (1998) Molecular basis of type III hyperlipoproteinemia in Germany. Hum Mutat 11:417–423 Friedewald WT, Levy RI, Fredrickson DS (1972) Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin Chem 18:499–502 Futema M, Plagnol V, Li K et al (2014) Whole exome sequencing of familial hypercholesterolaemia patients negative for LDLR/APOB/PCSK9 mutations. J Med Genet 51:537–544 Futema M, Shah S, Cooper JA et al (2015) 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 61:231–238 Futema M, Whittall RA, Kiley A et al (2013) 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 229:161–168 Gallus GN, Dotti MT, Federico A (2006) Clinical and molecular diagnosis of cerebrotendinous xanthomatosis with a review of the mutations in the CYP27A1 gene. Neurol Sci 27:143–149 Garcia CK, Wilund K, Arca M et al (2001) Autosomal recessive hypercholesterolemia caused by mutations in a putative LDL receptor adaptor protein. Science 292:1394–1398 Genser B, Silbernagel G, De Backer G et al (2012) Plant sterols and cardiovascular disease: a systematic review and meta-analysis. Eur Heart J 33:444–451 Grenkowitz T, Kassner U, Wuhle-Demuth M et al (2016) Clinical characterization and mutation spectrum of German patients with familial hypercholesterolemia. Atherosclerosis 253:88–93 Hegele RA, Ban MR, Cao H et al (2015) Targeted next-generation sequencing in monogenic dyslipidemias. Curr Opin Lipidol 26:103–113 Hegele RA, Ban MR, Hsueh N et al (2009) A polygenic basis for four classical Fredrickson hyperlipoproteinemia phenotypes that are characterized by hypertriglyceridemia. Hum Mol Genet 18:4189–4194 Hegele RA, Ginsberg HN, Chapman MJ et al (2014) The polygenic nature of hypertriglyceridaemia: implications for definition, diagnosis, and management. Lancet Diabetes Endocrinol 2:655–666 Hovingh GK, Brownlie A, Bisoendial RJ et al (2004) A novel apoA-I mutation (L178P) leads to endothelial dysfunction, increased arterial wall thickness, and premature coronary artery disease. J Am Coll Cardiol 44:1429–1435 Humphries SE, Whittall RA, Hubbart CS et al (2006) Genetic causes of familial hypercholesterolaemia in patients in the UK: relation to plasma lipid levels and coronary heart disease risk. J Med Genet 43:943–949 Johansen CT, Dube JB, Loyzer MN et al (2014) LipidSeq: a next-generation clinical resequencing panel for monogenic dyslipidemias. J Lipid Res 55:765–772 Johansen CT, Hegele RA (2011) Genetic bases of hypertriglyceridemic phenotypes. Curr Opin Lipidol 22:247–253 Jones B, Jones EL, Bonney SA et al (2003) Mutations in a Sar1 GTPase of COPII vesicles are associated with lipid absorption disorders. Nat Genet 34:29–31 Khera AV, Won HH, Peloso GM et al (2016) Diagnostic yield and clinical utility of sequencing familial hypercholesterolemia genes in patients with severe hypercholesterolemia. J Am Coll Cardiol 67:2578–2589 Klose G, Laufs U, März W et al (2014) Familial hypercholesterolemia: developments in diagnosis and treatment. Dtsch Arztebl Int 111:523–529 Kostner KM, März W, Kostner GM (2013) When should we measure lipoprotein (a)? Eur Heart J 34:3268–3276 Laufs U, Scharnagl H, Halle M et al (2015) Treatment options for statin-associated muscle symptoms. Dtsch Arztebl Int 112:748–755 Leren TP, Finborud TH, Manshaus TE et al (2008) Diagnosis of familial hypercholesterolemia in general practice using clinical diagnostic criteria or genetic testing as part of cascade genetic screening. Community Genet 11:26–35 Lewis GF, Xiao C, Hegele RA (2015) Hypertriglyceridemia in the genomic era: a new paradigm. Endocr Rev 36:131–147 Link E, Parish S, Armitage J et al (2008) SLCO1B1 variants and statin-induced myopathy – a genomewide study. N Engl J Med 359:789–799 Ljunggren SA, Levels JH, Hovingh K et al (2015) Lipoprotein profiles in human heterozygote carriers of a functional mutation P297S in scavenger receptor class B1. Biochim Biophys Acta 1851:1587–1595 Marks D, Thorogood M, Neil HA et al (2003) A review on the diagnosis, natural history, and treatment of familial hypercholesterolaemia. Atherosclerosis 168:1–14 März W, Baumstark MW, Scharnagl H et al (1993) 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 92:2922–2933 März W, Kleber ME, Scharnagl H et al (2017) Clinical importance of HDL cholesterol. Herz 42(1):58–66 März W, Ruzicka V, Pohl T et al (1992) Familial defective apolipoprotein B‑100: mild hypercholesterolemia without atherosclerosis in a homozygous patient. Lancet 340:1362 März W, Scharnagl H, Laufs U (2016) Statin-assoziierte Muskelbeschwerden: Mythos oder Wirklichkeit? Herzmedizin 2016:13–19 Mignarri A, Magni A, Del Puppo M et al (2016) Evaluation of cholesterol metabolism in cerebrotendinous xanthomatosis. J Inherit Metab Dis 39:75–83 Modesto KM, Dispenzieri A, Gertz M et al (2007) Vascular abnormalities in primary amyloidosis. Eur Heart J 28:1019–1024 Musunuru K, Pirruccello JP, Do R et al (2010) Exome sequencing, ANGPTL3 mutations, and familial combined hypolipidemia. N Engl J Med 363:2220–2227 Nauck MS, Köster W, Dörfer K et al (2001) Identification of recurrent and novel mutations in the LDL receptor gene in German patients with familial hypercholesterolemia. Hum Mutat 18:165–166 Nauck MS, Nissen H, Hoffmann MM et al (1998) 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 44:1388–1396 Nauck MS, Scharnagl H, Nissen H et al (2000) 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 151:525–534 Nordestgaard BG, Chapman MJ, Ray K et al (2010) Lipoprotein(a) as a cardiovascular risk factor: current status. Eur Heart J 31:2844–2853 Pasanen MK, Neuvonen M, Neuvonen PJ et al (2006) SLCO1B1 polymorphism markedly affects the pharmacokinetics of simvastatin acid. Pharmacogenet Genomics 16:873–879 Piepoli MF, Hoes AW, Agewall S et al (2016) 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 37:2315–2381 Putz-Bankuti C, Datz C, März W et al (2006) Clinical-pathological conference series from the Medical University of Graz : case no. 131: elevated transaminases in a 30-year-old male. Wien Klin Wochenschr 118:769–775 Reiner Z, Catapano AL, De Backer G et al (2011) ESC/EAS Guidelines for the management of dyslipidaemias: the Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS). Eur Heart J 32:1769–1818 Reiner Z, Guardamagna O, Nair D et al (2014) Lysosomal acid lipase deficiency – an under-recognized cause of dyslipidaemia and liver dysfunction. Atherosclerosis 235:21–30 Ritsch A, Scharnagl H, Eller P et al (2010) Cholesteryl ester transfer protein and mortality in patients undergoing coronary angiography: the Ludwigshafen Risk and Cardiovascular Health study. Circulation 121:366–374 Rust S, Rosier M, Funke H et al (1999) Tangier disease is caused by mutations in the gene encoding ATP-binding cassette transporter 1. Nat Genet 22:352–355 Schaaf CP, Koster J, Katsonis P et al (2011) Desmosterolosis-phenotypic and molecular characterization of a third case and review of the literature. Am J Med Genet A 155A:1597–1604 Schaefer EJ, Santos RD, Asztalos BF (2010) Marked HDL deficiency and premature coronary heart disease. Curr Opin Lipidol 21:289–297 Silbernagel G, Chapman MJ, Genser B et al (2013) High intestinal cholesterol absorption is associated with cardiovascular disease and risk alleles in ABCG8 and ABO: evidence from the LURIC and YFS cohorts and from a meta-analysis. J Am Coll Cardiol 62:291–299 Silbernagel G, Fauler G, Hoffmann MM et al (2010) The associations of cholesterol metabolism and plasma plant sterols with all-cause and cardiovascular mortality. J Lipid Res 51:2384–2393 Silbernagel G, Fauler G, Renner W et al (2009) The relationships of cholesterol metabolism and plasma plant sterols with the severity of coronary artery disease. J Lipid Res 50:334–341 Soutar AK, Naoumova RP (2007) Mechanisms of disease: genetic causes of familial hypercholesterolemia. Nat Clin Pract Cardiovasc Med 4:214–225 Stitziel NO, Stirrups KE, Masca NG et al (2016) Coding variation in ANGPTL4, LPL, and SVEP1 and the risk of coronary disease. N Engl J Med 374:1134–1144 Stroes ES, Thompson PD, Corsini A et al (2015) Statin-associated muscle symptoms: impact on statin therapy – European Atherosclerosis Society Consensus Panel Statement on Assessment, Aetiology and Management. Eur Heart J 36:1012–1022 Talmud PJ, Futema M, Humphries SE (2014) The genetic architecture of the familial hyperlipidaemia syndromes: rare mutations and common variants in multiple genes. Curr Opin Lipidol 25:274–281 Talmud PJ, Shah S, Whittall R et al (2013) Use of low-density lipoprotein cholesterol gene score to distinguish patients with polygenic and monogenic familial hypercholesterolaemia: a case-control study. Lancet 381:1293–1301 Taylor A, Wang D, Patel K et al (2010) Mutation detection rate and spectrum in familial hypercholesterolaemia patients in the UK pilot cascade project. Clin Genet 77:572–580 Teupser D, Baber R, Ceglarek U et al (2010) Genetic regulation of serum phytosterol levels and risk of coronary artery disease. Circ Cardiovasc Genet 3:331–339 Umans-Eckenhausen MA, Defesche JC, Van Dam MJ et al (2003) Long-term compliance with lipid-lowering medication after genetic screening for familial hypercholesterolemia. Arch Intern Med 163:65–68 Vergeer M, Korporaal SJ, Franssen R et al (2011) Genetic variant of the scavenger receptor BI in humans. N Engl J Med 364:136–145 Versmissen J, Oosterveer DM, Yazdanpanah M et al (2008) Efficacy of statins in familial hypercholesterolaemia: a long term cohort study. BMJ 337:a2423 Walma EP, Wiersma TJ (2006) NHG-Standpunt Diagnostiek en behandeling van familiaire hypercholesterolemie. Huisarts Wet 49:202–204 Wierzbicka-Rucinska A, Janczyk W, Lugowska A et al (2016) Diagnostic and therapeutic management of children with lysosomal acid lipase deficiency (LAL-D). Review of the literature and own experience. Dev Period Med 20:212–215 Wild PS, Zeller T, Schillert A et al (2011) A genome-wide association study identifies LIPA as a susceptibility gene for coronary artery disease. Circ Cardiovasc Genet 4:403–412 Young SG, Davies BS, Voss CV et al (2011) GPIHBP1, an endothelial cell transporter for lipoprotein lipase. J Lipid Res 52:1869–1884 Zanoni P, Khetarpal SA, Larach DB et al (2016) Rare variant in scavenger receptor BI raises HDL cholesterol and increases risk of coronary heart disease. Science 351:1166–1171 Zhao Z, Tuakli-Wosornu Y, Lagace TA et al (2006) Molecular characterization of loss-of-function mutations in PCSK9 and identification of a compound heterozygote. Am J Hum Genet 79:514–523