Angeborene Störungen im Lipoproteinstoffwechsel
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.
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