Zusammenfassung
Die homozygote Sichelzellerkrankung (HbSS Krankheit) ist paradigmatisch für den komplexen Einfluss von genetisch modifizierenden Faktoren auf das klinische Bild einer monogenen Krankheit. Insbesondere beeinflusst die genetisch bedingte Variabilität der HbF-Konzentration die klinische Ausprägung der HbSS-Krankheit erheblich. Die erfolgreiche, mit einer verminderten Morbidität einhergehende medikamentöse Erhöhung der HbF-Konzentration zeigt, dass die Kenntnis der modulierenden genetischen Faktoren neue Möglichkeiten der therapeutischen Intervention eröffnen kann. In geringerem Maße lässt sich eine Assoziation von Schwere der Erkrankung und koinzident auftretender α-Thalassämie erkennen. Beide Faktoren, HbF und α-Thalassämie, können alleine die Vielfalt und Variabilität des klinischen Spektrums der HbSS-Krankheit nicht ausreichend erklären. Mit Methoden der Genomforschung wurden relevante Genloki identifiziert, die möglicherweise zur Abschätzung der Wahrscheinlichkeit des Auftretens schwerer Komplikationen der Sichelzellerkrankung wie etwa von Schlaganfällen genutzt werden können. Die subtile Analyse der genetisch modifizierenden Einflussfaktoren wird das Management von Patienten mit Sichelzellkrankheit nach dem Vorliegen von Ergebnissen prospektiver Studien somit voraussichtlich wesentlich beeinflussen.
Abstract
Homozygous sickle cell (HbSS) disease is paradigmatic for the complex influence of genetic modifiers of a monogenic disease. The genetically determined variability of HbF concentration has a strong impact on the clinical phenotype. The pharmacologically induced increase of HbF leads to a reduced morbidity which demonstrates that the knowledge of genetic modifiers enables the development of new therapeutic strategies. The presence of α-thalassemia also ameliorates the disease phenotype albeit not to the same extent as HbF does. Both factors, HbF and α-thalassemia are insufficient to explain the clinical variability of HbSS disease. The introduction of genome analysis has now provided the tools to identify relevant gene loci that will likely be helpful in estimating the probability of severe complications such as the occurrence of stroke. Following the validation in prospective studies, the subtle analysis of genetic modifiers will therefore influence the management of patients with sickle cell disease.
Schlüsselwörter
Sichelzellerkrankung - genetische Modulation - fetales Hämoglobin (HbF) - α-Thalassämie - single nucleotide polymorphism (SNP)
Key words
sickle cell disease - genetic modulation - fetal haemoglobin (HbF) - α-thalassemia - single nucleotide polymorphism (SNP)
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Kathrin Hartmann
Universitätsklinik für Kinder- und Jugendmedizin, Pädiatrische Onkologie, Hämatologie und Immunologie
Im Neuenheimer Feld 153
69120 Heidelberg
eMail: Kathrin.Hartmann@med.uni-heidelberg.de
