Zusammenfassung
Das Pseudoexfoliations (PEX)-Glaukom ist ein hypertensives, chronisches, sekundäres Offenwinkelglaukom, das verglichen mit anderen Glaukomformen eine höhere Progressionsrate und größere Vulnerabilität für einen Glaukomschaden aufweist. Das zugrunde liegende Krankheitsbild des PEX-Syndroms repräsentiert einen genetisch determinierten, generalisierten, fibrotischen Prozess, der zu progressiven Ablagerungen eines abnormalen extrazellulären Materials in den Kammerwasserabflussstrukturen und weiteren intra- und extraokulären Geweben führt. Erhöhte Konzentrationen fibrogener Wachstumsfaktoren wie TGF-β1, verminderte Aktivitäten proteolytischer Enzyme, subklinische entzündliche Prozesse sowie vermehrter zellulärer und oxidativer Stress sind an diesem fibrotischen Allgemeinprozess kausal beteiligt. Genetische Studien konnten eine signifikante Assoziation zwischen bestimmten Polymorphismen im LOXL1 (Lysyloxidase-like 1)-Gen, das für ein quervernetzendes Matrixenzym kodiert, mit PEX-Syndrom/Glaukom identifizieren. Unsere Analysen konnten zeigen, dass LOXL1 einerseits an der Bildung und Akkumulation des PEX-Materials in den Abflussstrukturen und damit an der Druckerhöhung beteiligt ist, andererseits auch bindegewebige und biomechanische Veränderungen der Lamina cribrosa induziert und damit zu einem PEX-spezifischen Risiko für ein Sekundärglaukom prädisponiert. Aus diesen pathophysiologischen Befunden ergeben sich direkte therapeutische Konsequenzen für das Management von PEX-Patienten im Sinne einer akkuraten Diagnostik, einer engmaschigen Kontrolle und einer rigorosen Umsetzung drucksenkender Maßnahmen.
Abstract
Pseudoexfoliation (PEX) syndrome is a genetically determined, generalized disease of the extracellular matrix leading to the progressive deposition of an abnormal fibrillar material in various intraocular and extraocular tissues including the trabecular meshwork. It thus represents the most common identifiable cause of open-angle glaucoma and a leading cause of blindness worldwide. The PEX-specific fibrotic matrix process, a stress-induced elastosis, is characterized by an excessive production and abnormal cross-linking of elastic microfibrils into fibrillar PEX aggregates. Co-modulating factors triggering this fibrotic process include elevated concentrations of fibrogenic growth factors, such as TGF-β1, reduced activity of proteolytic enzymes, subtle inflammatory processes and various external stress factors, such as oxidative stress. Genetic studies identified a highly significant association between several polymorphisms in the LOXL1 (lysyl oxidase-like 1) gene with both PEX syndrome and PEX glaucoma. As these LOXL1 risk variants were found to occur in almost 100% of PEX patients throughout all geographical populations worldwide, LOXL1 appears to represent a principal risk factor for manifestation of the PEX phenotype. LOXL1 is a pivotal cross-linking enzyme in extracellular matrix metabolism and seems to be specifically required for elastic fiber formation and stabilization. The available data suggest that LOXL1 enzyme function and expression are dysregulated in PEX tissues and thereby play a central role in glaucoma development. On the one hand, increased expression of LOXL1 and elastic fiber components contributes to the formation of abnormally cross-linked PEX aggregates in the outflow pathways leading to increased outflow resistance and intraocular pressure. On the other hand, reduced expression and inadequate tissue levels of LOXL1 may lead to degenerative tissue alterations, particularly in the lamina cribrosa adversely affecting the biomechanical properties of this critical tissue. This PEX-specific elastinopathy of the lamina cribrosa rendering PEX eyes more vulnerable to pressure-induced optic nerve damage may constitute an independent risk factor for glaucoma development. The findings may have direct consequences for the clinical management of PEX patients underlining the need for an exact diagnosis, a strict IOP-reducing therapy and a close and regular follow-up.
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Schlötzer-Schrehardt, U. Neue pathogenetische Erkenntnisse zum Pseudoexfoliations-Syndrom/Glaukom. Ophthalmologe 109, 944–951 (2012). https://doi.org/10.1007/s00347-012-2531-1
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DOI: https://doi.org/10.1007/s00347-012-2531-1