Zusammenfassung
Die autosomal-rezessive Glykogenspeichererkrankung Typ 2 (GSD2, Morbus Pompe) ist durch Mangel des Glykogens degradierenden lysosomalen Enzyms α-1,4-Glucosidase (saure Maltase, acid alpha-glucosidase GAA) verursacht. Seit 2006 ist als sog. Ophan Drug Alglucosidase-alfa in Europa und den USA zur Behandlung der GSD2 zugelassen. Klinische Studien mit Alglucosidase-alfa bei infantiler und juveniler Pompe-Erkrankung zeigten eine Verlängerung der Überlebenszeit, der statomotorischen Entwicklung, und Verbesserung der Kardiomyopathie. Daher wird die Enzymersatztherapie auch für adulte Patienten eingesetzt und es liegen Erfolg versprechende Kasuistiken für diese Altersgruppe vor. Seit 2005 wird eine weitere Studie für diese Altersgruppe durchgeführt. Es zeichnen sich aber pathophysiologisch begründbare Einschränkungen der Wirksamkeit bei den Erwachsenen ab, insbesondere da weder das Überleben noch die Kardiomyopathie in dieser Altersgruppe relevante Zielparameter sein können. Die Enzymersatztherapie beruht auf einer rezeptormediierten Endozytose von rekombinantem humanem GAA. Dies ist besonders im Herzmuskel erfolgreich, aber im Skelettmuskel ist der Glykogenabbau in Typ-2-Fasern eingeschränkt. Neueste Untersuchungen zur Pathogenese zeigten neben dem Enzymmangel eine profunde Störung des lysosomalen autophagischen Abbauweges. Es findet sich eine progressive altersabhängige Zunahme von autophagischen Vakuolen in Kombination mit erweiterten, glykogengefüllten Lysosomen im Muskelgewebe. Teile des substituierten Enzyms scheinen in diesen autophagischen Zonen gefangen und erreichen nicht ihr Zielorganell, die Lysosomen. Zusätzlich sind mitochondriale Veränderungen, Lipofuszinablagerungen und eine Zerstörung des kontraktilen Apparates nachweisbar. Diese Zellstrukturänderungen sind relevante Faktoren für die Muskelschwäche und Ausdauereinschränkung der GSD2 Patienten. In dieser Arbeit werden aktuellen Aspekte zur Pathophysiologie vorgestellt und eine Zusammenfassung der Ergebnisse der Enzymersatztherapie berichtet.
Abstract
Glycogen storage disease type 2 (GSD2, Pompe disease) is caused by a deficiency of glycogen-degrading lysosomal enzyme acid alpha-glucosidase (GAA). In 2006 alglucosidase alfa was authorized as orphan drug treatment option of all phenotypes of GSD2. Results of clinical trails in infantile and juvenile Pompe disease with alglucosidase alfa showed prolonged survival, motor gains, and reversal of cardiomyopathy. These principal disease improvements by enzyme replacement therapy (ERT) in children led to spread the use of this therapy to the adult patients. Although there are some promising reports of successful ERT in adults, there seems to be some shortcomings of ERT in adults. The therapy, which relies on receptor-mediated endocytosis of recombinant human GAA (rhGAA), appears to be successful in cardiac muscle, but to a lesser degree in skeletal muscle, especially in clearing glycogen stores from type 2 muscle fibers. Recent investigations demonstrated a profound disturbance of the lysosomal degradative autophagic pathway. A progressive age-dependent autophagic built-up in addition to enlargement of glycogen-filled lysosomes was found in muscle tissue. Part of the substituted enzyme is trapped in these autophagic areas instead of reaching its lysosomal target. Furthermore, asides swollen, glycogen packed lysosomes, pronounced autophagia, mitochondrial alterations, lipofuscin, and direct contractile texture disturbances, like Z-line thickening and smearing are relevant for muscle weakness and power endurance handicap, seen in men and mice. In this report, an update on the pathophysiology and a summary of the current state of ERT in GSD2 will be given.
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PD Dr. med. Benedikt G. H. Schoser
Friedrich-Baur-Institut, Neurologische Klinik, Ludwig-Maximilians-Universität München
Ziemssenstraße 1 a
80336 München
Email: bschoser@med.uni-muenchen.de