Abstract

FR.12.01

Lysosomal storage disorders: Clinical manifestation and therapeutic options

Michael Beck
Universitäts-Kinderklinik, Johannes Gutenberg-Universität Mainz

Lysosomal storage disorders result from genetic defects of enzymes that are responsible for stepwise degradation of endogenous macromolecules such as proteins, carbohydrates and lipids. Over 40 disorders have been described. They tend to be multisystemic, affecting several organs, and are always progressive. Furthermore, lysosomal storage disorders are characerized by a considerable clinical variability, regarding the rate of progression as well as the organ involvement.
In 1991 it could be demonstrated that the biweekly infusion of a modified ß-glucocerebrosidase, extracted and purified from human placenta, has a significant therapeutic effect in patients affected by Gaucher disease. This treatment resulted in an increase of hemoglobin and platelets and a reduction of spleen size. The efficacy of the enzyme preparation, now produced by gene technology, has been confirmed in thousands of Gaucher patients. In the last years, enzyme preparations have been developed also for other lysosomal storage disorders. For patients with Fabry disease two different enzyme preparations are available: Agalsidase alfa (Replagal®), produced in a human cell line, and agalsidase beta (Fabrazyme®), produced in CHO cells. Both enzymes have been shown to be able to reduce pain, to reduce left ventricular mass and to stabilize kidney function. However, agalsidase alfa and agalsidase beta do not seem to have any effect on the cerebrovascular complications of Fabry disease.
For three types of mucopolysaccharidoses enzyme replacement therapy is available: Aldurazyme® for MPS I (Hurler and Scheie disease), Elaprase® for MPS II (Hunter disease) and Naglazyme® for MPS VI (Maroteaux-Lamy disease). It could be shown in several studies, that treatment with these enzymes leads to increase of general endurance (as demonstrated by the 6-minute-walk-test), improvement of lung function, reduction in liver size and improvement of joint mobility. These enzymes do not have any effect on the manifestation of the central nervous system, as they are not able to enter the blood-brain barrier. The clinical effects of long-term therapy are not known until now.
The enzyme preparation Myozyme® has been demonstrated to have positive clinical effects in patients with all forms of Pompe`s disease, the infantile, juvenile and adult type. In infantile form, the enzyme does not only increase muscle strength, but also leads to a rapid decline of left ventricular mass.
In summary, all enzyme preparations are effective in improving some signs and symptoms and to halt the progression of the disease, however, they are not able to cure the patient.

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