Enzyme-replacement Therapy in Classic Infantile Pompe Disease: Long-term outcome, dosing and the role of antibodies

__Abstract__ The introduction of enzyme-replacement therapy (ERT) in 2006 has dramatically increased the interest in Pompe disease. In the three decades following the discovery of acid a-glucosidase deficiency as cause of the disease by H.G. Hers in 1963 only very few research laboratories world-wide were studying Pompe disease, investigating the genetic background, the molecular details of acid alpha-glucosidase deficiency, were cloning the gene, making knockout mouse models, and developing ERT. After the start of the first clinical trial of ERT in 199914 more centers got gradually involved and at present over 1,800 patients world-wide are receiving ERT. The number of publications on Pompe disease has risen from 2 in 1963 to 140 in 2012. While untreated patients with classic infantile Pompe disease usually die before the age of one year, the oldest treated patient with classic infantile Pompe disease at Erasmus MC University Medical Center is at present 15 years old. The aims of this thesis were to delineate the long-term outcome of infants treated with ERT, to identify and evaluate the influence of prognostic factors on the effect of ERT, and to explore the effects of a higher and more frequent dosing regimen and of neonatal screening. This first introductory chapter provides information on the incidence and genetics, clinical spectrum, disease pathology, the natural course, and the diagnosis of Pompe disease. It also summarizes the reported effects of ERT and the current limitations that have led to the studies described in this thesis.

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