Pompe disease was named after the Dutch pathologist Dr. J.C. Pompe who presented in 1932 the case of a 7-month old infant who had died of idiopathic hypertrophy of the heart. In addition to the cardiac problems, the infant had generalised muscle weakness. Dr. Pompe made the crucial observation that the baby's symptoms were associated with massive storage of glycogen in virtually all tissues. Dr. M. Putschar reported a similar case in the same year. In the listing of metabolic glycogen storage diseases, made by Dr. G.T. Cori in 1954, Pompe disease was ranked as number 'two' and named 'Glycogen Storage Disease type II' (GSD II).
Lysosomes and α-glucosidase
In 1955 Prof. Christian DeDuve, a Nobel Price winner, wrote history with his discovery of a new intracellular compartment that he named 'lysosome': literally a body or compartment in which things are taken apart. Lysosomes contain hydrolytic enzymes that are required for the degradation of a wide variety of biological substances. Eight years later (1963), Prof. H.G. Hers discovered that the glycogen storage in Pompe disease is caused by the deficiency of the lysosomal enzyme 'acid α-glucosidase'. World-wide, this was the first finding of an inherited lysosomal enzyme deficiency. It led to the concept of 'lysosomal storage disease' and, indirectly, to the enzymatic definition of many other lysosomal storage disorders in the following years.
The assay of α-glucosidase activity became a diagnostic tool. As maltose is a convenient substrate in this assay, Pompe disease acquired 'acid maltase deficiency' as a third name. It did not take long to discover acid maltase deficiency in patients with skeletal muscle weakness, in the absence of cardiac involvement. These patients were reported to have 'childhood', 'juvenile' or 'adult' (late-onset) forms of Pompe disease.
Mutations in the α-glucosidase gene
From 1963 onwards attention was focused on deciphering the cause of clinical diversity. Patients with late-onset, slowly progressive forms of Pompe disease appeared to have in general more residual acid α-glucosidase activity than patients with early-onset, rapidly progressive forms of the disease. The years from 1980 until approximately 1990 were marked by studies on the biosynthesis and primary structure of acid α-glucosidase, culminating in the cloning of the acid α-glucosidase gene between 1986 and 1990. It then became possible to search for abnormalities ('mutations') in the acid α-glucosidase gene of Pompe disease patients. At present (2007), over two hundred pathogenic mutations are known, and a pattern of genotype-phenotype correlations starts to emerge. Molecular analysis at the protein and DNA level has been incorporated in the diagnostic and prognostic procedures of the laboratories and the practice of genetic counsellors.
Enzyme replacement therapy
With the acid α-glucosidase gene at hand serious and successful attempts were taken to realise large scale production of recombinant human α-glucosidase for therapeutic use (enzyme replacement therapy). Already in 1965 Pompe disease patients received intravenous doses of partially purified α-glucosidases from various sources in order to remove the lysosomal glycogen from their tissues. The rationale behind this type of treatment is based on the fact that tissues and cells in these tissues are able to engulf biological compounds and deliver them to the lysosomes. As we understand it now, these early clinical trials failed due to poor quality and an insufficient dose of the α-glucosidases that were administered. The development of biotechnology has changed that situation dramatically. Human recombinant acid α-glucosidase can now be produced in the milk of transgenic animals and in Chinese hamster ovary cells (see figure). In spring 2006 enzyme replacement therapy derived from Chinese hamster ovary cells (Myozyme, manufactured by Genzyme) received marketing approval in both the European Union and the United States.
Production of acid α-glucosidase in Chinese hamster ovary (CHO-) cells and in the milk of transgenic rabbits.
Research at Erasmus MC
At Erasmus MC we have been working on the development of enzyme replacement therapy since 1984. First it was shown that the lysosomal glycogen storage in cultured muscle cells of patients could be corrected by supplying α-glucosidase. Later, in 1991, we succeeded to demonstrate uptake of α-glucosidase in heart and muscle of mice when given intravenously. In 1995, the first lot of human recombinant α-glucosidase was produced in Chinese hamster ovary cells followed by the production of α-glucosidase in the milk of mice and rabbits (1998).
In January 1999, the first clinical study on the safety and efficacy of recombinant human α-glucosidase from rabbit milk started at Erasmus MC Sophia Children's Hospital. Now, nine years later, approximately 100 children and adults with Pompe disease are treated with enzyme replacement therapy (Myozyme) at Erasmus MC.
Click here for an overview of the published clinical studies on the effects of enzyme replacement therapy.
Click here for an overview of the research currently performed at Erasmus MC.
Last updated 8 september 2008 © Pompe Center, 2008.
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