Pompe's disease - RePub - Erasmus Universiteit Rotterdam

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Introduction Chapter 1 1.1 Lysosomal storage diseases Pompe’s disease or Glycogen Storage Disease type II (Pompe’s, disease OMIM 232300) is a lysosomal storage disorder with an autosomal recessive mode of inheritance. The disease is caused by the defi ciency of the lysosomal enzyme acid α-glucosidase (acid maltase). Lysosomes are cytoplasmic organelles with an acidic interior containing a great variety of enzymes capable of hydrolysing most biologic materials (1, 2). Primary lysosomes pinch off from the Golgi apparatus and fuse with other membrane bound vesicles containing the lysosomal substrates, to form secondary lysosomes. These substrates are either derived from the extra cellular space through endocytosis or from within the cell through autophagy. A major function of the lysosome is degradation of intra- and extra cellular macromolecules in the process of normal cellular recycling and tissue remodeling. Other functions of the lysosome are more cell type specifi c. For instance, lysosomes play a special role in erythrocyte maturation, in macrophage activity and in bone resorption by osteoclasts (3). At present, approximately 40 lysosomal enzymes have been identifi ed (3, 4). They are glycoproteins that are synthesised in the endoplasmic reticulum in a precursor form. The initial protein undergoes extensive modifi cation including proteolytic cleavage, glycosylation and addition of recognition markers for compartmentalisation into the primary lysosomes. The concept of lysosomal storage diseases arose from studies of glycogen storage disease type II. The demonstration of lysosomal accumulation of glycogen as a result of acid αglucosidase defi ciency led Hers et al. to defi ne a lysosomal storage disease as an inborn error of metabolism in which a single lysosomal enzyme defi cit causes abnormal deposition of a substrate in vacuoles (lysosomes) (2). In time this defi nition was expanded to encompass diseases related to defi ciencies of other proteins necessary for lysosomal function such as activator proteins and lysosomal membrane proteins. The spectrum of lysosomal storage disorders includes mucopolysaccharidosis, lipidosis, oligo-saccharidosis and others. Most diseases are inherited in an autosomal recessive mode, with the exception of Fabry’s disease (OMIM 301500) and mucopolysaccharidosis II (MPS II, Hunters disease, OMIM 309900), which are X-linked recessive (5). In the years following the introduction of the lysosomal concept, the primary enzyme defi ciencies of many of the lysosomal disorders were gradually discovered (fi g.1). Later, genes were cloned and mutations were identifi ed. When the disease loci became known and the knowledge of the human genome increased, some lysosomal disorders were fi rst identifi ed by their gene rather than by their protein defect, as for instance in juvenile Ceroïd lipofuscinosis (CLN3, OMIM 204200) (6). Fig. 1. Discovery of desease related lysosomal defects in time Number 50 40 30 20 10 0 GSDII 1963 function gene 1970 1975 1980 1985 1990 1995 2000 2005 Year CLN3 11
Chapter 1 In lysosomal storage disorders, the affected cell type usually plays a major role in the degradation of the (accumulated) substrate. For example, cerebral white matter is affected in patients with defects in the degradation of sphingolipids. Connective tissue is involved in mucopolysaccharide storage disorders. The symptoms are obviously related to the site of accumulated undegradable materials, but the exact cause of cell death or dysfunction is often unclear. All the disorders are progressive and can be fatal. Defi nitive diagnosis is accomplished by measuring specifi c enzyme activities or function in leukocytes or cultured skin fi broblasts or other tissue specimens, selected on the basis of clinical symptoms. Light or electron microscopy, and DNA analysis can confi rm the diagnosis. There is extensive heterogeneity within each of the disorders, exemplifi ed by infantile, juvenile or adult onset of symptoms, mostly related to residual (enzyme) function. The different types of mutations within the same gene totally eliminating or partially reducing the enzyme activity or lysosomal protein function explain this. In addition, expression of modifying genes also infl uences the phenotype (7, 8). 1.2 Cell biology of lysosomes Processing of lysosomal enzymes The nucleotide sequence of the DNA contains all the information necessary for protein synthesis, modifi cation, transport, and function. There are signals for routing to the various organelles of the eukaryotic cell, post-translational modifi cation, and folding instructions for proper function (Fig. 2). Fig. 2. Procressing of lysosomal enzymes 12 P P Dol Secretory protein Secretory Granule Rough endoplasmatic reticulum Lysosome Golgi UDP UMP Plasma membrane P P P P Lysosomal enzyme Plasma membrane P P P P Acidified compartment P P Modification from the metabolic and molecular bases of inherited disease edition VIII 2001 McGraw-Hill NY. P P Low pH P glucose mannose galactose N-acetylglucosamine sialic acid phosphate protein core
Page 2 and 3: Pompe’s disease The mouse as mode
Page 4 and 5: Pompe’s disease The mouse as mode
Page 6: Contents Chapter 1 Introduction 11
Page 10: 1Introduction
Page 15 and 16: Chapter 1 Network are associated wi
Page 17 and 18: Chapter 1 the indirect approach can
Page 19 and 20: Chapter 1 Diagnosis Clinical Diagno
Page 21 and 22: Chapter 1 Fig. 3. Targeting vectors
Page 23 and 24: Chapter 1 muscles in approximately
Page 25 and 26: Chapter 1 1.7 Scope The studies des
Page 27 and 28: Chapter 1 47. Rudolph, C., et al.,
Page 29 and 30: Chapter 1 112. Dorling, P.R., J.M.
Page 32: 2 Cardiac Remodeling and Contractil
Page 35 and 36: Chapter 2 Experimental groups The a
Page 37 and 38: Chapter 2 Macroscopy The wet weight
Page 39 and 40: Chapter 2 Pooling of all individual
Page 41 and 42: Chapter 2 Hemodynamics during isofl
Page 43 and 44: Chapter 2 Discussion The major fi n
Page 45 and 46: Chapter 2 References 1. Bharati S,
Page 48: 3 Long Term Intravenous Treatment o
Page 51 and 52: Chapter 3 gene, we have focused on
Page 53 and 54: Chapter 3 pattern of alpha-glucosid
Page 55 and 56: Chapter 3 Alpha-glucosidase activit
Page 57 and 58: Chapter 3 and 4, respectively. The
Page 59 and 60: Chapter 3 For patient 1 the mental
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Chapter 3 R.M. Koppenol, T. de Vrie
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4 Morphological Changes in Muscle T
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Chapter 4 Therapeutic regimen Pharm
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Chapter 4 Fig. 2. Pre treatment var
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Chapter 4 Fig. 4. Effect of ERT on
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Chapter 4 Table 2. Patients scores
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Chapter 4 enzyme. Moreover, when th
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5Hearing loss in Infantile Pompe’
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Chapter 5 Methods Patients Seven pa
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Chapter 5 revealed a hearing loss o
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Chapter 5 Fig. 3. Threshold levels
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Chapter 5 Discussion Hearing loss i
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6 Both Low and High Uptake Forms of
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Chapter 6 healthy volunteers, we st
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Chapter 6 was extracted from human
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Chapter 6 from bovine testes (bAGLU
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Chapter 6 Fig. 5. Immunocytochemica
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Chapter 6 glucuronidase, and is obv
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Chapter 6 van Deel MSc for technica
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7Discussion
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Chapter 7 Cardiac function The mous
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Chapter 7 After the fi rst three mo
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Chapter 7 in 2004. This is 40 years
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Chapter 7 the skeletal muscle. The
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Chapter 7 46. Baudhuin, P., H.G. He
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age are ventilator dependent and wh
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om de morfologie van de spieren te
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naar de ziekte van Pompe bij kinder
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Publications Cardiac remodeling and
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Dankwoord Of ‘Mice and men’ zou
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