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1. Introduction
2. Outline
3. MLD is a lysosomal storage disorder
4. Degradation of sulfatide by ASA
5. Myelin is a membrane of oligodendrocytes
6. Demyelination is a pathology of MLD
7. Patient suffering from MLD
8. Handwriting of a MLD patient
9. MLD is clinically heterogeneous
10. Genetics of MLD
11. Structure of the human ASA gene
12. 3 mRNA generated from ASA gene
13. Mutations in the human ASA gene
14. Only three mutations are frequent
15. Genotype-phenotype correlation in MLD
16. ASA activity in fibroblasts
17. Biochemical consequences of mutations
18. Molecular explanations for complete activity loss
19. Different types of mutations in ASA gene
20. Structure of human ASA
21. Many defective ASA are severely misfolded
22. Molecular basis for residual ASA activity
23. ASA dimers form octamers in the lysosome
24. ASA forms octamers
25. Pro 426 is involved in octamerization
26. Consequences of Pro 426 for leucine substitution
27. ASA pseudodeficiency
28. Deficiency of ASA is not a proof for MLD
29. Size of pseudodeficiency ASA
30. Glycosylation sites in ASA pseudodeficiency
31. Amount of pseudodeficiency ASA
32. ASA mRNA species in pseudodeficiency
33. Possible changes in mRNA species
34. Structure of the ASA pseudodeficiency allele
35. Diagnostic example
36. Therapeutic trials in a mouse model
37. Sulfatide storage in the brain of ASA deficient mice
38. Sulfatide storage in glia and neurons
39. Ultrastructure of storage material (1)
40. Ultrastructure of storage material (2)
41. ASA deficient mice do not demyelinate
42. Acoustic ganglion degeneration
43. Progressive neurologic symptoms
44. Properties of ASA deficient mice
45. Therapeutic trials in ASA knock out mice
46. AAV5 ASA injections in ASA knock out mice
47. Reduction of sulfatide storage after injections
48. Functional improvements after injections
49. Enzyme replacement studies
50. Sulfatide reduction in kidney after ASA injection
51. Sulfatide reduction in sciatic nerve
52. CNS pathology after 4 weekly doses of ASA (1)
53. CNS pathology after 4 weekly doses of ASA (2)
54. Improvement of neurologic symptoms
55. Summary

Topics Covered

• Metabolic defect in metachromatic leukodystrophy
• Genetics
• Genotype/phenotype correlations
• Biochemical consequences of selected mutations
• Diganostic problems due to arylsulfatase A pseudodeficiency
• Gene therapy and enzyme replacement trials in an animal model

Links

Series:

• Protein Epidemiology

Categories:

• Biochemistry
• Cell Biology
• Clinical Practice

Therapeutic Areas:

• Cardiovascular & Metabolic

Talk Citation

Publication History

• Published on October 1, 2007
• Archived on August 13, 2020

Financial Disclosures

• Prof. Volkmar Gieselmann has not informed HSTalks of any commercial/financial relationship that it is appropriate to disclose.