What are Lysosomal Storage Disorders (LSDs)?

Lysosomal storage Disorders (LSDs) are a group of approximately 45 rare genetic disorder caused by deficiency of certain enzymes in certain compartments of the cells. All LSDs share a common pathogenesis: a genetic defect in one or more specific lysosomal enzymes, activator protein or membrane protein, resulting in deficient enzymatic activity. In other words, when the lysosome does not function normally, excess products destined for breakdown and recycling is stored in the cell.

The lysosome itself was discovered in 1955 and by 1960 its role in cellular digestion was well understood. Pompe disease was the first to be formally diagnosed. By 1970s the scientific community had recognized many more LSDs and categorized them based on the type of enzymatic defect and/or stored substrate product.

The symptoms of Lysosomal Storage Disease vary, depending on the particular disorder and other variables like the age of onset, and can be mild to severe. They can include developmental delay, movement disorders, seizures, dementia, deafness and/or blindness. Some people with Lysosomal Storage Disease have enlarged livers (hepatomegaly) and enlarged spleens (splenomegaly), pulmonary and cardiac problems, and bones that grow abnormally.

A patient with LSD not only develops physical deformation in cell structures throughout the body, but these cells often die resulting in a wide variety of clinical symptoms. If diagnosed late and/or left untreated patients are at risk of developing significant, irreversible damage and loss of body functions, and life-threatening complications.

LSDs encompass a broad group of rare, inherited metabolic conditions resulting from defects in lysosomal function. Here’s a comprehensive
list of known LSDs:

Glycogen Storage Diseases

1. Pompe Disease (Glycogen Storage Disease Type II)

 

Sphingolipidoses

2. Gaucher Disease
3. Fabry Disease
4. Niemann-Pick Disease Types A and B (SMPD1-related)
5. Niemann-Pick Disease Type C (NPC1 and NPC2-related)
6. Tay-Sachs Disease
7. Sandhoff Disease
8. Metachromatic Leukodystrophy (MLD)
9. Krabbe Disease (Globoid Cell Leukodystrophy)
10. Farber Disease
11. GM1 Gangliosidosis
12. GM2 Gangliosidosis (Tay-Sachs and Sandhoff Diseases)
13. Schindler Disease
14. Fabry-Anderson Disease

 

Mucopolysaccharidoses (MPS)

15. MPS I (Hurler, Scheie, and Hurler-Scheie Syndromes)
16. MPS II (Hunter Syndrome)
17. MPS III (Sanfilippo Syndrome, Types A, B, C, D)
18. MPS IV (Morquio Syndrome, Types A and B)
19. MPS VI (Maroteaux-Lamy Syndrome)
20. MPS VII (Sly Syndrome)
21. MPS IX (Hyaluronidase Deficiency)

Oligosaccharidoses

22. Aspartylglucosaminuria
23. Fucosidosis
24. Mannosidosis (Alpha and Beta)
25. Sialidosis
26. Schindler Disease
27. Galactosialidosis

 

Glycoproteinoses

28. Alpha-Mannosidosis
29. Beta-Mannosidosis
30. Aspartylglucosaminuria
31. Fucosidosis
32. Sialidosis
33. Galactosialidosis
34. Mucolipidosis II (I-Cell Disease)
35. Mucolipidosis III (Pseudo-Hurler Polydystrophy)

Lipidoses

36. Wolman Disease
37. Cholesteryl Ester Storage Disease
38. Farber Lipogranulomatosis

 

Neuronal Ceroid Lipofuscinoses (NCL)

39. Infantile NCL (CLN1/PPT1)
40. Late Infantile NCL (CLN2/TPP1)
41. Juvenile NCL (CLN3)
42. Adult NCL (CLN4/Kufs)
43. CLN5 Disease
44. CLN6 Disease
45. CLN7 Disease
46. CLN8 Disease
47. CLN10 Disease (CTSD)
48. CLN11 Disease (GRN)

 

Mucolipidoses

49. Mucolipidosis II (I-Cell Disease)
50. Mucolipidosis III (Pseudo-Hurler Polydystrophy)
51. Mucolipidosis IV

 

Cystine Storage Diseases

52. Cystinosis

 

Sialic Acid Storage Diseases

53. Salla Disease
54. Infantile Free Sialic Acid Storage Disease

 

Other LSDs

55. Multiple Sulfatase Deficiency (Austin Disease)
56. Danon Disease (LAMP2 Deficiency)
57. Pycnodysostosis
58. Hereditary Inclusion Body Myopathy 2 (GNE Myopathy)
59. Niemann-Pick Disease, Type D

This list includes many of the known LSDs, but the field of Lysosomal Storage Disorders is continually evolving as new conditions are
identified and better understood.

Treatment

There are no cures for lysosomal storage diseases and treatment is mostly symptomatic, although bone marrow transplantation and enzyme replacement therapy (ERT) have been successful in some cases.  In addition, umbilical cord blood transplantation is being performed at specialized centers for a number of these diseases. In addition, substrate reduction therapy, a method used to decrease the accumulation of storage material, is currently being evaluated for some of these diseases. Furthermore, chaperone therapy, a technique used to stabilize the defective enzymes produced by patients, is being examined for certain of these disorders. Gene therapy involves replacing the patient’s mutated gene with a normal copy to allow proper enzyme production. However, it is still in the pre-clinical phase (animal studies) and much research is needed.

Diagnosis

The majority of the patients are initially screened by enzyme assay, which is the most efficient method to arrive at a definitive diagnosis. In some families where the disease-causing mutation(s) is known and in certain genetic isolates, mutation analysis may be performed. In addition, after a diagnosis is made by biochemical means, mutation analysis may be performed for certain disorders.