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lysosomal storage diseases

Friday 21 November 2003

Lysosomal storage diseases are due to inherited deficiencies in various enzymes involved in basic metabolic processes. Lysosomal storage disorders can result from the lack of any protein essential for the normal function of lysosomes.

Some lysosomal storage diseases result from the accumulation of lipids in degradative compartments of the endocytic pathway. For example, Niemann-Pick syndromes types A and B are characterized by the accumulation of sphingomyelin, whereas cholesterol typically accumulates in Niemann-Pick type C. These two different lipids, sphingomyelin and cholesterol, are normal constituents of specific lipid microdomains called rafts.


With an inherited deficiency of a functional lysosomal enzyme, catabolism of its substrate remains incomplete, leading to the accumulation of the partially degraded insoluble metabolite within the lysosomes.

Stuffed with incompletely digested macromolecules, these organelles become large and numerous enough to interfere with normal cell functions, giving rise to the so-called lysosomal storage disorders.

- reduced synthesis of lysosomal enzymes ("missing enzyme syndromes")

- Synthesis of a catalytically inactive protein that cross-reacts immunologically with the normal enzyme. Thus, by immunoassays the enzyme levels appear to be normal.
- Defects in post-translational processing of the enzyme protein.

  • Included in this category is a failure to attach the mannose-6-phosphate "marker," the absence of which prevents the enzyme from following its correct path to the lysosome. Instead the enzyme is secreted outside the cell.

- Lack of an enzyme activator or protector protein.
- Lack of a substrate activator protein.

  • In some instances, proteins that react with the substrate to facilitate its hydrolysis may be missing or defective.

- Lack of a transport protein required for egress of the digested material from the lysosomes


- Several distinctive and separable conditions are included among the lysosomal storage diseases. In general, the distribution of the stored material, and hence the organs affected, is determined by two interrelated factors:

- (1) the tissue where most of the material to be degraded is found
- (2) the location where most of the degradation normally occurs.

For example, brain is rich in gangliosides, and hence defective hydrolysis of gangliosides, as occurs in GM1 and GM2 gangliosidoses, results primarily in storage within neurons and neurologic symptoms.

Defects in degradation of mucopolysaccharides affect virtually every organ because mucopolysaccharides are widely distributed in the body. Because cells of the mononuclear phagocyte system are especially rich in lysosomes and are involved in the degradation of a variety of substrates, organs rich in phagocytic cells, such as the spleen and liver, are frequently enlarged in several forms of lysosomal storage disorders.

The ever-expanding number of lysosomal storage diseases can be divided into rational categories based on the biochemical nature of the accumulated metabolite, thus creating such subgroups as the glycogenoses, sphingolipidoses (lipidoses), mucopolysaccharidoses (MPS), and mucolipidoses.

Only one among the many glycogenoses results from a lysosomal enzyme deficiency, and so this family of storage diseases is considered later. Only the most common disorders among the remaining groups are considered here.

- Tay-Sachs Disease (GM2 Gangliosidosis: Hexosaminidase α-Subunit Deficiency)


- glycogenoses (GSDs)

  • type 2-Pompe disease α-1,4-Glucosidase (lysosomal glucosidase > Glycogen)

- sphingolipidoses

  • GM1-gangliosidoses (GM1 ganglioside β-galactosidase > GM1 ganglioside > galactose-containing oligosaccharides)
    • Type 1-infantile, generalized
    • Type 2-juvenile
  • GM2-gangliosidoses
    • Tay-Sachs disease (Hexosaminidase-α subunit > GM2-ganglioside)
    • Sandhoff disease (Hexosaminidase-β subunit > GM2-ganglioside, globoside)
    • GM2 gangliosidosis, variant AB Ganglioside activator protein (GM2-ganglioside)

- sulfatidoses

- mucopolysaccharidoses (MPS)

  • MPSIH (Hurler disease) (α-L-Iduronidase > Dermatan sulfate, heparan sulfate)
  • MPSII (Hunter disease) (l-Iduronosulfate sulfatase)

- mucolipidoses (ML)

  • I-cell disease (ML2) and pseudo-Hurler polydystrophy (Deficiency of phosphorylating enzymes essential for the formation of mannose-6-phosphate recognition marker; acid hydrolases lacking the recognition marker cannot be targeted to the lysosomes but are secreted extracellularly >
    mucopolysaccharide, glycolipid)

- Other diseases of complex carbohydrates

  • fucosidosis (α-fucosidase > fucose-containing sphingolipids and glycoprotein fragments)
  • mannosidosis (α-mannosidase > mannose-containing oligosaccharides)
  • aspartylglycosaminuria (aspartylglycosamine amide hydrolase > aspartyl-2-deoxy-2-acetamido-glycosylamine)

- Other lysosomal storage diseases

  • Wolman disease (acid lipase > cholesterol esters, triglycerides)
  • acid phosphate deficiency (Lysosomal acid phosphatase, phosphate esters)

See also

- lysosomes
- lysosomal proteins
- Storage diseases


- Brooks DA, Muller VJ, Hopwood JJ. Stop-codon read-through for patients affected by a lysosomal storage disorder. Trends Mol Med. 2006 Aug;12(8):367-73. PMID: 16798086

- Futerman AH, van Meer G. The cell biology of lysosomal storage disorders. Nat Rev Mol Cell Biol. 2004 Jul;5(7):554-65. PMID: 15232573

- Simons K, Gruenberg J. Jamming the endosomal system: lipid rafts and lysosomal storage diseases. Trends Cell Biol. 2000 Nov;10(11):459-62. PMID: 11050411