Sphingolipid-Inherited Diseases of the Central Nervous System

  • S. L. Hoops
  • T. Kolter
  • K. Sandhoff
Reference work entry


The sphingolipidoses are a group of inherited lysosomal storage diseases, which are caused by a defect in one or more sphingolipid degradation steps. The subsequent accumulation of nondegradable material in one or more organs leads to the expression of the disease.

Sphingolipids are integral parts of the plasma membrane of eukaryotic cells, where they form characteristic patterns. They contribute to the glycocalix of the cell and are believed to play a role in cell adhesion phenomena, in the barrier function of the skin, in the immune system, in signal transduction processes, and during embryogenesis. After their biosynthesis at intracellular membranes, they reach the plasma membrane, where they contribute to membrane function. The constitutive degradation of glycosphingolipids takes place on the surface of intraendosomal and intralysosomal membrane structures by the action of specific acid exohydrolases, sphingolipid activator proteins (SAPs), and anionic phospholipids. The deficiency of one of the proteins involved in sphingolipid degradation can cause sphingolipidosis.

The storage of nondegradable compounds, the nature of the storage material, the cell-type specific expression of glycosphingolipids, and the residual activity of the degrading system are significant factors that contribute to the clinical manifestations of sphingolipidoses. However, the pathogenesis of these diseases is poorly understood until now.

In this chapter, we summarize the characteristics of GM1-Gangliosidosis, GM2-Gangliosidoses (including B-variant or Tay-Sachs disease; 0-variant, or Sandhoff's disease, and AB-variant), Fabry's disease, Niemann-Pick disease (NPD) (types A and B), Metachromatic Leukodystrophy (MLD), Gaucher's disease, Krabbe's disease, and Farber's disease, which are all sphinglipidoses affecting the central nervous system.

Most sphingolipidoses are as yet incurable diseases. Both, the ratio of substrate influx into the lysosomes and the degradation capacity can be addressed by therapeutic approaches. The current strategies for restoration of the defective degradation capacity within the lysosome are enzyme replacement therapy (ERT), cell-mediated therapy (CMT) including bone marrow transplantation (BMT) and cell-mediated “cross correction,” gene therapy, and enzyme-enhancement therapy with chemical chaperones. The reduction of substrate influx into the lysosomes can be achieved by substrate deprivation therapy. Patients suffering from adult forms of Gaucher's disease and Fabry's disease have been successfully treated by ERT.


Enzyme Replacement Therapy Lysosomal Storage Disease Metachromatic Leukodystrophy Acid Ceramidase Globoid Cell Leukodystrophy 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

List of Abbreviations:


Arylsulfatase A (ASA)


Acid sphingomyelinase




Bone marrow transplantation


Ceramide (N-Acylsphingosine)


Cell-mediated therapy


Central nervous system




Endoplasmic reticulum


Enzyme replacement therapy


















GM2 activator-protein




Herpes simplex viral vector






Multiple drug resistance


Metachromatic Leukodystrophy




N-Acetylneuraminic acid


Niemann-Pick disease, type C


Niemann-Pick disease


Sphingolipid activator protein






Triosephosphate isomerase


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© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  • S. L. Hoops
  • T. Kolter
  • K. Sandhoff

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