Sphingolipidoses E75.3

Sphingolip(o)idoses are hereditary lipid storage diseases (enzymopathies) and belong to the rare lysosomal storage diseases. Hereditary lysosomal enzyme defects or deficits or defects of the transport or activator proteins lead to a pathological intracellular accumulation of non-degradable lipoids (thesaurismosis). Sphingolipids are important components of membrane structures and play a role in cell proliferation and differentiation. There are several clinical variants of each individual enzyme disorder, almost all of which affect the CNS and often manifest themselves in childhood. Sphingolipidoses are inherited autosomal recessively (except Fabry: X-recessive). Their pathogenesis has only been partially researched so far.

The following diseases with dermatological relevance are counted among the sphingolipidoses (see also table 1):

• Fabry disease
• M. Gaucher
• Aspartyl glucosaminuria
• Niemann-Pick disease
• M. Farber (disseminated lipogranulomatosis)
• Beta-mannosidosis
• Fucosidosis
• Kanzaki disease
• GM1-Gangliosidosis
• Tay-Sachs disease (GM2-Gangliosidose): Beginning in early childhood with cafe-au-lait stains, vitiligo, canities praecox, progressive loss of mental and physical functions (paralysis, dementia, blindness), characteristic ocular fundus changes (grey-white zone around the fovea centralis: "cherry-red spot") Death mostly in the 2-3 years of age. Histology: Balloon-like neurons in the CNS, glial proliferation, demyelination, ganglioside accumulation (GM2: 90-95% vs 5% normal).
• Further sphingolipidoses (without cutaneous symptoms):
  • Sulfatide lipoidosis (metachromatic leukodystrophy: manifestation mostly before the age of 3 years, but occasionally occurring in adults. Patients usually die at the age of 5 years. The clinical picture begins with gait disturbances and developmental arrest followed by speech impediment, paralysis and other severe neurological deficits).
  • Krabbe's disease (globoidal cell leukodystrophy): Begins in the 4th-6th month of life with degeneration of the white matter; usually leads to death before the 2nd year of life).

• Enzyme replacement therapy: missing enzymes, e.g. ß-glucocerebrosidase in M. Gaucher, are substituted with biotechnologically produced enzymes. Because of the blood-brain barrier, enzyme replacement therapies are limited to non-neural storage diseases (Gaucher, Fabry).
• Substrate deprivation: Lysosomal substrate flux is reduced by inhibition of sphingolipid anabolism, i.e. biosynthesis. These therapeutic procedures can lead to immunosuppression and formation of toxic metabolites.

1. Delgado A et al (2007) Chemical Tools to Investigate Sphingolipid Metabolism and Functions. ChemMedChem 25: epub