Residual galactosylsphingosine (psychosine) beta-galactosidase activities and associated GALC mutations in late and very late onset Krabbe disease

Clin Chim Acta. 2002 Mar;317(1-2):77-84. doi: 10.1016/s0009-8981(01)00791-4.


Background: Krabbe disease (globoid-cell leukodystrophy; GLD) is caused by mutations in the GALC gene. Beta-galactocerebrosidase (GALC) is a specific beta-galactosidase which is defective in GLD. About 90% of GLD patients have an infantile course by fatal cerebral demyelination, but 10% have a later onset (LOGLD) of symptoms and survive for one or several decades.

Methods: Activities of GALC towards galactosylceramide (GC) and galactosylsphingosine (psychosine; PS) were determined in white blood cells and cultured fibroblasts derived from GLD patients and controls using tritium-labelled natural substrates. In the galactosylsphingosine (psychosine) beta-galactosidase (GALC-PS) assay, a thin layer chromatographic technique was used to separate enzymatically released radioactive galactose.

Results: Both galactosylceramide beta-galactosidase (GALC-GC) and GALC-PS activities were reduced by at least 85% of the normal in all but 2 of the 10 GLD patients studied. In particular, one 23-year-old severely demyelinated LOGLD patient was strongly deficient (11% of the normal) in GALC-GC but apparently normal for GALC-PS activity. This patient's GALC genotype was the 30-kb-deleted/502T allele combined with a wild-type allele in the 1637C background known to slightly reduce GALC-GC activity. Further, of six LOGLD patients, both of 62- and 63-year-old brothers had the deleted allele combined with an 809G>A mutated 1637C allele. The sibs had strongly reduced GALC-GC and GALC-PS activities but became clinically remarkable only in their 50s with a severe mental downhill course in one of them.

Conclusions: A GALC genotype with one deleted and one polymorphic GALC activity-reducing allele can lead to enzymatic and clinical signs of LOGLD in the absence of marked GALC-PS deficiency. If an active PS hydrolysis in the fibroblasts of a LOGLD patient also reflected such hydrolysis in the brain, the psychosine hypothesis for GLD may need to be revised.

MeSH terms

  • Age of Onset
  • Child, Preschool
  • Female
  • Fibroblasts / enzymology
  • Galactosylceramidase / genetics*
  • Galactosylceramidase / metabolism*
  • Glycoside Hydrolases*
  • Homozygote
  • Humans
  • Leukocytes / enzymology
  • Leukodystrophy, Globoid Cell / enzymology*
  • Leukodystrophy, Globoid Cell / epidemiology
  • Leukodystrophy, Globoid Cell / genetics*
  • Male
  • Middle Aged
  • Mutation
  • beta-Galactosidase / genetics*


  • galactosylsphingosine (psychosine) beta-galactosidase
  • Glycoside Hydrolases
  • exo-beta-D-galactofuranosidase
  • beta-Galactosidase
  • Galactosylceramidase