title: Residual galactosylsphingosine (psychosine) beta-galactosidase activities and associated GALC mutations in late and very late onset Krabbe disease.
abstract: 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.
authors.affiliation: Institut für Hirnforschung, Universität Tübingen, Calwer Strasse 3, D-72076, Tübingen, Germany. Harzer-Rottenburg@t-online.de
authors.forename: Klaus
authors.initials: K
authors.lastname: Harzer
authors.forename: Rupert
authors.initials: R
authors.lastname: Knoblich
authors.forename: Arndt
authors.initials: A
authors.lastname: Rolfs
authors.forename: Peter
authors.initials: P
authors.lastname: Bauer
authors.forename: Jürgen
authors.initials: J
authors.lastname: Eggers
mesh_terms: D017668:Age of Onset; D002675:Child, Preschool; D005260:Female; D005347:Fibroblasts / Q000201:enzymology; D005698:Galactosylceramidase / Q000235:genetics* / Q000378:metabolism*; D006026:Glycoside Hydrolases; D006720:Homozygote; D006801:Humans; D007962:Leukocytes / Q000201:enzymology; D007965:Leukodystrophy, Globoid Cell / Q000201:enzymology* / Q000453:epidemiology / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D001616:beta-Galactosidase / Q000235:genetics*
chemical_list: C455849:galactosylsphingosine (psychosine) beta-galactosidase; D006026:Glycoside Hydrolases; C023112:exo-beta-D-galactofuranosidase; D001616:beta-Galactosidase; D005698:Galactosylceramidase