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.