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Clin Chim Acta. 2002 Mar;317(1-2):77-84.

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

Author information

  • 1Institut für Hirnforschung, Universität Tübingen, Calwer Strasse 3, D-72076, Tübingen, Germany. Harzer-Rottenburg@t-online.de

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.

PMID:
11814461
[PubMed - indexed for MEDLINE]
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