Residual galactosylsphingosine (psychosine) β-galactosidase activities and associated GALC mutations in late and very late onset Krabbe disease
- 作者：Harzer ; Klaus ; Knoblich ; Rupert ; Rolfs ; Arndt ; Bauer ; Peter ; Eggers ; Jü ; rgen
- 关键词：Krabbe disease ; Psychosine ; Psychosine β ; -galactosidase ; β ; -galactocerebrosidase ; GALC mutation ; White blood cells ; Fibroblasts ; GALC ; β ; -galactocerebrosidase ; GALC-GC ; galactosylceramide β ; -galactosidase ; GALC-PS ; galactosylsphingosine (p
- 刊名：Clinica Chimica Acta
- 出版年：2002
- 期刊代码：54_00098981
- 类别：med
- 出版时间：March, 2002
- 卷：317
- 期：1-2
- 页码：77-84
- 文件大小：142 K
摘要
Background: Krabbe disease (globoid-cell leukodystrophy; GLD) is caused by mutations in the GALC gene. β-galactocerebrosidase (GALC) is a specific β-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) β-galactosidase (GALC-PS) assay, a thin layer chromatographic technique was used to separate enzymatically released radioactive galactose. Results: Both galactosylceramide β-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.