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Hereditary and Metabolic Diseases of the Central Nervous System in Adults
Published in Philip B. Gorelick, Fernando D. Testai, Graeme J. Hankey, Joanna M. Wardlaw, Hankey's Clinical Neurology, 2020
This is an autosomal recessive disease caused by a mutation of the GALC gene which encodes for galactocerebrosidase (GALC). The deficiency of this lysosomal enzyme leads to the accumulation of several sphingolipids, including galactosylceramide and psychosine, which result in oligodendrocyte death and demyelination. Disease frequency is 1:100,000, and 1:150 carriers. Males and females are equally affected. Onset is in infancy (90%) to the fifth decade (10% juvenile to adult).
Krabbe disease/galactosylceramide lipidosis/globoid cell leukodystrophy
Published in William L. Nyhan, Georg F. Hoffmann, Aida I. Al-Aqeel, Bruce A. Barshop, Atlas of Inherited Metabolic Diseases, 2020
In both mouse and man, levels of psychosine were increased in brain and peripheral nerves [70, 71]. This compound, galactosylsphingosine, which differs from the cerebroside in the absence of the fatty acid, is not present in large amounts, but it is essentially absent from normal brain. The terminal galactose is cleaved from this compound, too, by the enzyme that is defective in Krabbe disease. Psychosine is a natural detergent and highly toxic [72]. Oligodendroglia appear to be selectively destroyed by psychosine formed within them.
A new compound heterozygous mutation in adult-onset Krabbe disease
Published in International Journal of Neuroscience, 2020
Xianghe Meng, Yingjiao Li, Yajun Lian, Yujuan Li, Liyuan Du, Nanchang Xie, Cui Wang
KD is an autosomal recessive neurodegenerative disorder caused by a lack of lysosomal cysteine protease, galactocerebrosidase (GALC) due to mutations of the galactocerebrosidase-encoding GALC [8]. The accumulation of psychosine results in the death of oligodendrocytes and Schwann cells, both of which are essential to myelin formation. GALC has been mapped to chromosome 14q31 [9], and has 17 exons spanning approximately 60 kb of genomic DNA [10]. Thus far, more than 120 mutations of GALC have been reported worldwide [11]. Enzymatic activity measurement and exome sequencing of GALC would shorten the typically long diagnostic delay and allow earlier consideration of hematopoietic stem cell transplantation as a treatment option for adults [12,13].
Synthesis and structure-activity relationships of cerebroside analogues as substrates of cerebroside sulphotransferase and discovery of a competitive inhibitor
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2020
Wenjin Li, Joren Guillaume, Younis Baqi, Isabell Wachsmann, Volkmar Gieselmann, Serge Van Calenbergh, Christa E. Müller
The natural substrates of CST in nerve tissues are β-galactosylceramides (3) which are converted into 3-O-sulphogalactosylcerebroside that constitutes about 4% of total myelin lipids. They are sphingolipids consisting of (i) a sphingosine residue, (ii) a β-galactose, and (iii) a fatty acid residue attached via an amide linkage. Natural galactosylceramide (3) may contain different saturated or unsaturated (hydroxy)fatty acid residues with chain lengths mostly between C18 and C27, frequently C24. Galactosylceramide displayed a Km value of 60.3 µM determined in our recently developed capillary electrophoresis-based assay and was the best substrate of all compounds investigated in the present study19. The corresponding β-glucosylceramide (9) were shown to be much weaker substrates with only 19% conversion compared to that of 3 (set at 100%) determined under the same conditions. Another natural sphingolipid that had previously been shown to be a substrate of CST is psychosine (8) which is lacking the fatty acid residue of galactosylceramides (3). Psychosine was still efficiently sulphurylated by the enzyme showing an only moderately reduced Km value of 103 µM in the same assay19. A synthetic galactosylceramide analogue, β-KRN7000 (10), in which the double bond of the sphingosine core structure is hydrated and, therefore, contains an additional hydroxy group, led to reduced conversion (42% compared to 100% for galactosylceramide) and an increased Km value of 550 µM (compared to 60 µM for galactosylceramide) determined under the same conditions. Interestingly, the α-galactoside anomer of compound 10, KRN7000 (18) showed about the same conversion rate and Km value indicating that for this series of more polar, hydrated sphingosine-derived synthetic lipids, the enzyme did not discriminate between α- and β-glycosidic configuration. Thus, we investigated further α-galactosyl-lipids (11–17, 19–22) derived from KRN7000 (18) mainly with modification of the fatty acid residue. KRN7000 (18) had previously been found to display immunostimulatory and antitumor activity in several in vivo models, and was advanced to clinical trials29–31.