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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
The syndrome was first described by Krabbe in 1916 [1]. He reported five patients, of whom four represented two sets of siblings. All were normal at birth, but had rapidly progressive neurologic deterioration from an early onset at 4–6 months until death by the age of 1.5–2 years. In addition to a detailed description of clinical features of the disease, he clearly documented the pathognomonic neuropathologic features of the disorder, including the accumulation of large multinucleated globoid cells. Chemical analysis documented the accumulation of cerebroside in these cells [2, 3] and the induction of globoid cells uniquely by the intracerebral administration of galactocerebroside [4, 5]. The enzymatic defect (Figure 93.1) was discovered in 1970 by Suzuki and colleagues [6, 7], in galactocerebrosidase (galactosylceramide-β-galactosidase) (EC 3.2.1.46). The cDNA has been cloned [8], and the gene was mapped to chromosome 14q24.3–32.1 [9, 10]. A considerable number and variety of mutations have been identified [11]. A single mutation, a 30 kb deletion (502Tdel) has accounted for a large number of Northern European, US, and Mexican patients [12, 13].
Diseases of the Nervous System
Published in George Feuer, Felix A. de la Iglesia, Molecular Biochemistry of Human Disease, 2020
George Feuer, Felix A. de la Iglesia
In Krabbe’s disease or globoid leukodystrophy, the brain shows a very extensive lack of myelin in the cerebral hemisphere, cerebellum, and brain stem. Glial cells grow over the affected demyelinated areas and the accumulation of globoid cells is seen. There is some reduction in the total amounts of cerebrosides in the brain, although the cerebroside: sulfatide ratio is increased. Krabbe’s disease is considered to be a galactocerebroside lipidosis of the white matter (Table 3). The activity of several enzymes involved in sphingolipid metabolism of the brain and other tissues is altered. In particular, in Krabbe’s disease, galactocerebrosidase the activity is decreased by 10% of the normal brain.
Multiple Sclerosis
Published in Irun R. Cohen, Perspectives on Autoimmunity, 2020
The identity of the myelin antigen or antigens which are important in MS is not fully defined, and it is likely that different antigens may be involved in the initiation of the disease process and its later phases. Most attention has been focused on MBP — because it is easily manipulated, its structure is well known, and it is an effective encephalitogen in animals9,110,111 — and also on galactocerebroside (GC), which induces formation of strongly demyelinative antibody.112,113 There are, nevertheless, other less easily studied candidate antigens, which may prove to have a role in MS (Table 4).
Radiation-induced neuropathological changes in the oligodendrocyte lineage with relevant clinical manifestations and therapeutic strategies
Published in International Journal of Radiation Biology, 2022
Upon differentiation into preoligodendrocytes, PDGFRα expression declines (May et al. 2014) and these cells start to express galactosylceramide/sulfatides and pro-oligodendroblast antigen (POA), both of which are recognized by the O4 antibody (Deng and Poretz 2003; Jantzie et al. 2013). They become post-migratory, but remain proliferative (Grinspan and Franceschini 1995) while gaining morphological complexity. Subsequently, preoligodendrocytes further differentiate into less proliferative, immature non-myelinating oligodendrocytes that express galactocerebroside (GalC or O1) (Ono et al. 2001; Yang et al. 2011). In addition, immature oligodendrocytes express 2′-3-cyclic nucleotide 3′-phosphodiesterase (CNPase), an early myelin marker (Gottle et al. 2015) that continues to be expressed in mature myelin (Verrier et al. 2013), as well as G-protein coupled receptor 17 (GPR17) (Fumagalli et al. 2011). These immature oligodendrocytes possess increased number of processes and extensions protruding from their cell bodies (See et al. 2004).
A review on neuropharmacological role of erucic acid: an omega-9 fatty acid from edible oils
Published in Nutritional Neuroscience, 2022
J. B. Senthil Kumar, Bhawna Sharma
Galactosylceramides (Figure 1(G)) and its sulphated version called sulfatide with long-chain fatty acid moieties, in particular 24:0 and 24:1 fatty acids, are considered to be the most typical myelin lipids [45]. The incorporation of these type of saturated and long-chain fatty acid are believed to influence the membrane thickness and the packing density of lipids within myelin. Mice that lack the enzyme UDP-galactose ceramide galactosyltransferase (CGT) (transfers galactose to ceramide in the biosynthesis of galactocerebroside) do not synthesise galactosylceramide and sulfatide and develop severe neurological deficits a few weeks after birth [41]. Similarly, a decrease in sulfogalactosyl ceramide (Figure 1(G)) has been reported in both grey matter and white matter of post mortem brains from AD subjects with mild dementia.
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
A series of analogues of the natural CST substrate galactocerebroside with variations in the galactose moiety (α- and β-glycosides, substitution of the sugar moiety), in the hydroxylated alkyl chain, and in the fatty acid residue was designed and synthesised. β-KRN700021 and α-glycosides 11, 13–16 and 18–21 were prepared as previously described.22–27 The synthetic route to obtain α-galactosylceramides 12, 17 and 22 is depicted in Scheme 1.