Krabbe Disease Leukodystrophies

As 1 of the 12 known leukodystrophies, Krabbe disease produces impaired myeiin sheath deveiop-ment with progressive neurodegeneration of both the CNS and the peripherai nervous system. 

Figure 16-5. The pathway of sphingolipid catabolism. Diseases that result from specific enzyme deficiencies are as follows (1) GM, gangliosidosis (2) GM2 gangliosidosis (Tay-Sachs disease) (3) sialidosis (4) Fabry disease (5) Gaucher disease (6) Niemann-Pick disease (7) Krabbe disease (8) metachromatic leukodystrophy (9) Farber disease. Cer, Ceramide Glc, glucose Gal, galactose GalNAc, A -acetylgalactosamine NANA, N-acetyfiieuraminic acid.

Krabbe disease (Globoid-cell leukodystrophy) Galactosylceramidase Galactosylceramide psycosine... 

Other lysosomal storage disorders include G j gangliosidoses, G gangliosidoses, Gaucher disease, Niemann-Pick disease, Fabry disease, fucosidosis, Schindler disease, metachromatic leukodystrophy, Krabbe disease, multiple sulfatase deficiency, Farber disease, and Wolman disease. Table 28-1 illustrates the enzyme deficiencies found in some of these disorders. 

R. Koike, S. Tsuji, Y. Fukumaki, K. Hayashi, and T. Kobayashi. 1997. Adult onset globoid cell leukodystrophy (Krabbe disease) Analysis of galactosylceramidase cDNA from four Japanese patients. Hum Genet 100 450-456. 

Kolodny, E. H., S. Raghavan, and W. Krivit. 1991. Late-onset Krabbe disease (globoid cell leukodystrophy) Clinical and biochemical features of 15 cases. Dev Neurosci 13 232-239. Korenke, G. C., H. J. Christen, B. Kruse, D. H. Hunneman, and F. Hanefeld. 1997. Progression of X-linked adrenoleukodystrophy under interferon-I therapy. J Inherit Metab Dis V20 59-66. Krabbe, K. 1916. A new familial, infamtUe form of diffuse brain sclerosis. Brain 39 74-114. 

Lyon, G., B. Hagberg, P. Evrard, C. Allaire, L. Pavone, and V. M. 1991. Symptomatology of late onset Krabbe s leukodystrophy The European experience. Dev Neurosci 13 240-244. Maestri, N. E., and T. H. Beaty. 1992. Predictions of a 2-locus model for disease heterogeneity Application to adrenoleukodystrophy. Am J Hum Genet 44 576-582. 

Suzuki, K., and K. Suzuki. 1985. Genetic galactosylceramidase deficiency (globoid cell leukodystrophy, Krabbe disease) in different mammalian species. Neurochem Pathol 3 53-68. 

Wenger, D. A., M. A. Rafi, and P. Luzi. 1997. Molecular genetics of Krabbe disease (globoid ceU leukodystrophy) Diagnostic and clinical implications. Hum Mutat 10 268-279. 

Wenger, D. A., K. Suzuki, Y. Suzuki, and K. Suzuki. 2001. Globoid cell leukodystrophy (Krabbe disease), p. 3669-3694. In AL, Beaudet, Scriver, CR, Sly WAS, VaUe D, Childs B, Vogelstein B (eds.), The Metabolic and Molecular Basis of Inherited Disease, 8th ed. McGraw-Hill, New York. 

Lees, M. B., and H. W. Moser The chemical pathology of Krabbe disease and metachromatic leukodystrophy. In Cerebral sphingolipidoses, p. 179. Eds S.M. Aronson and B. W. Volk. New York-London Academic Press 1962. 

Suzuki, K., 1977, Globoid cell leukodystrophy (Krabbe disease) and GMl-gangliosidosis, in Practical Enzymology of the Sphingolipidoses (R. H. Glew and S. P. Peters, eds.), Liss, New York, pp. 101-136. 

Diagnosis of Globoid Cell Leukodystrophy (Krabbe s Disease)". Blochem. Blophys. Res. Commun., (1971), 1363-1366. 

Other leukodystrophies are associated with the lysosomal and peroxisomal disorders in which specific lipids or other substances accumulate due to a deficiency in a catabolic enzyme - for example Krabbe s disease, meta-chromatic leukodystrophy (MLD) and adrenoleuko-dystrophy (ALD) [1,2]. (These are discussed in detail in Ch. 40.) Similarly, disorders of amino acid metabolism can lead to hypomyelination - for example phenylketonuria and Canavan s disease (spongy degeneration) [1, 2, 25] (Ch. 40). The composition of myelin in the genetically... 

Globoid cell leukodystrophy (Krabbe s disease) Galactosylceramidase Galactosylsphingosine Galactosylceramide... 

Lysosomal storage abnormalities, such as glycogenosis (Pompe s disease). Tay-Sachs, Krabbe s. Gaucher s, and Fabry s diseases, as well as melachromatic leukodystrophy, aspariylgiycosaminuria, and Niemann-Pick disease. Also included in this category are mucopolysaccharidoses. Hunter s, Scheie s, and Hurler s syndromes. 

Figure 9.20 Degradation of sphingolipids. Lipid storage diseases are indicated by brackets as follows TS, Tay-Sachs ML, metachromatic leukodystrophy GG, generalized gangliosidosis G, Gaucher s disease NP, Niemann-Pick disease K, Krabbe s disease F, Fabry s disease. The sulfate residue on galactocerebroside is located on position 3 of the galactose residue. Note the sequential nature of the process if one step cannot take place, all subsequent steps cannot take place, either.

Suzuki K. Biochemical pathogenesis of genetic leukodystrophies comparison of metachromatic leukodystrophy and globoid cell leukodystrophy (Krabbe s disease). Neuropediatrics 1984 15 32-36. 

In Krabbe s disease (globoid leukodystrophy) there is accumulation of galactocerebroside in the white matter of the diild s nervous system, as lysosomes lack the enzyme galactoceiebrosid. There is poor myelinization, optic atrophy, mental retardation and, typically, death within 1-2 years of the condition s onset in in ncy. 

Krabbe s disease (Globoid leukodystrophy) Mental retardation, almost total absence of myelin, globoid bodies in white matter of brain Galactocerebroside Galactocerebroside -galactosidase... 

Krabbe S disease, or Krabbe s leukodystn hy, or Galactosylceramide lipidosis, or Globoid cell leukodystrophy (a sphingolipidosis) (see Fig. 3). 

Krabbe s Disease, or Globoid Lipoidosis. The brain of these patients usually appears normal, except for a reduction in size. On section, leukodystrophy of the centrum ovale, the brain stem, and the cerebellum is detectable. Histologically, demyelinization, astrocy-... 

Cerebrosides and sphingomyelin are believed to accumulate in the globoid bodies. In fact, the injection of cerebrosides into rats has led to the appearance in the white matter of cells that resemble globoid cells. The biochemical defect in Krabbe s disease is still unknown, but two clues are available. There are no defects in sphingomyelin breakdown, there is a shift in the ratio of cerebrosides to sulfatides (from 3 to 1 in the normal individuals to 12 to 1 in those with leukodystrophy. These observations have led to the suggestion [127-130] that the lipidosis results from a deficiency of a sulfate-transferring enzyme (see Fig. 3-43). 

Further reading Suzuki, K. and Suzuki, Y. (1978). Galacto-sylceramide lipidosis. Globoid cell leukodystrophy (Krabbe s disease). In Stanbury, J.B., Wyngaarden, J.B. and Fredrickson, D.S. (eds.) The Metabolic Basis of Inherited Disease, 4th Edn., p. 747. (New York McGraw-Hill)... 

A group of inherited diseases in which there are deficiencies of specific lysosomal hydrolases. The diseases are characterized by the deposition of complex lipids. They include Gaucher s disease, Fabry s disease, Krabbe s disease, Tay-Sachs disease, generalized gangliosidosis, Niemann-Pick disease and metachromatic leukodystrophy. 

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