Leukodystrophies genetics

Kantor, L., Harding, H. P., Ron, D., Schiffmann, R., Kaneski, C. R., Kimball, S. R., and Elroy-Stein, O. (2005). Heightened stress response in primary fibroblasts expressing mutant eIF2B genes from CACH/VWM leukodystrophy patients. Hum. Genet. 118, 99—106. 

Gieselmann, V., Matzner, U., Hess, B. et al. Metachromatic leukodystrophy molecular genetics and an animal model. /. Inherit. Metab. Dis. 21 564-574,1998. 

The human leukodystrophies are inherited disorders of central nervous system white matter. These disorders are characterized by a diffuse deficiency of myelin caused by a variety of genetic lesions and often manifest before 10 years of age (Table 38-1). Some are caused by mutations in the PLP gene and resemble the PLP animal mutants described in Chapter 4 [ 1,23]. As with the animal models, depending on the nature of the mutation, they vary from a severe form in connatal Pelizaeus-Merzbacher disease (PMD) through an intermediate phenotype in classical PMD to a mild phenotype in spastic paraplegia. It is noteworthy that some mutations of the PLP gene also cause a peripheral neuropathy [24], very probably related to the expression of low levels of PLP in peripheral nerve (see Ch. 4). 

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... 

Rafi MA, Coppola S, Liu SL, Rao HZ, Wenger DA (2003) Disease-causing mutations in cis with the common arylsulfatase A pseudodeficiency allele compound the difficulties in accurately identifying patients and carriers of metachromatic leukodystrophy. Mol Genet Metab 79 83-90... 

Whitfield PD, Sharp PC, Johnson DW, Nelson P, Meikle PJ (2001) Characterization of urinary sulfatides in metachromatic leukodystrophy using electrospray ionization-tandem mass spectrometry. Mol Genet Metab 73 30-37... 

A genetic disease, the 18q-syndrome is a rare leukodystrophy presenting a genomic deletion that includes the MBP gene. Proton magnetic resonance data indicate demyelination or increased myelin turnover rather than dysmyelination (Hausleretal., 2005). 

Tominaga K, Matsuda J, Kido M, Naito E, Yokota I, Toida K, Ishimura K, Suzuki K, Kuroda Y (2004) Genetic background markedly influences vulnerability of the hippocampal neuronal organization in the twitcher mouse model of globoid ceU leukodystrophy. J Neurosci Res 77 507-516... 

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

Butterworth, J., Broadhead, D. M., and Keay, A. J., Low arylsulfatase A activity in a family without metachromatic leukodystrophy. Clin. Genet. 14, 213-218 (1978). 

Dubois, G., Harzer, K.. and Bauman, N., Very low arylsulfatase A and cerebroside sulfatase activities in leukocytes of healthy members of metachromatic leukodystrophy family. Am. J. Hum. Genet. 29, 191-194 (1977). 

Mehl, E., and Jatzkewitz, H., Evidence for the genetic block in metachromatic leukodystrophy. Biochem. Biophys. Res. Commun. 19, 407-411 (1965). 

In the human genetic disease X-linked adreno-leukodystrophy (ADL), peroxisomal oxidation of very long chain fatty acids is defective. The ADL gene encodes the peroxisomal membrane protein that trans-... 

The Genetics of Myelination in Metabolic Brain Disease The Leukodystrophies... 

Since the initial discovery of each of the 18 distinct leukodystrophies, significant progress has been made in both the basic and clinical sciences, leading to better understanding and treatment of this class of genetic disorders. These advances... 

Baslow, M. 2000. Canavan s spongiform leukodystrophy A clinical anatomy of a genetic metabolic CNS disease — An analytical review. J. Mol. Neurosci 15 61-69. 

Chen, Y. Q., M. A. Rafi, G. de Gala, and D. A. Wenger. 1993. Cloning and expression of cDNA encoding human grilactocerebrosidase, the enzyme deficient in globoid cell leukodystrophy. Hum Mol Genet 2 1841-1845. 

De Gasperi, R., M. A. Gama Sosa, E. L. Sartorato, S. Battistini, H. MacFarlane, J. F. Gusella, W. Krivit, and E. H. Kolodny. 1996. Molecular heterogeneity of late-onset forms of globoid-cell leukodystrophy. Am J Hum Genet 59 1233-1242. 

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. 

Hogan, G. R., L. Gutmann, and S. M. Chou.1969. The peripheral neuropathy of Krabbe s (globoid) leukodystrophy. Neurology 19 1094—1100 Igisu, H., and K. Suzuki. 1984. Progressive accumulation of toxic metabolite in a genetic leukodystrophy. Science 224 753-755. 

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. 

Matsuda, J, Vanier, MT, Saito, Y, Tohyama, J, Suzuki, K and Suzuki, K (2001) A mutation in the saposin A domain of the sphingolipid activator protein (prosaposin) gene results in a late-onset, chronic form of globoid cell leukodystrophy in the mouse. Hum Mol Genet, 10, 1191-1199. 

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