Leukodystrophy

The disruption of C1C-2 in mice leads to male infertility, blindness, and leukodystrophy, and was attributed to defective extracellular ion homeostasis in narrow clefts. C1C-2 yields currents that slowly activate upon hyperpolarization. It is also activated by cell swelling and by extracellular acidification. Structural determinants that are essential for these types of activation were identified by mutagenesis. There is a report that C1C-2 might be mutated in human epilepsy, but this has not been confirmed in fiuther studies. 

Kaback, M. M. and Howell, R. R. "Infantile Metachromatlc Leukodystrophy. Heterozygote Detection in Skin Fibroblasts and Possible Application to Intrauterine Diagnosis". New Engl. J. Med., (1970), 2S2, 1336-1340. 

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

Ellis, W. G. Schneider E. L. McCulloch, J. R. Suzuki R. and Epstein, C. J. "Fetal Globoid Cell Leukodystrophy (Rrabbe s Disease) Pathological and Biochemical Examination". Arch. Neurol., (1973), 29, 253-257. 

Fogli, A., Schiffmann, R., Bertini, E., Ughetto, S., Combes, P., Eymard-Pierre, E., Kaneski, C. R., Pineda, M., Troncoso, M., Uziel, G., Surtees, R., Pugin, D., et al. (2004a). The effect of genotype on the natural history of eIF2B-related leukodystrophies. 

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. 

Neuropathies can result from mutations that alter the structure or level of expression of PNS myelin proteins (e.g. overexpression of PMP22 in Charcot-Marie-Tooth syndrome (CMT) type 1A), the metabolism of myelin lipids (e.g. metachromatic leukodystrophy), or the capacity of PNS neurons to support their axons in patients with CMT caused by mutations of KIF1B [4] or NF-L [5, 6]. Both acquired and inherited amyloid neuropathies can result from the deposition of poorly soluble proteins, for example cryoglobulins or mutant transthyretins, in and around endoneurial bloodvessels [7-9]. 

Familial demyelinative/dysmyelinative and axonal neuropathies may also be caused by impaired lysosomal lipid metabolism. Metachromatic leukodystrophy (sulfatide lipidosis) results from mutations of the arylsulfatase A gene, which encodes a lysosomal enzyme required for sulfatide turnover. Myelin is affected in both CNS and PNS, though dysfunction is restricted to the PNS in some patients, and the onset of symptoms can occur at any time between infancy and adulthood. Bone marrow transplantation can slow disease progression and improve nerve conduction velocities [57]. (See in Ch. 41.)... 

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 647... 

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... 

Krabbe s leukodystrophy AR Galactocerebroside- P-galactosidase Globoid cells contain galactocerebroside see text 1,2, Ch. 40... 

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

Metachromatic leukodystrophy is due to a defect in arylsulfatase A (ASA). There are three major forms late infantile, juvenile and adult. The overall incidence is 1 40,000. In the late infantile and early juvenile forms, which comprise about 80% of patients, the initial symptoms involve the motor system, with falls, loss of ability to walk, flaccid paralysis, difficulty in swallowing, loss of speech, vision, seizures, decerebrate state and death 1-7 years after onset of symptoms. In the adolescent and... 

Globoid leukodystrophy Metachromatic leukodystrophy X-linked adrenoleukodystrophy Refsum s disease Cystinosis... 

Krivit, W., Peters, C. and Shapiro, E. G. Bone marrow transplantation as effective treatment of central nervous system disease in globoid cell leukodystrophy, metachro-matic leukodystrophy, adrenoleukodystrophy, mannosidosis, fucosidosis, aspartylglucosaminuria, Hurler, Maroteaux-Lamy, and Sly syndromes, and Gaucher disease type III. Curr. Opin. Neurol. 12 167-176,1999. 

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. 

Very rare disorders include juvenile metachromatic leukodystrophy, adrenoleucodystrophy, Wilson s disease These conditions are associated with movement disorders, particularly gait disturbance. It is important to attempt to distinguish between primary and secondary (antipsychotic related) movement disorders These conditions are characterized by a progressive loss of cognitive skills (in contrast to the more relative decline seen in schizophrenia and other developmental disorders, where a loss of previously learned skill is unusual)... 

Iversen SD 5-HT and anxiety. Neuropharmacology 23 156-164, 1984 Iwamori M, Moser HW, Kishimoto Y Steroid sulfatase in brain comparison of sulfohydrolase activities for various steroid sulfates in normal and pathological brains, including various forms of metachromatic leukodystrophy. J Neurochem 27 1389-1395, 1976... 

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