Diseases metachromatic leukodystrophy

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. 

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.)... 

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

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)... 

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... 

The most commonly used therapy to treat LSDs is heterologous bone marrow transplantation (BMT). This treatment provides both normal bone marrow and bone marrow-derived cells, which release enzyme continuously. Unfortunately, BMT is associated with several problems and risks including the availability of a suitable donor, poor response to therapy, and sustained immune suppression. BMT therapies for MPS I, MPS II, MPS III, metachromatic leukodystrophy, and non-neuronopathic forms of Gaucher disease have demonstrated promising results. In most successful cases, the pathology is reversed in the visceral organs with variable or unclear success in the CNS (Laine et al., 2004). 

Matzner, U., Hartmann, D., Lullmann-Rauch, R., Coenen, R., Rothert, F., Mansson, J. E., Fredman, P., D Hooge, R., De Deyn, P. P. and Gieselmann, V. (2002). Bone marrow stem cell-based gene transfer in a mouse model for metachromatic leukodystrophy Effects on visceral and nervous system disease manifestations. Gene Ther. 9, 53-63. 

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.

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.

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

As with all muscle relaxants, abnormal reactions can occur in patients with neuromuscular diseases. In addition, muscle fibrillation has been reported, possibly due to pancuronium, in a patient with metachromatic leukodystrophy (33). 

Metachromatic leukodystrophy is another lysosomal storage disorder caused by a deficiency of arylsulfatase A which leads to the accumulation of 3-0-sulfogalactosylceramide. The defect results in severe demyelination. The disease often takes a presentation of an under- and mis-diagnosed psychiatric affection long before neurological symptoms appear and MRI displays the anatomical lesions. MRI reveals a diffuse demyelination, bilateral and often symmetrical, initially limited to the periventricular areas. 

SevinC., Verot L., Benraiss A., Van Dam D., BonninD., Nagels G., Fouquet F., Gieselmann V., Vanier M.T., De Deyn P.P., Aubourg P., Cartier N., Partial cure of established disease in an animal model of metachromatic leukodystrophy after intracerebral adeno-associated virus-mediated gene transfer, Gene therapy 14 (2007) 405-414. 

The physiological significance of this kind of activator protein is demonstrated by two fatal lipid storage diseases that are caused by deficiencies of activator proteins rather than of the degrading enzymes variant AB of infantile Gm2 gangliosidosis results from a defect of the Gm2 activator protein (Gonzelmann and Sandhoff, 1978 Hechtman et al., 1982 Hirabayashi et al., 1983), whereas a deficiency of the sulfatide/GMi activator leads to an atypical variant of juvenile metachromatic leukodystrophy (Stevens et al., 1981 Inui et al., 1983). 

A variant form shows a far wider range of stored products, including glycosaminoglycans and cholesteryl sulphate. In this there is deficit of aryl sulphatases A, B and C. Thus, this is a disease that is a mucopolysaccharidosis of the Maroteaux-Lamy type, superimposed upon classical metachromatic leukodystrophy, with a lack of aryl sulphatase C leading to a further accumulation of a steroidal sulphate. 

In some patients, exhibiting symptoms of the juvenile type of metachromatic leukodystrophy, the disease is caused by a defect in saposin B, an activator that is necessary for full arylsulfatase activity [2]. 

For treatment, some patients with metachromatic leukodystrophy have had bone marrow transplantations performed. This procedure may slow the progression of the disease [3]. 

Paigen (1970) further proposed that a number of other inborn metabolic deficiencies may represent defects in architectural genes which regulate the subcellular distribution of specific acid hydrolases. Among these diseases would be included certain mucopolysaccharidoses characterized by a loss of one component of galactosidase (Ho and O Brien, 1969) and metachromatic leukodystrophy in which arylsulfatase A is missing (Austin, et at, 1963, 1965 Mehl and Jatzkewitz, 1965, 1968). 

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. 

Moser, H. W., and M. Lees Sulfatide lipidosis Metachromatic leukodystrophy. In The metabolism of inherited disease, p. 539. Eds J. B. Stanbury, J. B. Wyngaarden, and D. S. Fredrickson. New York McGraw-Hill Book Company 1966. 

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