Metachromatic leukodystrophy

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

In metachromatic leukodystrophy, the brain is often heavier than normal. The leukodystrophy is diffuse, as in the globoid type. Demyelinization, astrocytosis, and histiocytosis are found in the areas of leukodystrophy. Metachromatic globules are dispersed in the white matter and within histiocytes. Groups of neurons containing metachromatic lipids are also often found (see... 

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. 

Metachromatic leukodystrophy AR Aryl sulfatase A Accumulation of sulfatide in brain see text 1,2, Ch. 40... 

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... 

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... 

In case of a deficiency of arylsulfatase A, at least one other sulfatase should be measured to exclude multiple sulfatase deficiency (see Chap. 4.1 for the assays of arylsulfatase and other sulfatases). Sulfatide excretion in urine should be measured (see assay below) and/or mutation analysis should to performed to confirm the diagnosis, especially if the clinical symptoms are atypical and in order to exclude a pseudodeficiency of arylsulfatase A. The enzyme should always be measured in the parents to check for the presence of compound heterozygosity of a metachromatic leukodystrophy and a pseudodeficiency allele. This is very important for the interpretation of the results of arylsulfatase A assays, especially when performed in asymptomatic or presymptomatic siblings or in the context of a prenatal diagnosis. Sulfatide should also be measured in case a normal arylsulfatase A activity is found in a patient with symptoms characteristic of (juvenile) metachromatic leukodystrophy. Increased urinary sulfatide excretion is indicative of an activator protein/saposin deficiency (Fig. 4.4.1). 

Natowicz MR, Prence EM, Chaturvedi P, Newburg DS (1996) Urinary sulfatides and the diagnosis of metachromatic leukodystrophy. Clin Chem 42 232-238... 

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... 

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). 

Metachromatic leukodystrophy Arylsulfatase a Sulfated gly-colipids Neurological, hyoptonia, ocular Mouse Retrovirus Ex vivo (Matzner et al., 2000a,b, 2002) Lenivirus Intracranial... 

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.

Metachromatic leukodystrophy Mental retardation Psychological disturbances in adult form Yellow-brown staining of nerves seen with cresyl violet dye... 

Systematic large studies of the incidence of HEXA abnormalities among patients in common diagnostic categories such as schizophrenia are in short supply. What studies have been done encourage further work (Goodman, 1994). Studies of another inborn error of metabolism associated with schizophrenia syndromes, metachromatic leukodystrophy, have shown a high incidence of abnormalities in... 

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