Lysosomal disorders

Primary lysosomal hydrolase defects 685 Other types of lysosomal disorder 688... 

Other types of lysosomal disorder. These are listed in Table 41-3. 

The diagnosis of lysosomal disorders is usually based on enzymatic assays in white blood cells or cultured skin fibroblasts [ 1 ]. Molecular studies required for identification of carriers. Initial diagnosis of peroxisomal disorders... 

Platt, F. M. and WalHey, S. U. Lysosomal Disorders of the Brain. New York Oxford University Press, 2004. 

Hopwood, J. J., Crawley, A. C. and Taylor, R. M. Spontaneous and engineered mammalian storage disease models. In F. M. Platt and S. U. Walkley (eds), Lysosomal Disorders of the Brain. New York Oxford University Press, 2004, pp. 257-289. 

EC 3.1.6.1) is a lysosomal enzyme that hydrolyzes sulfuric acid ester bonds. The enzyme exists in two forms, arylsulfatases A and B, that differ in substrate specificity and in sensitivity toward inhibitors [142][143]. Human tissues contain more arylsulfatase A than arylsulfatase B. The natural substrates of these enzymes are complex lipids such as cerebroside 3-sulfate, and gly-cosaminoglycans such as chondroitin 4-sulfate and derman sulfate [144], Deficiencies of these enzymes are associated with a number of lysosomal disorders. 

In some disorders there is a clearly recognisable phenotype, often a named syndrome that has later been linked to a specific biochemical cause. However, once the biochemical basis of such a syndrome has been recognised it often becomes apparent that milder variants, formes frustes showing only some of the features of the classical syndrome, are relatively common. The diagnostic assay then changes from being a rarely used confirmatory test to one that is requested relatively frequently for a variety of less specific indications. The same phenomenon is seen where the abnormal phenotype develops progressively, as in most of the lysosomal disorders, and a bat-... 

The lysosomal disorder SASD is characterized by accumulation of the free acid monosaccharide sialic acid in the lysosomal compartment of the cell. Diagnosis is based on the demonstration of abnormal excretion of free, not OGS-bound sialic acid in urine, coupled with accumulation of free sialic acid in cultured fibroblasts, and on microscopic evidence of vacuoles (increased and swollen lysosomes filled with light electron-lucent material in skin biopsy and peripheral blood lymphocytes). The inheritance is autosomal recessive. There are different clinical forms of this disorder an adult form, called Salla disease (SD) or Finnish sialuria (OMIM 604369) infantile SASD (ISSD OMIM 269920) and an intermediate form, severe Salla disease [3,16]. 

Certain studies have sought to correlate the immunological identities of a-L-fucosidases from various mammalian sources, with a view to their utilization in replacement therapy in cases of lysosomal disorders involving this enzyme.266... 

Triggs-Raine, B. et al., Mutations in HYAL1, a member of a tandemly distributed multigene family encoding disparate hyaluronidase activities, cause a newly described lysosomal disorder,mucopolysaccharidosis IX, Proc. Natl Acad. Sci. USA, 96, 6296, 1999. 

There are other lysosomal disorders in addition to those shown in Figure 9.20 and Table 9.1. For instance, several types of fucosidoses exist, which affect such structures as glycoproteins and blood group substances. Sialidoses also exist. However, lysosomal fucosidase and sialidase (neuraminidase) deficiencies do not affect the degradation of gangliosides. 

Wraith JE. Clinical aspects and diagnosis. In Lysosomal Disorders of the Brain. Platt FM, Walkley SU, eds. 2004. Oxford University Press, New York. 

Chemical Libraries Screening for Biologically Active Small Molecules Protein Misfolding and Disease, Chemical Biology of Lysosomal Disorders... 

Jeyakumar M, Dwek RA, Butters TD, Platt FM (2005) Storage soluhons treating lysosomal disorders of the brain. Nat Rev Neurosci 6 713—725... 

Unfortunately, to our knowledge, LB are not well characterized with respect to their chemical nature and origin. Perhaps there is a relationship to lipofuscin pigments and lysosomal disorders or breakdown of cytoskeleton, possibly due to excess Ca +, to yield inclusions similar to the NFT or amyloid plaques of AD. Indeed, it was shown recently by immunohistochemistry that LB in cortex and SN contain epitopes similar to the APP found in Alzheimer brains (Arai et al., 1992). 

N. de Geest, E. Bonten, L. Mann, J. de Sousa-Hitzler, C. Hahn, and A. d Azzo, Systemic and neurologic abnormalities distinguish the lysosomal disorders siali-dosis and galactosialidosis in mice, Mol Genet., 11 (2002) 1455-1464. 

Di Rocco M, et al. Different molecular mechanisms leading to white matter hypomyelination in infantile onset lysosomal disorders. Neuropediatrics. 

Suzuki, K, Praia, RL and Suzuki, K (1998) Mouse models of human lysosomal disorders. Brain Pathol, 8, 195-215. 

Zhou, X, Morreau, H., d Azzo, A. et al (1995) Mouse model for the lysosomal disorder galactosiaUdosis and correction of the phenotype with overexpressing erythroid precursor cells. Genes and Development, 9,2623-2634. 

Fig. 19.2. Clinical approach to the diagnosis of oligosaccharidoses and related lysosomal disorders with early (infantile) onset. Associated with CNS involvement of various types. Facial dysmorphism and/or skeletal (vertebral) involvement suggestive of dysostosis multiplex. Bold conditions associated with abnormal oligosacchariduria italics conditions associated with abnormal mucopolysacchariduria. The percentage of patients showing macular cherry-red spot (when present) is indicated in parentheses. Absence of visceromegaly...

As with the original definition, neonatal screening refers to a rapid mass spectro-metric measurement of all the most prominent AC and the most of the AA, all as markers of possible IBM (namely AA disorders, fatty acid oxidation disorders, and lysosomal disorders). 

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