Multiple sulfatase deficiency

Multiple sulfatase deficiency (MSD). The clinical presentation of MSD includes features of MLD and the MPS, with the features that resemble MLD, such as gait disturbances, psychomotor retardation and polyneuropathy predominating. MPS-like features, such as facial coarsening, hepatosplenomegaly and joint stiffness, are present to a milder and variable extent. A reduction in the activity of all sulfatases is the key diagnostic abnormality. Von Figura and associates have demonstrated that catalytic activity of all sulfatases requires a post-translational modification in which a cysteine residue (cysteine 69 in arylsulfatase A) is oxidized to an aldehyde. It is this modification that is defective in MSD [5]. 

Dierks, T., Schmidt, B., Borissenko, L. V. et al. Multiple sulfatase deficiency is caused by mutations in the gene encoding the human Ca-formylglycine generating enzyme. Cell 113 435-444, 2003. 

Fig. 4.1.9 Electrophoresis pattern of different types of MPS (indicated beneath the corresponding band). Standards (STD) and normal controls (N) were also run on each gel. GAGs are labeled on the left side of the figure. The picture was kindly provided by Dr. E Buerger, Metabolic Center Heidelberg, Germany. GM1 GM1-gangliosidosis, MSD multiple sulfatase deficiency ML II mucolipidosis II, LZ loading zone of the gel...

Fibroblasts from patients with multiple sulfatase deficiency may show 6-15% of normal activity. Similarly, fibroblasts from patients with mucolipidoses II and III have about 15% of normal activity, while serum activity is approximately 20-fold increased. 

Patients with multiple sulfatase deficiency also show low N-acetylglucosamine-6-sulfatase activity. Therefore, arylsulfatase A or another sulfatase should also be determined in case of low results for a single sulfatase, especially when jS-galactosidase activity is in the normal range for that sample. 

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). 

Sulfatases are unusual in having a residue of formylglycine at the active site. This is generated oxidatively from cysteine in human enzymes923/923a and from serine in some bacterial sulfatases.924 9243 Absence of this modification results in a multiple sulfatase deficiency disease. A probable mechanism of sulfatase... 

F-1) The mucopolysaccharidoses are proteoglycan disorders that generally result from a hereditary lysosomal defect in enzymes that normally degrade mucopolysaccharides (in most cases heparan sulfate and dermatan sulfate). This leads to the accumulation of different mucopolysaccharides, which may be associated with a variety of different findings, commonly including mental retardation and various skeletal abnormalities. These diseases include Hunter disease, Hurler and Scheie disease, I-cell disease , Maroteaux-Laury disease, Morquio syndrome, Mucolipidoses VH disease, multiple sulfatase deficiency, and Sanfilippo A and B diseases, which will not be elaborated on further here. Often these conditions can be detected in advance on amniocentesis. 

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. 

Austin, J. H., Multiple sulfatase deficiency. Arch. Neurol. (Chicago) 28, 258-264 (1973). 

Eto, Y., Rampini, S., Wiesmann, U., and Herschkowitz, N. N., Enzymic studies of sulfatases in tissues of the normal human and in metachromatic leukodystrophy with multiple sulfatase deficiencies. ]. Neurochem. 23, 1161-1170 (1974a). 

Fiddler, M. B., Vine, D., Shapira, E., and Nadler, H. L., Is multiple sulfatase deficiency due to defective regulation or sulfohydrolase expression. Nature (London) 282, 98 (1979). 

Horwitz, A. L., Warshawsky, L., King, J., and Burns, G., Rapid degradation of steroid sulfatase in multiple sulfatase deficiency. Biochem. Biophys. Res. Commun. 135, 389-396 (1986). 

Kresse, H, and Holtfrerich, D., Thiosulfate-mediated increase of arylsulfatase activities in multiple sulfatase deficiency disorder fibroblasts. Biochem. Biophys. Res. Commun. 97, 41-48 (1980). 

Moser, H. W., Sugita, M., Harbison, M. D., and Williams, M. Liver glycolipid steroid sulfates and steroid sulfatases in a form of metachromatic leukodystrophy associated with multiple sulfatase deficiencies. In Sphingolipids, Sphingolipidosis, and Allied Disorders (D. W. Volk, and S. M. Aronson, eds.), pp. 429-450, Plenum, New York, 1972. 

Waheed, A., Hasilik, A., and Von Figura, K., Enhanced breakdwon of arylsulfatase A in multiple sulfatase deficiency. Eur. J. Biochem. 123, 317-321 (1982b). 

The activity of ASs depends upon the posttranslational modification of highly conserved residues cysteine in eukaryotes " " and in some prokaryotes, " " " and serine in other prokaryotes. " This posttranslational modification is enzymatically mediated and results in the oxidation of the cysteine or serine to yield an aldehyde residue, referred to as a formylglycine (FGly). " The inability to perform this step results in the occurrence of multiple sulfatase deficiency in humans, an autosomal recessive disease in which the activities of all sulfatases are sharply reduced. ... 

Multiple sulfatase deficiency Posttranslational modification of a cysteine in at least 12 sulfatases 272200... 

In another disease, multiple sulfatase deficiency (MSD) or Austin disease, the activities of all known sulfatases are strongly reduced. The phenotype of the patients is clinically characterized as a combination of symptoms of metachromatic... 

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