Mucopolysaccharidoses , lysosomal

As part of a study on the neurochemistry of the genetic hyperglycoamino-glycanuria conditions (mucopolysaccharidoses), lysosomal enzymes including a- and j8-D-galactosidases in patients of four types and normals have been investigated in brain and liver. ... 

The GAGs are synthesized by the sequential actions of a battery of specific enzymes (glycosyltransferases, epimerases, suhotransferases, etc) and are degraded by the sequential action of lysosomal hydrolases. Genetic deficiencies of the latter result in mucopolysaccharidoses (eg, Hurler syndrome). 

Genetic defects in the degradation of glycoproteins are representative of lysosomal storage disorders. Each disease is caused by a deficiency of a lysosomal hydrolase, accumulation and urinary excretion of substrates, a progressive clinical course and considerable phenotypic variation. These disorders also manifest the clinical symptoms normally associated with genetic mucopolysaccharidoses, namely coarse facies, dysostosis multiplex and/or ocular involvement. 

Degradation of the glycosaminoglycan heparan sulfate by lysosomal enzymes, indicating sites of enzyme deficiencies in some representative mucopolysaccharidoses. 

Correct answer = C. In mucopolysaccharidoses, synthesis of proteoglycans is unaffected, both in terms of the structure and the amount of material synthesized. The diseases are caused by a deficiency of one of the lysosomal, hydrolytic enzymes responsible for the degradation of glycosaminogly-cans (not the core protein). 

Lysosomal storage abnormalities, such as glycogenosis (Pompe s disease). Tay-Sachs, Krabbe s. Gaucher s, and Fabry s diseases, as well as melachromatic leukodystrophy, aspariylgiycosaminuria, and Niemann-Pick disease. Also included in this category are mucopolysaccharidoses. Hunter s, Scheie s, and Hurler s syndromes. 

Gaucher disease, and Krabbe disease. LSDs are classified as mucopolysaccharidoses (MPS), lipidoses, or mucolipidoses depending on the nature of the stored material. Over 40 LSDs are known and they have a collective incidence of approximately 1 in 7000-8000 live births (Meikle et al., 1999 Poorthuis et al., 1999 Winchester et al., 2000). Most of the genes for these lysosomal proteins have been cloned, permitting mutation analysis in individual cases. 

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. 

Fucosidosis, being a so-called mucolipidosis, can be grouped among the mucopolysaccharidoses. It is due to a-fucosidase deficiency (localized on chromosome Ip 34). The storage products are deposited in the form of granular or lamellar inclusions in the lysosomes. This autosomal recessive disorder was first observed by P. Durand et al. in 1967 and clarified by F. Van Hoof et al. in 1968. Besides hepatomegaly, splenomegaly may also sometimes occur. 

Excessive accumulation of proteins, nucleic acids, carbohydrates, and lipids can result from deficiency of one or more lysosomal hydrolases. Lysosomal storage diseases are classified by the stored material. Accumulation of gly-cosaminoglycans results in mucopolysaccharidoses. Common causes of this disorder include Hunter syndrome, Hurler syndrome, and Sanfihppo syndrome. Sanfdippo syndrome is inherited in an autosomal recessive pattern and clinically evident by profound mental retardation, lack of normal developmental milestones, and significant language delay. Sanfdippo syndrome results in an excess of heparan sulfate and can be caused by a variety of enzyme deficiencies. 

Figure 29-1. Lysosomal degradation of heparan sulfate. Dark arrows indicate the site of action of the enzyme, which is listed in italics. Mucopolysaccharidoses (MPS) due to a deficiency of the indicated enzymes are listed in bold to the right of the enzyme.

Mucopolysaccharidoses occur when there is a genetic deficiency of the enzymes involved in the lysosomal breakdown of the glycosaminoglycans. 

Table 20-1 Lysosomal Storage Diseases Sphingolipidoses and Mucopolysaccharidoses... 

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