Chapter 136

## Abstract

Abstract

1. The mucopolysaccharidoses (MPS) are a group of lysosomal storage disorders caused by deficiency of enzymes catalyzing the degradation of glycosaminoglycans (mucopolysaccharides). Depending on the enzyme deficiency, the catabolism of dermatan sulfate, heparan sulfate, keratan sulfate, chondroitin sulfate, or hyaluronan may be blocked, singly or in combination. Lysosomal accumulation of glycosaminoglycan molecules results in cell, tissue, and organ dysfunction. Glycosaminoglycan fragments generated by alternative pathways are excreted in urine. There are 11 known enzyme deficiencies that give rise to 7 distinct MPS. Table 136-1 presents the affected enzymes and glycosaminoglycans, and the corresponding syndromes and subtypes.

2. The stepwise degradation of glycosaminoglycans requires four exoglycosidases, five sulfatases, and one nonhydrolytic transferase. Endoglycosidases also participate in the degradation. The genes and cDNAs encoding most of these enzymes have been cloned, leading to elucidation of their primary structure, to production of recombinant enzymes, and to identification of mutations causing disease.

3. The MPS share many clinical features, although in variable degrees. These include a chronic and progressive course, multisystem involvement, organomegaly, dysostosis multiplex, and abnormal facies. Hearing, vision, airway, cardiovascular function, and joint mobility may be affected. Profound mental retardation is characteristic of MPS IH (Hurler syndrome), the severe form of MPS II (Hunter syndrome), and all subtypes of the MPS III (Sanfilippo syndrome), but normal intellect may be retained in other MPS. The bony lesions of MPS IV (Morquio syndrome) are specific to that disorder. There is clinical similarity between different enzyme deficiencies, and, conversely, a wide spectrum of clinical severity within any one enzyme deficiency. Supportive management—with particular attention to respiratory and cardiovascular complications, loss of hearing and vision, communicating hydrocephalus, and spinal cord compression—can greatly improve the quality of life for patients and their families.

4. The MPS are rare diseases. They are transmitted in an autosomal recessive manner except for MPS II, which is X-linked. Mutations underlying any one MPS are very heterogeneous, but one or a few mutant alleles may predominate in specific populations. Most are point mutations or small changes in the gene, although major DNA rearrangements and large deletions occur in MPS II. Correlation of disease severity with genotype is sometimes possible, but the effect of missense mutations is generally difficult to predict.

5. Enzyme assays are available for diagnosis, including prenatal diagnosis, of all the MPS. Identification of heterozygotes on the basis of enzyme activity is generally difficult or insufficiently accurate. Because of the heterogeneity of mutations, diagnosis and carrier testing by DNA analysis requires knowledge of the mutant alleles in the family under consideration.

6. There are numerous animal models of MPS. In addition to the models derived from mutations that have occurred naturally in dogs, cats, rats, mice, and goats, there are several mouse models created by targeted disruption of the corresponding mouse gene. The biochemical and pathologic features of these animal models is generally quite similar to those of their human counterparts, but the clinical presentations may be milder.

7. The MPS have long been considered potentially amenable to therapy by exogenously supplied enzyme. The success of bone marrow transplantation in altering the course of some MPS demonstrated that enzyme from donor hematopoietic cells could reduce glycosaminoglycan storage in somatic tissues of the recipient. Unfortunately, the variable neurologic benefit and the high risk associated with bone marrow transplantation limit the value of this form of therapy. Enzyme replacement is under active development, while gene therapy is at a much earlier stage. The animal models of MPS are proving extremely useful for developing and testing novel therapies.

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