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  • Updated 02.06.2020
  • Released 11.17.1993
  • Expires For CME 02.06.2023

Mucopolysaccharidoses

Introduction

Overview

The mucopolysaccharidoses are a group of 7 disorders caused by deficiency of any of 11 lysosomal 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 in isolation or in combination. A new type of mucopolysaccharidosis that is not caused by enzyme deficiency but by VPS33A gene mutations has been described. Accumulation of glycosaminoglycans results in cell, tissue, or organ dysfunction. Severe intellectual disability is characteristic of MPS I H (Hurler syndrome), the severe form of MPS II (Hunter syndrome), and all subtypes of MPS III (Sanfilippo syndrome), including acquired autistic behavior, but normal intellect may be retained in other mucopolysaccharidoses. Secondary neurologic complications may occur, such as hearing loss, hydrocephalus, or spinal cord compression that may develop at any stage of the disease and independent of therapy. Specific therapy with enzyme replacement has been approved for MPS I, MPS II, MPS IVA, and MPS VI. Novel brain-penetrating enzyme replacement therapy is being tried in patients with mucopolysaccharidoses I and mucopolysaccharidoses II.

Key points

• The mucopolysaccharidoses are a group of storage disorders caused by the deficiency of enzymes catalyzing the degradation of glycosaminoglycans (mucopolysaccharides).

• Most patients with mucopolysaccharidosis I, II, and III develop variable degrees of intellectual disability, often with autistic features.

• Specific therapy consisting of enzyme replacement, systemic brain-penetrating or intrathecal, and gene therapy are being developed in a number of mucopolysaccharidoses.

• Non-specific therapy, such as early ventricular-peritoneal shunt of obstructive hydrocephalus, is important too.

• Signs of spinal cord compression should prospectively be sought, including after initiation of enzyme replacement therapy.

Historical note and terminology

The mucopolysaccharidoses are a group of inherited single-gene metabolic disorders that result from deficiencies in the lysosomal enzymes required for the degradation of mucopolysaccharides. Hunter and Hurler provided the first reports of patients with the typical constellation of clinical features seen in the mucopolysaccharidoses: coarse facies short stature, corneal clouding (in Hurler, but not Hunter Syndrome), skeletal anomalies, and hepatosplenomegaly (91; 92). This constellation of findings subsequently came to be referred to as "gargoylism." Further in-depth historical accounting of the mucopolysaccharidoses, since Hunter's and Hurler's first reports, can be reviewed elsewhere (123; 85).

Brante identified the material stored in these patients as mucopolysaccharides and, thus, proposed the term "mucopolysaccharidoses" to describe these disorders (17). Dorfman and Lorincz identified heparan sulfate and dermatan sulfate in the urine of a patient with Hurler syndrome (49). Van Hoof and Hers surmised that excessive mucopolysaccharide accumulated in these patients secondary to deficiencies of specific lysosomal hydrolases involved in the degradation of mucopolysaccharides, and that the storage of mucopolysaccharides occurred in the lysosome (202). Hers defined the characteristics of lysosomal storage diseases (78). McKusick proposed a system of classification of the mucopolysaccharidoses into 6 separate entities, based on phenotype, family patterns, and pattern of specific mucopolysaccharides in the urine (124).

In classic experiments utilizing cultured fibroblasts, Dr. Elizabeth Neufeld and her colleagues demonstrated a deficiency of "corrective factors" in individual mucopolysaccharidoses (54; 08; 07). These corrective factors were purified over the next few years, and they were determined to be the various enzymes involved in the stepwise degradation of mucopolysaccharides. Dr. Neufeld's studies led to further classification of the mucopolysaccharidoses because 2 separate defects were found to cause the same phenotype (Sanfilippo syndrome type A and B), and it was also determined that Hurler and Scheie syndromes resulted from deficiency of the same factor, despite their widely different phenotype. This indicated that Hurler and Scheie syndromes probably occurred in homozygotes for 2 different alleles.

There are currently 11 known enzyme deficiencies that give rise to 7 distinct mucopolysaccharidoses. A new lysosomal storage disease state was described in 1996 by Natowicz and colleagues. The disease state has since been identified as a new mucopolysaccharidosis, MPS IX. They identified 2 mutations in the HYAL1 allele. They also believe this finding predicts the existence of other hyaluronidase deficiencies (136; 194). It is now apparent that, like most genetic disorders, there is a continuous spectrum of phenotypes from the severe to the mildly affected. It may now be preferable to consider speaking of these disorders in terms of specific enzyme deficiency (Table 1) rather than eponym (218). Since the 1990s, the techniques of molecular genetics have been employed in the study of mucopolysaccharidoses to further enhance classification, diagnosis, and carrier detection and to develop novel approaches to treatment through gene therapy (77). A novel disorder with impaired glycosaminoglycans metabolism caused by a mutation in the VPS33A gene in the Yakut population in the eastern Siberian region called Sakha has been described (106). Although the detailed mechanism and disease pathophysiology, as well as the domain-specific function of VPS33A remain to be elucidated, the author found that VPS33A regulates lysosomal acidification and glycosaminoglycan metabolism rather than the expected regulation of endocytosis or autophagy (106). Clinical phenotypes of this disease are similar to conventional mucopolysaccharidosis caused by enzymatic deficiencies, although there were in some patients other abnormalities such as cerebral hypomyelination, hypertrophic cardiomyopathy, bone marrow dysfunction, and kidney disease. Nevertheless, this disease should hence be considered as a differential diagnosis for mucopolysaccharidosis (106).

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