Mucopolysaccharidoses

Raphael Schiffmann MD (Dr. Schiffmann, Director of the Institute of Metabolic Disease at Baylor Research Institute, received research grants from Amicus Therapeutics, Protalix Biotherapeutics, and Shire.)
Originally released November 17, 1993; last updated December 18, 2016; expires December 18, 2019

This article includes discussion of mucopolysaccharidoses, gargoylism, Hunter syndrome, Hurler-Scheie syndrome, Hurler syndrome, Maroteaux-Lamy syndrome, Morquio syndrome, mucopolysaccharidosis, Sanfilippo syndrome, Scheie syndrome, and Sly syndrome. The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations.

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. 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. The safety and efficacy of intrathecal enzyme administration is being evaluated in patients with MPS I and 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 or intrathecal, is 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 (Hunter 1917; Hurler 1919). 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 (McKusick 1978; Hopwood and Morris 1990).

Brante identified the material stored in these patients as mucopolysaccharides and, thus, proposed the term "mucopolysaccharidoses" to describe these disorders (Brante 1952). Dorfman and Lorincz identified heparan sulfate and dermatan sulfate in the urine of a patient with Hurler syndrome (Dorfman and Lorincz 1957). 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 (van Hoof and Hers 1964). Hers defined the characteristics of lysosomal storage diseases (Hers 1965). 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 (McKusick et al 1965).

In classic experiments utilizing cultured fibroblasts, Dr. Elizabeth Neufeld and her colleagues demonstrated a deficiency of "corrective factors" in individual mucopolysaccharidoses (Fratantoni et al 1969; Barton and Neufeld 1971; Bach et al 1972). 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 (Natowicz 1996; Triggs-Raine et al 1999). 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 (Wraith 1995). 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 (Haurigot et al 2013).

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