Sly Syndrome (Mucopolysaccharidosis Type VII)

Updated: Nov 30, 2017
  • Author: Germaine L Defendi, MD, MS, FAAP; Chief Editor: Maria Descartes, MD  more...
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Overview

Background

Sly syndrome, also called mucopolysaccharidosis type VII (MPS VII), is a very rare lysosomal storage disease that has an autosomal-recessive inheritance pattern. Sly syndrome is named after William S. Sly, an American biochemist and physician. Dr. Sly and his research team described a patient with skeletal features similar to those observed in other patients previously diagnosed with MPS. [1] Sly syndrome is caused by deficiency of the enzyme beta-glucuronidase, [2] and it was the first MPS for which the altered gene was localized to an autosome chromosome, the long arm of chromosome 7 (7q11.21; OMIM #253220).

The mucopolysaccharidoses (MPSs) are a group of inherited lysosomal storage disorders that are caused by a deficiency of specific lysosomal enzymes required for the degradation of glycosaminoglycans (GAGs), also known as mucopolysaccharides. MPSs show extensive genetic heterogeneity, both among and within gene loci.

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Pathophysiology

Mutations in the beta-glucuronidase (GUSB) gene cause Sly syndrome. This gene instructs the production of the beta-glucuronidase enzyme, which is involved in the breakdown of glycosaminoglycans (GAGs). This enzyme is required for the breakdown of several GAGs, including dermatan sulfate (DS), heparan sulfate (HS), and chondroitin sulfate (CS), which are large sugar molecules. [3] Accumulation of these molecules occurs in the lysosomes of various tissues and organ systems, including the central nervous system (CNS). Urinary excretion of HS, DS, and/or CS occurs, and the quantity may vary based on the diagnostic spectrum of clinical severity of Sly syndrome.

Genetics

The beta-glucuronidase (GUSB) gene (OMIM *611499) is located on the long arm of chromosome 7 (7q), at band q11.21. The gene location is 21-kb long and contains 12 exons. This gene defect in GUSB causes Sly syndrome. More than 45 different mutations have been identified, approximately 90% of which are point mutations. Limited clinical data reflect disease severity and can be attributed to genotype and remaining catalytic enzyme activity.

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Epidemiology

Frequency

Sly syndrome is a rare form of mucopolysaccharidosis with an estimated worldwide frequency of 1 per 250,000 births.

United States

Sly syndrome is extremely rare in the United States, and few cases have been described.

International

In a 1997 study cataloging the incidence of MPSs in Northern Ireland, Nelson reported that no living cases of Sly syndrome were observed from 1958 to 1985. Three cases of nonimmune hydrops fetalis were believed to result from Sly syndrome, based on placental histology and parental enzyme studies. [4]

Mortality/Morbidity

Only a small sample of cases is available from which to extrapolate mortality figures for Sly syndrome. Fetal deaths due to nonimmune hydrops fetalis have been noted. In mild cases, survival to age 19-20 years has been reported. Neurodegenerative complications, upper respiratory tract infections, and gastrointestinal tract conditions contribute to reduced survival rates.

Sex

Sly syndrome has no sexual predilection, as the gene responsible is located on an autosome, and not a sex chromosome. Genetic inheritance is Mendelian autosomal recessive.

Age

Sly syndrome may be present at birth. Some affected individuals present with severe prenatal defects. In other forms, clinical abnormalities may develop within the first few years of life. In milder forms, clinical features may not be evident until later in life.

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Prognosis

Fetal deaths have been reported in severe cases. In patients with milder cases, survival to age 19-20 years has been reported.

Upper respiratory tract infections, neurodegenerative complications, and gastrointestinal conditions contribute to a reduced life expectancy.

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Patient Education

Encourage families to seek guidance from a medical geneticist and genetic counselor for counseling, diagnosis, genetic testing options and resources.

Support groups and organizations that patients and their families may find helpful are the following:

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