Sly Syndrome (Mucopolysaccharidosis Type VII) 

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

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.

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.

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.

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.

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:

 

Presentation

History

As with most other mucopolysaccharidoses (MPSs), the severity of symptoms in patients with Sly syndrome (mucopolysaccharidosis type VII [MPS VII]) varies widely. Sly syndrome is a progressive, debilitating, and life-threatening disease that affects multiple organ systems.

Most severe cases of Sly syndrome present as nonimmune hydrops fetalis. Neonatal jaundice may be present at birth.

Clinical findings include macrocephaly with coarse facial features, shortened neck, variable degree of corneal opacities, auditory impairment, valvular cardiac disease, hepatosplenomegaly, inguinal and umbilical hernias, recurrent upper respiratory infections due to skeletal chest abnormalities, hirsutism, and joint contractures.

Corneal opacities may develop at any time in patients older than 1 year.

Marked growth retardation and dysostosis multiplex may develop in severe cases.

Mental retardation is a common feature of Sly syndrome but is usually moderate and nonprogressive. Other CNS concerns include hydrocephalus and neurodegenerative processes.

In milder forms of Sly syndrome, symptoms appear at age 4 years or older. 

Physical

Clinical presentations of Sly syndrome include the following:

  • Severe and early onset form (present at birth or within the first 4 years of life): Prenatal form presents with nonimmune hydrops fetalis. Severe neonatal form presents with neonatal cholestasis with hepatosplenomegaly
  • Late onset (frequently in patients >4 years): Patients present with milder symptoms.

Major clinical manifestations include the following:

  • Dysmorphic features; macrocephaly, coarse facial features, frontal prominence, premature closure of sagittal lambdoid sutures, and a shortened neck.
  • Corneal clouding or opacity is also a feature, although it varies in age of onset. Iris colomba may be observed.
  • Auditory impairment can occur.
  • Visceral involvement and hepatosplenomegaly is a characteristic feature.
  • Gastrointestinal symptoms and ascites may develop.
  • Abnormal skeletal findings include: dysostosis multiplex, J-shaped sella turcica, platyspondyly, thoracolumbar gibbus, odontoid hypoplasia, acetabular dysplasia (dislocated hip), narrow sciatic notches, joint contractures, pointed proximal metacarpals, metatarsus adductus, short stature, dwarfism, kyphoscoliosis, and wide rib cage/shield chest (pectus carinatum).
  • Connective tissue involvement includes inguinal and umbilical hernias and, rarely, vascular anomalies.
  • Growth and development is affected by postnatal short stature, hypotonia, and neurological disorders that ultimately lead to mental retardation. Mental retardation is often moderate, nonprogressive, and most pronounced in speech and language development. [5]
  • Lymphedema/edema, heart disease (eg, valvular heart disease), and aortic regurgitation may develop.
  • Patients may be hirsute.
  • Chronic inflammatory lung disease and recurrent respiratory infections are common.

Causes

Causes of Sly syndrome include the following:

  • Deficiency of the lysosomal enzyme beta-glucuronidase.
  • Accumulation of the undegraded mucopolysaccharides dermatan sulfate (DS), heparan sulfate (HS), and chondroitin sulfate (CS) in tissues and organs
  • Storage of excess mucopolysaccharides, contributing to numerous morphologic abnormalities

Genetic causes include the following:

  • The metabolic defect in patients with Sly syndrome has an autosomal-recessive mode of inheritance (as is true of the other MPSs, except for MPS II or Hunter syndrome, which are inherited as a sex-linked recessive trait).
  • Various mutations lead to a wide variety of phenotypes in patients with Sly syndrome.
  • The beta-glucuronidase gene has been mapped to the long arm of autosome chromosome 7 (7q), band 11.21.
 

DDx

Differential Diagnoses

 

Workup

Laboratory Studies

Disease-specific tests

Granulocytes studies reveal the presence of coarse metachromatic inclusions in patients with Sly syndrome (mucopolysaccharidosis type VII [MPS VII]).

Mucopolysacchariduria or increased levels of urinary glycosaminoglycan (either chondroitin sulfate [CS] alone or dermatan sulfate [DS], heparan sulfate [HS], and CS combined) is observed.

Diagnosis is confirmed by demonstration of beta-glucuronidase deficiency in cultured leukocytes or fibroblasts. Pseudodeficient alleles make mild forms more difficult to identify and make prenatal diagnosis difficult.

Molecular analysis of the GUSB gene may be performed.

Prenatal diagnosis

Prenatal diagnosis of beta-glucuronidase deficiency may also be offered to expectant couples with a history of a previously affected child, using the following methods:

  • Enzyme assay of amniotic fluid
  • Molecular analysis amniotic cells and chorionic villi cells

Imaging Studies

Skeletal features of Sly syndrome become evident in the first few years of life. In many patients, radiographic studies may reveal J-shaped sella turcica odontoid hypoplasia, dysostosis multiplex, acetabular hypoplasia (dislocated hips), platyspondyly (flattening of the vertebral bodies), and thoracolumbar kyphoscoliosis.[6]

 

Treatment

Medical Care

Supportive care

Prognosis is poor for antenatal forms of Sly syndrome (mucopolysaccharidosis type VII [MPS VII]), most often leading to death in utero. Neonatal and childhood forms have a very limited life expectancy, whereas milder forms have a greater prolonged survival.

As in some other MPS types, symptomatic treatment is essential for survival of patients with milder cases and late-onset forms. Although the available medical and surgical interventions do not address the underlying cause of the disease or reverse/arrest the progression of the disease, these approaches may greatly improve the quality of life for both patients and their families.

The symptomatic intervention for Sly syndrome includes, but is not limited to, treatment and management of CNS anomalies, respiratory and cardiovascular complications, auditory and visual impairments, gastrointestinal symptoms, skeletal manifestations, and arthropathies.

Disease-specific treatment

Treatment that directly targets the underlying cause of the disease and prevents accumulation of substrate is in development for several inherited metabolic storage disorders. Promising studies are underway in various animal models of Sly syndrome (eg, mutant mice,[7] cats, dogs). These approaches include the following:

  • Bone marrow or cord blood transplantation, which endogenously restores production of the missing functional enzyme. [8]
  • Enzyme replacement therapy (ERT), which supplements exogenously deficient enzyme production via recombinant DNA technology. [9]
  • Gene transfer and modified fibroblast implants that supply the patient with a functional gene to produce the deficient enzyme.

Enzyme replacement therapy

The US Food and Drug Administration (FDA) has approved vestronidase alfa-vjbk (Mepsevii) for the treatment of Sly syndrome (mucopolysaccharidosis type VII [MPS VII]) in pediatric and adult patients. This enzyme replacement therapy is intended to replace the deficient lysosomal enzyme beta-glucuronidase in patients with Sly syndrome. Approval was based on a clinical trial program that included 23 patients with MPS VII; the patients ranged in age from 5 months to 25 years. Patients received vestronidase alfa-vjbk at doses up to 4 mg/kg IV every 2 weeks for up to 164 weeks. Efficacy was primarily assessed through the 6-minute walk test (6MWT) in 10 patients who could perform the test.

After 24 weeks, the mean difference in distance walked relative to placebo was 18 meters. Additional follow-up for up to 120 weeks suggested continued improvement in 3 patients and stabilization in the remaining 7 patients. After 120 weeks of exposure, one patient demonstrated a 21% improvement over baseline in forced vital capacity (FVC% predicted) on pulmonary function testing in addition to a 105-meter improvement in the 6MWT. Two other patients with baseline hepatosplenomegaly had reduction in liver volume (24% and 53%) and spleen volume (28% and 47%) after 36 weeks of treatment. The effect of vestronidase alfa-vjbk on the CNS manifestations of MPS VII has not been determined.[10]

Surgical Care

Corrective surgery may be necessary in patients with joint contractures and other skeletal abnormalities.

Corneal transplants may be required if problems in vision become severe.

Patients with Sly syndrome (MPS VII) have sensitivity to anesthesia. Postsurgical pulmonary complications can occur.

Consultations

Patients with Sly syndrome require referral to a pediatrician and a pediatric neurologist, ophthalmologist, audiologist, cardiologist, gastroenterologist, orthopedic surgeon, and general surgeon. Consider referrals to developmental pediatrics and physical therapy.

Refer patients and their families to medical geneticists for diagnosis and genetic counseling.

 

Medication

Medication Summary

The treatment of Sly syndrome (mucopolysaccharidosis type VII [MPS VII]) is symptomatic and supportive.

Enzyme Replacement Therapy

Class Summary

Enzyme replacement therapy may provide clinically important benefits (eg, improved pulmonary function and walking ability, reduced excess carbohydrates stored in organs).

Vestronidase alfa-vjbk (Mepsevii)

Recombinant human lysosomal beta glucuronidase (GUS) is intended to provide exogenous GUS enzyme for uptake into cellular lysosome; mannose-6-phosphate (M6P) residues on the oligosaccharide chains allow binding of the enzyme to cell surface receptors, leading to cellular uptake of the enzyme, targeting to lysosomes and subsequent catabolism of accumulated GAGs in affected tissues.