eMedicine Specialties > Pediatrics: Genetics and Metabolic Disease > Metabolic Diseases

Mucopolysaccharidosis Type VII

Maryam Banikazemi, MD, Assistant Professor of Clinical Pediatrics, Department of Clinical and Molecular Genetics, Columbia University College of Physicians and Surgeons; Director of Newborn Screening Program, Director of Lysosomal Storage Disorders Program, Department of Pediatrics, Columbia University Medical Center
Surendra Varma, MD, Vice-Chairman and Program Director, University Distinguished Professor, Department of Pediatrics, Texas Tech University School of Medicine

Updated: Dec 5, 2008

Introduction

Background

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) (mucopolysaccharides). MPSs show extensive genetic heterogeneity, both among and within loci.

Mucopolysaccharidosis type VII (MPS VII) is a very rare lysosomal storage disease. MPS VII, traditionally known as Sly syndrome, was characterized for the first time in a patient with skeletal features similar to those observed in other patients with MPS. Sly syndrome is caused by deficiency of the enzyme β -glucuronidase. Historically, MPS VII is of interest because it was the first MPS (excluding the sex-linked gene for Hunter syndrome) for which the mutant gene was localized to chromosome 7.

Pathophysiology

In MPS VII the molecular defect on the gene that encodes β-glucuronidase protein (GUSB) leads to deficiency of the enzyme β-glucuronidase. This enzyme is required for the breakdown of several GAGs, including dermatan sulfate (DS), heparan sulfate (HS), and chondroitin sulfate (CS). Accumulation of DS, HS, and CS takes place in the lysosome of many systems and tissues, including the CNS. The pattern of urinary excretion of HS, DS, and/or CS may vary based on the subtype of MPS VII involved.

Genetics

The GUSB is located on chromosome 7q11.21-7q11.22, is 21-kb long, and contains 12 exons. The defect in GUSB is responsible for Sly syndrome. More than 45 mutation different mutations have been identified, approximately 90% of which were point mutations. The limited data reflect the severity of disease in part can be attributed to the genotype and residual catalytic enzyme activity.

Frequency

United States

MPS VII is extremely rare, and few cases have been described.

International

In his extensive study of MPSs in Northern Ireland in 1997, Nelson reported that no living cases of MPS VII were observed from 1958-1985. Three cases of nonimmune hydrops fetalis were believed to be MPS VII on the basis of placental histology and enzyme studies in the parents.¹

Mortality/Morbidity

Only a small sample of cases is available from which to extrapolate mortality figures for MPS VII. Fetal deaths have been noted several times. In mild cases, survival to age 19-20 years has been reported. Upper respiratory tract infections, neurodegenerative complications, and GI tract conditions may contribute to reduced survival rates.

Sex

Males and females are affected in equal numbers. Transmission is autosomal recessive.

Age

As a point of emphasis, Sly syndrome is one of the few MPSs and lysosomal storage diseases that may be clinically evident at birth, and even the most severe defects may appear prenatally. In other forms, defects may present during the first years of life. In the milder forms, clinical features may not be evident until later.

Clinical

History

Similar to most other mucopolysaccharidoses (MPSs), severity of symptoms in patients with MPS VII widely varies. Mucopolysaccharidosis type VII (MPS VII) is a progressive, debilitating, and often life-threatening disease that affects multiple organ-system.

• In most severe cases, the condition presents as hydrops fetalis. Neonatal jaundice may be present at birth. Dysostosis multiplex is also associated with the severe form of Sly syndrome.
• Coarse facial features with macrocephaly, hepatomegaly, hepatosplenomegaly, inguinal and umbilical hernias, and repeated upper respiratory infections may be observed.
• Severe growth retardation may be prominent during the first 2 years of life in patients with severe disease.
• In the milder forms of Sly syndrome, patients aged 4 years or older demonstrate symptoms.
• Corneal opacities may develop at any time in patients older than 1 year.
• Mental retardation is a common feature of Sly syndrome but is usually moderate and nonprogressive.

Physical

Clinical presentation of MPS VIII includes the following:

• Severe and early onset form (present at birth or during the first 4 y of life): This includes the prenatal form, as with nonimmune hydrops fetalis and severe neonatal forms presenting with neonatal cholestasis with hepatosplenomegaly.
• Late onset (frequently in patients aged >4 y): Patients develop milder symptoms.

Major clinical manifestations include the following:

• Dysmorphic features, such as coarse face, macrocephaly, frontal prominence, premature closure of sagittal lambdoid sutures, and short neck, may be observed.
• Corneal clouding or opacity is also a feature, although it varies in age of onset. Iris colomba may be observed.
• Visceral involvement and hepatosplenomegaly is a characteristic feature.
• GI symptoms and ascites may develop.
• Abnormal skeletal findings include short stature and dwarfism, dislocated hip, joint contractures, kyphoscoliosis, and wide rib cage/shield chest.
• Connective tissue involvement includes inguinal and umbilical hernias and, rarely, vascular anomalies.
• Growth and development is affected by presentation of 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.²
• Lymphedema/edema, heart disease (eg valvar heart disease), and aortic regurgitation may develop.
• Patients may develop hearing loss.
• Patients may have signs of hirsutism.
• Chronic inflammatory lung disease and recurrent respiratory infections are often a problem.

Causes

• Deficiency of the lysosomal enzyme b-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
  • The metabolic defect in patients with MPS VII has an autosomal recessive mode of inheritance (as is true of the other MPSs, except for MPS II or Hunter syndrome, which is transmitted as a sex-linked recessive trait).
  • Various mutations lead to a wide variety of phenotypes in patients with MPS VII.
  • The b-glucuronidase gene has been mapped to chromosome bands 7q21.11-q22.1.

Differential Diagnoses

Mucopolysaccharidosis Type IH
Mucopolysaccharidosis Type II

Other Problems to Be Considered

Mucolipidoses
Oligosaccharidosis

Workup

Laboratory Studies

Disease-specific tests

• Granulocytes studies reveal the presence of coarse metachromatic inclusions in patients with 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-D-glucuronidase deficiency in cultured leucocytes 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 for the enzyme deficiency may also be offered to parents with an affected child using the following methods:
  • Enzyme assay of amniotic fluid
  • Molecular analysis amniotic cells and chorionic villi cells

Imaging Studies

• The skeletal features of the disorder become evident in the first few years of life. In many patients, radiographic studies may reveal J -shaped turcica and odontoid hypoplasia, dysostosis multiplex, dislocated hips, platyspondyly (flattening of the vertebral bodies), and thoracolumbar kyphoscoliosis.

Treatment

Medical Care

Supportive care

Prognosis is poor for antenatal forms of 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 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 patients and their families.

The symptomatic intervention for MPS VII includes, but is not limited to, management of respiratory and cardiovascular complications, skeletal manifestations, arthropathy, loss of hearing and vision, GI symptoms, and communicating hydrocephalus.

• Bone marrow or cord blood transplantation, which endogenously restores production of missing functional enzyme⁴
• Enzyme replacement therapy, which supplements exogenously deficient enzyme produced by recombinant DNA technology
• Gene transfer and modified fibroblast implants that supply patient with a functional gene for the deficient enzyme

Surgical Care

• Corrective surgery may be necessary in patients with joint contractures and foot and hand deformities.
• Corneal transplants may be required if problems in vision become severe.

Consultations

• Patients may require referral to neurologists, orthopedic specialists, pediatricians, ophthalmologists, and audiologists.
• Refer patients to medical geneticists for diagnosis and genetic counseling.

Medication

Medication is not currently a component of care in mucopolysaccharidosis type VII (MPSVII). See Treatment.

Follow-up

Complications

• Patients with mucopolysaccharidosis type VII (MPS VII) have sensitivity to anesthesia.

Prognosis

• Fetal deaths have been reported in severe cases, whereas , in milder cases, survival to age 19-20 years is possible.
• Upper respiratory tract infections, neurodegenerative complications, and GI tract conditions contribute to a reduced median age of survival.

Patient Education

• Encourage families to see a medical geneticist for counseling and diagnosis.
• Support groups and organizations that patients may find helpful include the following:
  • Genetic Alliance at 202-966-5557
  • March of Dimes at 888-663-4637
  • National Organization for Rare Disorders at 800-999-6673
  • National MPS Society at 610-942-0100

Miscellaneous

Medicolegal Pitfalls

• Patients with mucopolysaccharidosis type VII (MPS VII) may have an unusual sensitivity to anesthesia because of airway malformations or cervical instability. Take precautions prior to any surgery involving a patient who has even a mild form of MPS.
• A legal risk occurs if parents of an affected individual are not informed regarding the risk in future pregnancies.

Special Concerns

• Because MPSs result from different genetic causes and share some features in common, determination of the precise genetic cause is essential. Making a distinction between MPS II (Hunter syndrome), which is sex-linked recessive, and the other MPSs, which are autosomal recessive, is especially critical to genetic counseling.

References

1. Nelson J. Incidence of the mucopolysaccharidoses in Northern Ireland. Hum Genet. Dec 1997;101(3):355-8. [Medline].

2. Wallace SP, Prutting CA, Gerber SE. Degeneration of speech, language, and hearing in a patient with mucopolysaccharidosis VII. Int J Pediatr Otorhinolaryngol. Jun 1990;19(2):97-107. [Medline].

3. Sly WS, Vogler C. Gene therapy for lysosomal storage disease: a no-brainer? Transplants of fibroblasts secreting high levels of beta-glucuronidase decrease lesions in the brains of mice with Sly syndrome, a lysosomal storage disease. Nat Med. Jul 1997;3(7):719-20. [Medline].

4. Vellodi A, Young EP, Cooper A, et al. Bone marrow transplantation for mucopolysaccharidosis type I: experience of two British centres. Arch Dis Child. Feb 1997;76(2):92-9. [Medline].

5. Emory AE, Rimoin DL, Connor JM, Pyeritz RE, eds. Emery and Rimoin's Principles and Practice of Medical Genetics. 3^rd ed. Pearson Professional; 1996:2077-8.

6. McKusick VA. Gene 253220. In: Mendelian Inheritance in Man: A Catalog of Human Genes and Genetic Disorders. Vol 3. Johns Hopkins University Press; 1998.

7. Meikle PJ, Hopwood JJ, Clague AE, Carey WF. Prevalence of lysosomal storage disorders. JAMA. Jan 20 1999;281(3):249-54. [Medline].

8. Neufeld E, Muenzer J. The Mucopolysaccharidoses. In: Scriver C, Beaudet A, Sly W, Valle D, eds. The Metabolic and Molecular Bases of Inherited Disease. New York, NY: McGraw Hill; 2001:3421-52.

9. Peters C, Shapiro EG, Anderson J, et al. Hurler syndrome: II. Outcome of HLA-genotypically identical sibling and HLA-haploidentical related donor bone marrow transplantation in fifty-four children. The Storage Disease Collaborative Study Group. Blood. Apr 1 1998;91(7):2601-8. [Medline].

10. Wasant P, Wattanaweeradej S, Raksadawan N, Kolodny EH. Lysosomal storage disorders in Thailand: the Siriraj experience. Southeast Asian J Trop Med Public Health. 1995;26 Suppl 1:54-8. [Medline].

11. Whitley CB, Belani KG, Chang PN, Summers CG, Blazar BR, Tsai MY. Long-term outcome of Hurler syndrome following bone marrow transplantation. Am J Med Genet. Apr 15 1993;46(2):209-18. [Medline].

12. Nampoothiri S, Kappanayil M, Hiran KR, Sunitha V. Sly Disease Mucopolysaccharidosis Type VII. Indian Pediatr. Oct 2008;45(10):859-61. [Medline].

Keywords

mucopolysaccharidosis type VII, MPS VII, Sly syndrome, beta-glucuronidase deficiency, Hunter syndrome, hydrops fetalis, upper respiratory tract infections, macrocephaly, hepatomegaly, hepatosplenomegaly, inguinal hernia, umbilical hernia, growth retardation, neonatal cholestasis, ascites, short stature, dwarfism, hearing loss, hirsutism, chronic inflammatory lung disease

Contributor Information and Disclosures

Author

Maryam Banikazemi, MD, Assistant Professor of Clinical Pediatrics, Department of Clinical and Molecular Genetics, Columbia University College of Physicians and Surgeons; Director of Newborn Screening Program, Director of Lysosomal Storage Disorders Program, Department of Pediatrics, Columbia University Medical Center
Maryam Banikazemi, MD is a member of the following medical societies: American Academy of Pediatrics and American Society of Human Genetics
Disclosure: Nothing to disclose.

Coauthor(s)

Surendra Varma, MD, Vice-Chairman and Program Director, University Distinguished Professor, Department of Pediatrics, Texas Tech University School of Medicine
Surendra Varma, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Pediatrics, American Diabetes Association, American Medical Association, American Thyroid Association, Endocrine Society, Medical Group Management Association, New York Academy of Sciences, Sigma Xi, Society for Pediatric Radiology, Southern Society for Pediatric Research, and Texas Medical Association
Disclosure: Nothing to disclose.

Medical Editor

Karl S Roth, MD, Professor and Chair, Department of Pediatrics, Creighton University School of Medicine
Karl S Roth, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Pediatrics, American College of Nutrition, American Pediatric Society, American Society for Clinical Nutrition, American Society of Nephrology, Association of American Medical Colleges, Medical Society of Virginia, New York Academy of Sciences, Sigma Xi, Society for Pediatric Research, and Southern Society for Pediatric Research
Disclosure: Nothing to disclose.

Pharmacy Editor

Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine
Disclosure: Pfizer Inc Stock Investment from broker recommendation; Avanir Pharma Stock Investment from broker recommendation

Managing Editor

Margaret McGovern, MD, PhD, Vice Chair, Professor, Department of Human Genetics, Mount Sinai School of Medicine
Margaret McGovern, MD, PhD is a member of the following medical societies: American Academy of Pediatrics and American Society of Human Genetics
Disclosure: Nothing to disclose.

CME Editor

Daniel Rauch, MD, FAAP, Director, Pediatric Hospitalist Program, Associate Professor, Department of Pediatrics, New York University School of Medicine
Daniel Rauch, MD, FAAP is a member of the following medical societies: Ambulatory Pediatric Association, American Academy of Pediatrics, and Society of Hospital Medicine
Disclosure: Baxter Honoraria Consulting; Pfizer Honoraria Consulting

Chief Editor

Bruce Buehler, MD, Professor, Department of Pediatrics, Pathology and Microbiology, Executive Director, Hattie B Munroe Center for Human Genetics and Rehabilitation, University of Nebraska Medical Center
Bruce Buehler, MD is a member of the following medical societies: American Academy for Cerebral Palsy and Developmental Medicine, American Academy of Pediatrics, American Association on Mental Retardation, American College of Medical Genetics, American College of Physician Executives, American Medical Association, and Nebraska Medical Association
Disclosure: Nothing to disclose.

The authors and editors of eMedicine gratefully acknowledge the contributions of previous author Donald Nash, MD, to the development and writing of this article.

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