eMedicine Specialties > Pediatrics: Genetics and Metabolic Disease > Metabolic Diseases
Mucopolysaccharidosis Type VII
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.
More on Mucopolysaccharidosis Type VII |
 Overview: Mucopolysaccharidosis Type VII |
| Differential Diagnoses & Workup: Mucopolysaccharidosis Type VII |
| Treatment & Medication: Mucopolysaccharidosis Type VII |
| Follow-up: Mucopolysaccharidosis Type VII |
| References |
| Next Page » |
References
Nelson J. Incidence of the mucopolysaccharidoses in Northern Ireland. Hum Genet. Dec 1997;101(3):355-8. [Medline].
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].
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].
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].
Emory AE, Rimoin DL, Connor JM, Pyeritz RE, eds. Emery and Rimoin's Principles and Practice of Medical Genetics. 3rd ed. Pearson Professional; 1996:2077-8.
McKusick VA. Gene 253220. In: Mendelian Inheritance in Man: A Catalog of Human Genes and Genetic Disorders. Vol 3. Johns Hopkins University Press; 1998.
Meikle PJ, Hopwood JJ, Clague AE, Carey WF. Prevalence of lysosomal storage disorders. JAMA. Jan 20 1999;281(3):249-54. [Medline].
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.
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].
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].
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].
Nampoothiri S, Kappanayil M, Hiran KR, Sunitha V. Sly Disease Mucopolysaccharidosis Type VII. Indian Pediatr. Oct 2008;45(10):859-61. [Medline].
Further Reading
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
