Metabolism Carbohydrate5 SECTIONof Disorders •

77 MUCOPOLYSACCHARIDOSIS VII

277.5

(b-Glucuronidase Deficiency, GUSB Deficiency, MPS VII, Sly Disease)

Chantal F. Morel, MD, FRCP(C)

Toronto, Ontario, Canada

Alex V. Levin, MD, MHSc, FAAP, FAAO, FRCSC

Toronto, Ontario, Canada

ETIOLOGY/INCIDENCE

β-Glucuronidase (GUSB) is a lysosomal enzyme that catalyzes the hydrolysis of β-glucuronide residues as part of the sequential degradation of the glycosaminoglycans chondroitin sulfate, dermatan sulfate and heparan sulfate. This enzyme is a homotetramer of four 651 amino acid chains. The autosomal recessive disorder known as mucopolysaccharidosis type VII (MPS VII, OMIM 253220) is due to deficiency of this enzyme which in turn leads to the accumulation of incompletely degraded glycosaminoglycans in secondary lysosomes in many tissues. The first patient was described by Sly in 1973. The incidence of the severe neonatal form is estimated at approximately 1 in 300,000 live births. Over 50 cases have been reported. The clinical manifestations are chronic and progressive, ranging from nonimmune hydrops fetalis to mild disease variants presenting in adults. Milder forms are less common. A pseudodeficiency is also known in which enzyme levels are reduced (>3%), the phenotype is normal, and there is no abnormal urinary excretion.

The GUSB gene has been cloned and found to contain 12 exons. It is located at chromosome 7q21.11. More than 50 mutations have been identified, including missense, nonsense, frame shifts, small deletions, and splice-site changes. Both homozygotes and compound heterozygotes have been reported. Most mutations are novel. Clinical heterogeneity is well recognized.

COURSE/PROGNOSIS

●Wide phenotypic variability categorized by some as mild, moderate, or severe and by others as juvenile, infantile, or neonatal/fetal, respectively.

●May present as in utero death and non-immune hydrops fetalis. Increased nuchal translucency in the first trimester of pregnancy has been observed.

Features of moderate to severe disease include:

●Characteristic coarse facies with epicanthus, midfacial hypoplasia, and telecanthus.

●Hepatosplenomegaly.

●Bone and joint abnormalities (dysostosis multiplex, kyphoscoliosis with vertebral deformities, sternum deformity), difficulties in ambulation.

●Recurrent respiratory disease.

●Cardiac abnormalities (myocardial thickening, valvular disease).

●Umbilical and/or inguinal hernia.

●Short stature.

●Mild to severe mental retardation, usually nonprogressive.

●Reduced life span, often with neonatal or infant death.

Ocular involvement may include:

●Progressive corneal clouding: usually mild and not noted until the end of the first decade but may be observed in some infants.

●Retinal dystrophy.

●Optic atrophy: late manifestation in survivors beyond the neonatal period.

●Papilledema.

●Abnormal storage of glycosaminoglycans in retinal pigmented epithelium, ciliary body epithelium, and corneal endothelium observed in animal models.

●Mild form that presents after the age of 4 years with variable severity of skeletal involvement, normal intelligence, normal facies, and clear corneas.

DIAGNOSIS

●High urinary excretion of glycosaminoglycans and large oligosaccharides.

●Vacuoles may be seen in peripheral lymphocytes and fibroblasts.

●Metachromatic granular inclusions (Alder bodies) in leukocytes; abnormalities also in some cells of obligate carriers or pseudodeficiency.

●Light and electron microscopy of neurons, muscle fibers, renal cells, hepatic cells or corneal stromal keratocytes show cytoplasmic inclusions representing partially degraded glycosaminoglycans in secondary lysosomes.

●Low leukocyte or fibroblast GUSB enzyme activity (0–2%).

●Gene mutation analysis.

●Prenatal diagnosis: measuring glycosaminoglycans in amniotic fluid, GUSB enzyme activity in cultured fetal cells, or molecular analysis of GUSB gene if proband’s diseasecausing mutations known.

TREATMENT

Systemic

●Direct enzyme replacement therapy (ERT) unsuccessful.

●Varying success with bone marrow transplantation: animal models show improved response following pre-treatment with ERT.

Ocular

●Penetrating keratoplasty or lamellar keratoplasty for significant corneal clouding, may result in visual gain although improvement may be moderated by retinal and/or optic nerve disease. Without systemic therapy, disease may recur in grafted cornea.

●Intraocular gene therapy in affected mice results in nearly normal levels of GUSB and decreased lysosomal storage within the retinal pigmented epithelium (RPE) and improved retinal function.

●Intravitreal gene therapy results in increased GUSB activ-

ity and reduced lysosomal storage in the certain areas of the CNS, suggesting diffusion and trans-synaptic transfer.

●BMT in mice with MPS VII decreases RPE lysosomal storage and improves retinal function.

●Systemic injection of recombinant adenovirus expressing GUSB in first 24 hours of life in affected mice may prevent

progression of corneal clouding, retinal degeneration and other systemic manifestations.

COMPLICATIONS

●Visual loss due to corneal, retinal or optic nerve involvement.

●Craniovertebral instability (potential risk at intubation for anaesthesia).

●Spinal cord compression.

●Hearing loss.

●Cardiac ischemia due to narrowing of coronary arteries.

●Obstructive airway disease.

●Joint stiffness, carpel tunnel syndrome.

COMMENTS

Corneal clouding is the most common ocular manifestation. Involvement of the retina and optic nerve occur less frequently. There are very few references in the medical literature describing the non corneal ocular phenotypes. The availability of animal models presents the opportunity for therapeutic trials, which may ultimately lead to a viable treatment in the realm of gene therapies.

SUPPORT GROUPS

National MPS (Mucopolysaccharidoses/Mucolipidoses) Society, Inc. 17 Kraemer Street

Hicksville, NY 11801 (516) 931-6338

Fax: (516) 822-2041

E-mail: Soc@aol.com

Home page: http://members.aol.com/mpssociety

Vaincre Les Maladies Lysosomales [French] 9 Place du 19 Mars 1962

Evry Cedex 91035, France (331) 609-1750

E-mail: VML@provnet.fr

Home page: http://www.provnet.fr/VML/

Society of Mucopolysaccharidosis (MPS) Disease, United Kingdom

7 Chessfield Park

Buckinghamshire HP6 6RU, UK

Canadian Society for Mucopolysaccharidosis and Related Diseases, Inc. Postal Box 64714

Unionville, Ontario, Canada L3R OM9 (905) 479-8701

Home page: http://neuro-www2mgh.harvard.edu/MPS/mpsmain.html

Lysosomal Storage Diseases: A Family Sourcebook Reference Chart Home page: http://mcrcr2.med.nyu.edu/murphp01/lysosome/lysosome. htm

REFERENCES

Bergwerk KE, Falk RE, Glasgow BJ, Rabinowitz YS: Corneal transplantation in a patient with mucopolysaccharidosis type VII (Sly disease). Ophthalmic Genet 21:17–20, 2000.

Geipel A, Berg C, Germer U, et al: Mucopolysaccharidosis VII (Sly disease) as a cause of increased nuchal translucency and non-immune fetal hydrops: study of a family and technical approach to prenatal diagnosis in early and late pregnancy. Prenat Diagn 22:487–500, 2002.

Hennig AK, Levy B, Ogilvie JM, et al: Intravitreal gene therapy reduces lysosomal storage in specific areas of the CNS in mucopolysaccharidosis VII mice. J Neurosci 23:3302–3307, 2003.

Hennig AK, Ogilvie JM, Ohlemiller KK, et al: AAV-mediated intravitreal gene therapy reduces lysosomal storage in the retinal pigmented epithelium and improves retinal function in adult MPS VII mice. Mol Ther 10:106–116, 2004.

Kamata Y, Okuyama T, Kosuga M, et al: Adenovirus-mediated gene therapy for corneal clouding in mice with mucopolysaccharidosis type VII. Mol Ther 4:307–312, 2001.

Kamata Y, Tanabe A, Kanaji A, et al: Long-term normalization in the central nervous system, ocular manifestations, and skeletal deformities by a single systemic adenovirus injection into neonatal mice with mucopolysaccharidosis VII. Gene Ther 10:406–414, 2003.

Neufeld EF, Muenzer J: The mucopolysaccharidoses. In: Scriver CR, Beaudet AL, Sly WS, Vale D, eds: The metabolic and molecular basis of inherited disease. 8th edn. Toronto, McGraw-Hill, 2001:3421–3452.

Ohlemiller KK, Vogler CA, Roberts M, et al: Retinal function is improved in a murine model of lysosomal storage disease following bone marrow transplantation. Exp Eye Res 71:469–481, 2000.

Storch S, Wittenstein B, Islam R, et al: Mutational analysis in the longest known survivor of mucopolysaccharidosis type VII. Hum Genet 112:190–194, 2003.

VII Mucopolysaccharidosis • 77 CHAPTER