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

Mucopolysaccharidosis Type VI

Paul R Harmatz, MD, Attending Physician, Department of Gastroenterology and Nutrition, Children's Hospital Oakland
Margaret McGovern, MD, PhD, Vice Chair, Professor, Department of Human Genetics, Mount Sinai School of Medicine

Updated: Dec 11, 2008

Introduction

Background

The mucopolysaccharidoses (MPSs) are a group of inherited disorders that result from the deficiency of 1 or more of the lysosomal enzymes required for glycosaminoglycan (GAG) catabolism. GAGs, which are a major constituent of connective tissues, are long-chain complex carbohydrates that are usually linked to proteins to form proteoglycans and include chondroitin 4-sulfate, chondroitin 6-sulfate, heparan sulfate, dermatan sulfate, keratan sulfate, and hyaluronic acid. Because GAGs are primarily found in connective tissue, the sites of pathology primarily include the skeleton, heart valves, and other areas with connective tissue stroma.

The clinical features of the MPSs result from lysosomal accumulation of partially degraded or undegraded GAGs and typically include coarse facies, corneal clouding, organomegaly, joint stiffness, dysostosis multiplex, hernias, short stature, and, in some disorders, mental retardation. The specific enzymatic deficiency and the resultant pattern of GAG degradation products determine the phenotype of each disorder. In general, dermatan, keratan, and chondroitin sulfate degradation products are associated with visceral manifestations, whereas the accumulation of heparan sulfate degradation products may be associated with mental deficiency.

Mucopolysaccharidosis type VI (MPS VI), which is inherited as an autosomal recessive trait, results from the deficiency of N- acetylgalactosamine 4-sulfatase (arylsulfatase B) activity and the lysosomal accumulation of dermatan sulfate. MPS VI is characterized by somatic features but not by mental retardation.

Pathophysiology

MPS VI is characterized by progressive connective-tissue organ involvement that results from continuous storage of dermatan sulfate in the skeleton, heart valves, spleen, liver, lung, dura, and cornea. Pathological examination of affected tissues reveals the presence of engorged lysosomes. Patients appear healthy at birth and have accelerated growth in the first year, followed by deceleration and short stature later in childhood. The diagnosis is usually made in early childhood when organomegaly, corneal clouding, coarse features, enlarged tongue, frequent respiratory illness or otitis media, and joint stiffness are all apparent. Other complications include hearing loss, chronic respiratory tract infections, sleep apnea, pulmonary hypertension, hydrocephalus, rapid-onset blindness, and cardiac valve insufficiency or stenosis.

Frequency

United States

The MPSs are rare disorders, and data concerning incidence are not widely available.

International

Several reports provide estimates of MPS VI incidence outside the United States. An Australian survey reported an incidence rate of 1 per 248,000 births from 1980-1996.¹ Reports from Germany, and northern Portugal noted birth incidences of 1 case per 432,610 births and 1 case per 238,095 births, respectively.^2,3

Mortality/Morbidity

MPS VI is characterized by substantial morbidity because of progressive accumulation of GAGs.

• Although mental development is normal, physical and visual defects can adversely affect psychomotor development.
• Growth may be normal for the first few years of life but then stops, resulting in dwarfism.
• Most patients have corneal clouding, which can interfere with vision. Sudden vision loss can occur and is related to increased intracranial pressure or possible compression of the optic nerve.
• Restricted joint movement is a common feature, and patients develop claw-hand deformities due to contractures.
• Cardiac involvement includes aortic and mitral valve dysfunction.
• Skeletal changes are typified by dysostosis multiplex.
• Cervical cord compression due to bony abnormality, atlanto-axial instability, and thickening of the dura can lead to extremity pain, loss of motor function and sensation in extremities, or both.
• Patients may also have restrictive airway disease, obstructive airway disease, or both.
• Age at death varies, and mild forms of the disease have been described with prolonged survival.

Race

MPS VI is panethnic, although increased birth frequency has been reported in certain populations (Turkish population living in Germany).²

Sex

MPS VI is inherited as an autosomal recessive trait and appears equally in males and females.

Age

MPS VI is an inherited disorder that typically manifests in early childhood with retarded growth, hepatosplenomegaly, and coarse facial features.

Clinical

History

• Individuals with mucopolysaccharidosis type VI (MPS VI) usually have a period of normal growth and development but later present when frequent respiratory infections or otitis media, inguinal or umbilical hernias, hepatosplenomegaly, coarse facial features, joint or spine abnormalities, and corneal clouding become evident.
• Because MPS VI is a recessive disorder, no family history is usually present.

Physical

• Facial features include the following:
  • Coarse facial features (Compare the facial features with those of other family members to best appreciate the coarsening.)
  • Macrocephaly
  • Enlarged tongue
  • Prominent forehead
  • Possible coarse texture of hair
• Hepatomegaly and splenomegaly are often present in patients with MPS VI.
• Umbilical and inguinal hernias are common.
• Growth may be normal for several years and may then stop, resulting in a final stature of 90-140 cm. A short trunk with lumbar lordosis is typically present.
• Corneal opacities can be detected with slitlamp examination.
• Restricted joint movement, including claw-hand deformities, appears in the first few years of life.
• Examination of the skin frequently reveals hirsutism.

Causes

MPS VI results from the deficiency of N- acetylgalactosamine 4-sulfatase (arylsulfatase B) and the lysosomal accumulation of dermatan sulfate.

Differential Diagnoses

Other Problems to Be Considered

Mucolipidoses

Workup

Laboratory Studies

• Urine glycosaminoglycan analysis can be performed using various qualitative or quantitative methods. These studies are useful for establishing the likely diagnosis of mucopolysaccharidosis (MPS) but do not provide a specific diagnosis, which requires enzymatic testing.
• Definitive diagnosis requires the determination of the specific lysosomal enzyme level in cultured fibroblasts or isolated leukocytes.
• Normal levels of a second sulfatase should be documented to exclude multiple sulfatase deficiency.

Imaging Studies

• Perform skeletal survey studies to reveal dysostosis multiplex. Findings may include the following:
  • Macrocephaly with an enlarged sella
  • Acetabulum hypoplasia
  • Ovoid deformities of the vertebrae
  • Anterior hypoplasia of the L1 and L2 vertebral bodies
  • Epiphyseal dysplasia of the proximal femur
  • Evidence of kyphoscoliosis
• Echocardiography can reveal valvular heart disease, which is common. Acute infantile cardiomyopathy has also been reported in mucopolysaccharidosis type VI (MPS VI).
• MRI of the brain and spine may demonstrate hydrocephalus or provide evidence for spinal cord compression, especially in the cervical region.
• Flexion-extension radiography of the C-spine may demonstrate atlantoaxial instability and subluxation of C1 on C2.

Other Tests

• Perform an audiological evaluation because deafness and hearing loss are common in MPS.
• Perform an ophthalmologic examination to identify corneal opacities, vision change, and optic nerve abnormalities, suggesting increased intracranial pressure.
• Perform pulmonary function tests to monitor restrictive and obstructive disease and perform a sleep study to evaluate for sleep apnea.

Histologic Findings

• Lysosomal engorgement in tissue biopsies is evident, as are vacuolated lymphocytes on peripheral blood smear.

Staging

• Urine glycosaminoglycan (GAG) level corrected for creatinine is a biochemical disease marker that can provide a crude estimate of disease severity and response to specific treatment (bone marrow transplantation [BMT] or enzyme replacement therapy).

Treatment

Medical Care

Patients with mucopolysaccharidosis type VI (MPS VI) require ongoing medical care from numerous subspecialists. In addition, patients should receive routine pediatric care, including immunizations. The US Food and Drug Administration (FDA)–approved enzyme replacement therapy with galsulfase (Naglazyme) has been shown to improve walking and stair-climbing capacity and to decrease urine glycosaminoglycan (GAG) levels in patients with MPS VI.

• Perform ongoing evaluations for the development of valvular cardiac disease. Such evaluations include annual echocardiograms. According to the American Heart Association (AHA) guidelines, patients should receive bacterial endocarditis prophylaxis before surgical or dental procedures.
• Many patients show evidence of restrictive airway disease, obstructive airway disease, or both. Conduct ongoing assessments for the development of clinically significant hypoventilation. Patients may benefit from oxygen or positive pressure therapy (continuous positive airway pressure [CPAP] or bilevel positive airway pressure [BIPAP]), especially when asleep if they have sleep apnea.
• Patients typically have contractures and hand deformities. A program of physical therapy may be beneficial in maintaining optimal function. Carpal tunnel syndrome may be present and asymptomatic and should be evaluated with nerve conduction on a regular basis.
• Patients who develop headache, vision change, or vomiting should be evaluated for increased intracranial pressure and hydrocephalus. Measuring intrathecal spinal fluid pressure to confirm increased intracranial pressure may be necessary.

Surgical Care

• Patients who develop clinically significant valvular heart disease may require valve replacement.
• Patients with obstructive airway disease sometimes benefit from tonsillectomy and adenoidectomy. Severe airway obstruction and hypoventilation may eventually require tracheostomy.
• Corneal transplants have been successful in restoring vision to patients with corneal clouding, although storage in the transplanted cornea may recur over time.
• Surgical decompression of the carpal tunnel to preserve median nerve function may be necessary.
• Neurosurgery may be required to place ventriculoperitoneal decompression shunts for hydrocephalus or increased intracranial pressure.
• Orthopedic surgery may be necessary to decompress the spinal cord or to stabilize the atlantoaxial junction.
• Patients often develop hip dysplasia and require hip replacement surgery

Consultations

• Geneticist: Refer all patients suspected of having an MPS to a medical geneticist. The geneticist is needed to provide definitive diagnosis and appropriate counseling of the family about recurrence risks.
• Cardiologist: Refer affected patients to a cardiologist because of the risk for valvular heart disease.
• Audiologist: Refer affected patients to an audiologist for periodic hearing evaluations because both conductive and sensorineural hearing loss can occur.
• Ophthalmologist: Obtain slitlamp and funduscopic examinations during the initial evaluation and then periodically thereafter. Corneal clouding can lead to significant visual impairment.
• Neurosurgeon or orthopedist: Spinal cord compression secondary to thickening of the dura in the cervical canal has been described. Spinal cord compression results in myelopathy, which may require surgical intervention.
• Pulmonologist: A pulmonologist should evaluate the patient regularly to identify airway obstruction, hypoventilation, or sleep apnea.

Diet

• No special dietary requirements are noted.

Activity

• Patients with MPS VI usually have some limitations on their level of activity because of contractures and joint stiffness.
• Patients with cardiac manifestations may be limited in their activity level.

Medication

Specific therapy for mucopolysaccharidosis type VI (MPS VI) is just beginning to emerge, with recent clinical trials showing benefit from a recombinant DNA glycoprotein enzyme replacement therapy.

Enzyme replacement therapy

Recombinant DNA variant of N -acetylgalactosamine 4-sulfatase has been shown to improve physical capabilities of individuals with MPS VI.

Galsulfase (Naglazyme)

Indicated for MPS VI, which is characterized by the absence or marked reduction of N -acetylgalactosamine 4-sulfatase; provides exogenous enzyme as treatment. Recombinant DNA glycoprotein (Chinese hamster ovary cell line) variant form of polymorphic human enzyme N -acetylgalactosamine 4-sulfatase. Clinical trials showed improvement in walking and stair-climbing capacity. Most patients in the clinical trials were pediatric patients; however, children <5 y were not included.

Dosing

Adult

1 mg/kg IV infused over at least 4 h qwk; may extend infusion up to 20 h if infusion reactions occur

Pediatric

<5 years: Not established
>5 years: Administer as in adults

Interactions

None reported

Contraindications

None known

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Nearly all patients develop antibodies to galsulfase (pretreat with antihistamine [eg, diphenhydramine] with or without antipyretics [eg, acetaminophen] 30-60 min prior to each infusion); severe infusion reactions have occurred despite pretreatment with antihistamines and antipyretics and may include angioneurotic edema, hypotension, dyspnea, bronchospasm, respiratory distress, apnea, and urticaria; common infusion-related reactions include fever, chills/rigor, headache, rash, and mild-to-moderate urticaria; nausea, vomiting, elevated blood pressure, retrosternal pain, abdominal pain, malaise, and joint pain may occur; initial infusion reactions may occur as late as week 55 of treatment; sedating antihistamines may cause sleep apnea; moderate-to-severe infusion-associated reactions can generally be managed by slowing infusion rate and providing corticosteroid pretreatment in the 24-h period before the infusion

Follow-up

Further Inpatient Care

• Obstructive airway disease can result from narrowing of the trachea, enlarged tongue, and redundant tissue in patients with mucopolysaccharidosis type VI (MPS VI). Tracheostomy has been performed in some patients. Tonsillectomy and adenoidectomy are also frequently performed to relieve obstruction.
• Many patients develop carpal tunnel syndrome, which may require nerve decompression.

Further Outpatient Care

• Physical therapy to maximize joint mobility is beneficial.

Inpatient & Outpatient Medications

• Patients with cardiac disease may require pharmacological therapy to manage cardiac failure. Monitor these patients closely with a pediatric cardiologist.

Transfer

• Transfer patients with MPS VI who require general anesthesia for any procedure to a facility equipped to handle the substantial anesthetic risks.

Deterrence/Prevention

• In most cases, a history of MPS VI is not present, and the affected child is the first affected individual in the family.
• In future pregnancies, prenatal diagnosis is possible.

Complications

• Vision loss due to corneal clouding is common. Corneal transplants have been reported.
• Hearing loss is common and may require hearing aids.
• Carpal tunnel syndrome is a common complication.
• Obstructive airway disease can result in snoring or even hypoventilation.
• Valvular heart disease is common and may require surgical intervention.
• Spinal cord compression with damage and paralysis may occur.

Prognosis

• MPS VI is a progressive disorder with significant morbidity and early mortality. As with many genetic inborn errors of metabolism, considerable variation exists among individual patients. Therefore, the prognosis for a particular patient must be determined after consideration of the presentation and complications.

Patient Education

• Counsel patients and their families about the autosomal recessive inheritance pattern of MPS VI, the risk for occurrence in future pregnancies, and the availability of prenatal diagnosis.

Miscellaneous

Medicolegal Pitfalls

• Failure to counsel parents of affected individuals about the risk of occurrence in future pregnancies
• Failure to offer parents prenatal diagnosis studies
• General anesthesia should be administered to patients with mucopolysaccharidosis type VI (MPS VI) only in facilities staffed with anesthesiologists familiar with the potential complications. The anesthesia risk is significant because of instability of the atlantoaxial joint. Specifically, induction of anesthesia can be difficult because of airway maintenance problems.

Special Concerns

• Anesthesia risk: MPS VI presents a significant anesthesia risk because of instability of the atlantoaxial joint. In particular, induction of anesthesia can be difficult because of problems maintaining the airway. Patients with MPS VI should undergo general anesthesia only in facilities staffed with anesthesiologists who are familiar with the potential complications.
• Experimental therapies: Bone marrow transplantation (BMT) has been attempted in numerous patients with MPS. Although BMT has been of particular interest in treating patients with MPS who are at risk for neurologic disease (as in MPS type IH), BMT has been limited by the associated mortality risk and the need for an appropriately matched donor. Refer patients and families interested in pursuing this option to a center with staff who are experienced in this procedure for patients with metabolic disease.

References

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

2. Baehner F, Schmiedeskamp C, Krummenauer F, et al. Cumulative incidence rates of the mucopolysaccharidoses in Germany. J Inherit Metab Dis. 2005;28(6):1011-7. [Medline].

3. Pinto R, Caseiro C, Lemos M, et al. Prevalence of lysosomal storage diseases in Portugal. Eur J Hum Genet. Feb 2004;12(2):87-92. [Medline].

4. Bagewadi S, Roberts J, Mercer J, Jones S, Stephenson J, Wraith JE. Home treatment with Elaprase and Naglazyme is safe in patients with mucopolysaccharidoses types II and VI, respectively. J Inherit Metab Dis. Dec 2008;31(6):733-7. [Medline].

5. Harmatz P, Giugliani R, Schwartz I. Enzyme replacement therapy for mucopolysaccharidosis VI: a phase 3, randomized, double-blind, placebo-controlled, multinational study of recombinant human N-acetylgalactosamine 4-sulfatase (recombinant human arylsulfatase B or rhASB) and follow-on, open-. J Pediatr. Apr 2006;148(4):533-539. [Medline].

6. Harmatz P, Kramer WG, Hopwood JJ, et al. Pharmacokinetic profile of recombinant human N-acetylgalactosamine 4-sulphatase enzyme replacement therapy in patients with mucopolysaccharidosis VI (Maroteaux-Lamy syndrome): a phase I/II study. Acta Paediatr Suppl. Mar 2005;94(447):61-8; discussion 57. [Medline].

7. Isbrandt D, Arlt G, Brooks DA, Hopwood JJ, et al. Mucopolysaccharidosis VI (Maroteaux-Lamy syndrome): six unique arylsulfatase B gene alleles causing variable disease phenotypes. Am J Hum Genet. Mar 1994;54(3):454-63. [Medline].

8. Jones KL. Smith's Recognizable Patterns of Human Malformation. 1997:468-9.

9. Karageorgos L, Harmatz P, Simon J. Mutational analysis of mucopolysaccharidosis type VI patients undergoing a trial of enzyme replacement therapy. Hum Mutat. Mar 2004;23(3):229-33. [Medline].

10. Krivit W. Stem cell bone marrow transplantation in patients with metabolic storage diseases. Adv Pediatr. 2002;49:359-78. [Medline].

11. Nelson J, Crowhurst J, Carey B, Greed L. Incidence of the mucopolysaccharidoses in Western Australia. Am J Med Genet A. Dec 15 2003;123(3):310-3. [Medline].

12. Neufeld EF, Muenzer J. The mucopolysaccharidoses. In: The Metabolic and Molecular Bases of Inherited Disease. 1995:2465-94.

13. O'Brien JF, Cantz M, Spranger J. Maroteaux-Lamy disease (mucopolysaccharidosis VI), subtype A: deficiency of a N-acetylgalactosamine-4-sulfatase. Biochem Biophys Res Commun. Oct 8 1974;60(3):1170-7. [Medline].

14. Poorthuis BJ, Wevers RA, Kleijer WJ, et al. The frequency of lysosomal storage diseases in The Netherlands. Hum Genet. Jul-Aug 1999;105(1-2):151-6. [Medline].

15. Swiedler SJ, Beck M, Bajbouj M. Threshold effect of urinary glycosaminoglycans and the walk test as indicators of disease progression in a survey of subjects with Mucopolysaccharidosis VI (Maroteaux-Lamy syndrome). Am J Med Genet A. Apr 15 2005;134(2):144-50. [Medline].

Keywords

Maroteaux-Lamy syndrome, mucopolysaccharidosis type VI, arylsulfatase B deficiency, polydystrophic dwarfism, type VI mucopolysaccharidosis, MPS, MPS VI, coarse facies, corneal clouding, organomegaly, joint stiffness, dysostosis multiplex, hernias, short stature, mental retardation, otitis media, hearing loss, chronic respiratory tract infections, sleep apnea, pulmonary hypertension, hydrocephalus, rapid-onset blindness, cardiac valve insufficiency, dwarfism, hepatosplenomegaly, macrocephaly, claw-hand deformities, hirsutism

Contributor Information and Disclosures

Author

Paul R Harmatz, MD, Attending Physician, Department of Gastroenterology and Nutrition, Children's Hospital Oakland
Paul R Harmatz, MD is a member of the following medical societies: American Association for the Study of Liver Diseases, American Gastroenterological Association, American Society of Hematology, American Society of Human Genetics, and North American Society for Pediatric Gastroenterology and Nutrition
Disclosure: BioMarin Pharmaceutical Inc. Consulting fee Consulting; BioMarin Pharmaceutical Inc. Honoraria Speaking and teaching

Coauthor(s)

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.

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 financial planner; Avanir Pharma Stock Investment from financial planner ; WebMD Salary and stock Employment and investment from financial planner

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.

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