AUTHOR INFORMATION

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Authored by Paul Richard Harmatz, MD, Consulting Staff, Department of Gastroenterology and Nutrition, Children’s Hospital Oakland

Coauthored by Margaret McGovern, MD, PhD, Vice Chair, Professor, Department of Human Genetics, Mount Sinai School of Medicine

Paul Richard Harmatz, MD, is a member of the following medical societies: American Association for the Study of Liver Diseases, American Gastroenterological Association, American Society of Human Genetics, North American Society for Pediatric Gastroenterology and Nutrition, and Society for Pediatric Research

Edited by Karl S Roth, MD, Chair, Professor, Department of Pediatrics, Creighton University School of Medicine; Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine.com, Inc; Margaret McGovern, MD, PhD, Vice Chair, Professor, Department of Human Genetics, Mount Sinai School of Medicine; Daniel Rauch, MD, FAAP, Director, Pediatric Hospitalist Program, Associate Professor, Department of Pediatrics, New York University School of Medicine; and Bruce A Buehler, MD, Professor, Department of Pathology and Microbiology, Chairman, Department of Pediatrics, Director, Hattie B Munroe Center for Human Genetics, University of Nebraska Medical Center

Author's Email:	Paul Richard Harmatz, MD
Editor's Email:	Karl S Roth, MD

eMedicine Journal, December 18 2006, VOLUME 7, Number 12

INTRODUCTION

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Background: The mucopolysaccharidoses (MPS) 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 MPS 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. 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, 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, 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:

• In the US: The MPS are rare disorders, and data concerning incidence are not widely available.

• Internationally: 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 (Nelson, 2003). Recent reports from Germany, the Netherlands, and northern Portugal noted birth incidences of 1 per 434,783, 1 per 667,000, and 1 per 238,095, respectively (Baehner, 2005; Poorthuis, 1999; Pinto, 2004).

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.
  
  
• 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.
  
  
• Patients may also have obstructive airway disease.
  
  
• Age at death is variable, and mild forms of the disease have been described with prolonged survival.

Race: MPS VI is panethnic.

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

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History:

• Affected individuals usually have a period of normal growth and development but later present when hepatosplenomegaly, coarse facial features, joint or spine abnormalities, and corneal clouding become evident.



• Because mucopolysaccharidosis type VI (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.

DIFFERENTIALS

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Mucopolysaccharidosis Type I H/S
Mucopolysaccharidosis Type IH
Mucopolysaccharidosis Type II
Mucopolysaccharidosis Type IS

WORKUP

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Lab Studies:

• Urine glycosaminoglycan analysis can be performed using various qualitative or quantitative methods. These studies are useful for establishing the likely diagnosis of 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 deficiencies.

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.

Staging: Urine 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

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Medical Care: Patients with mucopolysaccharidosis type VI (MPS VI) require ongoing medical care from a number of subspecialists. In addition, patients should receive routine pediatric care, including immunizations. 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 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 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 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:

• 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.



• Refer affected patients to a cardiologist because of the risk for valvular heart disease.



• Refer affected patients to an audiologist for periodic hearing evaluations because both conductive and sensorineural hearing loss can occur.



• Ophthalmology: Obtain slitlamp and funduscopic examinations during the initial evaluation and then periodically thereafter. Corneal clouding can lead to significant visual impairment.



• Neurosurgery or orthopedics: 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.



• A pulmonologist should evaluate the patient regularly to identify airway obstruction, hypoventilation, or sleep apnea.

Diet: No special dietary requirements exist.

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

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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.

Drug Category: Enzyme replacement therapy -- Recombinant DNA variant of N-acetylgalactosamine 4-sulfatase has been shown to improve physical capabilities of individuals with MPS VI.

Drug Name	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.
Adult Dose	1 mg/kg IV infused over at least 4 h qwk; may extend infusion up to 20 h if infusion reactions occur
Pediatric Dose	<5 years: Not established >5 years: Administer as in adults
Contraindications	None known
Interactions	None reported
Pregnancy	B - Usually safe but benefits must outweigh the risks.
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

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Further Inpatient Care:

• Obstructive airway disease can result from narrowing of the trachea, enlarged tongue, and redundant tissue. 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.

In/Out Patient Meds:

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

Transfer:

• Transfer patients with mucopolysaccharidosis type VI (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.

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

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Medical/Legal 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: BMT has been attempted in a number of patients with MPS. Although BMT has been of particular interest in treating patients with MPS who are at risk for neurologic disease (MPS 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.

TEST QUESTIONS

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CME Question 1: At the time of a routine health maintenance examination, a 15-month-old boy is noted to have hepatomegaly and coarse facial features. Which of the following laboratory tests is the most appropriate to obtain?

A: Thyroid function tests
B: Urine mucopolysaccharides
C: Urine organic acids
D: Serum amino acids
E: Urine reducing substances

The correct answer is B: In a child who presents with organomegaly and coarse facial features, consider a storage disease. Of the options presented, urine mucopolysaccharide is the only test that screens for a storage disorder.

CME Question 2: The parents of a 4-year-old boy with mucopolysaccharidoses (MPS) VI are concerned about their risk of a similarly affected child in future pregnancies. Which of the following is the most appropriate statement to include in counseling this family?

A: Their risk for an affected child in the next pregnancy is 25%.
B: MPS VI is a very rare disorder, and they should not worry about it occurring again.
C: They are at risk only if the fetus is male because the disorder is inherited as an X-linked trait.
D: They both should be tested now to determine if they are carriers of the disorder.
E: They are at increased risk, but no prenatal testing is currently available.

The correct answer is A: MPS VI is transmitted as an autosomal recessive trait; therefore, each pregnancy has a 25% recurrence risk. Because the couple already has an affected child, they are obligate carriers, and carrier testing in each of them is not necessary. Of the MPS disorders, only one, Hunter syndrome (MPS II), is inherited as an X-linked trait. Prenatal diagnosis based on measurement of arylsulfatase B is available.

Pearl Question 1 (T/F): Children with loss of developmental milestones should be evaluated for a lysosomal storage disease.

The correct answer is True: Loss of developmental milestones should always prompt an evaluation to determine if a storage disorder is the etiology.

Pearl Question 2 (T/F): The mucopolysaccharidoses are all inherited as autosomal recessive traits, except for Hunter syndrome.

The correct answer is True: Most of the inborn errors of metabolism are inherited as autosomal recessive traits. Some exceptions include Hunter syndrome and Fabry disease, which is a lipid storage disorder.

Pearl Question 3 (T/F): Mucopolysaccharidoses (MPS) are best diagnosed based on determining the specific MPS that is excreted in the urine.

The correct answer is False: The definitive diagnosis of an MPS requires demonstration of the specific enzymatic deficiency in cultured fibroblasts or peripheral blood lymphocytes.

Pearl Question 4 (T/F): Organomegaly is a consistent feature in all of the mucopolysaccharidoses (MPS).

The correct answer is False: Organomegaly is present in some, but not all, of the MPS disorders. For example, the Sanfilippo syndromes (MPS III) are not usually accompanied by organomegaly; therefore, the presence or absence of organomegaly is useful in determining the differential diagnoses.

BIBLIOGRAPHY

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• 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].
• 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 2006 Apr; 148(4): 533-539[Medline].
• 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 2005 Mar; 94(447): 61-8; discussion 57[Medline].
• 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 1994 Mar; 54(3): 454-63[Medline].
• Jones KL: Smith's Recognizable Patterns of Human Malformation. 1997: 468-469.
• Karageorgos L, Harmatz P, Simon J: Mutational analysis of mucopolysaccharidosis type VI patients undergoing a trial of enzyme replacement therapy. Hum Mutat 2004 Mar; 23(3): 229-33[Medline].
• Krivit W: Stem cell bone marrow transplantation in patients with metabolic storage diseases. Adv Pediatr 2002; 49: 359-78[Medline].
• Nelson J, Crowhurst J, Carey B, Greed L: Incidence of the mucopolysaccharidoses in Western Australia. Am J Med Genet A 2003 Dec 15; 123(3): 310-3[Medline].
• Neufeld EF, Muenzer J: The mucopolysaccharidoses. The Metabolic and Molecular Bases of Inherited Disease. 1995: 2465-2494.
• 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 1974 Oct 8; 60(3): 1170-7[Medline].
• Pinto R, Caseiro C, Lemos M, et al: Prevalence of lysosomal storage diseases in Portugal. Eur J Hum Genet 2004 Feb; 12(2): 87-92[Medline].
• Poorthuis BJ, Wevers RA, Kleijer WJ, et al: The frequency of lysosomal storage diseases in The Netherlands. Hum Genet 1999 Jul-Aug; 105(1-2): 151-6[Medline].
• 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 2005 Apr 15; 134(2): 144-50[Medline].

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