International Guidelines for the Management and Treatment of Morquio A Syndrome

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Abstract

Morquio A syndrome (mucopolysaccharidosis IVA) is a lysosomal storage disorder associated with skeletal and joint abnormalities and significant non-skeletal manifestations including respiratory disease, spinal cord compression, cardiac disease, impaired vision, hearing loss, and dental problems. The clinical presentation, onset, severity and progression rate of clinical manifestations of Morquio A syndrome vary widely between patients. Because of the heterogeneous and progressive nature of the disease, the management of patients with Morquio A syndrome is challenging and requires a multidisciplinary approach, involving an array of specialists. The current paper presents international guidelines for the evaluation, treatment and symptom-based management of Morquio A syndrome. These guidelines were developed during two expert meetings by an international panel of specialists in pediatrics, genetics, orthopedics, pulmonology, cardiology, and anesthesia with extensive experience in managing Morquio A syndrome. © 2014 The Authors. American Journal of Medical Genetics Part A published by Wiley Periodicals, Inc.

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Cardiac disease in patients with mucopolysaccharidosis: presentation, diagnosis and management

Elizabeth A. Braunlin, Paul Harmatz, Maurizio Scarpa … (2011)

The mucopolysaccharidoses (MPSs) are inherited lysosomal storage disorders caused by the absence of functional enzymes that contribute to the degradation of glycosaminoglycans (GAGs). The progressive systemic deposition of GAGs results in multi-organ system dysfunction that varies with the particular GAG deposited and the specific enzyme mutation(s) present. Cardiac involvement has been reported in all MPS syndromes and is a common and early feature, particularly for those with MPS I, II, and VI. Cardiac valve thickening, dysfunction (more severe for left-sided than for right-sided valves), and hypertrophy are commonly present; conduction abnormalities, coronary artery and other vascular involvement may also occur. Cardiac disease emerges silently and contributes significantly to early mortality. The clinical examination of individuals with MPS is often difficult due to physical and, sometimes, intellectual patient limitations. The absence of precordial murmurs does not exclude the presence of cardiac disease. Echocardiography and electrocardiography are key diagnostic techniques for evaluation of valves, ventricular dimensions and function, which are recommended on a regular basis. The optimal technique for evaluation of coronary artery involvement remains unsettled. Standard medical and surgical techniques can be modified for MPS patients, and systemic therapies such as hematopoietic stem cell transplantation and enzyme replacement therapy (ERT) may alter overall disease progression with regression of ventricular hypertrophy and maintenance of ventricular function. Cardiac valve disease is usually unresponsive or, at best, stabilized, although ERT within the first few months of life may prevent valve involvement, a fact that emphasizes the importance of early diagnosis and treatment in MPS.

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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-label extension study.

Laila Arash, , Ida Vanessa Schwartz … (2006)

The objective of this Phase 3 study was to confirm the efficacy and safety of recombinant human arylsulfatase B (rhASB) treatment of mucopolysaccharidosis type VI (MPS VI; Maroteaux-Lamy syndrome), a rare, fatal lysosomal storage disease with no effective treatment. Thirty-nine patients with MPS VI were evaluated in a randomized, double-blind, placebo-controlled, multicenter, multinational study for 24 weeks. The primary efficacy variable was the distance walked in a 12-minute walk test (12MWT), whereas the secondary efficacy variables were the number of stairs climbed in a 3-minute stair climb (3MSC) and the level of urinary glycosaminoglycan (GAG) excretion. All patients received drug in an open-label extension period for an additional 24 weeks. After 24 weeks, patients receiving rhASB walked on average 92 meters (m) more in the 12MWT (p=.025) and 5.7 stairs per minute more 3MSC (p=.053) than patients receiving placebo. Continued improvement was observed during the extension study. Urinary GAG declined by -227+/-18 microg/mg more with rhASB than placebo (p<.001). Infusions were generally safe and well tolerated. Patients exposed to drug experienced positive clinical benefit despite the presence of antibody to the protein. rhASB significantly improves endurance, reduces GAG, and has an acceptable safety profile.

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A phase II/III clinical study of enzyme replacement therapy with idursulfase in mucopolysaccharidosis II (Hunter syndrome).

Suresh Vijayaraghavan, B Ulbrich, Bernard A Conway … (2006)

To evaluate the safety and efficacy of recombinant human iduronate-2-sulfatase (idursulfase) in the treatment of mucopolysaccharidosis II. Ninety-six mucopolysaccharidosis II patients between 5 and 31 years of age were enrolled in a double-blind, placebo-controlled trial. Patients were randomized to placebo infusions, weekly idursulfase (0.5 mg/kg) infusions or every-other-week infusions of idursulfase (0.5 mg/kg). Efficacy was evaluated using a composite endpoint consisting of distance walked in 6 minutes and the percentage of predicted forced vital capacity based on the sum of the ranks of change from baseline. Patients in the weekly and every-other-week idursulfase groups exhibited significant improvement in the composite endpoint compared to placebo (P = 0.0049 for weekly and P = 0.0416 for every-other-week) after one year. The weekly dosing group experienced a 37-m increase in the 6-minute-walk distance (P = 0.013), a 2.7% increase in percentage of predicted forced vital capacity (P = 0.065), and a 160 mL increase in absolute forced vital capacity (P = 0.001) compared to placebo group at 53 weeks. Idursulfase was generally well tolerated, but infusion reactions did occur. Idursulfase antibodies were detected in 46.9% of patients during the study. This study supports the use of weekly infusions of idursulfase in the treatment of mucopolysaccharidosis II.

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Author and article information

Journal

Journal ID (nlm-ta): Am J Med Genet A

Journal ID (iso-abbrev): Am. J. Med. Genet. A

Journal ID (publisher-id): ajmg

Title: American Journal of Medical Genetics. Part a

Publisher: Blackwell Publishing Ltd (Oxford, UK )

ISSN (Print): 1552-4825

ISSN (Electronic): 1552-4833

Publication date (Print): January 2015

Publication date (Electronic): 24 October 2014

Volume: 167

Issue: 1

Pages: 11-25

Affiliations

[1 ]Salford Royal NHS Foundation Trust, Salford K

[2 ]New York University School of Medicine New York

[3 ]Department of Genetics/UFRGS and INAGEMP, Medical Genetics Service/HCPA Porto Alegrw, RS, Brazil

[4 ]University of California San Francisco Benioff Children's Hospital Oakland, Oakland California

[5 ]University Children's Hospital, Mainz Germany

[6 ]Nemours/Alfred I. duPont Hospital for Children, Wilmington Delaware

[7 ]Hospital for Sick Children, Toronto Ontario, Canada

[8 ]Fundacion Cardioinfantil, Bogotá, C/marca Colombia

[9 ]Murdoch Childrens Research Institute and University of Melbourne, Parkville Victoria, Australia

Author notes

*Correspondence to: Dr. Christian J. Hendriksz, Consultant Transitional Metabolic Medicine, Manchester Academic Health Science Centre, The Mark Holland Metabolic Unit, Salford Royal Foundation NHS Trust, Ladywell NW2-2nd Floor Room 107, Salford, Manchester M6 8HD., E-mail: Chris.Hendriksz@ 123456srft.nhs.uk

Conflicts of interest: The authors are grateful to Ismar Healthcare NV for their assistance in writing of the manuscript, which was funded by BioMarin Pharmaceutical Inc. The current management guidelines were based on the outcome of two advisory board meetings sponsored by BioMarin Pharmaceutical Inc. Dr. Hendriksz received financial support in person or by the institution from BioMarin in the following capacities: honoraria for lectures, chairman of advisory boards, consultant on projects, research trials and travel grants. Dr. Berger has worked as a consultant for BioMarin Pharmaceutical Inc and for Genzyme. Dr. Harmatz has worked as consultant and study investigator for BioMarin Pharmaceutical Inc. and has received an honorarium. Dr. Giugliani is member of the BioMarin sponsored Morquio Program Advisory Board, and has received travel grants and speaker fees from Actelion, Amicus, BioMarin, Genzyme, Shire and Synageva. The other authors do not have any conflicts of interest.

Article

DOI: 10.1002/ajmg.a.36833

PMC ID: 4309407

PubMed ID: 25346323

SO-VID: fadad684-79d2-4fad-aef2-5db7d620e8cb

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This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

International Guidelines for the Management and Treatment of Morquio A Syndrome

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Most cited references 70

Cardiac disease in patients with mucopolysaccharidosis: presentation, diagnosis and management

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-label extension study.

A phase II/III clinical study of enzyme replacement therapy with idursulfase in mucopolysaccharidosis II (Hunter syndrome).

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