- Simon Jones, MD
Simon Jones, MD
- Honorary Senior Lecturer
- University of Manchester
- Consultant in Paediatric Inborn Errors of Metabolism
- Manchester Centre for Genomic Medicine
- Robert Wynn, MD, MRCP, FRCPath
Robert Wynn, MD, MRCP, FRCPath
- Consultant in Paediatric Haematology and Blood and Marrow Transplantation
- Royal Manchester Children's Hospital
- Section Editors
- Sihoun Hahn, MD, PhD
Sihoun Hahn, MD, PhD
- Section Editor — Genetics
- Professor of Pediatrics
- University of Washington School of Medicine, Seattle Children's Hospital
- Marc C Patterson, MD, FRACP
Marc C Patterson, MD, FRACP
- Section Editor — Pediatric Neurology
- Professor of Neurology, Pediatrics, and Medical Genetics
- Chair, Division of Child and Adolescent Neurology
- Mayo Clinic College of Medicine
The mucopolysaccharidoses (MPS) are lysosomal storage disorders caused by the deficiency of enzymes required for the stepwise breakdown of glycosaminoglycans (GAGs), also known as mucopolysaccharides. These conditions are differentiated by their clinical features and age of presentation (table 1). The MPS can affect many different systems, including the respiratory, cardiovascular, skeletal, and neurologic systems. Enzyme replacement therapy (ERT) is available for some MPS. Other therapies focus on treatment of symptoms.
Treatment of the MPS is reviewed here. The clinical features and diagnosis of these disorders as well as associated complications are discussed separately. (See "Mucopolysaccharidoses: Clinical features and diagnosis" and "Mucopolysaccharidoses: Complications".)
OVERVIEW OF MANAGEMENT
Most therapies for MPS are directed toward treatment of complications and are not specific for the underlying abnormality. Supportive or symptomatic management can improve the quality of life for patients and their families, but they cannot prevent the inevitable decline in function. However, specific therapies, such as enzyme replacement or hematopoietic cell transplantation, may alter the natural history of these disorders. The choice of therapy depends upon the type of MPS and the disease severity in the specific patient. Management of complications is discussed in detail separately. (See "Mucopolysaccharidoses: Complications".)
ENZYME REPLACEMENT THERAPY
Enzyme replacement therapy (ERT) is approved in the United States (US), European Union (EU), and several other countries for patients with MPS I, MPS II, MPS IVA, and MPS VI (table 1) . Indications vary across the MPS, but generally ERT is used in patients with moderate to severe disease. The exception is patients <2 years of age with severe MPS I (Hurler), for whom hematopoietic cell transplantation is preferred if there is a suitable donor (see 'Hematopoietic cell transplantation' below). Clinical trials are underway for ERT for MPS VII.
MPS I — In patients with MPS I (Hurler, Hurler-Scheie, and Scheie syndromes), treatment with recombinant human alpha-L-iduronidase (laronidase), the deficient enzyme, reduces lysosomal storage in the liver and improves some clinical manifestations while stabilizing others [2-6]. Better outcome is achieved if laronidase is initiated before serious complications occur [6,7]. The recommended dose is 0.58 mg/kg (rounded up to the nearest whole vial) given intravenously (IV) once a week.To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information on subscription options, click below on the option that best describes you:
- Dietz HC. New therapeutic approaches to mendelian disorders. N Engl J Med 2010; 363:852.
- Kakkis ED, Muenzer J, Tiller GE, et al. Enzyme-replacement therapy in mucopolysaccharidosis I. N Engl J Med 2001; 344:182.
- Wraith JE, Clarke LA, Beck M, et al. Enzyme replacement therapy for mucopolysaccharidosis I: a randomized, double-blinded, placebo-controlled, multinational study of recombinant human alpha-L-iduronidase (laronidase). J Pediatr 2004; 144:581.
- Sifuentes M, Doroshow R, Hoft R, et al. A follow-up study of MPS I patients treated with laronidase enzyme replacement therapy for 6 years. Mol Genet Metab 2007; 90:171.
- Jameson E, Jones S, Remmington T. Enzyme replacement therapy with laronidase (Aldurazyme(®)) for treating mucopolysaccharidosis type I. Cochrane Database Syst Rev 2016; 4:CD009354.
- Laraway S, Mercer J, Jameson E, et al. Outcomes of Long-Term Treatment with Laronidase in Patients with Mucopolysaccharidosis Type I. J Pediatr 2016; 178:219.
- Gabrielli O, Clarke LA, Bruni S, Coppa GV. Enzyme-replacement therapy in a 5-month-old boy with attenuated presymptomatic MPS I: 5-year follow-up. Pediatrics 2010; 125:e183.
- Clarke LA, Wraith JE, Beck M, et al. Long-term efficacy and safety of laronidase in the treatment of mucopolysaccharidosis I. Pediatrics 2009; 123:229.
- Kakavanos R, Turner CT, Hopwood JJ, et al. Immune tolerance after long-term enzyme-replacement therapy among patients who have mucopolysaccharidosis I. Lancet 2003; 361:1608.
- Wraith JE, Beck M, Lane R, et al. Enzyme replacement therapy in patients who have mucopolysaccharidosis I and are younger than 5 years: results of a multinational study of recombinant human alpha-L-iduronidase (laronidase). Pediatrics 2007; 120:e37.
- Pitz S, Ogun O, Bajbouj M, et al. Ocular changes in patients with mucopolysaccharidosis I receiving enzyme replacement therapy: a 4-year experience. Arch Ophthalmol 2007; 125:1353.
- Dickson P, McEntee M, Vogler C, et al. Intrathecal enzyme replacement therapy: successful treatment of brain disease via the cerebrospinal fluid. Mol Genet Metab 2007; 91:61.
- Nestrasil I, Shapiro E, Svatkova A, et al. Intrathecal enzyme replacement therapy reverses cognitive decline in mucopolysaccharidosis type I. Am J Med Genet A 2017; 173:780.
- Munoz-Rojas MV, Vieira T, Costa R, et al. Intrathecal enzyme replacement therapy in a patient with mucopolysaccharidosis type I and symptomatic spinal cord compression. Am J Med Genet A 2008; 146A:2538.
- FDA News. FDA approves first treatment for Hunter syndrome. July 24, 2006. www.fda.gov/bbs/topics/NEWS/2006/NEW01418.html (Accessed on August 01, 2006).
- Muenzer J, Martins AM. Hunter syndrome: to treat or not to treat. Acta Paediatr 2008; 97:55.
- da Silva EM, Strufaldi MW, Andriolo RB, Silva LA. Enzyme replacement therapy with idursulfase for mucopolysaccharidosis type II (Hunter syndrome). Cochrane Database Syst Rev 2016; 2:CD008185.
- Wraith JE, Scarpa M, Beck M, et al. Mucopolysaccharidosis type II (Hunter syndrome): a clinical review and recommendations for treatment in the era of enzyme replacement therapy. Eur J Pediatr 2008; 167:267.
- Muenzer J, Bodamer O, Burton B, et al. The role of enzyme replacement therapy in severe Hunter syndrome-an expert panel consensus. Eur J Pediatr 2012; 171:181.
- Muenzer J, Wraith JE, Beck M, et al. A phase II/III clinical study of enzyme replacement therapy with idursulfase in mucopolysaccharidosis II (Hunter syndrome). Genet Med 2006; 8:465.
- Lampe C, Bosserhoff AK, Burton BK, et al. Long-term experience with enzyme replacement therapy (ERT) in MPS II patients with a severe phenotype: an international case series. J Inherit Metab Dis 2014; 37:823.
- Muenzer J, Beck M, Giugliani R, et al. Idursulfase treatment of Hunter syndrome in children younger than 6 years: results from the Hunter Outcome Survey. Genet Med 2011; 13:102.
- Tylki-Szymanska A, Jurecka A, Zuber Z, et al. Enzyme replacement therapy for mucopolysaccharidosis II from 3 months of age: a 3-year follow-up. Acta Paediatr 2012; 101:e42.
- Jones SA, Breen C, Heap F, et al. A phase 1/2 study of intrathecal heparan-N-sulfatase in patients with mucopolysaccharidosis IIIA. Mol Genet Metab 2016; 118:198.
- FDA News Release: FDA approves Vimizim to treat rare congenital enzyme disorder. http://www.fda.gov/newsevents/newsroom/pressannouncements/ucm386008.htm.
- Hendriksz CJ, Burton B, Fleming TR, et al. Efficacy and safety of enzyme replacement therapy with BMN 110 (elosulfase alfa) for Morquio A syndrome (mucopolysaccharidosis IVA): a phase 3 randomised placebo-controlled study. J Inherit Metab Dis 2014; 37:979.
- U.S. Food and Drug Administration. Center for Drug Evaluation and Research. www.accessdata.fda.gov/scripts/cder/drugsatfda (Accessed on September 26, 2006).
- Harmatz P, Whitley CB, Waber L, et al. Enzyme replacement therapy in mucopolysaccharidosis VI (Maroteaux-Lamy syndrome). J Pediatr 2004; 144:574.
- Naglazyme (galsulfase) product label. Biomarin Pharmaceutical Inc, Novato, CA.
- Harmatz P, Ketteridge D, Giugliani R, et al. Direct comparison of measures of endurance, mobility, and joint function during enzyme-replacement therapy of mucopolysaccharidosis VI (Maroteaux-Lamy syndrome): results after 48 weeks in a phase 2 open-label clinical study of recombinant human N-acetylgalactosamine 4-sulfatase. Pediatrics 2005; 115:e681.
- Harmatz P, Giugliani R, Schwartz I, et al. 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. J Pediatr 2006; 148:533.
- Brunelli MJ, Atallah ÁN, da Silva EM. Enzyme replacement therapy with galsulfase for mucopolysaccharidosis type VI. Cochrane Database Syst Rev 2016; 3:CD009806.
- Giugliani R, Lampe C, Guffon N, et al. Natural history and galsulfase treatment in mucopolysaccharidosis VI (MPS VI, Maroteaux-Lamy syndrome)--10-year follow-up of patients who previously participated in an MPS VI Survey Study. Am J Med Genet A 2014; 164A:1953.
- Auclair D, Finnie J, White J, et al. Repeated intrathecal injections of recombinant human 4-sulphatase remove dural storage in mature mucopolysaccharidosis VI cats primed with a short-course tolerisation regimen. Mol Genet Metab 2010; 99:132.
- Krivit W, Sung JH, Shapiro EG, Lockman LA. Microglia: the effector cell for reconstitution of the central nervous system following bone marrow transplantation for lysosomal and peroxisomal storage diseases. Cell Transplant 1995; 4:385.
- Prasad VK, Kurtzberg J. Transplant outcomes in mucopolysaccharidoses. Semin Hematol 2010; 47:59.
- 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 1998; 91:2601.
- Guffon N, Souillet G, Maire I, et al. Follow-up of nine patients with Hurler syndrome after bone marrow transplantation. J Pediatr 1998; 133:119.
- Vellodi A, Young EP, Cooper A, et al. Bone marrow transplantation for mucopolysaccharidosis type I: experience of two British centres. Arch Dis Child 1997; 76:92.
- Peters C, Balthazor M, Shapiro EG, et al. Outcome of unrelated donor bone marrow transplantation in 40 children with Hurler syndrome. Blood 1996; 87:4894.
- Whitley CB, Belani KG, Chang PN, et al. Long-term outcome of Hurler syndrome following bone marrow transplantation. Am J Med Genet 1993; 46:209.
- Hopwood JJ, Vellodi A, Scott HS, et al. Long-term clinical progress in bone marrow transplanted mucopolysaccharidosis type I patients with a defined genotype. J Inherit Metab Dis 1993; 16:1024.
- Malm G, Gustafsson B, Berglund G, et al. Outcome in six children with mucopolysaccharidosis type IH, Hurler syndrome, after haematopoietic stem cell transplantation (HSCT). Acta Paediatr 2008; 97:1108.
- Aldenhoven M, Boelens JJ, de Koning TJ. The clinical outcome of Hurler syndrome after stem cell transplantation. Biol Blood Marrow Transplant 2008; 14:485.
- Grigull L, Sykora KW, Tenger A, et al. Variable disease progression after successful stem cell transplantation: prospective follow-up investigations in eight patients with Hurler syndrome. Pediatr Transplant 2011; 15:861.
- Boelens JJ, Aldenhoven M, Purtill D, et al. Outcomes of transplantation using various hematopoietic cell sources in children with Hurler syndrome after myeloablative conditioning. Blood 2013; 121:3981.
- Rodgers NJ, Kaizer AM, Miller WP, et al. Mortality after hematopoietic stem cell transplantation for severe mucopolysaccharidosis type I: the 30-year University of Minnesota experience. J Inherit Metab Dis 2017; 40:271.
- Boelens JJ, Wynn RF, O'Meara A, et al. Outcomes of hematopoietic stem cell transplantation for Hurler's syndrome in Europe: a risk factor analysis for graft failure. Bone Marrow Transplant 2007; 40:225.
- Aldenhoven M, Wynn RF, Orchard PJ, et al. Long-term outcome of Hurler syndrome patients after hematopoietic cell transplantation: an international multicenter study. Blood 2015; 125:2164.
- Gullingsrud EO, Krivit W, Summers CG. Ocular abnormalities in the mucopolysaccharidoses after bone marrow transplantation. Longer follow-up. Ophthalmology 1998; 105:1099.
- Tandon V, Williamson JB, Cowie RA, Wraith JE. Spinal problems in mucopolysaccharidosis I (Hurler syndrome). J Bone Joint Surg Br 1996; 78:938.
- Field RE, Buchanan JA, Copplemans MG, Aichroth PM. Bone-marrow transplantation in Hurler's syndrome. Effect on skeletal development. J Bone Joint Surg Br 1994; 76:975.
- Masterson EL, Murphy PG, O'Meara A, et al. Hip dysplasia in Hurler's syndrome: orthopaedic management after bone marrow transplantation. J Pediatr Orthop 1996; 16:731.
- Hirth A, Berg A, Greve G. Successful treatment of severe heart failure in an infant with Hurler syndrome. J Inherit Metab Dis 2007; 30:820.
- Cox-Brinkman J, Boelens JJ, Wraith JE, et al. Haematopoietic cell transplantation (HCT) in combination with enzyme replacement therapy (ERT) in patients with Hurler syndrome. Bone Marrow Transplant 2006; 38:17.
- Wynn RF, Mercer J, Page J, et al. Use of enzyme replacement therapy (Laronidase) before hematopoietic stem cell transplantation for mucopolysaccharidosis I: experience in 18 patients. J Pediatr 2009; 154:135.
- Eisengart JB, Rudser KD, Tolar J, et al. Enzyme replacement is associated with better cognitive outcomes after transplant in Hurler syndrome. J Pediatr 2013; 162:375.
- Vellodi A, Young E, Cooper A, et al. Long-term follow-up following bone marrow transplantation for Hunter disease. J Inherit Metab Dis 1999; 22:638.
- McKinnis EJ, Sulzbacher S, Rutledge JC, et al. Bone marrow transplantation in Hunter syndrome. J Pediatr 1996; 129:145.
- Krivit W. Maroteaux-Lamy syndrome (mucopolysaccharidosis VI): Treatment by allogeneic bone marrow transplantation in 6 patients and potential for autotransplantation bone marrow gene insertion. Int Pediatr 1992; 7:1.
- Yamada Y, Kato K, Sukegawa K, et al. Treatment of MPS VII (Sly disease) by allogeneic BMT in a female with homozygous A619V mutation. Bone Marrow Transplant 1998; 21:629.
- Guffon N, Bertrand Y, Forest I, et al. Bone marrow transplantation in children with Hunter syndrome: outcome after 7 to 17 years. J Pediatr 2009; 154:733.
- Shapiro EG, Lockman LA, Balthazor M, Krivit W. Neuropsychological outcomes of several storage diseases with and without bone marrow transplantation. J Inherit Metab Dis 1995; 18:413.
- Krivit W, Whitley CB, Chang P, et al. Lysosomal storage diseases treated by bone marrow transplantation: Review of 21 patients. In: Bone marrow transplantation in children, Johnson E, Pochedly C (Eds), Raven Press, New York 1990. p.261.
- Neufeld EF, Muenzer J. The metabolic and molecular bases of inherited disease, Scriver C, Beaudet AL, Valle D, Sly W (Eds), McGraw-Hill, New York 2001. p.3421.
- Stein CS, Ghodsi A, Derksen T, Davidson BL. Systemic and central nervous system correction of lysosomal storage in mucopolysaccharidosis type VII mice. J Virol 1999; 73:3424.
- Watson GL, Sayles JN, Chen C, et al. Treatment of lysosomal storage disease in MPS VII mice using a recombinant adeno-associated virus. Gene Ther 1998; 5:1642.
- Sands MS, Wolfe JH, Birkenmeier EH, et al. Gene therapy for murine mucopolysaccharidosis type VII. Neuromuscul Disord 1997; 7:352.
- Ohashi T, Watabe K, Uehara K, et al. Adenovirus-mediated gene transfer and expression of human beta-glucuronidase gene in the liver, spleen, and central nervous system in mucopolysaccharidosis type VII mice. Proc Natl Acad Sci U S A 1997; 94:1287.
- Bosch A, Perret E, Desmaris N, Heard JM. Long-term and significant correction of brain lesions in adult mucopolysaccharidosis type VII mice using recombinant AAV vectors. Mol Ther 2000; 1:63.
- Baldo G, Wozniak DF, Ohlemiller KK, et al. Retroviral-vector-mediated gene therapy to mucopolysaccharidosis I mice improves sensorimotor impairments and other behavioral deficits. J Inherit Metab Dis 2013; 36:499.
- Haurigot V, Marcó S, Ribera A, et al. Whole body correction of mucopolysaccharidosis IIIA by intracerebrospinal fluid gene therapy. J Clin Invest 2013.
- Guffon N, Bin-Dorel S, Decullier E, et al. Evaluation of miglustat treatment in patients with type III mucopolysaccharidosis: a randomized, double-blind, placebo-controlled study. J Pediatr 2011; 159:838.
- Malinowska M, Wilkinson FL, Langford-Smith KJ, et al. Genistein improves neuropathology and corrects behaviour in a mouse model of neurodegenerative metabolic disease. PLoS One 2010; 5:e14192.