Enzyme replacement therapy and/or hematopoietic stem cell transplantation at diagnosis in patients with mucopolysaccharidosis type I: results of a European consensus procedure

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Abstract

Background

Mucopolysaccharidosis type I (MPS I) is a lysosomal storage disorder that results in the accumulation of glycosaminoglycans causing progressive multi-organ dysfunction. Its clinical spectrum is very broad and varies from the severe Hurler phenotype (MPS I-H) which is characterized by early and progressive central nervous system (CNS) involvement to the attenuated Scheie phenotype (MPS I-S) with no CNS involvement. Indication, optimal timing, safety and efficacy of the two available treatment options for MPS I, enzyme replacement therapy (ERT) and hematopoietic stem cell transplantation (HSCT), are subject to continuing debate. A European consensus procedure was organized to reach consensus about the use of these two treatment strategies.

Methods

A panel of specialists, including 8 specialists for metabolic disorders and 7 bone marrow transplant physicians, all with acknowledged expertise in MPS I, participated in a modified Delphi process to develop consensus-based statements on MPS I treatment. Fifteen MPS I case histories were used to initiate the discussion and to anchor decisions around either treatment mode. Before and at the meeting all experts gave their opinion on the cases (YES/NO transplantation) and reasons for their decisions were collected. A set of draft statements on MPS I treatment options composed by a planning committee were discussed and revised during the meeting until full consensus.

Results

Full consensus was reached on several important issues, including the following: 1) The preferred treatment for patients with MPS I-H diagnosed before age 2.5 yrs is HSCT; 2) In individual patients with an intermediate phenotype HSCT may be considered if there is a suitable donor. However, there are no data on efficacy of HSCT in patients with this phenotype; 3) All MPS I patients including those who have not been transplanted or whose graft has failed may benefit significantly from ERT; 4) ERT should be started at diagnosis and may be of value in patients awaiting HSCT.

Conclusions

This multidisciplinary consensus procedure yielded consensus on the main issues related to therapeutic choices and research for MPS I. This is an important step towards an international, collaborative approach, the only way to obtain useful evidence in rare diseases.

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Most cited references 32

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Mucopolysaccharidosis I: management and treatment guidelines.

R. Clarke, Joseph Muenzer, … (2008)

Disease management for mucopolysaccharidosis type I has been inconsistent because of disease rarity (approximately 1 case per 100,000 live births), phenotypic heterogeneity, and limited therapeutic options. The availability of hematopoietic stem cell transplantation and the recent introduction of enzyme replacement therapy for mucopolysaccharidosis I necessitate the establishment of system-specific management guidelines for this condition. Twelve international experts on mucopolysaccharidosis I met in January 2003 to draft management and treatment guidelines for mucopolysaccharidosis I. Initial guidelines were revised and updated in 2008, on the basis of additional clinical data and therapeutic advances. Recommendations are based on our extensive clinical experience and a review of the literature. All patients with mucopolysaccharidosis I should receive a comprehensive baseline evaluation, including neurologic, ophthalmologic, auditory, cardiac, respiratory, gastrointestinal, and musculoskeletal assessments, and should be monitored every 6 to 12 months with individualized specialty assessments, to monitor disease progression and effects of intervention. Patients are best treated by a multidisciplinary team. Treatments consist of palliative/supportive care, hematopoietic stem cell transplantation, and enzyme replacement therapy. The patient's age (>2 years or < or =2 years), predicted phenotype, and developmental quotient help define the risk/benefit profile for hematopoietic stem cell transplantation (higher risk but can preserve central nervous system function) versus enzyme replacement therapy (low risk but cannot cross the blood-brain barrier). We anticipate that provision of a standard of care for the treatment of patients with mucopolysaccharidosis I will optimize clinical outcomes and patients' quality of life.

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Enzyme-replacement therapy in mucopolysaccharidosis I.

I Walot, M Passage, Nicole R Hoft … (2001)

Mucopolysaccharidosis I is a lysosomal storage disease caused by a deficiency of the enzyme alpha-L-iduronidase. We evaluated the effect of enzyme-replacement therapy with recombinant human alpha-L-iduronidase in patients with this disorder. We treated 10 patients with mucopolysaccharidosis I (age, 5 to 22 years) with recombinant human alpha-L-iduronidase at a dose of 125,000 U per kilogram of body weight given intravenously once weekly for 52 weeks. The patients were evaluated at base line and at 6, 12, 26, and 52 weeks by detailed clinical examinations, magnetic resonance imaging of the abdomen and brain, echocardiography, range-of-motion measurements, polysomnography, clinical laboratory evaluations, measurements of leukocyte alpha-L-iduronidase activity, and urinary glycosaminoglycan excretion. Hepatosplenomegaly decreased significantly in all patients, and the size of the liver was normal for body weight and age in eight patients by 26 weeks. The rate of growth in height and weight increased by a mean of 85 and 131 percent, respectively, in the six prepubertal patients. The mean maximal range of motion of shoulder flexion and elbow extension increased significantly. The number of episodes of apnea and hypopnea during sleep decreased 61 percent. New York Heart Association functional class improved by one or two classes in all patients. Urinary glycosaminoglycan excretion decreased after 3 to 4 weeks of treatment; the mean reduction was 63 percent of base-line values. Five patients had transient urticaria during infusions. Serum antibodies to alpha-L-iduronidase were detected in four patients. In patients with mucopolysaccharidosis I, treatment with recombinant human alpha-L-iduronidase reduces lysosomal storage in the liver and ameliorates some clinical manifestations of the disease.

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Cumulative incidence rates of the mucopolysaccharidoses in Germany.

F Baehner, C Schmiedeskamp, F Krummenauer … (2005)

In order to estimate the cumulative incidence rates of the mucopolysaccharidoses (MPS) in Germany, a retrospective epidemiological survey covering the period between 1980 and 1995 was implemented. Multiple ascertainment sources were used to identify affected patients. A prevalence of approximately 0.69 cases per 100,000 births was obtained for MPS I (Hurler phenotype). Within the study period, 4 patients with Hurler/Scheie phenotype and 7 cases with Scheie disease were detected. The cumulative incidence for MPS II (Hunter syndrome) was estimated as 0.64 cases per 100,000 births (1.3 cases per 100,000 male live births); that for MPS III (Sanfilippo syndrome types A, B and C) as 1.57 cases in 100,000 births; that for MPS IV A (Morquio syndrome) as 0.38 cases in 100,000; and that for MPS VI (Maroteaux-Lamy syndrome) as 0.23 cases per 100,000 births. Two cases of MPS IVB (beta-galactosidase deficiency) have been identified, but no patients with MPS VII or MPS IX. A relatively high number of patients with MPS IIIB, MPS IVA and MPS VI were of Turkish origin. The crude rate for all types of mucopolysaccharidoses is approximately 3.53 cases in 100,000 live births. The cumulative incidence pattern of MPS in Germany was compared with the corresponding rates among other industrial nations obtained from recent literature: the crude cumulative rates for all types of mucopolysaccharidoses (3.4-4.5 in 100,000 live births) were similar among all published populations; however, different frequencies of the various forms of MPS were observed.

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Author and article information

Journal

Journal ID (nlm-ta): Orphanet J Rare Dis

Title: Orphanet Journal of Rare Diseases

Publisher: BioMed Central

ISSN (Electronic): 1750-1172

Publication date Collection: 2011

Publication date (Electronic): 10 August 2011

Volume: 6

Page: 55

Affiliations

[1 ]Department of Pediatrics and Amsterdam Lysosome Center 'Sphinx', Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands

[2 ]Department of Pediatrics, Pediatric Blood and Marrow Transplantation Program, University Medical Center Utrecht, Utrecht, The Netherlands

[3 ]Department of Pediatrics, Clinic for Kidney-, Liver- and Metabolic diseases, Hannover Medical School, Hannover, Germany

[4 ]Genetic Medicine, Manchester Academic Health Science Centre, University of Manchester, Central Manchester University Hospitals NHS Foundation Trust, St Mary's Hospital, Manchester, UK

[5 ]Department of Pediatric Clinical Epidemiology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands

[6 ]Pediatric Immunology-Hematology Unit, Necker-Enfants Malades Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France

[7 ]Villa Metabolica, Children's Hospital, Gutenberg-University, Mainz, Germany

[8 ]Department of Haematology/Oncology, Our Lady's Children's Hospital, Dublin, Ireland

[9 ]Rare Metabolic Diseases Unit, Department of Pediatrics, San Gerardo Hospital, Monza, Italy

[10 ]Bone Marrow Transplant Unit, Department of Pediatrics, San Gerardo Hospital, Monza, Italy

[11 ]Department of Pediatric Hematology/Oncology, Hannover Medical School, Hannover, Germany

[12 ]Reference Center for Inherited Metabolic Disorders, Necker-Enfants Malades Hospital, Paris, France

[13 ]Metabolic Unit, Great Ormond Street Hospital for Children NHS Trust, London, UK

[14 ]Department of Blood and Marrow Transplant, Royal Manchester Children's Hospital, Manchester, UK

Article

Publisher ID: 1750-1172-6-55

DOI: 10.1186/1750-1172-6-55

PMC ID: 3170181

PubMed ID: 21831279

SO-VID: eb525448-9d08-4c06-88a3-c4e2f53f55fd

License:

This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Enzyme replacement therapy and/or hematopoietic stem cell transplantation at diagnosis in patients with mucopolysaccharidosis type I: results of a European consensus procedure

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Most cited references 32

Mucopolysaccharidosis I: management and treatment guidelines.

Enzyme-replacement therapy in mucopolysaccharidosis I.

Cumulative incidence rates of the mucopolysaccharidoses in Germany.

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