OBJECTIVE. Disease management for mucopolysaccharidosis type I has been inconsistent because of disease rarity (∼1 case per 100000 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.
METHODS. 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.
RESULTS.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 ≤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).
CONCLUSION. 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.
I have a kitten that has just been diagnosed with this. Is there any new treatment? He has a good appetite pleased with his four legs but can't work his back legs very well muscles work but not weight-bearing. wisej77@gmail.com
Dear editor, Muenzer et al recently published an important and comprehensive management and treatment guideline for MPS1 on behalf of a consensus panel with the goal of providing standards for the care and monitoring of these complex patients (Pediatrics 2009;123;19-29). We, as an international blood and marrow transplantation group, including 4 major hematopoietic stem cell transplant centers (Duke, Minnesota, Manchester and Utrecht) providing care for these children are writing to delineate our view of the benefits and risks of transplantation in MPS I.
Transplant outcomes in children with severe phenotype MPS I have continuously improved over the almost 3 decades since transplantation therapy was first used to treat children with this disease. Much of the data referenced in regards to these outcomes, including the reports of Boelens and Peters, describe data that were collected on patients transplanted over a decade ago. The field of transplantation has evolved, since that time, resulting in decreased risks of graft failure and graft- versus-host disease, and decreasing or eliminating the use of radiation therapy in the preparative regimen. These changes have lead to greatly improved outcomes as evidenced by recent single and multicentre data showing engrafted survival rates approximating 90%, as individuals are identified early, and transplantation is expediently performed with grafts including cord blood infusions (1-4). It is possible that outcomes may further improve through the utilization of cord blood donor grafts and development of new transplant preparative regimens and algorithms for supportive care. The potential use of enzyme therapy prior to transplantation, especially for older or more severely ill patients, may also influence outcomes (5).
There are also data published that show the degree of substrate reduction following SCT is much reduced compared with following ERT (4, 6). As disease severity appears associated with levels of substrate accumulation, it seems reasonable to propose that those therapies that achieve the best reduction in accumulated substrate will provide the best clinical results. This may prove to be the case with transplantation. We accept that further long-term studies of clinical outcome are necessary to support these data on biochemical parameters and clinical outcome. These have been currently initiated and ongoing in our transplant centres including > 80% of the MPS1 patients transplanted over the last decades (according to the EBMT and CIBMTR registries).
Finally, there is little information regarding the efficacy or safety of intravenous ERT alone in preventing the long-term symptoms and signs of MPSI. Data only exists in regards to short term surrogate markers of disease, largely reflecting visceral enzyme delivery – e.g. liver size, substrate reduction etc. Immunological hypersensitivity reactions, both silent and clinically apparent, may occur after longer term exposure to ERT neutralizing enzyme activity and decreasing efficacy of this therapy after repeated doses of ERT. ERT is also offered at huge financial cost which will preclude its use in some countries where SCT is offered.
We feel that the question of “best therapy” for children with MPS I remains unanswered. As more information becomes available (e.g. the long term follow up study mentioned above), it may become clear that SCT may prove the treatment of choice in MPS I. We believe that trials extending SCT therapy to patients with milder disease, perhaps comparing long term outcomes of SCT with ERT, should be conducted. The transplant community is committed to finding ways to increase the safety of SCT focusing on reducing long-term toxicities, including infertility. In addition, earlier diagnosis, by newborn screening may further improve the outcomes.
References:
1) Boelens JJ, Rocha V, Aldenhoven M, Wynn RF, O’Meara A, Michel G et al, Risk Factor Analysis of Outcomes after Unrelated Cord Blood Transplantation in Patients with Hurler Syndrome, BBMT 2009, in press
2) Staba SL, Escolar ML, Poe M, Kim Y, Martin PL, Szabolcs P, Allison -Thacher J, Wood S, Wenger DA, Rubinstein P, Hopwood JJ, Krivit W, Kurtzberg J et al. Cord-blood transplants from unrelated donors in patients with Hurler's syndrome. N Engl J Med 2004; 350(19):1960-1969
3) Prasad VK, Mendizabal A, Parikh SH, Szabolcs P, Driscoll TA, Page K, Lakshminarayanan S, Allison J, Wood S, Semmel D, Escolar ML, Martin PL, Carter S, Kurtzberg J. Unrelated donor umbilical cord blood transplantation for inherited metabolic disorders in 159 pediatric patients from a single center: influence of cellular composition of the graft on transplant outcomes. Blood. 2008; 112: 2979-89.
4) Wynn RF, Mercer J, Page J, Carr TF, Jones S, Wraith JE, Use of enzyme replacement therapy (Laronidase) before Hemotopoietic stem cell transplantation for Mucopolysaccaridosis I: experience in 18 patients, J Pediatr. 2009;154:135-9
5) Tolar J, Grewal SS, Bjoraker KJ, Whitley CB, Shapiro EG, Charnas L, Orchard PJ. Combination of enzyme replacement and hematopoietic stem cell transplantation as therapy for hurler syndrome, Bone Marrow Transplant. 2008 Mar;41(6):531-5.
6) Wynn R.F. Wraith E, Mercer J, O’Meara A, Tylee K, Thornley M, Church HJ, Bigger BW, Improved metabolic correction in Lysosomal Storage Disease treated with Hematopoietic Stem Cell Transplant compared with Enzyme Replacement Therapy. J.Ped 2009, in press
Conflict of Interest:
None declared