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John J Hopwood - One of the best experts on this subject based on the ideXlab platform.
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Maroteaux Lamy Syndrome functional characterization of pathogenic mutations and polymorphisms in the arylsulfatase b gene
Molecular Genetics and Metabolism, 2008Co-Authors: Elena Garrido, John J Hopwood, Bru Cormand, Amparo Chabas, Daniel Grinberg, Lluisa VilageliuAbstract:Abstract Mucopolysaccharidosis VI (MPS VI; Maroteaux-Lamy Syndrome) is an autosomal recessive lysosomal disorder caused by deficiency of N- acetylgalactosamine-4-sulfatase (ARSB), which is required for the degradation of dermatan sulfate. We recently reported mutational screening of 12 Spanish and 4 Argentinian MPS VI patients. In the present study, seven missense mutations (c.245T>G [p.L82R], c.413A>G [p.Y138C], c.719C>T [p.S240F], c.922G>A [p.G308R], c.937C>G [p.P313A], c.1340G>T [p.C447F] and c.1415T>C [p.L472P]) were transiently expressed in COS-7 cells and 4-sulfatase activity was measured in cell extracts. All mutations resulted in less than 6% of wild-type enzyme activity, in most cases undetectable. Mutations were expressed in their original haplotype context with respect to two non-synonymous polymorphisms present in the ARSB protein, p.V358M and p.S384N. The three less frequent haplotype combinations yielded an ARSB activity of 16%, 57% and 70%, when compared to the most frequent haplotype (p.358V and p.384S). Western blot analyses showed that the expressed mutations significantly reduced the amount of mature protein. Sub-cellular localization studies of mutant ARSB proteins in fibroblasts of MPS VI patients were performed. RNA analysis confirmed that nonsense-mediated RNA decay had taken place for all mutant alleles (c.1143−1G>C, c.1143−8T>G, p.W322X, c.427delG and c.1142+2T>A) which were candidates for causing RNA degradation by this mechanism. In summary, all the ARSB mutations studied had a significant effect on enzyme activity, protein processing and/or mRNA stability.
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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 acetylga
Pediatrics, 2005Co-Authors: Paul Harmatz, David Ketteridge, Roberto Giugliani, Natalie Guffon, Elisa Leao Teles, Clara Sa M Miranda, Zifan Yu, Stuart J Swiedler, John J HopwoodAbstract:Objective. Mucopolysaccharidosis VI (MPS VI; Maroteaux-Lamy Syndrome) is a lysosomal storage disease caused by a deficiency of the enzyme N -acetylgalactosamine 4-sulfatase (ASB). This enzyme deficiency leads to a progressive disorder with multiple tissue and organ involvement. The disease is rare and is heterogeneous in its clinical presentation and progression. A potential treatment for this disease exists in the form of enzyme-replacement therapy (ERT) with recombinant human ASB (rhASB), and a phase 1/2 randomized, double-blind, 2-dose (0.2 and 1 mg/kg) study in 6 patients showed the treatment at 48 weeks to be well tolerated. Greater biochemical efficacy based on a urine glycosaminoglycan occurred in the high-dose (1 mg/kg) group, and functional improvement seemed greater in patients in the high-dose group with rapidly advancing disease. On the basis of the phase 1/2 results, a phase 2, open-label study in patients with rapidly advancing disease was initiated primarily to evaluate efficacy variables that measure endurance, mobility, and joint function in a larger group of patients. Methods. This was an open-label, multinational study of 10 MPS VI patients who received 48 weekly intravenous treatments with 1.0 mg/kg rhASB and had assessments of biochemical and clinical responses at regular intervals. Results. After 24 weeks of treatment, each patient on average experienced a 155-m (98%) improvement in the 12-minute walk, a 64-m (62%) improvement at the 6-minute time point of the 12-minute walk, and a 48-stair (110%) gain in the 3-minute stair climb versus the baseline mean values. Additional improvements after 48 weeks of treatment were observed, including mean values of 211 m (138%) in the 12-minute walk, 75 m (80%) at the 6-minute time point of the 12-minute walk, and 61-stair (147%) gain in the 3-minute stair climb versus the baseline mean values. Joint Pain and Stiffness Questionnaire scores improved by at least 50% by week 24 and were maintained at week 48, whereas there were only small improvements in active shoulder range of motion ( Conclusions. The results suggest that a 12-minute walk extends the dynamic range of the conventional 6-minute walk and, along with the 3-minute stair climb, provide a robust approach to documenting the improvement in endurance in MPS VI patients who undergo ERT with rhASB.
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enzyme replacement therapy in mucopolysaccharidosis vi Maroteaux Lamy Syndrome
The Journal of Pediatrics, 2004Co-Authors: Paul Harmatz, Chester B. Whitley, Julie Simon, Ellen Butensky, Lewis Waber, Ray Pais, Robert D Steiner, Barbara Plecko, Paige Kaplan, John J HopwoodAbstract:Abstract Objectives To evaluate the safety and efficacy of weekly treatment with human recombinant N-acetylgalactosamine 4-sulfatase (rhASB) in humans with mucopolysaccharidosis type VI (MPS VI). Study design An ongoing Phase I/II, randomized, two-dose, double-blind study. Patients were randomized to weekly infusions of either high (1.0 mg/kg) or low (0.2 mg/kg) doses of rhASB. Six patients (3 male, 3 female; age 7-16 years) completed at least 24 weeks of treatment, five of this group have completed at least 48 weeks. Results No drug-related serious adverse events, significant laboratory abnormalities, or allergic reactions were observed in the study. The high-dose group experienced a more rapid and larger relative reduction in urinary glycosaminoglycan that was sustained through week 48. Improvements in the 6-minute walk test were observed in all patients with dramatic gains in those walking Conclusions rhASB treatment was well-tolerated and reduced lysosomal storage as evidenced by a dose-dependent reduction in urinary glycosaminoglycan. Clinical responses were present in all patients, but the largest gains occurred in patients with advanced disease receiving high-dose rhASB.
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enzyme replacement therapy in mucopolysaccharidosis vi Maroteaux Lamy Syndrome
The Journal of Pediatrics, 2004Co-Authors: Paul Harmatz, Chester B. Whitley, Julie Simon, Ellen Butensky, Lewis Waber, Ray Pais, Robert D Steiner, Barbara Plecko, Paige Kaplan, John J HopwoodAbstract:OBJECTIVES: To evaluate the safety and efficacy of weekly treatment with human recombinant N-acetylgalactosamine 4-sulfatase (rhASB) in humans with mucopolysaccharidosis type VI (MPS VI). STUDY DESIGN: An ongoing Phase I/II, randomized, two-dose, double-blind study. Patients were randomized to weekly infusions of either high (1.0 mg/kg) or low (0.2 mg/kg) doses of rhASB. Six patients (3 male, 3 female; age 7-16 years) completed at least 24 weeks of treatment, five of this group have completed at least 48 weeks. RESULTS: No drug-related serious adverse events, significant laboratory abnormalities, or allergic reactions were observed in the study. The high-dose group experienced a more rapid and larger relative reduction in urinary glycosaminoglycan that was sustained through week 48. Improvements in the 6-minute walk test were observed in all patients with dramatic gains in those walking <100 meters at baseline. Shoulder range of motion improved in all patients at week 48 and joint pain improved in patients with significant pain at baseline. CONCLUSIONS: rhASB treatment was well-tolerated and reduced lysosomal storage as evidenced by a dose-dependent reduction in urinary glycosaminoglycan. Clinical responses were present in all patients, but the largest gains occurred in patients with advanced disease receiving high-dose rhASB.
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Mucopolysaccharidosis type VI (Maroteaux-Lamy Syndrome): a Y210C mutation causes either altered protein handling or altered protein function of N-acetylgalactosamine 4-sulfatase at multiple points in the vacuolar network.
Biochemistry, 2002Co-Authors: Tessa M. Bradford, John J Hopwood, Tom Litjens, Emma J. Parkinson, Doug A. BrooksAbstract:The lysosomal hydrolase N-acetylgalactosamine 4-sulfatase (4-sulfatase) is required for the degradation of the glycosaminoglycan substrates dermatan and chondroitin sulfate. A 4-sulfatase deficiency results in the accumulation of undegraded substrate and causes the severe lysosomal storage disorder mucopolysaccharidosis type VI (MPS VI) or Maroteaux−Lamy Syndrome. A wide variation in clinical severity is observed between MPS VI patients and reflects the number of different 4-sulfatase mutations that can cause the disorder. The most common 4-sulfatase mutation, Y210C, was detected in ∼10% of MPS VI patients and has been associated with an attenuated clinical phenotype when compared to the archetypical form of MPS VI. To define the molecular defect caused by this mutation, Y210C 4-sulfatase was expressed in Chinese hamster ovary (CHO-K1) cells for protein and cell biological analysis. Biosynthetic studies revealed that Y210C 4-sulfatase was synthesized at a comparable molecular size and amount to wild-type ...
Paul Harmatz - One of the best experts on this subject based on the ideXlab platform.
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growth charts for individuals with mucopolysaccharidosis vi Maroteaux Lamy Syndrome
JIMD reports, 2015Co-Authors: Adrian Quartel, Sue Graham, Rossella Parini, Christian J Hendriksz, Ping Lin, Paul HarmatzAbstract:Background: The skeletal phenotype of mucopolysaccharidosis VI (MPS VI) is characterized by short stature and growth failure. Objective: The purpose of this study was to construct reference growth curves for MPS VI patients with rapidly and slowly progressive disease. Methods: We pooled cross-sectional and longitudinal height for age data from galsulfase (Naglazyme®, BioMarin Pharmaceutical Inc.), treatment naive patients (n = 269) who participated in various MPS VI studies, including galsulfase clinical trials and their extension programs, the MPS VI clinical surveillance program (CSP), and the MPS VI survey and resurvey studies, to construct growth charts for the MPS VI population. There were 229 patients included in this study, of which data from 207 patients ≤25 years of age with 513 height measurements were used for constructing reference growth curves. Results: Height for age growth curves for the 5th, 10th, 25th, 50th, 75th, 90th, and 95th percentiles were constructed for patients with rapidly and slowly progressing disease defined by the pre-enzyme replacement therapy (ERT) uGAG levels of > or ≤200 μg/mg creatinine. The mean (SD) pre-ERT uGAG levels were 481.0 (218.6) and 97.8 (56.3) μg/mg creatinine for the patients ≤25 years of age with rapidly (n = 131) and slowly (n = 76) progressing MPS VI disease, respectively. The median growth curves for patients with ≤ and >200 μg/mg creatinine were above and below the median (50th percentile) growth curve for the entire MPS VI population. Conclusion: MPS VI growth charts have been developed to assist in the clinical management of MPS VI patients. Electronic supplementary material The online version of this chapter (doi:10.1007/8904_2014_333) contains supplementary material, which is available to authorized users.
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Growth charts for individuals with mucopolysaccharidosis VI (Maroteaux-Lamy Syndrome)
Molecular Genetics and Metabolism, 2014Co-Authors: Adrian Quartel, Sue Graham, Paul HarmatzAbstract:Background: The skeletal phenotype of mucopolysaccharidosis VI (MPS VI) is characterized by short stature and growth failure.
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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 acetylga
Pediatrics, 2005Co-Authors: Paul Harmatz, David Ketteridge, Roberto Giugliani, Natalie Guffon, Elisa Leao Teles, Clara Sa M Miranda, Zifan Yu, Stuart J Swiedler, John J HopwoodAbstract:Objective. Mucopolysaccharidosis VI (MPS VI; Maroteaux-Lamy Syndrome) is a lysosomal storage disease caused by a deficiency of the enzyme N -acetylgalactosamine 4-sulfatase (ASB). This enzyme deficiency leads to a progressive disorder with multiple tissue and organ involvement. The disease is rare and is heterogeneous in its clinical presentation and progression. A potential treatment for this disease exists in the form of enzyme-replacement therapy (ERT) with recombinant human ASB (rhASB), and a phase 1/2 randomized, double-blind, 2-dose (0.2 and 1 mg/kg) study in 6 patients showed the treatment at 48 weeks to be well tolerated. Greater biochemical efficacy based on a urine glycosaminoglycan occurred in the high-dose (1 mg/kg) group, and functional improvement seemed greater in patients in the high-dose group with rapidly advancing disease. On the basis of the phase 1/2 results, a phase 2, open-label study in patients with rapidly advancing disease was initiated primarily to evaluate efficacy variables that measure endurance, mobility, and joint function in a larger group of patients. Methods. This was an open-label, multinational study of 10 MPS VI patients who received 48 weekly intravenous treatments with 1.0 mg/kg rhASB and had assessments of biochemical and clinical responses at regular intervals. Results. After 24 weeks of treatment, each patient on average experienced a 155-m (98%) improvement in the 12-minute walk, a 64-m (62%) improvement at the 6-minute time point of the 12-minute walk, and a 48-stair (110%) gain in the 3-minute stair climb versus the baseline mean values. Additional improvements after 48 weeks of treatment were observed, including mean values of 211 m (138%) in the 12-minute walk, 75 m (80%) at the 6-minute time point of the 12-minute walk, and 61-stair (147%) gain in the 3-minute stair climb versus the baseline mean values. Joint Pain and Stiffness Questionnaire scores improved by at least 50% by week 24 and were maintained at week 48, whereas there were only small improvements in active shoulder range of motion ( Conclusions. The results suggest that a 12-minute walk extends the dynamic range of the conventional 6-minute walk and, along with the 3-minute stair climb, provide a robust approach to documenting the improvement in endurance in MPS VI patients who undergo ERT with rhASB.
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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 Paediatrica, 2005Co-Authors: Paul Harmatz, W G Kramer, Julie Simon, Ellen Butensky, Stuart J SwiedlerAbstract:Aim: Mucopolysaccharidosis VI (Maroteaux-Lamy Syndrome) is a lysosomal storage disease caused by a deficiency of the enzyme N-acetylgalactosamine 4-sulphatase (ASB). Enzyme replacement therapy with recombinant human ASB (rhASB) has been studied in a randomized, double-blind, two-dose (0.2 and 1.0 mg/kg/week) phase I/II study (n = 7) followed by an open-label single dose (1.0 mg/kg/week) extension study. We report the pharmacokinetic profile of rhASB and the impact of antibody development. Methods: Pharmacokinetic analysis was performed at weeks 1, 2, 12, 24, 83, 84 and 96. Infusions were administered over 4 hours using a ramp-up protocol. Plasma ASB and rhASB antibody concentrations and urine glycosaminoglycan (GAG) concentrations were determined. Results: The area under the plasma concentration-time curve (AUC 0 - t ) for the high-dose group increased from week 1 to week 2, but remained unchanged at weeks 12 and 24. A large difference in mean AUC 0 - t was observed between the low- and high-dose groups. Pharmacokinetic results at weeks 83, 84 and 96 were similar to those at week 24. Six patients developed antibodies to rhASB. One patient developed high antibody levels in combination with a high ASB concentration, while a second patient also developed high antibody levels with undetectable ASB concentrations. Antibodies from the second patient blocked detection of ASB. By week 72, antibody levels had decreased in all patients. The high-dose rhASB produced a more rapid and greater percentage reduction in urinary GAG concentrations than the lower dose (70% versus 55% at 24 weeks). Antibody levels did not appear to influence urinary GAG concentrations. Conclusion: Pharmacokinetic parameters appear to be independent of the duration of treatment and are not linear between the 0.2 and 1.0 mg/kg/week doses. Antibodies to rhASB develop in most patients, but their concentration decreases over time. Antibody formation may influence pharmacokinetic parameters during the early phases of treatment, although it appears to have limited impact on biochemical efficacy.
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enzyme replacement therapy in mucopolysaccharidosis vi Maroteaux Lamy Syndrome
The Journal of Pediatrics, 2004Co-Authors: Paul Harmatz, Chester B. Whitley, Julie Simon, Ellen Butensky, Lewis Waber, Ray Pais, Robert D Steiner, Barbara Plecko, Paige Kaplan, John J HopwoodAbstract:Abstract Objectives To evaluate the safety and efficacy of weekly treatment with human recombinant N-acetylgalactosamine 4-sulfatase (rhASB) in humans with mucopolysaccharidosis type VI (MPS VI). Study design An ongoing Phase I/II, randomized, two-dose, double-blind study. Patients were randomized to weekly infusions of either high (1.0 mg/kg) or low (0.2 mg/kg) doses of rhASB. Six patients (3 male, 3 female; age 7-16 years) completed at least 24 weeks of treatment, five of this group have completed at least 48 weeks. Results No drug-related serious adverse events, significant laboratory abnormalities, or allergic reactions were observed in the study. The high-dose group experienced a more rapid and larger relative reduction in urinary glycosaminoglycan that was sustained through week 48. Improvements in the 6-minute walk test were observed in all patients with dramatic gains in those walking Conclusions rhASB treatment was well-tolerated and reduced lysosomal storage as evidenced by a dose-dependent reduction in urinary glycosaminoglycan. Clinical responses were present in all patients, but the largest gains occurred in patients with advanced disease receiving high-dose rhASB.
Richard A. Cowie - One of the best experts on this subject based on the ideXlab platform.
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Craniovertebral abnormalities in Type VI mucopolysaccharidosis (Maroteaux-Lamy Syndrome).
Neurosurgery, 2001Co-Authors: John Thorne, Mohsen Javadpour, David G. Hughes, Ed Wraith, Richard A. CowieAbstract:INTRODUCTION: The craniovertebral abnormalities found in patients with Type VI mucopolysaccharidosis (Maroteaux-Lamy Syndrome) are described, and the indications for and outcomes of surgery in this group are assessed. METHODS: The clinical histories and radiological findings in all patients with Type VI mucopolysaccharidosis treated at Royal Manchester Children's Hospital during the past 10 years were reviewed. RESULTS: The typical findings in patients with this disease are of canal stenosis at the level of the foramen magnum and upper cervical spine with or without cord compression. The stenosis is secondary to thickening of the posterior longitudinal ligament. Atlantoaxial instability is rare. Of nine patients under regular clinical review, four underwent decompressive surgery for cervical cord compression. Three of the four showed improvement in their neurological symptoms and signs postoperatively. Of the children reviewed, six had radiological evidence of cord compression, although only those with neurological signs or symptoms were treated surgically. DISCUSSION: Despite the often formidable anesthetic challenge, surgery is indicated in those patients who present with progressive neurological deficit due to cervical myelopathy. Surgery can be undertaken safely if the associated medical problems in these children are recognized and managed appropriately.
Michael Beck - One of the best experts on this subject based on the ideXlab platform.
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management of life threatening tracheal stenosis and tracheomalacia in patients with mucopolysaccharidoses
JIMD reports, 2016Co-Authors: Christoph Kampmann, Michael Beck, Christiane M Wiethoff, R Huth, Gundula Staatz, Eugen Mengel, Stefan Gehring, Torsten Mewes, Tariq AbutairAbstract:Several different lysosomal storage diseases, mainly mucopolysaccharidosis (MPS) type I, II, and VI, are complicated by severe obstruction of the upper airways, tracheobronchial malacia, and/or stenosis of the lower airways. Although enzyme replacement therapies (ERTs) are available, the impact of these on tracheobronchial alterations has not been reported. By extending the life expectancy of MPS patients with ERTs, airway problems may become more prevalent at advanced ages. These airway abnormalities can result in severe, potentially fatal, difficulties during anesthetic procedures. Usually, upper airway obstruction is treated by tracheostomy. However, with lower airway malacia and/or stenosis, there are no procedures available to date to address these difficulties. We report the first cases using a new technique of tracheal stenting in patients with MPS type VI (Maroteaux–Lamy Syndrome) and type II (Hunter Syndrome) who had almost complete tracheal occlusion and total airway collapse. An updated literature review is also reported.
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enzyme replacement therapy for mucopolysaccharidosis vi growth and pubertal development in patients treated with recombinant human n acetylgalactosamine 4 sulfatase
Journal of pediatric rehabilitation medicine, 2010Co-Authors: Celeste Decker, Roberto Giugliani, Natalie Guffon, Elisa Leao Teles, Clara Sa M Miranda, Ida Vanessa Doederlein Schwartz, Edmond J Wraith, Michael Beck, Laila Arash, Maurizio ScarpaAbstract:Background and Methods Growth failure is characteristic of untreated mucopolysaccharidosis type VI (MPS VI: Maroteaux-Lamy Syndrome). Growth was studied in fifty-six MPS VI patients (5 to 29 years old) prior to and for up to 240 weeks of weekly infusions of recombinant human arylsulfatase B (rhASB) at 1 mg/kg during Phase 1/2, Phase 2, Phase 3 or Phase 3 Extension clinical trials. Height, weight, and Tanner stage data were collected. Pooled data were analyzed to determine mean height increase by treatment week, growth impacts of pubertal status, baseline urinary GAG, and age at treatment initiation. Growth rate for approximately 2 years prior to and following treatment initiation was analyzed using longitudinal modeling.
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enzyme replacement therapy for mucopolysaccharidosis vi growth and pubertal development in patients treated with recombinant human n acetylgalactosamine 4 sulfatase
Journal of pediatric rehabilitation medicine, 2010Co-Authors: Celeste Decker, Roberto Giugliani, Natalie Guffon, Elisa Leao Teles, Clara Sa M Miranda, Zifan Yu, Ida Vanessa Doederlein Schwartz, Edmond J Wraith, Michael Beck, Laila ArashAbstract:Background and Methods Growth failure is characteristic of untreated mucopolysaccharidosis type VI (MPS VI: Maroteaux-Lamy Syndrome). Growth was studied in fifty-six MPS VI patients (5 to 29 years old) prior to and for up to 240 weeks of weekly infusions of recombinant human arylsulfatase B (rhASB) at 1 mg/kg during Phase 1/2, Phase 2, Phase 3 or Phase 3 Extension clinical trials. Height, weight, and Tanner stage data were collected. Pooled data were analyzed to determine mean height increase by treatment week, growth impacts of pubertal status, baseline urinary GAG, and age at treatment initiation. Growth rate for approximately 2 years prior to and following treatment initiation was analyzed using longitudinal modeling.
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galsulfase enzyme replacement therapy for mucopolysaccharidosis type vi Maroteaux Lamy Syndrome
Therapy, 2006Co-Authors: Michael BeckAbstract:Since enzyme-replacement therapy has been successfully introduced for patients with Gaucher disease, Fabry disease and mucopolysaccharidosis Type I, the principle of this treatment has also been taken into consideration for individuals who are affected by mucopolysaccharidosis Type VI (Maroteaux–Lamy disease), a rare lysosomal storage disorder with multiple organ and tissue involvement. After enzyme-replacement therapy with recombinant human arylsulfatase B in a feline model of mucopolysaccharidosis VI showed a reduction in storage vacuoles in Kupffer cells and connective tissue, clinical trials were intitiated. A Phase I/II trial showed that regular infusions of recombinant arylsulfatase B were able to reduce urinary glycosaminoglycan excretion. In all patients, general endurance and shoulder range of motion improved. These results were confirmed by a following open-label Phase II study with ten patients who had more rapidly advanced disease. After a Phase III (double-blind, placebo-controlled) study had demonstrated the clinical efficacy of weekly infusion of recombinant human arylsulfatase B, this enzyme preparation was approved by the US Food and Drug Administration for the treatment of patients with mucopolysaccharidosis Type VI. The efficacy and safety of the enzyme preparation is discussed in this review.
Chester B. Whitley - One of the best experts on this subject based on the ideXlab platform.
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Maroteaux-Lamy Syndrome (mucopolysaccharidosis type VI): a single dose of galsulfase further reduces urine glycosaminoglycans after hematopoietic stem cell transplantation.
Molecular genetics and metabolism, 2010Co-Authors: Chester B. Whitley, Jeanine UtzAbstract:Abstract Background Maroteaux–Lamy Syndrome, or mucopolysaccharidosis (MPS) type VI, is the autosomal recessive lysosomal disorder resulting from deficient N-acetylgalactosamine 4-sulfatase (ARSB) and the consequent accumulation of glycosaminoglycan (GAG). Patients fully engrafted after hematopoietic stem cell transplantation (HSCT) demonstrate several indicators of metabolic correction such as reduction in liver size, absence of hepatic ultrastructural pathology, and patients do not develop cervical cord compression. Engrafted patients demonstrate reduction in urine GAG achieving near-normal levels. Hypothesis We presumed that HSCT engraftment from a normal individual would provide sufficient systemic enzyme to accomplish maximal metabolic correction, and that no additional benefit would accrue from additional therapy such as with intravenous recombinant human ARSB protein, galsulfase. Materials and methods A 22-year-old male had received an allogeneic bone marrow transplant from an HLA-identical sibling donor, and remained fully engrafted after 20 years. In response to his request regarding the potential benefit of enzyme replacement therapy, we administered a single, standard dose of galsulfase while monitoring urine GAG daily, before and after the treatment. Results Urine GAG declined from slightly high pre-treatment levels (7.63 mg GAG/mmol creatinine; range 7.0–8.5, N = 3) progressively declining below the age-specific normal range ( Conclusions Somewhat surprisingly, the biomarker urine GAG was significantly reduced after a single treatment of intravenous galsulfase thus suggesting that supplemental enzyme replacement therapy might improve the clinical outcome for donor-engrafted patients with MPS VI.
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enzyme replacement therapy in mucopolysaccharidosis vi Maroteaux Lamy Syndrome
The Journal of Pediatrics, 2004Co-Authors: Paul Harmatz, Chester B. Whitley, Julie Simon, Ellen Butensky, Lewis Waber, Ray Pais, Robert D Steiner, Barbara Plecko, Paige Kaplan, John J HopwoodAbstract:Abstract Objectives To evaluate the safety and efficacy of weekly treatment with human recombinant N-acetylgalactosamine 4-sulfatase (rhASB) in humans with mucopolysaccharidosis type VI (MPS VI). Study design An ongoing Phase I/II, randomized, two-dose, double-blind study. Patients were randomized to weekly infusions of either high (1.0 mg/kg) or low (0.2 mg/kg) doses of rhASB. Six patients (3 male, 3 female; age 7-16 years) completed at least 24 weeks of treatment, five of this group have completed at least 48 weeks. Results No drug-related serious adverse events, significant laboratory abnormalities, or allergic reactions were observed in the study. The high-dose group experienced a more rapid and larger relative reduction in urinary glycosaminoglycan that was sustained through week 48. Improvements in the 6-minute walk test were observed in all patients with dramatic gains in those walking Conclusions rhASB treatment was well-tolerated and reduced lysosomal storage as evidenced by a dose-dependent reduction in urinary glycosaminoglycan. Clinical responses were present in all patients, but the largest gains occurred in patients with advanced disease receiving high-dose rhASB.
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enzyme replacement therapy in mucopolysaccharidosis vi Maroteaux Lamy Syndrome
The Journal of Pediatrics, 2004Co-Authors: Paul Harmatz, Chester B. Whitley, Julie Simon, Ellen Butensky, Lewis Waber, Ray Pais, Robert D Steiner, Barbara Plecko, Paige Kaplan, John J HopwoodAbstract:OBJECTIVES: To evaluate the safety and efficacy of weekly treatment with human recombinant N-acetylgalactosamine 4-sulfatase (rhASB) in humans with mucopolysaccharidosis type VI (MPS VI). STUDY DESIGN: An ongoing Phase I/II, randomized, two-dose, double-blind study. Patients were randomized to weekly infusions of either high (1.0 mg/kg) or low (0.2 mg/kg) doses of rhASB. Six patients (3 male, 3 female; age 7-16 years) completed at least 24 weeks of treatment, five of this group have completed at least 48 weeks. RESULTS: No drug-related serious adverse events, significant laboratory abnormalities, or allergic reactions were observed in the study. The high-dose group experienced a more rapid and larger relative reduction in urinary glycosaminoglycan that was sustained through week 48. Improvements in the 6-minute walk test were observed in all patients with dramatic gains in those walking <100 meters at baseline. Shoulder range of motion improved in all patients at week 48 and joint pain improved in patients with significant pain at baseline. CONCLUSIONS: rhASB treatment was well-tolerated and reduced lysosomal storage as evidenced by a dose-dependent reduction in urinary glycosaminoglycan. Clinical responses were present in all patients, but the largest gains occurred in patients with advanced disease receiving high-dose rhASB.
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Syringomyelia in mucopolysaccharidosis type VI (Maroteaux-Lamy Syndrome) : imaging findings following bone marrow transplantation
Pediatric radiology, 1997Co-Authors: Stephen H. Hite, William Krivit, Stephen J. Haines, Chester B. WhitleyAbstract:We present the imaging findings in a patient with mucopolysaccharidosis (MPS) type VI (Maroteaux-Lamy Syndrome) who developed holocord syringomyelia. This represents the only reported case of syrinx formation in a child with MPS VI. Clinical, neurologic and spinal magnetic resonance imaging findings are presented. The patient has maintained a stable clinical and neurologic course over the period following allogeneic bone marrow transplant.