Maroteaux–Lamy syndrome (mucopolysaccharidosis type VI): A single dose of galsulfase further reduces urine glycosaminoglycans after hematopoietic stem cell transplantation
Introduction
Maroteaux–Lamy syndrome, or mucopolysaccharidosis (MPS) type VI, is the autosomal recessive lysosomal disorder resulting from deficient glycosaminoglycan N-acetylgalactosamine 4-sulfatase (EC 3.1.6.12) also known as arylsulfatase B (ARSB). The consequent accumulation of glycosaminoglycan (GAG) results in the pattern of abnormal skeletal development dysostotis multiplex as well as progressive arthropathy, hepatomegaly, pulmonary disease, multiple cardiac anomalies, corneal clouding, and cervical cord compression.
Hematopoietic stem cell transplantation (HSCT) has been done in a small but significant number of individuals [1], [2], [3], [4], [5], [6]. Detailed follow-up reports are available in a few cases [2], [5], [7], [8]. Patients fully engrafted after either allogeneic bone marrow transplantation (BMT) or umbilical core transplant (UCT) demonstrate several key indicators of metabolic correction and clinical response including reduction in liver size to normal, absence of hepatic ultrastructural pathology. Cervical cord compression does not seem to occur (personal observation) although a comprehensive study has not been done. Urine glycosaminoglycan levels fall dramatically after treatment [4], a well-recognized indicator of metabolic correction following donor stem cell engraftment [9].
Enzyme replacement therapy (ERT) with recombinant human N-acetylgalactosamine 4-sulfatase, galsulfase, has recently been developed [10], [11] as a mono-therapy. This is an alternative approach to HSCT treatment having demonstrable efficacy with lower morbidity and mortality [10], [11] although cervical cord compression is not addressed by intravenous (i.v.) ERT alone.
We presumed that HSCT achieving full donor engraftment from a normal individual would provide sufficient systemic enzyme and no additional benefit would accrue from supplemental ERT. However, the impact of combining HSCT and ERT has never been evaluated. A recent clinical experience provides some insight into this question.
Section snippets
Materials and methods
The proband had been diagnosed with Maroteaux–Lamy syndrome at 14 months of age and found to have elevated urine glycosaminoglycan and deficient leukocyte ARSB enzyme activity. Prior to diagnosis, the past medical history was notable for bilateral herniorrhaphy at 3 months of age, and bilateral PE-tube placement at 7 months of age and concomitant excision of an umbilical polyp. He received an allogeneic bone marrow transplant at 18 months of age, with stem cells derived from an HLA-identical sister
Results and discussion
The diagnosis of this patient had been established on the basis of elevated urine GAG and absent ARSB activity prior to transplantation. Twenty years after transplant, RFLP markers confirmed full donor engraftment from the sibling donor in the peripheral blood neutrophil series (100% ± 5%) and the lymphocytic series (100% ± 5%). Measurement of ARSB enzyme levels in peripheral leukocytes confirmed donor levels.
Prior to infusion of galsulfatase, determinations on 3 consecutive days found that urine
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Cited by (7)
WORLDSymposium™ 2020 Introduction
2020, Molecular Genetics and MetabolismHematopoietic Stem Cell Transplantation for Mucopolysaccharidoses: Past, Present, and Future
2019, Biology of Blood and Marrow TransplantationCitation Excerpt :Because HSCT cannot entirely correct secondary musculoskeletal disorders [120] but can improve cognitive and central nervous system function [8,55,64,121-126], the combination of ERT with HSCT can result in better outcomes than either treatment can produce alone. In 2010, Whitley et al. [127] reported the outcomes of a male with MPS VI who had received HSCT at age 18 months from an HLA-identical sibling who was a heterozygous carrier. At 20 years post-transplantation, this patient was still fully engrafted but had symptoms of progressive corneal opacification.
Glycosaminoglycan levels in dried blood spots of patients with mucopolysaccharidoses and mucolipidoses
2017, Molecular Genetics and MetabolismEnzyme augmentation therapy enhances the therapeutic efficacy of bone marrow transplantation in mucopolysaccharidosis type II mice
2014, Molecular Genetics and MetabolismCitation Excerpt :Before the availability of ERT, BMT was carried out in a small number of MPS II patients. One report indicated that a single dose of ERT to already transplanted MPS VI patient caused further reduction of urinary GAGs [30]. Another report indicated that supplementing BMT treated MPS VI patients with ERT caused further improvement of several clinical parameters, including joint movement, outcome of the 12 minute walk test and the outcome of the 3 minute stair-climbing test [31].
Newborn screening and diagnosis of mucopolysaccharidoses
2013, Molecular Genetics and MetabolismCitation Excerpt :Overall, establishment of the method to measure the disaccharides rather than hetergenous oligosaccharides make it feasible to interpret individual GAG values, leading to rapid and accurate diagnosis, prognosis, and monitoring therapies for MPS. At present, the following LC–MS/MS instruments have been confirmed to provide good resolution for disaccharide analysis by multiple laboratories; Alliance 2795XE HPLC system/Quattro micro tandem quadrupole (Waters Corp, Milford, MA, USA); Ultra performance liquid chromatography (UPLC) Acquity system/Xevo TQ-S (Waters Corp, Milford, MA, USA); HP1100 system (Agilent Technologies, Palo Alto, CA, USA)/API-4000 or API-5000 (AB Sciex, Foster City, CA, USA); Acquity HPLC system/Quattro Premier XE (Waters Corp, Milford, MA, USA); and 1260 infinity LC/6460 Triple Quad (Agilent Technologies, Palo Alto, CA, USA) [56–58,95–98,9–101,103–106, personal communication from Dr. K. Kida]. ΔDiHS-6S (HS); ΔDiHS-NS (HS); ΔDiHS-0S (HS); ΔDi-4S (DS); mono-sulfated KS — Galβ1-4GlcNAc(6S); di-sulfated KS — Gal(6S)β1-4GlcNAc(6S); and KS I (bovine cornea) digested with keratanase II to yield Galβ1-4GlcNAc(6S), Gal(6S)β1-4GlcNAc(6S), have all been used to produce standard curves for each specific GAG (Fig. 3).
Cardiac disease in patients with mucopolysaccharidosis: Presentation, diagnosis and management
2011, Journal of Inherited Metabolic Disease