Maroteaux–Lamy syndrome (mucopolysaccharidosis type VI): A single dose of galsulfase further reduces urine glycosaminoglycans after hematopoietic stem cell transplantation

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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 (< 6.5) over 10 days to the lowest level of 4.4, with a mean post-treatment level of 5.60 (N = 10).

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.

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

References (11)

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    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).

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