Publications by authors named "Jean Mercer"

33 Publications

Impact of long-term elosulfase alfa treatment on clinical and patient-reported outcomes in patients with mucopolysaccharidosis type IVA: results from a Managed Access Agreement in England.

Orphanet J Rare Dis 2021 Jan 21;16(1):38. Epub 2021 Jan 21.

Salford Royal NHS Foundation Trust, Salford, UK.

Background: We present baseline characteristics and follow-up data of a Managed Access Agreement (MAA), including patients with mucopolysaccharidosis IVA (MPS IVA) receiving elosulfase alfa enzyme replacement therapy (ERT) in England on a conditional basis. Patients enrolled in the MAA programme are reviewed on an annual basis. Therapy can be continued if patients are compliant, able to tolerate infusions, and meet four out of five pre-defined clinical and patient-reported outcomes (PRO) criteria. Baseline and follow-up clinical and PRO data are presented for all participants who completed ≥ 1 year of assessments in the MAA.

Results: The analysis included data from 55 patients, including 26 patients previously enrolled in clinical trials and 29 who started ERT after enrolling in the MAA. In patients with both baseline and follow-up data, mean 6-min walk test distance increased from 217 m at baseline to 244 m after a mean follow-up of 4.9 years. Improvement or stabilisation was seen regardless of age at treatment initiation or duration of treatment. Mean forced vital capacity and forced expiratory volume in 1 s were 0.87 L and 0.78 L, respectively at baseline and 1.05 L and 0.88 L after a mean follow-up of 5.5 years. PRO data showed overall improvements over time in Mobility, Self-care, and Caregiver assistance scores of the MPS-Health Assessment Questionnaire, relatively stable quality of life, and some improvements in pain scores.

Conclusions: The MAA data confirm the effects of elosulfase alfa on clinical and PRO results observed in the clinical trials and provide real-world evidence for long-term stabilisation in these measures, suggesting a positive impact on the natural history of MPS IVA.
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http://dx.doi.org/10.1186/s13023-021-01675-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7818902PMC
January 2021

Strategies for the Induction of Immune Tolerance to Enzyme Replacement Therapy in Mucopolysaccharidosis Type I.

Mol Ther Methods Clin Dev 2019 Jun 2;13:321-333. Epub 2019 Mar 2.

Stem Cell and Neurotherapies, Faculty of Medical and Human Sciences, University of Manchester, Manchester, UK.

Enzyme replacement therapy with laronidase is an established treatment for Mucopolysaccharidosis type I (MPS I), but its efficacy may be limited by the development of anti-drug antibodies, which inhibit cellular uptake of the enzyme. In a related disorder, infantile Pompe disease, immune tolerance induction with low-dose, short-course methotrexate appears to reduce antibody formation. We investigated a similar regimen using oral methotrexate in three MPS I patients. All patients developed anti-laronidase immunoglobulin G (IgG) and immunoglobulin M (IgM) antibodies, and they had clinically relevant levels of cellular uptake inhibition. We then explored several immune tolerance induction strategies in MPS I mice: (1) methotrexate, (2) combination of non-depleting anti-CD4 and anti-CD8 monoclonal antibodies, (3) methotrexate with anti-CD4 and anti-CD8 monoclonals, (4) anti-CD4 monoclonal, and (5) anti-CD8 monoclonal. Treated mice received 10 weekly laronidase injections, and laronidase was delivered with adjuvant on day 49 to further challenge the immune system. Most regimens were only partially effective at reducing antibody responses, but two courses of non-depleting anti-CD4 monoclonal antibody (mAb) ablated immune responses to laronidase in seven of eight MPS I mice (87.5%), even after adjuvant stimulation. Immune tolerance induction with methotrexate does not appear to be effective in MPS I patients, but use of non-depleting anti-CD4 monoclonal is a promising strategy.
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http://dx.doi.org/10.1016/j.omtm.2019.02.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6441787PMC
June 2019

Substrate accumulation and extracellular matrix remodelling promote persistent upper airway disease in mucopolysaccharidosis patients on enzyme replacement therapy.

PLoS One 2018 18;13(9):e0203216. Epub 2018 Sep 18.

Stem Cell and Neurotherapies, Division of Cell Matrix Biology & Regenerative Medicine, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of Manchester, Manchester, United Kingdom.

Introduction: Mucopolysaccharide diseases are a group of lysosomal storage disorders caused by deficiencies of hydrolase enzymes, leading to pathological glycosaminoglycan accumulation. A number of mucopolysaccharidosis (MPS) types are characterised by severe airway disease, the aetiology of which is poorly understood. There is ongoing evidence of significant clinical disease in the long-term despite disease modifying therapeutic strategies, including enzyme-replacement therapy (ERT). To provide a better understanding of this aspect of disease, we have characterised extracellular matrix (ECM) and inflammatory alterations in adenotonsillar tissue samples from 8 MPS patients.

Methods: Adenotonsillar samples from MPS I, IVA and VI ERT treated patients and from a single enzyme naïve MPS IIIA individual were compared to non-affected control samples using quantitative immunohistochemistry, qPCR and biochemical analysis.

Results: Significantly increased lysosomal compartment size and total sulphated glycosaminoglycan (p = 0.0007, 0.02) were identified in patient samples despite ERT. Heparan sulphate glycosaminoglycan was significantly elevated in MPS I and IIIA (p = 0.002), confirming incomplete reversal of disease. Collagen IV and laminin α-5 (p = 0.002, 0.0004) staining demonstrated increased ECM deposition within the reticular and capillary network of MPS samples. No significant change in the expression of the pro-inflammatory cytokines IL-1α, IL-6 or TNF-α was seen compared to control.

Conclusion: This study suggests a role for ECM remodelling contributing to the obstructive phenotype of airway disease in MPS. Current therapeutic strategies with ERT fail to normalise these pathological alterations within adenotonsillar samples. Our findings lend novel insight into the pathological cascade of events, with primarily structural rather than inflammatory changes contributing to the continuing phenotype seen in patients despite current therapeutic regimes.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0203216PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6143186PMC
February 2019

Transnasal adenoidectomy in mucopolysaccharidosis.

Int J Pediatr Otorhinolaryngol 2018 Aug 1;111:149-152. Epub 2018 May 1.

Royal Manchester Children's Hospital, Manchester University NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK; Division of Infection, Immunity and Respiratory Medicine, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK.

Background: Mucopolysaccharide (MPS) diseases are a heterogeneous group of inherited, metabolic disorders characterized by accumulation of partially degraded glycosaminoglycans (GAG) in multiple organ systems. Due to accumulation in the airway, patients often present with multilevel airway obstruction and obstructive sleep apnoea (OSA). Adenotonsillar surgery leads to a significant improvement in the severity of OSA in MPS patients. However, access to secure the airway and for conventional surgery can be challenging, due to limited neck extension, macroglossia and reduced mouth opening. This study was undertaken to evaluate the role of transnasal microdebridement and radiofrequent plasma ablation (Coblation) in adenoidectomy to treat OSA in patients with MPS and restricted airway access.

Methods: A retrospective case review was performed including patients with MPS undergoing adenoidectomy for OSA in the period between June 2015 and March 2017. In all cases, either a microdebrider (Gyrus Diablo) or a Coblation wand (EVAC70, Smith&Nephew) was used via a transnasal approach guided by nasendoscopy. The primary outcome was effect upon OSA, measured by sleep oximetry and parental report of benefit. The secondary outcomes were surgical complications and risk factors for persistent OSA after surgery.

Results: A total of nine patients were identified with a mean age of 9 years (range 3-14 years) at surgery. Post-operative sleep study data was available for eight patients (8/9). Six patients (6/8) had improvement in 4% oxygen desaturation index (ODI-4) with a mean of 8.11 pre-operatively (range 2.69-14.0) and 4.99 postoperatively (range 0.68-8.48). ODI-4 did not improve in two (2/8) patients. Irrespective of sleep oximetry results, improvement in OSA-related symptoms was noted by all parents postoperatively. No risk factors for persistent OSA were identified. Furthermore, no complications were noted in this cohort.

Conclusion: Transnasal Coblation and Microdebrider adenoidectomy is a safe and effective surgical treatment for OSA in patients with Mucopolysaccharidosis and adenoidal hypertrophy. As lifespan increases for patients with the Mucopolysaccharidoses, greater emphasis is being given to optimising airway management over the longer-term. This technical note describes the novel application of endoscopic techniques for the management of primary adenoidal hypertrophy when transoral access is restricted, or to debulk recurrent disease that would be challenging to remove via the standard transoral route.
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http://dx.doi.org/10.1016/j.ijporl.2018.04.028DOI Listing
August 2018

Long-term outcomes of systemic therapies for Hurler syndrome: an international multicenter comparison.

Genet Med 2018 11 8;20(11):1423-1429. Epub 2018 Mar 8.

Department of Pediatrics and Department of Experimental and Clinical Pharmacology, University of Minnesota, Minneapolis, Minnesota, USA.

Purpose: Early treatment is critical for mucopolysaccharidosis type I (MPS I), justifying its incorporation into newborn screening. Enzyme replacement therapy (ERT) treats MPS I, yet presumptions that ERT cannot penetrate the blood-brain barrier (BBB) support recommendations that hematopoietic cell transplantation (HCT) treat the severe, neurodegenerative form (Hurler syndrome). Ethics precludes randomized comparison of ERT with HCT, but insight into this comparison is presented with an international cohort of patients with Hurler syndrome who received long-term ERT from a young age.

Methods: Long-term survival and neurologic outcomes were compared among three groups of patients with Hurler syndrome: 18 treated with ERT monotherapy (ERT group), 54 who underwent HCT (HCT group), and 23 who received no therapy (Untreated). All were followed starting before age 5 years. A sensitivity analysis restricted age of treatment below 3 years.

Results: Survival was worse when comparing ERT versus HCT, and Untreated versus ERT. The cumulative incidences of hydrocephalus and cervical spinal cord compression were greater in ERT versus HCT. Findings persisted in the sensitivity analysis.

Conclusion: As newborn screening widens treatment opportunity for Hurler syndrome, this examination of early treatment quantifies some ERT benefit, supports presumptions about BBB impenetrability, and aligns with current guidelines to treat with HCT.
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http://dx.doi.org/10.1038/gim.2018.29DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6129229PMC
November 2018

The effect of haemopoietic stem cell transplantation on the ocular phenotype in mucopolysaccharidosis type I (Hurler).

Acta Ophthalmol 2018 Aug 14;96(5):494-498. Epub 2017 Dec 14.

Manchester Royal Eye Hospital, Manchester Academic Health Science Centre, Manchester, UK.

Purpose: To determine whether the ocular phenotype in patients with mucopolysaccharidosis type I (MPSI) Hurler is affected by the efficacy of previous haemopoietic stem cell transplantation (HSCT).

Design: A retrospective cohort study of patients with MPSI who had undergone treatment with HSCT.

Methods: Ocular phenotype was documented for each patient and compared to levels of biomarkers representing efficacy of previous transplantation.

Main Outcome Measures: Assessment of visual acuity (VA), severity of corneal clouding and the presence of optic neuropathy or retinopathy. Biomarker assessment included dermatan sulphate/chondroitin sulphate (DS/CS) ratio and iduronidase enzyme level.

Results: Severe corneal clouding was significantly greater in patients with lower iduronidase levels (p = 0.023) and raised DS/CS ratio (R  = 0.28 p = 0.043). Better VA was related to a higher iduronidase levels (R  = 0.15, p = 0.004) and lower DS/CS ratio (R  = 0.38, p = 0.001).

Conclusion: Improved ocular phenotypes in MPSI are associated with markers signifying efficacy of prior transplant. Early and effective HSCT may result in a better visual prognosis and reduction in ocular complications for patients with MPSI.
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http://dx.doi.org/10.1111/aos.13627DOI Listing
August 2018

Home infusion with Elosulfase alpha (Vimizim) in a UK Paediatric setting.

Mol Genet Metab Rep 2018 Mar 5;14:15-18. Epub 2017 Nov 5.

Willink Biochemical Genetics Unit, Manchester Centre for Genomic Medicine, Central Manchester University Hospitals NHS Foundation Trust, Saint Mary's Hospital, UK.

Enzyme replacement therapy is the only available treatment for Mucopolysaccharidosis type IVA (MPS IVA, Morquio syndrome). The treatment is lengthy and invasive involving weekly intravenous infusions of 4-5 h. This can cause significant disruption to normal family life so the provision of a safe and effective homecare service is essential. In order to deliver a safe service, robust standards must be in place; this includes appropriately trained members of homecare staff, detailed management for infusion related reactions (IRR) and appropriate venous access. In this report we demonstrate the criteria required to ensure a successful home treatment programme and describe our experience thus far.
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http://dx.doi.org/10.1016/j.ymgmr.2017.10.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5675729PMC
March 2018

IDUA mutational profile and genotype-phenotype relationships in UK patients with Mucopolysaccharidosis Type I.

Hum Mutat 2017 11 17;38(11):1555-1568. Epub 2017 Aug 17.

Manchester Centre for Genomic Medicine, St Mary's Hospital, Manchester Academic Health Science Centre (MAHSC), Manchester, UK.

Mucopolysaccharidosis Type I (MPS I) is a lysosomal storage disorder with varying degrees of phenotypic severity caused by mutations in IDUA. Over 200 disease-causing variants in IDUA have been reported. We describe the profile of disease-causing variants in 291 individuals with MPS I for whom IDUA sequencing was performed, focusing on the UK subset of the cohort. A total of 63 variants were identified, of which 20 were novel, and the functional significance of the novel variants is explored. The severe form of MPS I is treated with hematopoietic stem cell transplantation, known to have improved outcomes with earlier age at treatment. Developing genotype-phenotype relationships would therefore have considerable clinical utility, especially in the light of the development of newborn screening programs for MPS I. Associations between genotype and phenotype are examined in this cohort, particularly in the context of the profile of variants identified in UK individuals. Relevant associations can be made for the majority of UK individuals based on the presence of nonsense or truncating variants as well as other associations described in this report.
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http://dx.doi.org/10.1002/humu.23301DOI Listing
November 2017

Long term survival and cardiopulmonary outcome in children with Hurler syndrome after haematopoietic stem cell transplantation.

J Inherit Metab Dis 2017 05 10;40(3):455-460. Epub 2017 Mar 10.

Department of Paediatric Blood and Marrow Transplant, Royal Manchester Children's Hospital, Oxford Rd, Manchester, M13 9WL, UK.

Premature death in untreated children with Hurler syndrome (HS) in the first decade of life is largely due to life-threatening cardiopulmonary complications. We examined the long-term survival and cardiopulmonary outcome in 54 children undergoing haematopoietic stem cell transplantation (HSCT) at the Royal Manchester Children's Hospital from 1985 to 2008. The median age at first HSCT was 15.1 months. Eighteen had graft failure and nine died after first HSCT. Of 18 patients with graft failure, 17 underwent second HSCT and the remaining one was lost to follow-up (LOF). Twelve were alive-and-engrafted after second HSCT. The overall survival at one year and 20-years was the same at 73.7%. Six children were followed up at the referral centers and excluded from cardiopulmonary endpoint review. Of the 33 evaluable children for the cardiopulmonary endpoints, nine (27.3%) had normal cardiac assessment. Of the four children on angiotensin-converting-enzyme inhibitors, two had mild cardiomyopathy and two had aortic valvular replacement. Twenty (60%) had mild/moderate mitral and/or aortic insufficiencies. Two had overnight hypoxia needing nocturnal non-invasive support. Enzyme level and donor chimerism are important predictors of long-term cardiac outcome.
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http://dx.doi.org/10.1007/s10545-017-0034-6DOI Listing
May 2017

Outcomes of Long-Term Treatment with Laronidase in Patients with Mucopolysaccharidosis Type I.

J Pediatr 2016 Nov;178:219-226.e1

Willink Biochemical Genetic Unit, Manchester Centre for Genomic Medicine, Saint Mary's Hospital, Manchester, UK.

Objective: To evaluate long-term outcomes of laronidase enzyme replacement therapy in patients with attenuated mucopolysaccharidosis type I.

Study Design: Retrospective analyses of case notes, laboratory results, and data from clinical trials were used to evaluate urinary glycosaminoglycans, forced vital capacity (FVC), 6-minute walk test (6MWT), height-for-age Z score, cardiac valve function, corneal clouding, and visual acuity in 35 patients with attenuated mucopolysaccharidosis type I (Hurler-Scheie and Scheie syndromes) for up to 10 years following the initiation of laronidase therapy.

Results: Statistically significant (P < .001) reductions in mean urinary glycosaminoglycan levels relative to baseline were observed 6 months after treatment initiation and were sustained throughout follow-up. Disease remained stable after treatment initiation with no statistically significant changes in mean FVC, 6MWT, or height-for-age Z score. At last assessments, mitral and aortic valve function remained stable in 65% (22/34) of patients; corneal clouding remained stable in 78% (18/23); visual acuity remained stable in 33% (8/24) and improved in 42% (10/24) of patients. Younger patients (<10 years at treatment initiation) maintained disease measures closer to norms for age for FVC, 6MWT, and height and showed fewer deteriorations in mitral and aortic valve disease and corneal clouding compared with patients aged ≥10 years at treatment initiation.

Conclusion: Laronidase treatment resulted in disease stabilization in the majority of patients with a mean follow-up of 6.1 years. Data suggest that early treatment may result in better outcomes.
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http://dx.doi.org/10.1016/j.jpeds.2016.08.033DOI Listing
November 2016

Maternal mosaicism for deletion clarifies recurrence risk in MPS I.

Hum Genome Var 2016 6;3:16031. Epub 2016 Oct 6.

Department of Clinical Chemistry and Laboratory Medicine, Jena University Hospital , Jena, Germany.

Mucopolysaccharidosis I (MPS I) is a rare autosomal recessive multisystem lysosomal storage disorder. It is caused by biallelic loss-of-function variants in encoding alpha-l iduronidase. Here, we describe an individual affected by MPS I due to a paternally inherited deletion of exons 1 and 2, c.(?_-88)_(299+1_300-1)del and a whole-gene deletion of (?_-88?)_(*136?)del secondary to maternal somatic mosaicism. We define a previously unreported mutational mechanism for this disorder.
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http://dx.doi.org/10.1038/hgv.2016.31DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5052355PMC
October 2016

Progression of Hip Dysplasia in Mucopolysaccharidosis Type I Hurler After Successful Hematopoietic Stem Cell Transplantation.

J Bone Joint Surg Am 2016 Mar;98(5):386-95

Department of Pediatric Metabolic Diseases, Emma Children's Hospital and Amsterdam Lysosome Center "Sphinx," Academic Medical Center, Amsterdam, the Netherlands

Background: Dysostosis multiplex contributes substantially to morbidity in patients with Hurler syndrome (mucopolysaccharidosis type I Hurler phenotype [MPS I-H]), even after successful hematopoietic stem cell transplantation (HSCT). One of the hallmarks of dysostosis multiplex in MPS I-H is hip dysplasia, which often requires surgical intervention. We sought to describe in detail the course of hip dysplasia in this group of patients, as assessed by radiographic analysis, and to identify potential outcome predictors.

Methods: Longitudinal data were obtained from digitally scored pelvic radiographs of patients with MPS I-H using OrthoGon software for parameters including, but not limited to, the acetabular index, migration percentage, Smith ratio, and neck-shaft angle. Scoring was performed independently by two blinded observers. Additional information on genotype, enzyme replacement therapy pre-HSCT, donor chimerism, and enzyme activity post-HSCT were obtained. General trends and potential correlations were calculated with mixed-model statistics.

Results: Fifty-two patients (192 radiographs) were included in this analysis. Intraobserver and interobserver variation analysis showed an intraclass correlation coefficient ranging from 0.78 to 1.00. Among the twenty-one patients with follow-up beyond the age of five years, the acetabular index was in the range of severe hip dysplasia in up to 86% of the patients. Severe coxa valga was seen in 91% of the patients. Lateral and superior femoral displacement were highly prevalent, with the migration percentage outside the reference range in up to 96% of the patients. Finally, anterior pelvic tilt increased with age (p = 0.001). No correlations were identified between clinical parameters and radiographic findings.

Conclusions: Our study shows that progressive acetabular dysplasia as well as coxa valga and hip displacement are highly prevalent and progressive over time in patients with MPS I-H, despite successful HSCT. These data may provide essential natural history determinations for the assessment of efficacy of new therapeutic strategies aimed at improving skeletal outcomes in patients with MPS I-H.
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http://dx.doi.org/10.2106/JBJS.O.00601DOI Listing
March 2016

Enzyme replacement therapy prior to haematopoietic stem cell transplantation in Mucopolysaccharidosis Type I: 10 year combined experience of 2 centres.

Mol Genet Metab 2016 Mar 27;117(3):373-7. Epub 2016 Jan 27.

Bone Marrow Transplantation Unit, Royal Manchester Children's Hospital, Oxford Road, Manchester M13 9WL, UK. Electronic address:

Haematopoietic stem cell transplantation is the treatment of choice for the severe form of Mucopolysaccharidosis Type I, or Hurler syndrome. In many centres standard practice is to deliver enzyme replacement therapy alongside haematopoietic stem cell transplantation to improve the condition of the patient prior to transplant. We report the combined 10 year experience of this approach in two paediatric metabolic and transplant centres. Of 81 patients who underwent a first transplant procedure for Hurler, 88% (71/81) survived and 81% (66/81) were alive and engrafted at a median follow-up of 46 months (range 3-124 months). The incidence of grade II-IV acute and any chronic graft versus host disease was 17% and 11% respectively. Urinary glycosaminoglycans were significantly reduced after a period of enzyme replacement therapy, and further reductions were seen at 13-24 months and 25+months after transplantation. In several individuals with decreased cardiac contractility, an improvement of their condition during enzyme replacement therapy enabled them to undergo transplantation, with one individual receiving full intensity conditioning.
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http://dx.doi.org/10.1016/j.ymgme.2016.01.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5177791PMC
March 2016

Sleep disordered breathing in mucopolysaccharidosis I: a multivariate analysis of patient, therapeutic and metabolic correlators modifying long term clinical outcome.

Orphanet J Rare Dis 2015 Apr 10;10:42. Epub 2015 Apr 10.

Stem Cell & Neurotherapies, Faculty of Medical and Human Sciences, University of Manchester, Manchester, UK.

Background: The lysosomal storage disorder, mucopolysaccharidosis I (MPS I), commonly manifests with upper airway obstruction and sleep disordered breathing (SDB). The success of current therapies, including haematopoietic stem cell transplantation (HSCT) and enzyme replacement therapy (ERT) may be influenced by a number of factors and monitored using biomarkers of metabolic correction. We describe the pattern of SDB seen in the largest MPS I cohort described to date and determine therapies and biomarkers influencing the severity of long-term airway disease.

Methods: Therapeutic, clinical and biomarker data, including longitudinal outcome parameters from 150 sleep oximetry studies were collected in 61 MPS I (44 Hurler, 17 attenuated) patients between 6 months pre to 16 years post-treatment (median follow-up 22 months). The presence and functional nature of an immune response to ERT was determined using ELISA and a cellular uptake inhibition assay. Multivariate analysis was performed to determine significant correlators of airway disease.

Results: The incidence of SDB in our cohort is 68%, while 16% require therapeutic intervention for airway obstruction. A greater rate of progression (73%) and requirement for intervention is seen amongst ERT patients in contrast to HSCT treated individuals (24%). Multivariate analysis identifies poorer metabolic clearance, as measured by a rise in the biomarker urinary dermatan sulphate: chondroitin sulphate (DS:CS) ratio, as a significant correlator of increased presence and severity of SDB in MPS I patients (p = 0.0017, 0.008). Amongst transplanted Hurler patients, delivered enzyme (leukocyte iduronidase) at one year is significantly raised in those without SDB (p = 0.004). Cellular uptake inhibitory antibodies in ERT treated patients correlate with reduced substrate clearance and occurrence of severe SDB (p = 0.001).

Conclusion: We have identified biochemical and therapeutic factors modifying airway disease across the phenotypic spectrum in MPS I. Interventions maximising substrate reduction correlate with improved long-term SDB, while inhibitory antibodies impact on biochemical and clinical outcomes. Monitoring and tolerisation strategies should be re-evaluated to improve detection and minimise the inhibitory antibody response to ERT in MPS I and other lysosomal storage diseases. Future studies should consider the use of sleep disordered breathing as an objective parameter of clinical and metabolic improvement.
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http://dx.doi.org/10.1186/s13023-015-0255-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4450482PMC
April 2015

Hematopoietic cell transplantation for mucopolysaccharidosis patients is safe and effective: results after implementation of international guidelines.

Biol Blood Marrow Transplant 2015 Jun 20;21(6):1106-9. Epub 2015 Feb 20.

Pediatric Blood and Marrow Transplantation Program, University Medical Center Utrecht, Utrecht, The Netherlands. Electronic address:

Allogeneic hematopoietic cell transplantation (HCT) is the only treatment able to prevent progressive neurodegenerative disease in a selected group of mucopolysaccharidosis (MPS) disorders. However, its use was historically limited by the high risk of graft failure and transplantation-related morbidity and mortality. Therefore, since 2005 new international HCT guidelines for MPS disorders were proposed. The survival and graft outcomes of MPS patients receiving HCT according to these guidelines in 2 European centers of expertise were evaluated. Two consecutive conditioning regimens were used, busulfan/cyclophosphamide or fludarabine/busulfan-based, both with exposure-targeted i.v. busulfan. A noncarrier matched sibling donor (MSD), matched unrelated cord blood (UCB), or matched unrelated donor (MUD) were considered to be preferred donors. If not available, a mismatched UCB donor was used. Participants were 62 MPS patients (56 MPS type I-Hurler, 2 MPS type II, 2 MPS type III, and 2 MPS type VI) receiving HCT at median age 13.5 months (range, 3 to 44). Forty-one patients received a UCB donor, 17 MSD, and 4 MUD. High overall survival (95.2%) and event-free survival (90.3%) were achieved with only low toxicity: 13.3% acute graft-versus-host disease aGVHD) grades II to IV and 14.8% chronic GVHD (1.9% extensive). A mismatched donor predicted for lower event-free survival (P = .04). A higher age at HCT was a predictor for both aGVHD (P = .001) and chronic GVHD (P = .01). The use of a mismatched donor was a predictor for aGVHD (P = .01). Higher rates of full-donor chimerism were achieved in successfully transplanted UCB recipients compared with MSD/MUD (P = .002). If complying with the international HCT guidelines, HCT in MPS patients results in high safety and efficacy. This allows extension of HCT to more attenuated MPS types. Because a younger age at HCT is associated with reduction of HCT-related toxicity, newborn screening may further increase safety.
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http://dx.doi.org/10.1016/j.bbmt.2015.02.011DOI Listing
June 2015

Biomarker responses correlate with antibody status in mucopolysaccharidosis type I patients on long-term enzyme replacement therapy.

Mol Genet Metab 2015 Feb 29;114(2):129-37. Epub 2014 Oct 29.

Stem Cell & Neurotherapies, Centre for Genomic Medicine, University of Manchester, Manchester, UK.

Background: Antibody formation can interfere with effects of enzyme replacement therapy (ERT) in lysosomal storage diseases. Biomarkers are used as surrogate marker for disease burden in MPS I, but large systematic studies evaluating the response of biomarkers to ERT are lacking. We, for the first time, investigated the response of a large panel of biomarkers to long term ERT in MPS I patients and correlate these responses with antibody formation and antibody mediated cellular uptake inhibition.

Methods: A total of 428 blood and urine samples were collected during long-term ERT in 24 MPS I patients and an extensive set of biomarkers was analyzed, including heparan sulfate (HS) and dermatan sulfate (DS) derived disaccharides; total urinary GAGs (DMBu); urinary DS:CS ratio and serum heparin co-factor II thrombin levels (HCII-T). IgG antibody titers and the effect of antibodies on cellular uptake of the enzyme were determined for 23 patients.

Results: Median follow-up was 2.3 years. In blood, HS reached normal levels more frequently than DS (50% vs 12.5%, p=0.001), though normalization could take several years. DMBu normalized more rapidly than disaccharide levels in urine (p=0.02). Nineteen patients (83%) developed high antibody titers. Significant antibody-mediated inhibition of enzyme uptake was observed in 8 patients (35%), and this correlated strongly with a poorer biomarker response for HS and DS in blood and urine as well as for DMBu, DS:CS-ratio and HCII-T (all p<0.006).

Conclusions: This study shows that, despite a response of all studied biomarkers to initiation of ERT, some biomarkers were less responsive than others, suggesting residual disease activity. In addition, the correlation of cellular uptake inhibitory antibodies with a decreased biomarker response demonstrates a functional role of these antibodies which may have important clinical consequences.
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http://dx.doi.org/10.1016/j.ymgme.2014.10.012DOI Listing
February 2015

Parenting: section deserves a scolding.

Authors:
Jean Mercer

Science 2014 Sep;345(6204):1571

Richard Stockton College, Galloway, NJ 08205, USA.

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http://dx.doi.org/10.1126/science.345.6204.1571-bDOI Listing
September 2014

Does early use of enzyme replacement therapy alter the natural history of mucopolysaccharidosis I? Experience in three siblings.

Mol Genet Metab 2013 Jul 10;109(3):315-6. Epub 2013 May 10.

Genetic Medicine, Manchester Academic Health Science Centre, University of Manchester, Central Manchester University Hospitals NHS Foundation Trust, St. Mary's Hospital, Oxford Road, Manchester M13 9WL, UK.

Enzyme replacement therapy is widely used as treatment for mucopolysaccharidosis I (MPS I), and there is evidence that this produces improvement in certain clinical domains. There does appear to be variation in the response of clinical features to treatment once these are established. In a reported sibling pair, when enzyme replacement therapy was commenced pre-symptomatically in the younger child, the natural history of the condition appeared to be affected. We present data from three siblings treated with enzyme replacement therapy at different ages which supports this finding.
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http://dx.doi.org/10.1016/j.ymgme.2013.04.023DOI Listing
July 2013

Management of mucopolysaccharidosis type IH (Hurler's syndrome) presenting in infancy with severe dilated cardiomyopathy: a single institution's experience.

J Inherit Metab Dis 2013 Mar 21;36(2):263-70. Epub 2012 Jun 21.

Department of Paediatric Haematology, Royal Manchester Children's Hospital, Manchester, UK.

Mucopolysaccharidosis type IH (MPSIH) is a lysosomal storage disorder whose untreated course involves progressive multisystem deterioration and death within the first decade of life. Allogeneic haematopoietic stem cell transplantation (HSCT) is an established treatment modality that improves functional outcome and long-term survival. Optimal outcome requires transplantation early in life and with myeloablative conditioning. Severe cardiomyopathy can be present at diagnosis and may seemingly preclude this approach. We performed a retrospective review of those cases transplanted in Manchester since 2000 that initially presented with established cardiomyopathy, with a view to identifying general management principles. Of 44 MPSIH children transplanted in this period, 6 had displayed moderate or severe cardiomyopathy at presentation; symptomatic cardiac failure was the predominant presenting feature in five of these. Echocardiographic and clinical improvement in cardiac function was observed with extended enzyme replacement therapy (ERT) in all cases, with recovery of fractional shortening to ≥25 % achieved in all patients before coming to transplant (after median 19 weeks ERT). All were transplanted successfully, with good functional and cardiologic outcomes. However, cyclophosphamide conditioning was implicated in acute post-transplant cardiac decompensation in several cases. Our experiences highlight three important messages: (1) A diagnosis of MPSIH should be considered in any infant presenting with unexplained severe cardiac failure; (2) ERT pre-transplant can improve cardiac function sufficiently to permit safe HSCT using myeloablative conditioning; and (3) High dose cyclophosphamide should be avoided in conditioning these patients.
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http://dx.doi.org/10.1007/s10545-012-9500-3DOI Listing
March 2013

Hematopoietic stem cell transplantation improves the high incidence of neutralizing allo-antibodies observed in Hurler's syndrome after pharmacological enzyme replacement therapy.

Haematologica 2012 Sep 27;97(9):1320-8. Epub 2012 Feb 27.

Stem Cell & Neurotherapies, Faculty of Medical and Human Sciences, University of Manchester, Manchester, UK.

Background: Mucopolysaccharidosis type I is caused by deficiency of α-L-iduronidase. Currently available treatment options include an allogeneic hematopoietic stem cell transplant and enzyme replacement therapy. Exogenous enzyme therapy appears promising but the benefits may be attenuated, at least in some patients, by the development of an immune response to the delivered enzyme. The incidence and impact of alloimmune responses in these patients remain unknown.

Design And Methods: We developed an immunoglobulin G enzyme-linked immunosorbent assay as well as in vitro catalytic enzyme inhibition and cellular uptake inhibition assays and quantified enzyme inhibition by allo-antibodies. We determined the impact of these antibodies in eight patients who received enzyme therapy before and during hematopoietic stem cell transplantation. In addition, 20 patients who had previously received an allogeneic stem cell transplant were tested to evaluate this treatment as an immune tolerance induction mechanism.

Results: High titer immune responses were seen in 87.5% (7/8) patients following exposure to α-L-iduronidase. These patients exhibited catalytic enzyme inhibition (5/8), uptake inhibition of catalytically active enzyme (6/8) or both (4/8). High antibody titers generally preceded elevation of previously described biomarkers of disease progression. The median time to development of immune tolerance was 101 days (range, 26-137) after transplantation. All 20 patients, including those with mixed chimerism (22%), tested 1 year after transplantation were tolerized despite normal enzyme levels.

Conclusions: We found a high incidence of neutralizing antibodies in patients with mucopolysaccharidosis type I treated with enzyme replacement therapy. We also found that allogeneic hematopoietic stem cell transplantation was an effective and rapid immune tolerance induction strategy.
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http://dx.doi.org/10.3324/haematol.2011.058644DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3436232PMC
September 2012

Martial arts research: weak evidence.

Authors:
Jean Mercer

Science 2011 Oct;334(6054):310-1; author reply 311

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http://dx.doi.org/10.1126/science.334.6054.310-cDOI Listing
October 2011

The concept of psychological regression: metaphors, mapping, Queen Square, and Tavistock Square.

Authors:
Jean Mercer

Hist Psychol 2011 May;14(2):174-96

Richard Stockton College, Pomona, New Jersey, USA.

The term "regression" refers to events in which an individual changes from his or her present level of maturity and regains mental and behavioral characteristics shown at an earlier point in development. This definition has remained constant for over a century, but the implications of the concept have changed systematically from a perspective in which regression was considered pathological, to a current view in which regression may be seen as a positive step in psychotherapy or as a part of normal development. The concept of regression, famously employed by Sigmund Freud and others in his circle, derived from ideas suggested by Herbert Spencer and by John Hughlings Jackson. By the 1940s and '50s, the regression concept was applied by Winnicott and others in treatment of disturbed children and in adult psychotherapy. In addition, behavioral regression came to be seen as a part of a normal developmental trajectory, with a focus on expectable variability. The present article examines historical changes in the regression concept in terms of mapping to biomedical or other metaphors, in terms of a movement from earlier nativism toward an increased environmentalism in psychology, and with respect to other historical factors such as wartime events. The role of dominant metaphors in shifting perspectives on regression is described.
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http://dx.doi.org/10.1037/a0022710DOI Listing
May 2011

The craniocervical junction following successful haematopoietic stem cell transplantation for mucopolysaccharidosis type I H (Hurler syndrome).

J Inherit Metab Dis 2011 Jun 17;34(3):755-61. Epub 2011 Mar 17.

Department of Paediatrics, Children`s Hospital, Johannes Gutenberg-Universität Mainz, Langenbeckstr. 2 in 55131, Mainz, Germany.

Mucopolysaccharidosis I Hurler (MPS IH) is a progressive multisystemic disorder caused by alpha-L-iduronidase deficiency. First choice of treatment in MPS IH children is haematopoietic stem cell transplantation (HSCT). The effect of HSCT has been shown to have limited influence on skeletal manifestations by poor penetration of musculoskeletal tissues by the enzyme derived from donor leucocytes. Aim of this study was to investigate the effect of HSCT on the craniocervical junction (CCJ) in Hurler patients. We analysed retrospectively sequential magnetic resonance imaging (MRI) scans of 30 patients with Hurler disease treated by HSCT since 1982 at the Royal Manchester Children's Hospital, UK, in order to determine whether the patients suffer from dens hypoplasia. Results were compared with biochemical and clinical characteristics: Enzyme activity (EA), chimerism, urinary glycosaminoglycan (GAG) excretion and neurological status. Investigations were part of standard clinical procedures. Results are descriptive in presentation. In 26/30 patients a determination of odontoid hypoplasia was feasible. The majority showed a normal dens length and an increase with age. Only 3/26 revealed a dens hypoplasia. One of them had only partial donor engraftment (DE) with reduced EA, one of them suffered from chronic graft versus host disease (GVHD). One patient with only partial DE and reduced EA presented with initial dens hypoplasia until preadolescence but normalized later on. There may be a trend towards lower EA and the occurrence of DH in transplanted MPS patients - perhaps the dosage of enzyme plays a role in the correction of skeletal complications in this patient group. HSCT patients with incomplete DE and therefore lower EAs may require special attention and care.
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http://dx.doi.org/10.1007/s10545-011-9309-5DOI Listing
June 2011

Growth, final height and endocrine sequelae in a UK population of patients with Hurler syndrome (MPS1H).

J Inherit Metab Dis 2011 Apr 21;34(2):489-97. Epub 2011 Jan 21.

Royal Manchester Children's Hospital, Manchester, UK.

Objective: Hurler Syndrome, (MPSIH) is an inborn error of glycosaminoglycan metabolism. Haematopoietic stem cell transplantation (HSCT) has transformed the prognosis for these children. Prior to transplant patients receive chemotherapy or chemo-radiotherapy. Regular screening for the development of endocrine sequelae is therefore essential. We present for the first time data on final adult height and endocrine complications in children with MPSIH post HSCT.

Design: Retrospective case note study and a prospective programme of growth and endocrine assessment.

Patients: 22 patients were included, mean age at last assessment 12.2 (Range 6.3-21.6) years. Mean age at HSCT was 1.3 (SD 0.6) years. Conditioning included mostly busulphan and cyclophosphamide, with 5 patients receiving total body irradiation prior to second transplant.

Results: Height SDS decreased over time. Final height (FH) was attained in seven patients with male FH SDS -4.3 (Range -3.8, -5.1) and female FH SDS -3.4 (Range -2.9, -5.6). Eight of 13 patients tested had evidence of high growth hormone (GH) levels, while one had GH deficiency. Adrenal and thyroid function was normal in all. 11 patients were pubertal or post pubertal. Two females had pubertal failure requiring intervention. All male patients had spontaneous, complete puberty; however three patients have reduced testicular volumes. Five out of 13 patients tested had an abnormal oral glucose tolerance test.

Conclusion: Growth is impaired, primarily related to skeletal dysplasia, but also associated with GH resistance. Pubertal development may be compromised and abnormalities of glucose metabolism are common. We recommend a structured endocrine surveillance programme for these patients.
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http://dx.doi.org/10.1007/s10545-010-9262-8DOI Listing
April 2011

Heparin cofactor II-thrombin complex and dermatan sulphate:chondroitin sulphate ratio are biomarkers of short- and long-term treatment effects in mucopolysaccharide diseases.

J Inherit Metab Dis 2011 Apr 18;34(2):499-508. Epub 2010 Dec 18.

MPS Stem Cell Research Group, Faculty of Medical and Human Sciences, University of Manchester, Manchester, M13 9PT, UK.

Early detection of mucopolysaccharidosis (MPS) is an important factor in treatment success; therefore, good disease biomarkers are vital. We evaluate heparin cofactor II-thrombin complex (HCII-T) as a biomarker in serum and dried blood spots (DBS) of MPS patients. Serum HCII-T and urine dermatan sulphate:chondroitin sulphate (DS:CS) ratio are also compared longitudinally against clinical outcomes in MPSI, II and VI patients following treatment. Samples were collected from MPS patients at the Royal Manchester Children's Hospital. DS:CS ratio was obtained by measuring the area density of spots from 2D electrophoresis of urinary glycosaminoglycans. Serum and DBS HCII-T was measured by sandwich ELISA. Serum HCII-T is elevated approximately 25-fold in MPS diseases that store DS, clearly distinguishing untreated MPSI, II and VI patients from unaffected age-matched controls. Serum HCII-T is also elevated in MPSIII, which leads to storage of heparan sulphate, with an increase of approximately 4-fold over unaffected age-matched controls. Urine DS:CS ratio and serum HCII-T decrease in response to treatment of MPSI, II and VI patients. HCII-T appears to respond rapidly to perturbations in treatment, whilst DS:CS ratio responds more slowly. HCII-T is a suitable biomarker for MPSI, II and VI, and it may also be informative for MPS diseases storing HS alone, such as MPSIII, although the elevation observed is smaller. In treated MPS patients, HCII-T and DS:CS ratio appear to measure short-term and long-term treatment outcomes, respectively. The potential value of HCII-T measurement in DBS for newborn screening of MPS diseases warrants further investigation.
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http://dx.doi.org/10.1007/s10545-010-9254-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3063559PMC
April 2011

Improved metabolic correction in patients with lysosomal storage disease treated with hematopoietic stem cell transplant compared with enzyme replacement therapy.

J Pediatr 2009 Apr;154(4):609-11

Department of Haematology and BMT, Royal Manchester Children's Hospital, Manchester, United Kingdom.

We compared substrate reduction in patients with lysosomal storage disorder treated with hematopoietic stem cell transplant and found that it was significantly reduced compared with patients treated with pharmacological enzyme replacement therapy. These data might support the wider application of hematopoietic stem cell transplant in the treatment of lysosomal storage disorders.
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http://dx.doi.org/10.1016/j.jpeds.2008.11.005DOI Listing
April 2009

Use of enzyme replacement therapy (Laronidase) before hematopoietic stem cell transplantation for mucopolysaccharidosis I: experience in 18 patients.

J Pediatr 2009 Jan;154(1):135-9

Blood and Marrow Transplant Unit, Royal Manchester Children's Hospital, Manchester, UK.

We describe the use of enzyme replacement therapy in conjunction with hematopoietic stem cell transplantation in 18 consecutive patients with severe mucopolysaccharidosis type I. The survival and engraftment rate was 89% overall and 93% for the 15 patients who received full-intensity conditioning.
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http://dx.doi.org/10.1016/j.jpeds.2008.07.004DOI Listing
January 2009

Minding controls in curriculum study.

Authors:
Jean Mercer

Science 2008 Feb;319(5867):1185-6; author reply 1185-6

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http://dx.doi.org/10.1126/science.319.5867.1185DOI Listing
February 2008

One woman's balancing act.

Authors:
Jean Mercer

Science 2007 Dec;318(5858):1864-5

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http://dx.doi.org/10.1126/science.318.5858.1864cDOI Listing
December 2007