Publications by authors named "Eveline J Langereis"

10 Publications

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Treatment of thoracolumbar kyphosis in patients with mucopolysaccharidosis type I: results of an international consensus procedure.

Orphanet J Rare Dis 2019 01 18;14(1):17. Epub 2019 Jan 18.

Amsterdam UMC, University of Amsterdam, Pediatric Metabolic Diseases, Emma Children's Hospital and Amsterdam Lysosome Center "Sphinx", Meibergdreef 9, Amsterdam, Netherlands.

Background: In all patients with mucopolysaccharidosis type I (MPS I), skeletal disease (dysostosis multiplex) is a prominent, debilitating, condition related complication that may impact strongly on activities of daily living. Unfortunately, it is not alleviated by treatment with hematopoietic cell transplantation (HCT) or enzyme replacement therapy (ERT). Although early kyphosis is one of the key features of dysostosis multiplex, there is no international consensus on the optimal management. Therefore, an international consensus procedure was organized with the aim to develop the first clinical practice guideline for the management of thoracolumbar kyphosis in MPS I patients.

Methods: A literature review was conducted to identify all available information about kyphosis and related surgery in MPS I patients. Subsequently, a modified Delphi procedure was used to develop consensus statements. The expert panel included 10 spinal orthopedic surgeons, 6 pediatricians and 3 physiotherapists, all experienced in MPS I. The procedure consisted of 2 written rounds, a face-to-face meeting and a final written round. The first 2 rounds contained case histories, general questions and draft statements. During the face-to-face meeting consensus statements were developed. In the final round, the panel had the opportunity to anonymously express their opinion about the proposed statements.

Results: Eighteen case series and case reports were retrieved from literature reporting on different surgical approaches and timing of thoracolumbar kyphosis surgery in MPS I. During the face-to-face meeting 16 statements were discussed and revised. Consensus was reached on all statements.

Conclusion: This international consensus procedure resulted in the first clinical practice guideline for the management of thoracolumbar kyphosis in MPS I patients, focusing on the goals and timing of surgery, as well as the optimal surgical approach, the utility of bracing and required additional assessments (e.g. radiographs). Most importantly, it was concluded that the decision for surgery depends not only on the kyphotic angle, but also on additional factors such as the progression of the deformity and its flexibility, the presence of symptoms, growth potential and comorbidities. The eventual goal of treatment is the maintenance or improvement of quality of life. Further international collaborative research related to long-term outcome of kyphosis surgery in MPS I is essential as prognostic information is lacking.
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http://dx.doi.org/10.1186/s13023-019-0997-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6339313PMC
January 2019

Failure to shorten the diagnostic delay in two ultra-orphan diseases (mucopolysaccharidosis types I and III): potential causes and implications.

Orphanet J Rare Dis 2018 01 8;13(1). Epub 2018 Jan 8.

Department of Pediatric Metabolic Diseases, Emma Children's Hospital and Amsterdam Lysosome Center "Sphinx", Academic Medical Center, Meibergdreef 9, 1105, AZ, Amsterdam, The Netherlands.

Background: Rare diseases are often un- or misdiagnosed for extended periods, resulting in a long diagnostic delay that may significantly add to the burden of the disease. An early diagnosis is particularly essential if a disease-modifying treatment is available. The purpose of this study was to assess the extent of the diagnostic delay in the two ultra-rare diseases, i.e., mucopolysaccharidosis I (MPS I) and III (MPS III), both of which are lysosomal storage disorders with different phenotypic severities (MPS 1 is characterized by the severe Hurler and the more attenuated non-Hurler phenotypes, MPS III is characterized by the severe rapidly progressing (RP) phenotype and more attenuated slowly progressing (SP) phenotype). We investigated whether the diagnostic delay changed over the previous decades.

Results: The diagnostic delay, which is defined as the time between the first visit to a medical doctor for disease-related symptoms and the final diagnosis, was assessed using telephone interviews with patients diagnosed between 1988 and 2017 and/or their parents or legal guardian(s). In addition, the medical charts were reviewed. For MPS I (n = 29), the median diagnostic delay was 8 months (range 1-24 months) for Hurler patients and 28 months (range 2-147 months) for non-Hurler patients. For MPS III (n = 46), the median diagnostic delay was 33 months (range 1-365 months). No difference was observed between the RP and SP phenotypic groups. Comparing the diagnostic delay over time using 5-year time intervals, no reduction in the diagnostic delay was observed for MPS I or MPS III.

Conclusions: In the Netherlands, the time to diagnosis for patients with MPS I and MPS III has not changed between 1988 and 2017, and an extensive delay still exists between the first visit to a medical doctor for disease-related symptoms and the final diagnosis. The numerous campaigns launched to increase awareness, leading to earlier diagnosis of these rare disorders, particularly of MPS I, have failed to achieve their goal. Robust selected screening protocols embedded in national guidelines and newborn screening for disorders that meet the criteria for population screening may be the only effective approaches for reducing the diagnostic delay.
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http://dx.doi.org/10.1186/s13023-017-0733-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5759238PMC
January 2018

Incomplete biomarker response in mucopolysaccharidosis type I after successful hematopoietic cell transplantation.

Mol Genet Metab 2017 09 18;122(1-2):86-91. Epub 2017 May 18.

Department of Pediatric Metabolic Diseases, Emma Children's Hospital and Amsterdam Lysosome Center 'Sphinx', Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.

Background: Residual disease, primarily involving musculoskeletal tissue, is a common problem in patients with neuronopathic mucopolysaccharidosis type I (MPS I, Hurler or severe Hurler-Scheie phenotype) after a successful hematopoietic cell transplantation (HCT). The concentration of the GAG derived biomarkers heparan sulfate (HS) and dermatan sulfate (DS), may reflect residual disease and is used for monitoring biochemical response to therapies. This study investigates the response of HS and DS in blood and urine to HCT in MPS I patients.

Methods: In 143 blood- and urine samples of 17 neuronophatic MPS I patients, collected prior and post successful HCT, the concentration of the disaccharides derived after full enzymatic digestion of HS and DS were analyzed by multiplex liquid chromatography tandem-mass spectrometry (LC-MS/MS).

Results: Median follow up after HCT was 2.4years (range 0-11years). HCT led to a rapid decrease of both HS and DS. However, only 38% of the patients reached normal HS levels in blood and even less patients (6%) reached normal DS levels. In none of the patients normalization of HS or DS was observed in urine.

Conclusions: Biomarker response after HCT is incomplete, which may reflect residual disease activity. Novel therapeutic strategies should aim for full metabolic correction to minimize clinical manifestations.
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http://dx.doi.org/10.1016/j.ymgme.2017.05.009DOI Listing
September 2017

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

A Multiplex Assay for the Diagnosis of Mucopolysaccharidoses and Mucolipidoses.

PLoS One 2015 25;10(9):e0138622. Epub 2015 Sep 25.

Department of Pediatric Metabolic Diseases, Emma Children's Hospital and Amsterdam Lysosome Center 'Sphinx', Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; Laboratory for Genetic Metabolic Diseases, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.

Introduction: Diagnosis of the mucopolysaccharidoses (MPSs) generally relies on an initial analysis of total glycosaminoglycan (GAG) excretion in urine. Often the dimethylmethylene blue dye-binding (DMB) assay is used, although false-negative results have been reported. We report a multiplexed diagnostic test with a high sensitivity for all MPSs and with the potential to identify patients with I-cell disease (ML II) and mucolipidosis III (ML III).

Methods: Urine samples of 100 treatment naive MPS patients were collected and analyzed by the conventional DMB assay and a multiplex assay based on enzymatic digestion of heparan sulfate (HS), dermatan sulfate (DS) and keratan sulfate (KS) followed by quantification by LC-MS/MS. Specificity was calculated by analyzing urine samples from a cohort of 39 patients suspected for an inborn error of metabolism, including MPSs.

Results: The MPS cohort consisted of 18 MPS I, 16 MPS II, 34 MPS III, 10 MPS IVA, 3 MPS IVB, 17 MPS VI and 2 MPS VII patients. All 100 patients were identified by the LC-MS/MS assay with typical patterns of elevation of HS, DS and KS, respectively (sensitivity 100%). DMB analysis of the urine was found to be in the normal range in 10 of the 100 patients (sensitivity 90%). Three out of the 39 patients were identified as false-positive, resulting in a specificity of the LS-MS/MS assay of 92%. For the DMB this was 97%. All three patients with MLII/MLIII had elevated GAGs in the LC-MS/MS assay while the DMB test was normal in 2 of them.

Conclusion: The multiplex LC-MS/MS assay provides a robust and very sensitive assay for the diagnosis of the complete spectrum of MPSs and has the potential to identify MPS related disorders such as MLII/MLIII. Its performance is superior to that of the conventional DMB assay.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0138622PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4583541PMC
May 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

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

Treatment of hip dysplasia in patients with mucopolysaccharidosis type I after hematopoietic stem cell transplantation: results of an international consensus procedure.

Orphanet J Rare Dis 2013 Oct 3;8:155. Epub 2013 Oct 3.

Department of Pediatrics and Lysosome Center 'Sphinx', Academic Medical Center, University of Amsterdam, H7-270, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands.

Background: Mucopolysaccharidosis type I (MPS-I) is a lysosomal storage disorder characterized by progressive multi-organ disease. The standard of care for patients with the severe phenotype (Hurler syndrome, MPS I-H) is early hematopoietic stem cell transplantation (HSCT). However, skeletal disease, including hip dysplasia, is almost invariably present in MPS I-H, and appears to be particularly unresponsive to HSCT. Hip dysplasia may lead to pain and loss of ambulation, at least in a subset of patients, if left untreated. However, there is a lack of evidence to guide the development of clinical guidelines for the follow-up and treatment of hip dysplasia in patients with MPS I-H. Therefore, an international Delphi consensus procedure was initiated to construct consensus-based clinical practice guidelines in the absence of available evidence.

Methods: A literature review was conducted, and publications were graded according to their level of evidence. For the development of consensus guidelines, eight metabolic pediatricians and nine orthopedic surgeons with experience in the care of MPS I patients were invited to participate. Eleven case histories were assessed in two written rounds. For each case, the experts were asked if they would perform surgery, and they were asked to provide information on the aspects deemed essential or complicating in the decision-making process. In a subsequent face-to-face meeting, the results were presented and discussed. Draft consensus statements were discussed and adjusted until consensus was reached.

Results: Consensus was reached on seven statements. The panel concluded that early corrective surgery for MPS I-H patients with hip dysplasia should be considered. However, there was no full consensus as to whether such a procedure should be offered to all patients with hip dysplasia to prevent complications or whether a more conservative approach with surgical intervention only in those patients who develop clinically relevant symptoms due to the hip dysplasia is warranted.

Conclusions: This international consensus procedure led to the construction of clinical practice guidelines for hip dysplasia in transplanted MPS I-H patients. Early corrective surgery should be considered, but further research is needed to establish its efficacy and role in the treatment of hip dysplasia as seen in MPS I.
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http://dx.doi.org/10.1186/1750-1172-8-155DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3852175PMC
October 2013

An algorithm to predict phenotypic severity in mucopolysaccharidosis type I in the first month of life.

Orphanet J Rare Dis 2013 Jul 9;8:99. Epub 2013 Jul 9.

Introduction: Mucopolysaccharidosis type I (MPS I) is a progressive multisystem lysosomal storage disease caused by deficiency of the enzyme α-L-iduronidase (IDUA). Patients present with a continuous spectrum of disease severity, and the most severely affected patients (Hurler phenotype; MPS I-H) develop progressive cognitive impairment. The treatment of choice for MPS I-H patients is haematopoietic stem cell transplantation, while patients with the more attenuated phenotypes benefit from enzyme replacement therapy.

Methods: Thirty patients were included in this study. Genotypes were collected from all patients and all patients were phenotypically categorized at an age of > 18 months based on the clinical course of the disease. In 18 patients, IDUA activity in fibroblast cultures was measured using an optimized IDUA assay. Clinical characteristics from the first month of life were collected from 23 patients.

Results: Homozygosity or compound heterozygosity for specific mutations which are associated with MPS I-H, discriminated a subset of patients with MPS I-H from patients with more attenuated phenotypes (specificity 100%, sensitivity 82%). Next, we found that enzymatic analysis of IDUA activity in fibroblasts allowed identification of patients affected by MPS I-H. Therefore, residual IDUA activity in fibroblasts was introduced as second step in the algorithm. Patients with an IDUA activity of < 0.32 nmol x mg(-1) × hr(-1) invariably were MPS I-H patients, while an IDUA activity of > 0.66 nmol × mg(-1) × hr(-1) was only observed in more attenuated patients. Patients with an intermediate IDUA activity could be further classified by the presence of differentiating clinical characteristics, resulting in a model with 100% sensitivity and specificity for this cohort of patients.

Conclusion: Using genetic, biochemical and clinical characteristics, all potentially available in the newborn period, an algorithm was developed to predict the MPS I phenotype, allowing timely initiation of the optimal treatment strategy after introduction of NBS.
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http://dx.doi.org/10.1186/1750-1172-8-99DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3710214PMC
July 2013

Prevalence and risk factors for hypovitaminosis D in young patients with inflammatory bowel disease.

J Pediatr Gastroenterol Nutr 2011 Oct;53(4):361-4

Center for Inflammatory Bowel Disease, Children's Hospital Boston, Boston, MA 02115, USA.

Vitamin D plays an important role in bone homeostasis. We aimed to report the prevalence of hypovitaminosis D in children with inflammatory bowel disease (IBD) and risk factors associated with low serum 25-hydroxyvitamin D (25OHD) concentration in children with IBD. Risk factors for deficiency of this vitamin are similar to those in healthy children, with the addition of higher erythrocyte sedimentation rate. Both patients with ulcerative colitis and Crohn disease are at risk for hypovitaminosis D.
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http://dx.doi.org/10.1097/MPG.0b013e3182250b3eDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3188377PMC
October 2011