Eveline Langereis

The phenotypic spectrum of organic acidurias and urea cycle disorders. Part 2: the evolving clinical phenotype

BackgroundThe disease course and long-term outcome of patients with organic acidurias (OAD) and urea cycle disorders (UCD) are incompletely understood.AimsTo evaluate the complex clinical phenotype of OAD and UCD patients at different ages.ResultsAcquired microcephaly and movement disorders were common in OAD and UCD highlighting that the brain is the major organ involved in these diseases. Cardiomyopathy [methylmalonic (MMA) and propionic aciduria (PA)], prolonged QTc interval (PA), optic nerve atrophy [MMA, isovaleric aciduria (IVA)], pancytopenia (PA), and macrocephaly [glutaric aciduria type 1 (GA1)] were exclusively found in OAD patients, whereas hepatic involvement was more frequent in UCD patients, in particular in argininosuccinate lyase (ASL) deficiency. Chronic renal failure was often found in MMA, with highest frequency in mut0 patients. Unexpectedly, chronic renal failure was also observed in adolescent and adult patients with GA1 and ASL deficiency. It had a similar frequency in patients with or without a movement disorder suggesting different pathophysiology. Thirteen patients (classic OAD: 3, UCD: 10) died during the study interval, ten of them during the initial metabolic crisis in the newborn period. Male patients with late-onset ornithine transcarbamylase deficiency were presumably overrepresented in the study population.ConclusionsNeurologic impairment is common in OAD and UCD, whereas the involvement of other organs (heart, liver, kidneys, eyes) follows a disease-specific pattern. The identification of unexpected chronic renal failure in GA1 and ASL deficiency emphasizes the importance of a systematic follow-up in patients with rare diseases.

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

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.

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

BackgroundMucopolysaccharidosis 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.MethodsA 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.ResultsConsensus 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.ConclusionsThis 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.

A Multiplex Assay for the Diagnosis of Mucopolysaccharidoses and Mucolipidoses

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.

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

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.

Erratum to: The phenotypic spectrum of organic acidurias and urea cycle disorders. Part 1: the initial presentation (J Inherit Metab Dis, 10.1007/s10545-015-9839-3)

Stefan Kölker & Angeles Garcia Cazorla & Vassili Valayannopoulos & Allan M. Lund & Alberto B. Burlina & Jolanta Sykut-Cegielska & Frits A. Wijburg & Elisa Leão Teles & Jiri Zeman & Carlo Dionisi-Vici & Ivo Barić & Daniela Karall & Persephone Augoustides-Savvopoulou & Lise Aksglaede & Jean-Baptiste Arnoux & Paula Avram & Matthias R. Baumgartner & Javier Blasco-Alonso & Brigitte Chabrol & Anupam Chakrapani & Kimberly Chapman & Elisenda Cortès i Saladelafont & Maria L. Couce & Linda de Meirleir & Dries Dobbelaere & Veronika Dvorakova & Francesca Furlan & Florian Gleich & Wanda Gradowska & Stephanie Grünewald & Anil Jalan & Johannes Häberle & Gisela Haege & Robin Lachmann & Alexander Laemmle & Eveline Langereis & Pascale de Lonlay & Diego Martinelli & Shirou Matsumoto & Chris Mühlhausen & Hélène Ogier de Baulny & Carlos Ortez & Luis Peña-Quintana & Danijela Petković Ramadža & Esmeralda Rodrigues & Sabine Scholl-Bürgi & Etienne Sokal & Christian Staufner & Marshall L. Summar & Nicholas Thompson & Roshni Vara & Inmaculada Vives Pinera & John H. Walter & Monique Williams & Peter Burgard

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

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.

Erratum to: The phenotypic spectrum of organic acidurias and urea cycle disorders. Part 2: the evolving clinical phenotype (J Inherit Metab Dis, 10.1007/s10545-015-9840-x)

Stefan Kölker & Vassili Valayannopoulos & Alberto B. Burlina & Jolanta Sykut-Cegielska & Frits A. Wijburg & Elisa Leão Teles & Jiri Zeman & Carlo Dionisi-Vici & Ivo Barić & Daniela Karall & Jean-Baptiste Arnoux & Paula Avram & Matthias R. Baumgartner & Javier Blasco-Alonso & S. P. Nikolas Boy & Marlene Bøgehus Rasmussen & Peter Burgard & Brigitte Chabrol & AnupamChakrapani &Kimberly Chapman & Elisenda Cortès i Saladelafont & Maria L. Couce & Linda de Meirleir & Dries Dobbelaere & Francesca Furlan & Florian Gleich & Maria Julieta González & Wanda Gradowska & Stephanie Grünewald & Tomas Honzik & Friederike Hörster & Hariklea Ioannou & Anil Jalan & Johannes Häberle & Gisela Haege & Eveline Langereis & Pascale de Lonlay &DiegoMartinelli & ShirouMatsumoto &ChrisMühlhausen &ElaineMurphy &HélèneOgier de Baulny & Carlos Ortez & Consuelo C. Pedrón & Guillem Pintos-Morell & Luis Pena-Quintana & Danijela Petković Ramadža & Esmeralda Rodrigues & Sabine Scholl-Bürgi & Etienne Sokal & Marshall L. Summar & Nicholas Thompson & Roshni Vara & Inmaculada Vives Pinera & John H. Walter & Monique Williams & Allan M. Lund & Angeles Garcia Cazorla

Diagnosis, classification and treatment of mucopolysaccharidosis type I

Introduction: Mucopolysaccharidosis type I (MPS I) is a progressive lysosomal storage disease. Impaired degradation of glycosaminoglycans triggers complex pathophysiological cascades, leading to a heterogeneous multisystem disorder. Two treatment modalities are available: enzyme replacement therapy and hematopoietic stem cell transplantation. Despite these treatments, a significant residual disease burden is observed in most patients. Areas covered: This review provides an overview of the currently known pathophysiological mechanisms underlying disease manifestations in MPS I. Additionally, the clinical presentation of the wide phenotypic spectrum is discussed, as well as methods for the phenotypical classification of patients and available treatment options, with a special focus on the treatment of residual disease. Expert opinion: Residual disease is currently the most pressing issue in MPS I, often requiring multiple surgical interventions. Several strategies are being explored to decrease the residual disease burden including modifications to the current treatment regimens and new therapeutic approaches. Optimal management of disease manifestations requires international collaboration and a standardized follow-up to collect essential clinical data.