title: Sleep disordered breathing in mucopolysaccharidosis I: a multivariate analysis of patient, therapeutic and metabolic correlators modifying long term clinical outcome.
abstract: 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).
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Paediatric Otolaryngology, Royal Manchester Children's Hospital, Manchester, UK. rickypal100@gmail.com.|Stem Cell & Neurotherapies, Faculty of Medical and Human Sciences, University of Manchester, Manchester, UK. rickypal100@gmail.com.
authors.forename: Abhijit Ricky
authors.initials: AR
authors.lastname: Pal
authors.affiliation: Department of Paediatric Metabolic Diseases, Emma Children's Hospital, Academic Medical Centre, Amsterdam, The Netherlands. e.j.langereis@amc.uva.nl.
authors.forename: Eveline J
authors.initials: EJ
authors.lastname: Langereis
authors.affiliation: Stem Cell & Neurotherapies, Faculty of Medical and Human Sciences, University of Manchester, Manchester, UK. saif164@yahoo.com.|Department of Haematology/BMT, Royal Manchester Children's Hospital, Manchester, UK. saif164@yahoo.com.
authors.forename: Muhammad A
authors.initials: MA
authors.lastname: Saif
authors.affiliation: Willink Biochemical Genetics Unit, Manchester Centre for Genomic Medicine, St. Mary's Hospital, Manchester, UK. jean.mercer@cmft.nhs.uk.
authors.forename: Jean
authors.initials: J
authors.lastname: Mercer
authors.affiliation: Willink Biochemical Genetics Unit, Manchester Centre for Genomic Medicine, St. Mary's Hospital, Manchester, UK. heather.church@cmft.nhs.uk.
authors.forename: Heather J
authors.initials: HJ
authors.lastname: Church
authors.affiliation: Willink Biochemical Genetics Unit, Manchester Centre for Genomic Medicine, St. Mary's Hospital, Manchester, UK. Karen.tylee@cmft.nhs.uk.
authors.forename: Karen L
authors.initials: KL
authors.lastname: Tylee
authors.affiliation: Department of Haematology/BMT, Royal Manchester Children's Hospital, Manchester, UK. Robert.wynn@cmft.nhs.uk.
authors.forename: Robert F
authors.initials: RF
authors.lastname: Wynn
authors.affiliation: Department of Paediatric Metabolic Diseases, Emma Children's Hospital, Academic Medical Centre, Amsterdam, The Netherlands. f.a.wijburg@amc.uva.nl.
authors.forename: Frits A
authors.initials: FA
authors.lastname: Wijburg
authors.affiliation: Willink Biochemical Genetics Unit, Manchester Centre for Genomic Medicine, St. Mary's Hospital, Manchester, UK. simon.jones@cmft.nhs.uk.
authors.forename: Simon A
authors.initials: SA
authors.lastname: Jones
authors.affiliation: Department of Paediatric Otolaryngology, Royal Manchester Children's Hospital, Manchester, UK. iain.bruce@cmft.nhs.uk.
authors.forename: Iain A
authors.initials: IA
authors.lastname: Bruce
authors.affiliation: Stem Cell & Neurotherapies, Faculty of Medical and Human Sciences, University of Manchester, Manchester, UK. brian.bigger@manchester.ac.uk.
authors.forename: Brian W
authors.initials: BW
authors.lastname: Bigger
mesh_terms: D015415:Biomarkers / Q000652:urine; D002648:Child; D002675:Child, Preschool; D056947:Enzyme Replacement Therapy; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007223:Infant; D008297:Male; D008059:Mucopolysaccharidosis I / Q000378:metabolism* / Q000628:therapy* / Q000652:urine; D015999:Multivariate Analysis; D012189:Retrospective Studies; D012891:Sleep Apnea Syndromes / Q000378:metabolism* / Q000628:therapy* / Q000652:urine
chemical_list: D015415:Biomarkers