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

Abhijit Ricky Pal,Simon A Jones,Muhammad A Saif,Frits A Wijburg,Robert F Wynn,Jean Mercer,Brian W Bigger,Karen L Tylee,Eveline J Langereis,Iain A Bruce,Heather J Church

doi:10.1186/s13023-015-0255-4

Abstract

BackgroundThe 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.MethodsTherapeutic, 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.ResultsThe 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).ConclusionWe 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.

Highlights

The lysosomal storage disorder, mucopolysaccharidosis I (MPS I), commonly manifests with upper airway obstruction and sleep disordered breathing (SDB)
We describe sleep oximetry data in the largest MPS I cohort to date identifying demographic and biochemical factors, including the impact of inhibitory antibodies, that affect the presence and severity of sleep disordered breathing following treatment with either enzyme replacement therapy (ERT) or haematopoietic stem cell transplantation (HSCT)
Forty-one of 44 Hurler were treated with HSCT with a median age at transplantation of 14 months old, while 3

Summary

Introduction

The lysosomal storage disorder, mucopolysaccharidosis I (MPS I), commonly manifests with upper airway obstruction and sleep disordered breathing (SDB). A common manifestation of upper airway disease in MPS I is with sleep disordered breathing (SDB) and obstructive sleep apnoea syndrome (OSAS) [6,7]. Sleep disordered breathing describes a spectrum of symptoms and signs characterized by an abnormal respiratory and ventilatory pattern during sleep, encompassing snoring, upper airways resistance syndrome and OSAS. These occur as a consequence of increased upper airway resistance due to the multilevel skeletal, oral, adenotonsillar, laryngeal and tracheal involvement seen in MPS I [8,9,10]. Treat, moderate to severe SDB has behavioural and physiological consequences, including failure to thrive, neurocognitive and developmental delay and, in severe cases, cardiorespiratory sequellae [12,13]

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