Modifiers and aetiological factors relating to airway pathology in mucopolysaccharidosis

Abstract

The mucopolysaccharidoses are a family of seven rare inherited metabolic disorders caused by specific lysosomal enzyme deficiencies responsible for catabolism of glycosaminoglycan (GAG) substrates. Subsequent accumulation of partially degraded GAGs leads to cellular dysfunction and progressive multisystem disease, presenting with visceral, cardiorespiratory, musculoskeletal and neurocognitive manifestations. The severe form of MPS I, Hurler syndrome, may be successfully treated with haematopoietic stem cell transplant (HSCT), while attenuated forms of MPS I and MPS II, IVA and VI are currently managed with enzyme replacement therapy. Progressive, multilevel airway and respiratory involvement is a well-recognised feature of a number of types of MPS and contributes to the premature morbidity and mortality seen in this disease. The literature regarding this aspect of disease is limited and current knowledge is informed by descriptive studies of small cohorts. The association between outcomes, metabolic and aetiological factors have not been adequately investigated. Following formal systematic review methodology, we have quantitatively assessed the current literature on obstructive sleep apnoea (OSA) in MPS. The prevalence of OSA in MPS prior to treatment is 81%, with MPS I most severely affected. Subsequent assessment of a cohort of 61 MPS I patients, has demonstrated excellent long-term outcomes following HSCT, while identifying causal associations between clinical disease regression, measured by urinary substrate biomarkers, and an improvement in airway obstruction. Multivariate analysis has confirmed that early initiation of treatment and optimal donor selection in HSCT contributes to improved outcomes. Using assays to detect and quantify the function of inhibitory antibodies against ERT, we have identified a cohort of patients with impaired metabolic correction and severe airway obstruction.Finally, analysis of adenotonsillar samples donated by patients and examination of the respiratory tract in a murine model of MPS I allowed us to investigate aetiological factors contributing to airway pathology. Adenotonsillar tissue displayed evidence of alteration in extracellular matrix protein deposition, suggesting remodelling of tissue contributes to the obstructive phenotype observed in patients. We further demonstrated an absence of inflammation in both patient tissue samples and within the lower respiratory tract in mice. Overall, we have ascertained factors which may improve clinical outcomes in the management of airway disease and identified aetiological components contributing to the cascade of events leading to obstructive airway pathology in MPS.

Date of Award	31 Dec 2015
Original language	English
Awarding Institution	The University of Manchester
Supervisor	Iain Bruce (Supervisor), Brian Bigger (Supervisor) & Simon Jones (Supervisor)