Mucopolysaccharidosis type IIIA (MPS IIIA) is characterised by neurological and skeletal pathologies caused by reduced activity of the lysosomal hydrolase, sulphamidase, and the subsequent primary accumulation of undegraded heparan sulphate (HS). Respiratory pathology is considered secondary in MPS IIIA and the mechanisms are not well understood. Changes in the amount, metabolism and function of pulmonary surfactant, the substance that regulates alveolar interfacial surface tension and modulates lung compliance and elastance, have been reported in MPS IIIA mice. Here we investigated changes in lung function in 20-week old control and MPS IIIA mice with a closed and open thoracic cage, diaphragm contractile properties and potential parenchymal remodeling. MPS IIIA mice had increased compliance and airway resistance and reduced tissue damping and elastance compared with control mice. The chest wall impacted lung function as observed by an increase in airway resistance and a decrease in peripheral energy dissipation in the open compared to the closed thoracic cage state in MPS IIIA mice. Diaphragm contractile forces showed a decrease in peak twitch force, maximum specific force and the force-frequency relationship but no change in muscle fibre cross-sectional area in MPS IIIA mice compared with control mice. Design-based stereology did not reveal any parenchymal remodelling or destruction of alveolar septa in the MPS IIIA mouse lung. In conclusion, the increased storage of HS which leads to biochemical and biophysical changes in pulmonary surfactant, also affects lung and diaphragm function, but has no impact on lung or diaphragm structure at this stage of the disease.
Keywords: Sanfilippo syndrome; design-based stereology; diaphragm function; lung structure and function; lysosomal storage disease.