Abstract
Severe mucopolysaccharidosis type II (MPS II) is a progressive lysosomal storage disease caused by mutations in the IDS gene, leading to a deficiency in the iduronate-2-sulfatase enzyme that is involved in heparan sulphate and dermatan sulphate catabolism. In constitutive form, MPS II is a multi-system disease characterised by progressive neurocognitive decline, severe skeletal abnormalities and hepatosplenomegaly. Although enzyme replacement therapy has been approved for treatment of peripheral organs, no therapy effectively treats the cognitive symptoms of the disease and novel therapies are in development to remediate this. Therapeutic efficacy and subsequent validation can be assessed using a variety of outcome measures that are translatable to clinical practice, such as behavioural measures. We sought to consolidate current knowledge of the cognitive, skeletal and motor abnormalities present in the MPS II mouse model by performing time course behavioural examinations of working memory, anxiety, activity levels, sociability and coordination and balance, up to 8 months of age. Cognitive decline associated with alterations in spatial working memory is detectable at 8 months of age in MPS II mice using spontaneous alternation, together with an altered response to novel environments and anxiolytic behaviour in the open-field. Coordination and balance on the accelerating rotarod were also significantly worse at 8 months, and may be associated with skeletal changes seen in MPS II mice. We demonstrate that the progressive nature of MPS II disease is also seen in the mouse model, and that cognitive and motor differences are detectable at 8 months of age using spontaneous alternation, the accelerating rotarod and the open-field tests. This study establishes neurological, motor and skeletal measures for use in pre-clinical studies to develop therapeutic approaches in MPS II.
Highlights
Mucopolysaccharidosis type II (MPS II, OMIM #309900 [1]), known as Hunter syndrome, is an X-linked lysosomal storage disorder that affects 1.3 per 100,000 male live births [2,3,4]
mucopolysaccharidosis type II (MPS II) is caused by mutations in the IDS gene, leading to a deficiency in iduronate2-sulfatase enzyme (EC 3.1.6.13), and results in impaired degradation of both heparan sulphate and dermatan sulphate and subsequent unregulated accumulation in the lysosomal compartment [5]
Exploratory behaviour in a novel environment in the MPS II mouse model was tested in an open-field arena
Summary
Mucopolysaccharidosis type II (MPS II, OMIM #309900 [1]), known as Hunter syndrome, is an X-linked lysosomal storage disorder that affects 1.3 per 100,000 male live births [2,3,4]. MPS II is caused by mutations in the IDS gene, leading to a deficiency in iduronate2-sulfatase enzyme (EC 3.1.6.13), and results in impaired degradation of both heparan sulphate and dermatan sulphate and subsequent unregulated accumulation in the lysosomal compartment [5]. MPS II patients present with chronic and progressive multi-system disease affecting a multitude of different organs including the bones, joints and heart. Severe MPS II includes progressive neurocognitive decline, skeletal abnormalities known as dysostosis multiplex, short stature, joint stiffness and hepatosplenomegaly [4, 6]. Death usually occurs in mid-teens due to obstructive airway disease and cardiac failure [5, 7, 8]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
