Abstract
BackgroundMucopolysaccharidosis (MPS) IIIB (Sanfilippo Syndrome type B) is caused by a deficiency in the lysosomal enzyme N-acetyl-glucosaminidase (Naglu). Children with MPS IIIB develop disturbances of sleep, activity levels, coordination, vision, hearing, and mental functioning culminating in early death. The murine model of MPS IIIB demonstrates lysosomal distention in multiple tissues, a shortened life span, and behavioral changes.Principal FindingsTo more thoroughly assess MPS IIIB in mice, alterations in circadian rhythm, activity level, motor function, vision, and hearing were tested. The suprachiasmatic nucleus (SCN) developed pathologic changes and locomotor analysis showed that MPS IIIB mice start their daily activity later and have a lower proportion of activity during the night than wild-type controls. Rotarod assessment of motor function revealed a progressive inability to coordinate movement in a rocking paradigm. Purkinje cell counts were significantly reduced in the MPS IIIB animals compared to age matched controls. By electroretinography (ERG), MPS IIIB mice had a progressive decrease in the amplitude of the dark-adapted b-wave response. Corresponding pathology revealed shortening of the outer segments, thinning of the outer nuclear layer, and inclusions in the retinal pigmented epithelium. Auditory-evoked brainstem responses (ABR) demonstrated progressive hearing deficits consistent with the observed loss of hair cells in the inner ear and histologic abnormalities in the middle ear.Conclusions/SignificanceThe mouse model of MPS IIIB has several quantifiable phenotypic alterations and is similar to the human disease. These physiologic and histologic changes provide insights into the progression of this disease and will serve as important parameters when evaluating various therapies.
Highlights
Mucopolysaccharidosis III (MPS III, Sanfilippo Syndrome) is a lysosomal storage disease that results from a deficiency in any of four lysosomal enzymes required for the complete degradation of proteoglycans containing heparan sulfate
We demonstrate that the murine model of MPS IIIB develops progressive deterioration of balance, vision, and hearing
We show that the development of histological changes in the MPS IIIB mouse correlates with the functional changes in balance and vision
Summary
Mucopolysaccharidosis III (MPS III, Sanfilippo Syndrome) is a lysosomal storage disease that results from a deficiency in any of four lysosomal enzymes required for the complete degradation of proteoglycans containing heparan sulfate. Affected children appear normal in the first few years of life, but become aggressive and hyperactive [1,2], develop sleep disturbances [3,4] and have severe developmental delays as they age. They regress mentally and develop loss of hearing [5], vision [6,7] and balance. Children with MPS IIIB develop disturbances of sleep, activity levels, coordination, vision, hearing, and mental functioning culminating in early death. These physiologic and histologic changes provide insights into the progression of this disease and will serve as important parameters when evaluating various therapies
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