Development of sensory, motor and behavioral deficits in the murine model of Sanfilippo syndrome type B

• Published in: PloS one Vol. 2; no. 8; p. e772
• Main Authors: Heldermon, Coy D, Hennig, Anne K, Ohlemiller, Kevin K, Ogilvie, Judith M, Herzog, Erik D, Breidenbach, Annalisa, Vogler, Carole, Wozniak, David F, Sands, Mark S
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 22-08-2007; Public Library of Science (PLoS)
• Subjects: Abnormalities; Acetylglucosaminidase - deficiency; Age; Analysis; Animal models; Animal tissues; Animals; Behavior; Behavior, Animal - physiology; Biology; Bone marrow; Brain stem; Cerebellum - cytology; Cerebellum - pathology; Child; Children; Circadian Rhythm - physiology; Circadian rhythms; Dark adaptation; Disease Models, Animal; Ear; Ear, Inner - pathology; Ear, Middle - pathology; Electroretinograms; Electroretinography; Enzymes; Epithelium; Evoked Potentials, Auditory - physiology; Female; Genetics and Genomics/Disease Models; Genetics and Genomics/Gene Therapy; Genetics and Genomics/Medical Genetics; Glucosaminidase; Hair cells; Hearing - physiology; Hearing loss; Humans; Inclusion bodies; Inner ear; Life span; Lysosomes - enzymology; Lysosomes - pathology; Male; Medicine; Metabolic disorders; Mice; Mice, Inbred C57BL; Mice, Knockout; Middle ear; Morphology; Motor Activity - physiology; Mucopolysaccharidosis; Mucopolysaccharidosis III - enzymology; Mucopolysaccharidosis III - pathology; Mucopolysaccharidosis III - physiopathology; Neurological Disorders; Neuroscience/Behavioral Neuroscience; Neuroscience/Motor Systems; Neuroscience/Sensory Systems; Pathology; Pediatrics and Child Health/Developmental and Pediatric Neurology; Phenotype; Retina; Retina - pathology; Retinal pigment epithelium; Rotarod Performance Test; Sleep; Studies; Suprachiasmatic nucleus; Suprachiasmatic Nucleus - cytology; Suprachiasmatic Nucleus - pathology; Vision; Vision, Ocular - physiology; United States > US; Missouri
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0000772

Mucopolysaccharidosis (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.
To 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.
The 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.