OBJECTIVE: Mucopolysaccharidosis type I (MPS I) is an autosomal recessive disorder caused by a mutation in the gene encoding the enzyme alpha-L-iduronidase. This enzyme is responsible for degradation of dermatan and heparan sulfates. Enzyme deficiency results in their accumulation in lysosomes of virtually all organs, resulting in severe somatic and neurological changes. Clinical findings of otitis media with mixed hearing loss are common. Cellular and molecular mechanisms of ear pathology and hearing loss are not understood. The purpose of this study is to describe the age-related audiologic and histopathologic changes of the ear in the mouse model of MPS I. METHODS: Auditory brainstem responses (ABR) were obtained to clicks and tone bursts at 1-32kHz, and pathological changes to middle and inner ears were studied with light and electron microscopy in 53 mice that included: (1) wild type (+/+)-five at 2 months, five at 4-6 months, and five at 13-19 months; (2) heterozygotes (+/-)-four at 2 months, five at 4-6 months, and eight at 13-19 months; and (3) homozygotes (-/-)-five at 2 months, six at 4-6 months, and five at 13-19 months. Histopathology was also done on five newborn -/- mice. RESULTS: In newborns, no lysosomal storage was observed and the ear appeared age appropriately normal. In all other -/- mice, cells with lysosomal storage vacuoles were observed in spiral ligament, spiral prominence, spiral limbus, basilar membrane, epithelial and mesothelial cells of Reissner's membrane, endothelial cells of vessels, and some ganglion cells; their number increased with aging. Hair cell loss was not observed at 2 or 6 months, but there was total loss of the organ of Corti in year-old mice. Hearing of -/- mice was significantly decreased at all ages compared to +/+ and +/-. Hearing loss progressed from mild to moderate loss at 2 months to profound at 6 months and total deafness by 1 year of age. CONCLUSIONS: Progressive age-related changes suggest early therapeutic intervention to prevent sensory cell damage and hearing loss.
OBJECTIVE:Mucopolysaccharidosis type I (MPS I) is an autosomal recessive disorder caused by a mutation in the gene encoding the enzyme alpha-L-iduronidase. This enzyme is responsible for degradation of dermatan and heparan sulfates. Enzyme deficiency results in their accumulation in lysosomes of virtually all organs, resulting in severe somatic and neurological changes. Clinical findings of otitis media with mixed hearing loss are common. Cellular and molecular mechanisms of ear pathology and hearing loss are not understood. The purpose of this study is to describe the age-related audiologic and histopathologic changes of the ear in the mouse model of MPS I. METHODS: Auditory brainstem responses (ABR) were obtained to clicks and tone bursts at 1-32kHz, and pathological changes to middle and inner ears were studied with light and electron microscopy in 53 mice that included: (1) wild type (+/+)-five at 2 months, five at 4-6 months, and five at 13-19 months; (2) heterozygotes (+/-)-four at 2 months, five at 4-6 months, and eight at 13-19 months; and (3) homozygotes (-/-)-five at 2 months, six at 4-6 months, and five at 13-19 months. Histopathology was also done on five newborn -/- mice. RESULTS: In newborns, no lysosomal storage was observed and the ear appeared age appropriately normal. In all other -/- mice, cells with lysosomal storage vacuoles were observed in spiral ligament, spiral prominence, spiral limbus, basilar membrane, epithelial and mesothelial cells of Reissner's membrane, endothelial cells of vessels, and some ganglion cells; their number increased with aging. Hair cell loss was not observed at 2 or 6 months, but there was total loss of the organ of Corti in year-old mice. Hearing of -/- mice was significantly decreased at all ages compared to +/+ and +/-. Hearing loss progressed from mild to moderate loss at 2 months to profound at 6 months and total deafness by 1 year of age. CONCLUSIONS: Progressive age-related changes suggest early therapeutic intervention to prevent sensory cell damage and hearing loss.
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