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A.K. Hennig, M. Griffey, M.S. Sands, R.L. Gunkel, M.K. Murphy, J.M. Ogilvie; Electroretinogram Changes and Retinal Degeneration in Knockout Mouse Models of Four Lysosomal Storage Diseases . Invest. Ophthalmol. Vis. Sci. 2006;47(13):5780.
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© ARVO (1962-2015); The Authors (2016-present)
Lysosomal storage diseases (LSD) are inborn errors of metabolism that impair lysosome functioning, resulting in progressive systemic disease. Although genetically heterogeneous, they share many common features, often including retinal degeneration. We have characterized electroretinogram (ERG) responses of knockout mouse models of Mucopolysaccharidosis (MPS) I, MPS IIIB, Infantile Neuronal Ceroid Lipofuscinosis (INCL), and acid sphingomyelinase deficiency (ASMD).
ERGs of dark– and light–adapted knockout mice and wild–type littermates were recorded in response to a 10 ms flash of 76.2 cd–sec/m2 intensity light. Histological assessment and lysosomal enzyme activity assays were performed to correlate ERG findings with pathologic and biochemical markers of disease progression.
All of these knockout strains showed progressive decreases in dark–adapted ERG amplitudes. The decreases in mean b–wave amplitudes reached significance at 8 weeks of age (w) for INCL and ASMD, 22 w for MPS I, and 30 w for MPS IIIB mice. Decreases in light–adapted ERGs first reached significance at 8 w for ASMD, 12 w for INCL, and 52 w for MPS I mice. Cone responses from MPS IIIB mice remained indistinguishable from normal littermates' to at least 53 w. Mean responses for wild–type littermate controls for each strain also varied from each other, despite the fact that all were on a C57Bl/6 background. The severity of retinal dysfunction correlated well with rod outer segment shortening and/or loss of photoreceptors but not, in some models, with lysosomal storage severity in the retinal pigmented epithelium (RPE). In MPS I mice the RPE remained relatively unaffected, although vacuolization progressed in the ciliary body, sclera, and choroid. In MPS IIIB mice the RPE appeared hyperplastic at 4–8 w; lysosomal distension was minimal at 34 w.
The age when ERG responses became significantly decreased, and the subsequent rate of decline, varied among the different LSD knockout mouse models. Retinal degeneration in these models may not result solely from RPE impairment due to lysosomal storage. These findings provide information necessary for designing therapeutic regimens that use visual assessment as a measure of treatment efficacy in these mice.
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