Abstract
Purpose :
Neuronal ceroid lipofuscinoses (NCL) are a group of rare inherited neurodegenerative lysosomal storage disorders. Mutations in CLN6 cause a late infantile NCL variant leading to vision loss, dementia and motor deficits. We previously reported histological and some ocular phenotype data of CLN6nclf mice (Mirza, Volz et al. 2013), an established model for variant-late infantile NCL. The aim of this study was to extensively characterize this degeneration by means of scotopic and photopic ERG.
Methods :
CLN6nclf mice and controls were assessed between one and eight months. ERGs were obtained after 12 hours of dark adaptation. After single flash scotopic responses (intensities -3.5 to 1.0 log cds/m2), responses to flickering stimuli with an intensity of 0.5 log cds/m2and frequencies ranging from 4 to 25 Hz were recorded to evaluate the temporal characteristics. Dual rod pathways were investigated by means of 15 Hz flicker response recordings to increasing intensities (-3.5 to 1.0 log cds/m2). After 10 minutes adaptation to white background illumination (25 cd/m2) responses to single flash photopic and flickering stimuli (intensity 0.5 log cds/m2) with frequencies ranging from 4 to 25 Hz were recorded.
Results :
In contrast to the scotopic findings where a- and b-wave are affected early, at 2 months of age the amplitudes of the photopic b-wave (single flash ERG) were already reduced in CLN6nclf mice compared to wild-type controls with almost normal a-wave. The reduction of the a-wave is following, but the b-wave reduction is always predominant being consistent with a dominantly inner retinal degeneration. Initially, there is little implicit time prolongation in the photopic ERG which becomes significant after 6 months of age. In the flicker ERG all frequencies are similarly affected. Both rod pathways seem to be affected similarly as indicated by the 15 Hz-ERGs.
Conclusions :
In this study, we identified electrophysiological parameters indicating early onset malfunctioning beginning in the outer retina and rapidly spreading to the inner retina. The rods are the first cells affected by the degeneration, followed a few months later by the cones. When compared to other NCL mouse models, CLN6nclf mice have the most severe and progressive decline in visual function. Since the retina is affected earlier than the brain, analysis of the retinal function is a helpful diagnostic tool for testing experimental therapies.
This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.