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Kristen E. Bowles, Catherine A. Cukras, Rafael C. Caruso, Amy Turriff, Susan Vitale, Yuri V. Sergeev, Patrick Lopez, Leanne Reuter, Paul A. Sieving; X-linked Retinoschisis: Age And Mutation Type Effect On Retinal Function Measured By ERG. Invest. Ophthalmol. Vis. Sci. 2011;52(14):2379.
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X-linked retinoschisis (XLRS) is a leading cause of juvenile macular degeneration affecting males, however, disease natural history remains elusive. Retinoschisin protein is present in the photoreceptor-bipolar cell synapse. We performed a cross sectional ERG study of 68 XLRS subjects (132 eyes), age 4-86 years, to evaluate the effect of age and mutation on retinal function.
ISCEV standard ERGs were recorded. Patients were genotyped for RS1. Deletion, frame shift, and start codon mutations were categorized as severe. Missense mutations were further separated into severe or non-severe based on molecular modeling (Sergeev, Human Molecular Genetics, (2010)). ERG response versus age or mutation type were analyzed by linear regression and adjusted for the correlation between eyes of an individual.
68 subjects (132 eyes) were studied; 41 (81 eyes) had severe mutations (mean 31.1 yr) and 27 (51 eyes) had mild mutations (mean 29.5 yr). Significant associations with age were seen: a prolonged a-wave implicit time (0.12 ms/yr, p<0.0001), decreased a-wave amplitude (-1.13 µV/yr, p=0.0002); and decreased b-wave amplitude (-2.21 µV/yr, p<0.0001); increased 30Hz flicker time to peak (0.10 ms/yr, p<0.0001), and decreased 30Hz flicker amplitude (-0.29 µV/yr, p=0.014). Subjects with severe mutations had significantly lower b-wave amplitude (-54.62µV, p=0.0005) and b/a ratio (-0.24, p=0.005), but no difference was seen with mutation type versus a-wave implicit time or amplitude (p=0.48, 0.40, respectively). Wave form deterioration made b-wave implicit timing measurements ambiguous.
ERGs in subjects with XLRS correlate with age and mutation. Disproportionate loss of the b-wave amplitude compared to a-wave amplitude is seen in older compared to younger subjects, suggestive of accumulated synaptic damage or depolarizing bipolar cell pathology. Severe mutations in RS1 are associated with a greater reduction of b-wave amplitude than are mild mutations, suggesting greater synaptic or bipolar cell disruption in patients with highly disorganized or no RS1 protein. These results are consistent with KO RS1 mouse studies, providing additional evidence that the primary site of dysfunction is at the synaptic or bipolar cell level.
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