Comparison of the Electrophysiological and Clinical Characteristics of 57 Individuals With Different Mutations of RS1

Abstract

Purpose: : To compare the clinical phenotype and electroretinogram (ERG) parameters of retinal function in 57 individuals with different mutations of the RS1 gene.

Methods: : Fifty seven patients (aged 1-67 years; median 26 years) were ascertained with mutations in RS1. Forty three patients had missense mutations (group A); 14 had nonsense, splice site or frame-shifting insertions/deletions (group B). ISCEV-standard pattern and full-field ERGs (PERG; ERGs) were performed in 44 cases; 13 were tested using a paediatric or simplified ERG protocol. ON-OFF ERGs and S-cone ERGs were examined in most adults. Fundus autofluorescence (AF) was reviewed in 19 and optical coherence tomography (OCT) in 21 cases.

Results: : The dark-adapted bright flash ERG waveform was electronegative in 44 of 57 individuals. Photopic 30Hz flicker ERG was delayed in 41 of 43 cases. ON-OFF ERG b-waves were subnormal in 16 of 44 (electronegative in 11) and delayed in 11; d-waves were subnormal in 1 and delayed in 7 cases. S-cone ERGs were delayed in 9 and were subnormal in 14 of 21 cases.In group A, the scotopic bright flash ERG b:a ratio was 0.45-1.4 (normal in 2) and the photopic single flash ERG b:a ratio was 0.9-5.1 (delayed in 21 of 33). The mean pattern ERG P50 in group A was 0.95µV (SD 0.86 uV). In group B, the scotopic bright flash ERG b:a ratio was 0.46-0.97 and the photopic single flash ERG b:a ratio was 0.95-3.2 (delayed in all). The mean pattern ERG P50 in group B was 0.38µV (SD 0.57uV).AF abnormalities were variable but included stellate patterns of high and low density (5 cases), central or paracentral low density associated with RPE atrophy (3), irregular increased AF at the fovea (3) or high density foci (1 case). AF was normal in 2 cases. OCT showed schitic cavities in 14, macular atrophy in 4 and was normal in 3.

Conclusions: : Clinical and functional phenotypes in X-linked retinoschisis are highly variable but most affected individuals manifest an abnormal b:a ratio in the scotopic bright flash ERG, in keeping with dysfunction that is post-phototransduction. Cone system dysfunction is commonly associated with an abnormal ON response with less frequent additional OFF response involvement. Missense mutations of RS1 result in a wider range of ERG abnormalities than mutations associated with protein truncation or abnormal protein secretion.

Keywords: electroretinography: clinical • retinal degenerations: hereditary • imaging/image analysis: clinical