Long-term 12 year follow-up of X-linked congenital retinoschisis

Abstract

Purpose: To investigate the retinal structure and function during the progression of X-linked retinoschisis (XLRS) from childhood to adulthood.

Methods: Ten patients clinically diagnosed with XLRS were investigated at 6-15 years of age (mean age 9 years) with a follow-up 8 to 14 years later (mean 12 years). The patients underwent regular ophthalmic examination as well as testing of best corrected visual acuity (BCVA), visual field (VF) and assessment of full-field electroretinography (ERG) during their first visit. During the follow-up, the same clinical protocols were repeated. In addition, macular structure and function was examined with multifocal electroretinography (mfERG) and optical coherence tomography (OCT). The patients were 18-25 years of age (mean age 21 years) at the follow-up examination. All exons and exon-intron boundaries of RS1-gene were sequenced for gene mutations in 9 out of the 10 patients.

Results: Best corrected VA and VF were stable during this follow-up period. No significant progression in cone or rod function could be measured by full-field ERG. Multifocal electroretinography and OCT demonstrated a wide heterogeneity of macular changes in retinal structure and function at the time of follow-up visit. Three different mutations were detected in these nine patients, including a known nonsense mutation in exon 3, a novel insertion in exon 5 and an intronic mutation at 5' splice site of intron 3.

Conclusions: Clinical follow-up (mean 12 years) of ten young XLRS patients (mean age of 9 years) with a typical congenital retinoschisis phenotype revealed no significant decline in retinal function during this time period. MfERG and OCT demonstrated a wide variety of macular changes including structure and dysfunction. The XLRS disease was relatively stable during this period of observation and would afford opportunity for therapy studies to judge benefit against baseline and against the fellow eye.

FIGURE 1

Best corrected visual acuity (BCVA)(Snellen) at 1^st and 2^nd visit plotted against age (years) at examination. Regression line at 1^st visit with positive correlation with age (Pearson Correlation 0.531 p=0.016), at 2^nd visit no correlation (Pearson Correlation −0.108 p=0.670).

FIGURE 2

Box plot of full field ERG measurements from both eyes at 1^st and 2^nd visit compared with normal ERG (18–25 years old n=10). (a) 30Hz flicker amplitude (µV). (b) White bright flash b-wave amplitude (µV). (c) 30Hz flicker implicit time (ms). (d) Calculated b / a-wave ratio on right eyes. Outliers are marked with a circle and extreme cases with an asterisk.

FIGURE 3

Decreased macula function (multifocal electroretinography) and structural alteration with foveal and lamellar retinoschisis (Fundus image and optical coherence tomography) at last visit (3 cases).

FIGURE 4

Full-field electroretinography traces at 1^st and 2^nd visit (3 cases). White light as a measurement of mixed rod cone function and 30 Hz flicker as a measurement of cone function. Note different scale for normal ERG traces.

FIGURE 5

Sequence chromatograms showing the (a) insertion mutation in exon 5 {c.421_422 ins A (p Arg141GlnX3)}. Mutation was numbered according to Gene Bank NM_000330. Nucleotide 1 is A of the ATG initiation codon (CDS 36–710). (b) T>C transversion in intron 3 of RS1 gene. The genomic reference sequence is ENSG00000102104. The mutation was numbered the following way: the number of the last nucleotide of preceding exon 3 (=nt 184) and a plus sign and the position of T in intron(+35) which is c.184 + 35T>C. Description of the same mutation in the earlier format: (g.IVS3 + 35T>C). The normal sequences from the corresponding region are also shown in the upper panel.

FIGURE 6

Pedigree of patients. Members from family 190 and family 179 previously examined. Circles indicate found mutations in this study.