Autosomal Recessive NRL Mutations in Patients with Enhanced S-Cone Syndrome

Abstract

Enhanced S-cone syndrome (ESCS) is mainly associated with mutations in the NR2E3 gene. However, rare mutations in the NRL gene have been reported in patients with ESCS. We report on an ESCS phenotype in additional patients with autosomal recessive NRL (arNRL) mutations. Three Moroccan patients of two different families with arNRL mutations were enrolled in this study. The mutation in the DNA of one patient, from a consanguineous marriage, was detected by homozygosity mapping. The mutation in the DNA of two siblings from a second family was detected in a targeted next-generation sequencing project. Full ophthalmic examination was performed, including best-corrected visual acuity, slit-lamp biomicroscopy, funduscopy, Goldmann kinetic perimetry, optical coherence tomography, fundus autofluorescence, and extended electroretinography including an amber stimulus on a blue background and a blue stimulus on an amber background. One patient carried a homozygous missense mutation (c.508C>A; p.Arg170Ser) in the NRL gene, whereas the same mutation was identified heterozygously in the two siblings of a second family, in combination with a one base-pair deletion (c.654del; p.Cys219Valfs*4) on the other allele. All patients had reduced visual acuity and showed a typical clumped pigmentary retinal degeneration (CPRD). Foveal schisis-like changes were observed in the oldest patient. An electroretinogram (ERG) under dark-adapted conditions showed absent responses for low stimulus strengths and reduced responses for high stimulus strengths, with constant b-wave latencies despite increasing stimulus strength. A relatively high amplitude was detected with a blue stimulus on an amber background, while an amber stimulus on a blue background showed reduced responses. The arNRL mutations cause a phenotype with typical CPRD. This phenotype has previously been described in patients with ESCS caused by NR2E3 mutations, and rarely by NRL mutations. Based on our findings in ERG testing, we conclude that S-cone function is enhanced in our patients in a similar manner as in patients with NR2E3-associated ESCS, confirming previous reports of NRL as a second gene to cause ESCS.

Keywords: S-cone-specific ERG; autosomal recessive NRL; enhanced S-cone syndrome; hereditary retinal dystrophy.

Figure 1

Fundus photographs and optical coherence tomography (OCT) of the right eye of patient 32666 at age 29, patient 32595 at age 8 and patient 32594 at age 7. Fundus autofluorescence (FAF) of the left eye of patient 32666 at age 29. All fundus images (A,D,F) show a pink optic disk, relatively normal arterioles (D,F) or slightly attenuated arterioles (A). All show midperipheral pronounced retinal pigment epithelium (RPE) atrophy with nummular pigmentations, and a preserved macular region. Subtle yellow dots are visible along the border of atrophic and preserved RPE. A vertical line was observed in patient 32594 ((F), arrow), suggesting subretinal fibrosis. OCT images show cystoid maculopathy with intact ellipsoid zone (EZ) (B), and a normal architecture of the retinal layers (E,G). FAF image of the left eye of patient 32666 (C) shows pronounced hypoautofluorescence outside the vascular arcade with central hyperfluorescent spots, and spoke-like relative increased autofluorescence in the macula.

Figure 2

Electroretinography of subject 32594 with arNRL mutations. ERG results of proband 32594 with arNRL mutation c.508C>A and c.654del. The dark-adapted ERG shows absent rod responses for low stimulus strengths and reduced combined rod-cone responses for high stimulus strengths, with constant a-wave latencies despite increasing stimulus strength. The light-adapted ERG shows reduced and delayed responses to a 3 cd·s·m⁻² stimulus (cone response). Light-adapted responses show a relatively high amplitude for a blue stimulus on an amber background, and reduced responses for an amber stimulus on a blue background. Also shown are ERG results of age-matched individuals with autosomal dominant NRL mutation c.152C>A (adNRL) with retinitis pigmentosa, homozygous NR2E3 mutation c.119-2A>C (arNR2E3) with ESCS, and a normal individual.