Cone structure in patients with usher syndrome type III and mutations in the Clarin 1 gene

Abstract

Objective: To study macular structure and function in patients with Usher syndrome type III (USH3) caused by mutations in the Clarin 1 gene (CLRN1).

Methods: High-resolution macular images were obtained by adaptive optics scanning laser ophthalmoscopy and spectral domain optical coherence tomography in 3 patients with USH3 and were compared with those of age-similar control subjects. Vision function measures included best-corrected visual acuity, kinetic and static perimetry, and full-field electroretinography. Coding regions of the CLRN1 gene were sequenced.

Results: CLRN1 mutations were present in all the patients; a 20-year-old man showed compound heterozygous mutations (p.N48K and p.S188X), and 2 unrelated women aged 25 and 32 years had homozygous mutations (p.N48K). Best-corrected visual acuity ranged from 20/16 to 20/40, with scotomas beginning at 3° eccentricity. The inner segment-outer segment junction or the inner segment ellipsoid band was disrupted within 1° to 4° of the fovea, and the foveal inner and outer segment layers were significantly thinner than normal. Cones near the fovea in patients 1 and 2 showed normal spacing, and the preserved region ended abruptly. Retinal pigment epithelial cells were visible in patient 3 where cones were lost.

Conclusions: Cones were observed centrally but not in regions with scotomas, and retinal pigment epithelial cells were visible in regions without cones in patients with CLRN1 mutations. High-resolution measures of retinal structure demonstrate patterns of cone loss associated with CLRN1 mutations.

Clinical relevance: These findings provide insight into the effect of CLRN1 mutations on macular cone structure, which has implications for the development of treatments for USH3.

Trial registration: clinicaltrials.gov Identifier: NCT00254605.

Figures

Figure 1

Visual field loss in 3 patients with Usher syndrome type III. Goldmann (GVF) and Humphrey (HVF) visual fields showed peripheral scotomas. Fundus-guided microperimetry (MP-1) showed reduced sensitivity in the central 8° (green indicates normal; and red and orange, reduced sensitivity). VA indicates visual acuity.

Figure 2

Fundus and spectral domain optical coherence tomography (SDOCT) images in 3 patients with Usher syndrome type III. Black outlines indicate areas imaged by adaptive optics scanning laser ophthalmoscopy (AOSLO); and white lines, SDOCT scans. The inner segment ellipsoid (ISe) was disrupted for all the patients and correlated with lack of visible cone mosaics in AOSLO images. IR indicates infrared; and VA, visual acuity.

Figure 3

High-resolution images for 3 patients with Usher syndrome type III show reduced cones and inner segment ellipsoid disruption (red boxes). Green lines indicate spectral domain optical coherence tomography B-scans; white dots, fixation; blue boxes, cone spacing z scores; and black circles, individual retinal epithelial pigment (RPE) cells. Scale bars represent 1° (black) and 0.5° (white). IS indicates inner segment; OS, outer segment.

Figure 4

Cone spacing vs distance from fovea. Cone spacing measurements on adaptive optics scanning laser ophthalmoscopy in patients 1 and 2 were compared with those from 24 control subjects (gray dots). Solid black line indicates mean reference values; and dashed lines, 95% CIs.