Optic atrophy and inner retinal thinning in CACNA1F-related congenital stationary night blindness

Abstract

Purpose : Hemizygous pathogenic variants in CACNA1F lead to defective signal transmission from photoreceptors to bipolar cells and cause incomplete congenital stationary night blindness (iCSNB). Knowledge of inner retinal changes in iCSNB is limited. This study measured macular ganglion cell layer-inner plexiform layer (GCL-IPL) thickness and optic disc pallor to assess if subjects carrying pathogenic variants in CACNA1F have inner retinal thinning and optic atrophy in excess of the expected degree of disc pallor seen in myopia.

Methods : Ocular phenotypic data including distance and color vision, refraction, optical coherence tomography (OCT) GCL-IPL thickness and electroretinogram (ERG) were collected from 22 subjects with molecularly confirmed CACNA1F-iCSNB. OCT data was collected from an age-matched control population (n=87) without organic ocular pathology, subdivided into 3 groups based on spherical equivalent (SE) refractive error: (1) emmetropia or hyperopia: SE ≥0D, (2) low myopia: SE ≤-0.5 and >-6.00D, and (3) high myopia: SE ≤-6.00D. ERG parameters were correlated against GCL-IPL thickness. Optic disc photos were evaluated by a pediatric neuro-ophthalmologist noting the presence and extent of disc pallor in clock hours.

Results : Mean patient age was 14.3 years (range 6-58 years); mean refractive error was -6.32D (range -20.50 to +2.50D); 68% (15 of 22) were myopic. Distance vision was universally reduced (mean 0.42 LogMAR) and six had abnormal color vision. Mean GCL-IPL thickness in patients was significantly lower (55.00µm) compared to controls (84.57µm) as well as compared to emmetropia or hyperopia (88.25µm), low myopia (83.07µm) and high myopia (78.59µm) control sub-groups (p<<0.001). The GCL-IPL thickness correlated with scotopic standard (p=0.04) and bright-flash (p=0.014) ERG b/a ratios, and photopic b-wave amplitude (p=0.05). Twenty-one patients had some degree of disc pallor (bilateral in 19). There was no correlation between GCL-IPL thickness and extent of disc pallor or mutation class. Fifteen putative disease-causing variants were identified: 5 missense, 4 nonsense, 3 frameshift, 2 splice site and 1 silent variant predicted to affect splicing; 5 variants were novel.

Conclusions : This study establishes macular inner retinal thinning and optic atrophy as features of CACNA1F-related iCSNB which are independent of myopia and could impact potential future treatment strategies.

This is a 2021 ARVO Annual Meeting abstract.