Diagnostic Challenges in Hereditary Retinal Degenerations With Very Low Levels of Vitamin A

Abstract

Purpose: : Visual function requires initiation of the phototransduction cascade by light-induced activation of opsins that have bound retinal in cis configuration. Very low levels of 11-cis retinal strongly desensitize rod and cone photoreceptors, and also melanopsin-containing ganglion cells. If this situation persists, a retinitis pigmentosa-like retinal degeneration may develop. Here, we discuss limitations of the diagnostic value of electroretinography (ERG) in such conditions due to changes in retinal sensitivity.

Methods: : The functional impact of very low vitamin A levels was studied in mice carrying the R91W mutation in Rpe65, and in human patients with sRBP (serum retinol-binding protein) deficiency. ERGs to single white-flash stimuli were recorded binocularly in both scotopic and photopic (light-adapted 10 min. at 30 cd*s/m²) conditions using a Ganzfeld system. In mice, the origin of ERG responses from rod or cone system was assessed by cross-breeding with cone-specific rhodopsin knockout mice.

Results: : ERG sensitivity in Rpe65^R91W mutant mice was ‘right shifted’ by about 1.2 - 1.5 logarithmic units as a consequence of a reduction in 11-cis retinal to 3 - 6% when compared with age-matched wild-type animals. Rod system responses were further desensitized and reduced by the ‘equivalent light’ effect due to a large fraction of naked opsin, causing a higher degree of overlap between rod and cone system sensitivity ranges. Separation of rod and cone contributions to the different ERG protocols was thus achievable by genetical ablation of rod function only. Importantly, the usual rod-desensitizing background of 30 cd/m² was ineffective to suppress rod system responses under these conditions.

Conclusions: : Low vitamin A levels constitute a major challenge for functional testing. Retinal responsiveness is usually too much impaired to allow a reliable assessment of the degree of physical degeneration. In addition, rod desensitization with constant background light becomes less effective with decreasing vitamin A levels, and may preclude a physiological separation of rod and cone system contributions. This is important to keep in mind when conducting and interpreting ERG data in respective diseases.

Keywords: vitamin A deficiency • electroretinography: non-clinical • electroretinography: clinical