Impaired Ganglion Cell Function Objectively Assessed by the Photopic Negative Response in Affected and Asymptomatic Members From Brazilian Families With Leber's Hereditary Optic Neuropathy.

Gabriel Izan Santos Botelho,Sung Eun Song Watanabe,Arthur Gustavo Fernandes,Alfredo Arrigo Sadun,Célia Harumi Tengan,Paula Baptista Eliseo Da Silva,Paula Yuri Sacai,Daniel Martins Rocha,Rubens Belfort,Solange Rios Salomão,Valerio Carelli,Adriana Berezovsky,Rustum Karanjia,Felipo Victor Moura

doi:10.3389/fneur.2020.628014

Abstract

Purpose: The photopic negative response (PhNR) is an electrophysiological method that provides retinal ganglion cell function assessment using full-field stimulation that does not require clear optics or refractive correction. The purpose of this study was to assess ganglion cell function by PhNR in affected and asymptomatic carriers from Brazilian families with LHON.Methods: Individuals either under suspicion or previously diagnosed with LHON and their family members were invited to participate in this cross-sectional study. Screening for the most frequent LHON mtDNA mutations was performed. Visual acuity, color discrimination, visual fields, pattern-reversal visual evoked potentials (PRVEP), full-field electroretinography and PhNR were tested. A control group of healthy subjects was included. Full-field ERG PhNR were recorded using red (640 nm) flashes at 1 cd.s/m2, on blue (470 nm) rod saturating background. PhNR amplitude (μV) was measured using baseline-to-trough (BT). Optical coherence tomography scans of both the retinal nerve fiber layer (RNFL) and ganglion cell complex (GCC) were measured. PhNR amplitudes among affected, carriers and controls were compared by Kruskal-Wallis test followed by post-hoc Dunn test. The associations between PhNR amplitude and OCT parameters were analyzed by Spearman rank correlation.Results: Participants were 24 LHON affected patients (23 males, mean age=30.5 ± 11.4 yrs) from 19 families with the following genotype: m.11778G>A [N = 15 (62%), 14 males]; m.14484T>C [N = 5 (21%), all males] and m.3460G>A [N = 4 (17%), all males] and 14 carriers [13 females, mean age: 43.2 ± 13.3 yrs; m.11778G>A (N = 11); m.3460G>A (N = 2) and m.14484T>C (N = 1)]. Controls were eight females and seven males (mean age: 32.6 ± 11.5 yrs). PhNR amplitudes were significantly reduced (p = 0.0001) in LHON affected (−5.96 ± 3.37 μV) compared to carriers (−16.53 ± 3.40 μV) and controls (−23.91 ± 4.83; p < 0.0001) and in carriers compared to controls (p = 0.01). A significant negative correlation was found between PhNR amplitude and total macular ganglion cell thickness (r = −0.62, p < 0.05). Severe abnormalities in color discrimination, visual fields and PRVEPs were found in affected and subclinical abnormalities in carriers.Conclusions: In this cohort of Brazilian families with LHON the photopic negative response was severely reduced in affected patients and mildly reduced in asymptomatic carriers suggesting possible subclinical abnormalities in the latter. These findings were similar among pathogenic mutations.

Highlights

Leber’s hereditary optic neuropathy (LHON) is a disease characterized by a sub-acute, painless loss of central vision, either simultaneously or in one eye followed by the other eye within weeks to months, affecting mainly young male adults between 15 and 35 years of age [1]
photopic negative response (PhNR) (BT, between PhNR amplitude (BT)/b and Peak to trough (PT)/b) amplitudes were significantly reduced (p < 0.0001) in LHON affected (BT = −5.96 ± 3.37 μV) compared to carriers (BT = −16.53 ± 3.4 μV) and controls (BT = −23.91 ± 4.83 μV), and in carriers compared to controls (p < 0.0001)
The Receiver operating characteristic (ROC) analysis confirmed that the PhNR (BT) amplitude showed the best discrimination between control, LHON carrier and affected groups confirming findings from the Brazilian pedigree with m.11778G>A/haplogroup J LHON (SOA-BR) pedigree [32]

Summary

Introduction

Leber’s hereditary optic neuropathy (LHON) is a disease characterized by a sub-acute, painless loss of central vision, either simultaneously or in one eye followed by the other eye within weeks to months, affecting mainly young male adults between 15 and 35 years of age [1]. The loss of vision is due to selective vulnerability of retinal ganglion cells (RGCs) in the papillomacular bundle that causes central scotoma and subsequent optic atrophy [2, 3]. LHON is the most common of the mtDNA diseases, but epidemiological studies on prevalence and incidence involving different countries are scarce. LHON is more frequent in males with the male/female ratio varying from 3:1 to 8:1, depending on the LHON mutation and the population studied [1, 7].

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