Botelho Gabriel Izan Santos, Salomão Solange Rios, Tengan Célia Harumi, Karanjia Rustum, Moura Felipo Victor, Rocha Daniel Martins, da Silva Paula Baptista Eliseo, Fernandes Arthur Gustavo, Watanabe Sung Eun Song, Sacai Paula Yuri, Belfort Rubens, Carelli Valerio, Sadun Alfredo Arrigo, Berezovsky Adriana
Departamento de Oftalmologia e Ciências Visuais, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil.
Departamento de Neurologia e Neurocirurgia, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil.
Front Neurol. 2021 Jan 18;11:628014. doi: 10.3389/fneur.2020.628014. eCollection 2020.
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. 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/m, 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 Dunn test. The associations between PhNR amplitude and OCT parameters were analyzed by Spearman rank correlation. 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 [ = 15 (62%), 14 males]; m.14484T>C [ = 5 (21%), all males] and m.3460G>A [ = 4 (17%), all males] and 14 carriers [13 females, mean age: 43.2 ± 13.3 yrs; m.11778G>A ( = 11); m.3460G>A ( = 2) and m.14484T>C ( = 1)]. Controls were eight females and seven males (mean age: 32.6 ± 11.5 yrs). PhNR amplitudes were significantly reduced ( = 0.0001) in LHON affected (-5.96 ± 3.37 μV) compared to carriers (-16.53 ± 3.40 μV) and controls (-23.91 ± 4.83; < 0.0001) and in carriers compared to controls ( = 0.01). A significant negative correlation was found between PhNR amplitude and total macular ganglion cell thickness ( = -0.62, < 0.05). Severe abnormalities in color discrimination, visual fields and PRVEPs were found in affected and subclinical abnormalities in carriers. 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.
明视负反应（PhNR）是一种电生理方法，它使用全视野刺激来评估视网膜神经节细胞功能，这种刺激不需要清晰的光学条件或屈光矫正。本研究的目的是通过PhNR评估来自巴西LHON家系的受累者和无症状携带者的神经节细胞功能。疑似或先前被诊断为LHON的个体及其家庭成员被邀请参与这项横断面研究。对最常见的LHON线粒体DNA突变进行了筛查。测试了视力、色觉、视野、图形翻转视觉诱发电位（PRVEP）、全视野视网膜电图和PhNR。纳入了一组健康受试者作为对照组。使用红色（640 nm）闪光在1 cd.s/m、蓝色（470 nm）视杆细胞饱和背景下记录全视野视网膜电图PhNR。使用基线到波谷（BT）测量PhNR振幅（μV）。测量了视网膜神经纤维层（RNFL）和神经节细胞复合体（GCC）的光学相干断层扫描。通过Kruskal-Wallis检验和Dunn检验比较受累者、携带者和对照组之间的PhNR振幅。通过Spearman等级相关性分析PhNR振幅与OCT参数之间的关联。参与者包括来自19个家系的24例LHON受累患者（23例男性，平均年龄=30.5±11.4岁），具有以下基因型：m.11778G>A [n = 15（62%），14例男性]；m.14484T>C [n = 5（21%），均为男性]和m.3460G>A [n = 4（17%），均为男性]，以及14例携带者[13例女性，平均年龄：43.2±13.3岁；m.11778G>A（n = 11）；m.3460G>A（n = 2）和m.14484T>C（n = 1）]。对照组为8例女性和7例男性（平均年龄：32.6±11.5岁）。与携带者（-16.53±3.40 μV）和对照组（-23.91±4.83；P<0.0001）相比，LHON受累者的PhNR振幅显著降低（P = 0.0001），与对照组相比，携带者的PhNR振幅也显著降低（P = 0.01）。发现PhNR振幅与黄斑区神经节细胞总厚度之间存在显著负相关（r = -0.62，P<0.05）。在受累者中发现了严重的色觉、视野和PRVEP异常，在携带者中发现了亚临床异常。在这个巴西LHON家系队列中，受累患者的明视负反应严重降低，无症状携带者轻度降低，提示后者可能存在亚临床异常。这些发现在致病突变之间相似。
