The Value of Electroretinography in Identifying Candidate Genes for Inherited Retinal Dystrophies: A Diagnostic Guide

Abstract

Inherited retinal dystrophies (IRDs) are a group of heterogeneous diseases caused by genetic mutations that specifically affect the function of the rod, cone, or bipolar cells in the retina. Electroretinography (ERG) is a diagnostic tool that measures the electrical activity of the retina in response to light stimuli, and it can help to determine the function of these cells. A normal ERG response consists of two waves, the a-wave and the b-wave, which reflect the activity of the photoreceptor cells and the bipolar and Muller cells, respectively. Despite the growing availability of next-generation sequencing (NGS) technology, identifying the precise genetic mutation causing an IRD can be challenging and costly. However, certain types of IRDs present with unique ERG features that can help guide genetic testing. By combining these ERG findings with other clinical information, such as on family history and retinal imaging, physicians can effectively narrow down the list of candidate genes to be sequenced, thereby reducing the cost of genetic testing. This review article focuses on certain types of IRDs with unique ERG features. We will discuss the pathophysiology and clinical presentation of, and ERG findings on, these disorders, emphasizing the unique role ERG plays in their diagnosis and genetic testing.

Keywords: X-linked retinoschisis; cone dystrophy with supernormal rod response; cone–rod dystrophies; congenital stationary night blindness; electronegative ERG; electroretinography; enhanced S-cone syndrome; fundus albipunctatus; inherited retinal dystrophies.

Figure 1

The retina anatomy and various electrophysiological tests gathering collective cellular reactions from multiple levels of the retina.

Figure 2

The schematic of genes and encoded proteins involved in phototransduction and the visual cycle. Genes in different colored fonts indicate the responsibility for various inherited retinal diseases (IRDs): orange for fundus albipunctatus, blue for Oguchi retinopathy, green for Riggs-type congenital stationary night blindness (CSNB), purple for GUCY2D-related cone–rod dystrophy, and grey for Leber congenital amaurosis or retinitis pigmentosa (RP). Genes in the graph are specifically expressed in rods, except for GUCY2D, expressed in both rods and cones. The diagram shows the process in rods, but the proteins used in cones are the same, except that rhodopsin should be replaced with cone-opsins. (A) Phototransduction. Rhodopsin is located in the outer segments of rods and consists of 11-cis-retinal chromophore and opsin. To begin, light stimulates 11-cis-retinal to isomerize into all-trans-retinal and changes the shape of opsins, activating transducin, the G-protein coupled to rhodopsin. This, in turn, activates photoreceptor phosphodiesterase (PDE), which hydrolyzes cyclic guanosine monophosphate (cGMP) and leads to the closure of the cyclic nucleotide-gated ion channel (CNGC). Therefore, photoreceptors are hyperpolarized, reducing glutamate release to bipolar cells. The recovery of phototransduction involves two parts: first, rhodopsin activity is terminated by rhodopsin kinase (GRK1) and arrestin; second, calcium efflux through sodium/calcium–potassium exchanger (NCKX) activates guanylyl cyclase (GC), which replenishes cGMP. (B) Visual cycle. To maintain phototransduction processing, the visual cycle recycles retinoids between the photoreceptors and RPE to replenish 11-cis-retinal in the rhodopsin. Key enzymes involved in this process include lecithin retinol acyl transferase (LRAT), RPE65 protein, and 11-cis-retinol dehydrogenase (RDH), which are encoded by genes responsible for IRDs—LRAT, RPE65, and RDH5, respectively. The process requires all-trans-retinol, or vitamin A, to be repleted from choroid capillaries.

Figure 3

The reference ranges of standard full-field ERG (ffERG) according to the ISCEV protocol. The diagram illustrates the measurement of the amplitudes (solid vertical lines) and implicit times (broken horizontal lines marked as “t”) of the standard ERG components, which consist of a-waves and b-waves of dark-adapted (DA) and light-adapted (LA) single-flash responses. Moreover, the origins of the a-waves and b-waves in retinal cells are shown.

Figure 4

The fundus and ERG images of Riggs-type CSNB, cCSNB, and iCSNB in a Taiwanese cohort. Patient 1 has RHO-mutated Riggs-type CSNB, patient 2 has GRM6-mutated cCSNB, and patient 3 has NYX-mutated iCSNB. Panel (A) shows the ERG patterns, while panel (B) shows the fundus examination results. These patients present with similar clinical features and imaging, while the distinctive ERG patterns play a pivotal role in identifying candidate genes for definitive diagnosis [21].

Figure 5

The typical findings from X-linked retinoschisis (XLRS) in a Taiwanese cohort [40]. (A) ERG results revealing electronegative DA 3 ERG and reduced scotopic response. (B) Spoke-wheel-like pattern at the macula. (C) Fluorescein angiography (FA) shows non-leaking cystoid macular edema (CME). (D) Schisis and increased thickness at the macula.

Figure 6

The findings on CXR-related cone–rod dystrophy in a Taiwanese case. (A) ERG report revealing reduced scotopic response and electronegative DA 3 ERG. (B) Fundus examination.

Figure 7

The findings on fundus albipunctatus in a Taiwanese case [66]. (A) ERG results revealing recovery of the DA 3 ERG response after prolonged scotopic adaptation. (B) Fundus examination with retinal white dots at the posterior pole, sparing the fovea. (C) Fundus autofluorescence (FAF) showing mottling hypo-autofluorescent signals.

Figure 8

The findings on a patient with Enhanced S-cone syndrome (ESCS), also known as Goldmann–Favre syndrome [77]. (A) Three distinct ERG features, including extinguished DA 0.1 ERG, similar waveforms in DA 3 or 10 ERG reports and LA 3 ERG, and a larger a-wave in LA 3 ERG than in LA 30 Hz ERG. Moreover, excess S-cones can be verified by observing an elevated signal in S-cone ERG. (B) Fundus examination revealing retinal white dots.

Figure 9

The findings on a patient with cone dystrophy with supernormal rod response (CDSRR), who was initially mistaken as having HCQ retinopathy [84]. The distinct ERG patterns helped pinpoint the candidate gene for a definite diagnosis. (A) ERG report showing a supernormal rod response to bright flash intensity in the setting of cone and rod dystrophy. (B) Fundus imaging showing symmetric atrophic lesion at the central macula in both eyes.