Negative electroretinograms: genetic and acquired causes, diagnostic approaches and physiological insights

Abstract

The dark-adapted human electroretinogram (ERG) response to a standard bright flash includes a negative-going a-wave followed by a positive-going b-wave that crosses the baseline. An electronegative waveform (or negative ERG) results when the b-wave is selectively reduced such that the ERG fails to cross the baseline following the a-wave. In the context of a normally sized a-wave, it indicates a site of retinal dysfunction occurring after phototransduction (commonly at the photoreceptor to bipolar cell synapse). This is an important finding. In genetic disease, the pattern of ERG abnormality can point to variants in a small group of genes (frequently those associated with congenital stationary night blindness and X-linked retinoschisis, but negative ERGs can also be seen in other conditions including syndromic disease). In acquired disease, there are numerous causes, but specific features may point to melanoma-associated retinopathy (MAR). In some cases, the visual symptoms precede the diagnosis of the melanoma and so the ERG findings can initiate investigations facilitating early detection and treatment. Negative ERGs can occur in other paraneoplastic conditions, and in a range of other diseases. This review will outline the physiological basis for the negative ERG, report prevalences in the literature from different cohorts, discuss the range of causes, displaying examples of a number of ERG phenotypes, highlight features of a clinical approach to patients, and briefly discuss further insights relating to current flows shaping the a-wave trough and from single-cell transcriptome analysis.

Cell Type-Selective Loss of Peroxisomal β-Oxidation Impairs Bipolar Cell but Not Photoreceptor Survival in the Retina

“…The b-wave, on the other hand, which represents the activity of the interneurons, showed a significantly reduced response in both scotopic and photopic conditions, starting from the age of 6 M and deteriorating over age ( Figure 4 A). A selective reduction in the b-wave is also called a negative ERG [ 38 , 39 ]. The b-wave originates from the depolarization of the inner retinal cell types.…”

“…The negative ERG, i.e., impaired b-waves despite normal a-waves, in Crx-Mfp2 −/− and Crx-Pex5 −/− mice also points to a hampered signal transduction at the level of photoreceptor–bipolar cells. In other mouse models negative ERGs were related to either presynaptic defects in photoreceptor terminals or postsynaptic defects in bipolar cells [ 38 , 39 , 41 ]. Presynaptic defects result for example from incorrect assembly or functioning of the photoreceptor ribbon synapse, such as in Bsn Ex4/5 , Ribeye −/− and Crx-Pomt1 −/− mutant mice [ 49 , 50 , 51 , 52 ].…”

Electrical responses from human retinal cone pathways associate with a common genetic polymorphism implicated in myopia

“…We also analyzed responses from a second patient with cCSNB from another genetic cause (biallelic pathogenic variants in the TRPM1 gene) ( 22 – 25 ). This patient showed the same shape of responses to the various stimuli as seen in the patient with NYX -associated cCSNB (illustrated in SI Appendix , Fig.…”

“…found that mice with nyx mutations were initially more hyperopic than wild-type mice, but were more susceptible to form deprivation myopia ( 36 ). In humans with congenital ON-pathway loss (complete CSNB), high myopia is usually seen; however, CACNA1F -associated disease (sometimes termed “incomplete” CSNB), which entails attenuation of both ON- and OFF-pathway signals, is also associated with myopia ( 25 ). Mechanisms driving myopia in the general population are likely to relate to more subtle aspects of the balance between ON- and OFF-pathway signaling, possibly at particular periods in development, rather than profound global attenuation of one pathway or the other.…”

Prevalence of electronegative electroretinograms in a healthy adult cohort

“…1 In response to standard dark-adapted flashes (as defined by the International Society for Clinical Electrophysiology of Vision (ISCEV)), 1 2 an electronegative ERG usually indicates dysfunction occurring after phototransduction (eg, at the level of the photoreceptor synapse or bipolar cell). The finding of an electronegative ERG, particularly a normal-sized a-wave and reduced b-wave, is of clinical significance, [3][4][5]…”