Abstract
Purpose :
Inherited retinal diseases (IRDs) are classically diagnosed and classified by the electroretinogram (ERG) rod and cone response amplitudes, and the pattern of ERG responses is associated with various clinical diagnoses. Certain gene defects cause primarily cone dysfunction, such as CNGA3, which causes achromatopsia. Other gene defects can cause a cone-rod dystrophy (cone>rod dysfunction), such as ABCA4. Some genes defects cause rod-cone dystrophies (rod>cone dysfunction), known as retinitis pigmentosa (RP), including rhodopsin.
Methods :
This study compares residual cone and mixed rod-cone response amplitudes across 5095 ERGs of 1239 subjects with IRDs caused by 84 different genes. The mixed rod and cone response was elicited by 0.5 Hz white flashes at 0.22 cd*s/m2 after dark adaptation. The cone specific response was elicited by 30 Hz flashes after light adaptation. The residual of a curve fit of the cone versus mixed response amplitudes was calculated, which can be considered as a type of cone/rod amplitude ratio.
Results :
The lowest cone/rod ratio, indicating primary cone dysfunction, was seen in KCNV2 defects, which causes “cone dystrophy with a supernormal rod electroretinogram”. AIPL1 defects, which also cause an unusual ERG, also had large residual rod signals with low cone signals. These two genes, along with achromatopsia genes such as CNGA3 & CNGB3, have the lowest cone/rod ratios. The highest cone/rod ratios, indicating primarily rod dysfunction, were frequently seen in genes that cause dominant RP, such as rhodopsin, KLHL7, and IMPHD1. (Different relative rankings are obtained with amplitude-independent calculations.) ABCA4, and to a lesser extent RPGR, showed a wide spectrum of ratios, consistent with their ability to cause RP versus cone-rod dystrophy in different subjects. Findings for additional genes are discussed.
Conclusions :
This study shows, in an unbiased way, which IRD genes cause more rod versus cone-specific defects, in many human subjects. This pattern likely reflects the underlying biology of the different gene functions and might have implications for therapeutic approaches to gene replacement for IRDs.
This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.