A five-year follow-up of ABCA4 carriers showing deterioration of retinal function and increased structural changes

To investigate whether the reduced retinal function and morphological retinal changes previously demonstrated in ABCA4 carriers had remained stationary or had deteriorated over time at 5-year follow-up to further explore if carriers of an autosomal recessive trait also express a weak phenotype, although this is not expected for an autosomal recessive disorder.

Thirteen ABCA4 carriers from a previous study that included parents to patients with well known genetically verified ABCA4-associated retinal degenerations were reexamined 5 years after the initial examination. As novel genes and new variants in already established genes are continuously reported, all subjects underwent renewed genetic testing with a next-generation sequencing (NGS) panel that included 288 genes associated with retinal dystrophies and an analysis of deep intronic mutations and copy number variations in the ABCA4 gene. Moreover, to evaluate any changes in retinal function and/or structure over time, clinical reassessment with Goldmann perimetry, visual acuity testing, fundus photography, fundus autofluorescence (FAF) imaging, optical coherence tomography (OCT), full-field electroretinography (ffERG), and multifocal ERG (mfERG) were performed 5 years after the initial investigation. The values of the ffERG parameters were compared between the two time points (the measurements obtained in the initial study versus the measurements at 5-year follow-up) and with the controls. The mfERG results of the carriers were compared with those of the controls.

The renewed genetic testing confirmed the previously established ABCA4 mutations but also revealed the hypomorph ABCA4 variant c.5603A>T in five ABCA4 carriers. In three of them, the variant was found to be associated with known disease-causing alleles that always carry the c.5603A>T in cis. According to recent publications, the subjects could still be considered ABCA4 carriers because both variants are on the same allele. In the remaining two subjects, c.5603A>T could be in trans with the previously known ABCA4 variant, and the subjects were therefore excluded from the study since they could no longer be considered as carriers only. Statistical comparison of ffERG parameters showed significant reduction of the isolated rod, -as well as the combined rod-cone amplitudes over the five years of follow-up, but not compared with the controls. Concerning macular function, mfERG amplitudes were reduced for all rings in the carriers compared with the controls. Fundus photographs demonstrated morphological changes in 64% of the carriers, and 36% of them had further changes at follow-up. FAF images showed alterations in 55% of the carriers, with increased changes in 36% of them. Abnormalities on OCT were observed in 82% of the carriers, of whom 9% had newly found abnormalities at follow-up.

At 5-year follow-up, the ABCA4 carriers, who previously demonstrated reduced macular function, presented with deterioration of general retinal function, including reduced isolated rod and mixed rod-cone ffERG responses combined with a slight increase in morphological changes in some subjects. This indicates that carriership of at least some ABCA4 variants may cause a condition similar to a subgroup of dry age-related macular degeneration (AMD). In the long run, this might be of importance concerning the possibilities to also treat this subgroup of AMD patients with future gene-based and pharmacological drugs targeting ABCA4-associated disorders.