# ABCA4-associated disease in childhood and adolescence– a phenotype study

## TL;DR

This study examines the variability of ABCA4-related retinal disease in children, showing that adult clinical trial criteria may not apply to pediatric patients.

## Contribution

The study highlights the need for distinct inclusion criteria and endpoints for pediatric ABCA4-related disease trials due to significant heterogeneity in children.

## Key findings

- ABCA4-associated retinal disease in children is highly heterogeneous, complicating the definition of reliable clinical trial inclusion criteria.
- Definitely decreased autofluorescence, commonly used in adult trials, is unsuitable for pediatric cohorts due to its low prevalence.
- Over half of the observed ABCA4 genetic variants were missense mutations, and central photoreceptor atrophy was common in most patients.

## Abstract

Aim of this study is to analyse the clinical picture of a pediatric ABCA4-related retinal disease cohort to evaluate possible inclusion criteria and outcome measures in children for future interventions.

In this retrospective chart review study, cross-sectional data on the phenotype and genotype of patients under 18 years of age with ABCA4-associated retinal disease from the clinic for inherited retinal dystrophies at the University of Tuebingen were collected.

38 minor patients from 34 independent families with genetically confirmed ABCA4-associated disease were included in the study. Mean age was 10.3 years. 45 distinct genetic variants were observed. Thirteen patients had apparent homozygous ABCA4 genotypes. The other carried two, three or four heterozygous ABCA4 variants. More than half of the variants were missense variants (25/45, 55.6%). Mean best-corrected visual acuity was 0.80 logMAR. On optical coherence tomography, in 29 patients (78%) central photoreceptors were atrophic. Eight patients (22%) revealed a persistence of the central photoreceptor layers with visible external limiting membrane (ELM). In four of those, the ELM was markedly thickened. Only four patients revealed a definitely decreased autofluorescence in the macula.

ABCA4-associated disease is already very heterogeneous in children, impeding the definition of reliable inclusion criteria for clinical trials. Although definitely decreased autofluorescence is a good endpoint in ABCA4-related disease trials, it is not suitable in pediatric cohorts due to its very low prevalence.

The online version contains supplementary material available at 10.1007/s00417-025-06884-9.

So far, observational studies have primarily examined adults and have used these findings to define endpoints for interventional studies, which also serve as a reference for interventional studies in children Most clinical trials currently use the measurement of definitely decreased autofluorescence

So far, observational studies have primarily examined adults and have used these findings to define endpoints for interventional studies, which also serve as a reference for interventional studies in children

Most clinical trials currently use the measurement of definitely decreased autofluorescence

We have closely examined the variability of Stargardt disease in children Our results suggest that the same inclusion criteria and endpoints used for adults should not be applied to children, e.g. definitely decreased autofluorescence is not suitable in pediatric cohorts because it has only a very low prevalence

We have closely examined the variability of Stargardt disease in children

Our results suggest that the same inclusion criteria and endpoints used for adults should not be applied to children, e.g. definitely decreased autofluorescence is not suitable in pediatric cohorts because it has only a very low prevalence

The online version contains supplementary material available at 10.1007/s00417-025-06884-9.