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About one in 10,000 people are estimated to be affected by vision loss due to the macular dystrophy Stargardt disease. People with Stargardt disease have inherited pathogenic variants in the ABCA4 gene from both their parents. These pathogenic variants can range from mild to severe with a corresponding effect on the disease phenotype.
In 2020, the Radboudumc published a study that showed that when comparing Stargardt patients with a mild genetic variant to Stargardt patients without mild variants, the former group showed significantly more women than men. A (larger) study from the Columbia University in New York from 2021 tried to replicate these findings with their own dataset. They found that both groups showed slightly more women (56% and 53% respectively) and that there was no significant difference between these groups. They wrote that the conclusions of the Radboudumc study by Runhart et al. should be rigorously scrutinised. After all, the genetic variants in the ABCA4 gene that cause Stargardt disease are located on chromosome 1 of which everyone has two copies, regardless of their sex. Furthermore, they mention that it has been extensively reported that women show more healthcare seeking behaviour than men. The fact that people in the former, milder, group usually have a disease onset in adulthood whereas the latter group which usually shows a disease onset in childhood, might explain the overrepresentation of women, due to the difference in parental influence on the diagnosis of children versus adults.
However, none of the studies that report that women go to the doctor more often than men, fully took into account the different healthcare needs between women and men (for example, related to pregnancy, menstruation, contraception and menopause), nor whether women were treated equally successfully for their medical complaints. Furthermore, Stargardt disease also shows high variability in onset and severity when patients have the same ABCA4 variants indicating that these might not explain the full disease phenotype. Interestingly, the same group from Columbia University published an article in 2022 suggesting that factors outside the ABCA4 gene could affect the disease onset and phenotype. Therefore, it remained unclear if women with Stargardt disease are affected differently than men.
This April, researchers from the Radboudumc together with multiple international collaborators, including groups from the Lille Hospital University, France, and the Moorfields Eye Hospital in London, UK, were able to shed more light on this topic. They first reevaluated the overrepresentation of women in Stargardt disease through a meta-analysis. This time with a slightly different approach: instead of comparing the subgroups of Stargardt disease to each other, they simply sought to find out if women were overrepresented in both groups independently, reasoning that sex or gender could affect all Stargardt patients, while having a bigger impact on the subgroup of patients with a mild genetic variant. Their results show that among patients with a mild genetic variant ~59% are women, whereas among patients with genetic variants that likely have a more severe effect, ~50% of the patients were women. Then, they compared the ratio of women and men in adult onset Stargardt disease patients and patients with other types of adult onset inherited retinal dystrophies in the Radboudumc genetic database. Significantly more women (56%) were present in the Stargardt group than in the other retinal dystrophy group (47%). It therefore seems clear that gender or sex has an effect on Stargardt disease specifically and that this affect is only seen when people have a milder form of Stargardt disease. The next step will be to find out the disease mechanism behind this.
Publication
Representation of Women Among Individuals With Mild Variants in ABCA4-Associated Retinopathy: A Meta-Analysis Stéphanie S Cornelis, Joanna IntHout, Esmee H Runhart, Olivier Grunewald, Siying Lin, Zelia Corradi, Mubeen Khan, Rebekkah J Hitti-Malin, Laura Whelan, G Jane Farrar, Dror Sharon, L Ingeborgh van den Born, Gavin Arno, Mark Simcoe, Michel Michaelides, Andrew R Webster, Susanne Roosing, Omar A Mahroo, Claire-Marie Dhaenens, Frans P M Cremers; Study Group Collaborators, Affiliations expand
PMID: 38602673 PMCID: PMC11009866 (available on 2025-04-11) DOI: 10.1001/jamaophthalmol.2024.0660
