A cross-sectional analysis of nearly 700 patients with genetically confirmed autosomal recessive Stargardt disease (STGD1) did not support a recently reported female predilection among patients with mild ABCA4 alleles. These findings were published in JAMA Ophthalmology.

STGD1 is the most common form of inherited retinal degeneration caused by mutations in the ABCA4, according to researchers at Columbia University. A recent study found a link between certain mild ABCA4 alleles and female sex, concluding that sex is a potential contributing factor in the development of STGD1.

To attempt to replicate those findings, investigators analyzed sequencing and clinical data from 644 unrelated patients with genetically confirmed STGD1. From the data collected from June 1999 to October 2020, the team examined sex, best-corrected visual acuity (BCVA), and age at onset among patients with STGD1 with and without mild ABCA4 alleles.


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A total of 644 patients with STGD1 with at least 2 pathogenic variants were included in the study. The mean (SD) age was 38.6 (17.2) years, and 352 participants (54.7%) were female. The proportion of women was slightly higher in the entire cohort and most allele categories, although none of the differences were statistically significant, according to researchers. The proportion of women carrying the c.5603A>T p.(Asn1868Ile) allele was 7% (95% CI, -9 to 23) higher than in the subgroup not carrying any mild alleles (P =.32). The proportion of women carrying the c.5882G>A p.(Gly1961Glu) allele was 2% (95% CI, −12 to 15) higher than in the subgroup not carrying any mild alleles (P =.77). The difference between the total mild allele subcohort and the no mild allele subcohort was 3% (95% CI, −8 to 14; P =.48). 

Compared with patients in the no mild allele category, patients with mild alleles exhibited significantly delayed disease onset (mean [SD] age, 23.1 [11.6] for those with the c.5882G>A allele and 31.7 [13.5] years for those with the c.5603A>T allele vs 18.6 [11.8] years for those with no mild alleles; P <.001) and preserved visual acuity (5882G>A subgroup: mean [SD] logMAR, 0.65 [0.66]; 95% CI, 0.63-0.68; c.5603A>T subgroup: 0.64 [0.39]; 95% CI, 0.58-0.70; those with no mild alleles: 1.00 [0.57]; 95% CI, 0.96-1.03; P <.001).

Investigators of the current study concluded that their independent analysis of a larger cohort did not support the association between sex and certain mild ABCA4 alleles. 

The study had several limitations, including that its participant pool may not represent STGD1 across all populations. The proportion of observed features, such as sex, are dependent on several factors, including the differences in health-seeking behavior between sexes, the investigators note. Additionally, age of onset was self-reported by patients as the time symptoms were first noticed, which may not reflect the actual time of disease onset. Best-corrected visual acuity may vary due to factors such as ambient lighting and the efforts of the patient and test facilitator. While a visual acuity test provides a reasonable assessment of central macular health, it may not reflect disease changes in other parts of the retina, according to the researchers.

Reference

Lee W, Zernant J, Nagasaki T, Allikmets R. Reevaluating the association of sex with abca4 alleles in patients with stargardt disease. JAMA Ophthalmol. Published online April 01, 2021. doi:10.1001/jamaophthalmol.2021.0460