Certain inherited retinal diseases are characterized by large cystoid macular lesions

(Image Credit: AdobeStock/Tartila)

Reviewed by Mandeep S. Singh, MD, PhD

Optical coherence tomography (OCT) analysis of measurements of cystoid macular lesions (CMLs) obtained from a cohort of patients with genetically confirmed inherited retinal diseases (IRDs) showed that patients with different IRD phenotypes can develop very large CMLs (VLCMLs).¹ This information is relevant because it may help to inform clinical associations, mechanistic research, and trial design, according to senior author Mandeep S. Singh, MD, PhD, from the Wilmer Eye Institute at Johns Hopkins Hospital and the Department of Genetic Medicine at Johns Hopkins University, both in Baltimore, Maryland.

Singh pointed out that more than 50% of patients with IRDs develop CMLs2-5; however, despite this recognition, the molecular pathogeneses of the lesions are unknown and there are no definitive treatments. The approach that the authors developed in this study may provide a cost-effective way to define a phenotypic subgroup of VLCMLs for targeted research, because molecular and biochemical studies on all CML cases are prohibitively expensive.

In their cross-sectional study, Singh, first author Bani Antonio-Aguirre, MD, MPH, and Carlthan Ling, MD, set out to identify the VLCML phenotype, estimate the frequency, and determine associated genotypes.

The investigators searched electronic records from January 2020 to December 2021 and identified patients with VLCMLs using the Mahalanobis distance.^2,3 They explained that the “Mahalanobis distance (also referred to as the greatest robust distance) describes, statistically, how ‘far’ the value of any single value is from the population mean. A larger value indicates a greater ‘distance’ from the mean, and large values are typically associated with statistical outliers or unusually extreme sample values.”

Specifically, in this study, the cases with VLCML were identified using the robust Mahalanobis distance of the correlation between the central foveal thickness (CFT) and the total macular volume and a 99.9% probability ellipse. The distribution of the OCT parameters was calculated by genotype and phenotype.

Data analysis

The study included 173 eyes of 103 participants (47.6% women). The median patient age was 55.9 years. Patients exhibited disease-causing mutations in 30 genes, the most common of which were USH2A (n= 18), RP1 (n= 12), and ABCA4 (n= 11), the authors reported.

Two cases of VLCMLs were identified that occurred in distinct genetic types of IRDs. One patient received a diagnosis of enhanced S-cone syndrome and the other a diagnosis of autosomal recessive bestrophinopathy.

The distance analysis showed that the frequency of VLCMLs was 1.94% (ie, in 4 eyes of 2 patients) and occurred in patients with the NR2E3 (119-2A>C) and BEST1 (1120_1121insG) gene mutations.

The CFTs measured in the 2 cases were highly relevant. The median CFT in the patients that did not have VLCMLs was 269 μm. In contrast, the median CFT value in the 2 patients with VLCMLs was 1490 μm, a difference that reached significance (P < .001).

In commenting on their findings, the authors said, “We applied robust distance analysis to CML OCT measurements data derived from a cohort of patients with genetically confirmed IRDs to identify cases that exceeded a biostatistical threshold definition of normality. We identified 2 cases with VLCML occurring in distinct genetic types of IRDs. These data indicated that certain patients [with] IRDs with CMLs may present with extreme structural changes and suggested that the extreme phenotype may occur more broadly in multiple IRD genotypes. The presence of extreme or outlier values of CML thickness could be important to consider in the context of clinical research design. Future studies could consider the range and extreme outlier values of CML thickness when determining inclusion criteria and biostatistical plans for observational and interventional studies.”

Mandeep S. Singh, MD, PhD

E: singhcorrespauth@gmail.com

Singh is from the Wilmer Eye Institute at Johns Hopkins Hospital and the Department of Genetic Medicine at Johns Hopkins University, both in Baltimore, Maryland. He has no financial interest in this subject matter.

References:

1. Antonio-Aguirre B, Ling C, Singh MS. Very large cystoid macular lesions identified using outlier analysis of genetically confirmed inherited retinal disease cases. Ophthalmic Genet. 2023; 1-7. doi:10.1080/13816810.2023.2212757

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