Female single-copy carriers of X-linked inherited retinal diseases experience a range of retinal degeneration from almost normal to severe.
Female carriers of X-linked inherited retinal diseases who have a single copy of the disease-causing variant were previously thought to be relatively symptom-free, but researchers now know that they have retinal problems ranging from almost normal to severe retinal degeneration.
“This study has shown that female carriers of choroideremia and X-linked [retinitis pigmentosa] report significantly worse visual symptoms, compared to healthy controls,” Sena A. Gocuk, DOptom, MPhil, and colleagues wrote in AJO International.
The researchers used the validated Michigan Retinal Degeneration Questionnaire (MRDQ) to investigate self-reported visual impairment in a large international cohort of female carriers of X-linked retinal diseases.
Overall, 237 female carriers of X-linked retinal diseases (choroideremia, 74.3%; X-linked retinitis pigmentosa [RP], 25.7%) and 100 age-matched healthy controls completed the questionnaire (median ages: 51 vs 47.5, respectively).
Respondents indicated their visual symptoms involving everyday activities in seven visual domains: central vision, color vision, contrast sensitivity, photopic peripheral vision, scotopic function, mesopic peripheral vision, and photosensitivity. Female carriers had significantly worse visual disability than controls. Compared with female carriers younger than 50, those older than 50 had significantly greater visual function impairment across all domains except photosensitivity.
Dr. Gocuk and Jacque Duncan, MD, who was not involved in the study, talked with Physician’s Weekly (PW) about the study results.
PW: Why was it important to do this study?
Dr. Gocuk: This study was crucial to better understand the visual challenges faced by female carriers of X-linked inherited retinal diseases. Given that these carriers can experience significant visual impairments impacting daily life, providing targeted clinical care and support is vital. Additionally, the findings highlight the need for further research and awareness and the importance of considering carriers in upcoming retinal gene therapy clinical trials.
We need to shift our perception of the term “carriers” to include people who not only carry a single copy of the disease-causing genetic variant but are also affected by the condition to varying degrees.
Dr. Duncan: Understanding the experiences of patients affected by retinal degeneration from their direct feedback using a standardized questionnaire developed specifically for patients with retinal degeneration is a valuable and necessary step toward developing novel validated outcome measures that can evaluate the effect of potential treatments.
Did the results surprise you?
Dr. Gocuk: The results were not entirely surprising, given the known impact of X-linked inherited retinal diseases (IRDs) on vision. However, the extent of self-reported visual impairment in female carriers underscores the clinical relevance of these findings.
Dr. Duncan: Prior studies have also reported that female carriers of X-linked retinal degeneration have vision loss. The current study is important because it used a standardized questionnaire developed specifically to solicit patients’ experience of vision loss in rod-cone degeneration using the MRDQ.
How could the findings impact patient care?
Dr. Duncan: The findings may help validate the MRDQ as an instrument for use in clinical trials of treatments for female carriers of X-linked retinal degenerations.
Dr. Gocuk: The study’s findings can significantly impact patient care by underscoring the necessity for routine and comprehensive visual assessments for female carriers of X-linked IRDs, even those with mild phenotypes. Furthermore, the study highlights the need for psychological support, management of expectations, and provision of educational resources to help carriers manage their condition, ultimately aiming to improve their quality of life.
What strengths or limitations of the study are noteworthy?
Dr. Gocuk: This was a large global study assessing visual symptoms using a validated questionnaire designed specifically for people with IRDs. However, to increase responses, we relied on self-reported data without clinical confirmation of carrier status or severity of retinal disease.
Dr. Duncan: The strengths are using a standardized questionnaire developed for patients with retinal degeneration and the large, multicenter group of female carriers of X-linked retinal degeneration.
Although the study enrolled many participants, the sample size may not have been large enough to identify differences between carriers of X-linked retinitis pigmentosa and choroideremia, and the investigators combined all the patients to compare them with healthy women. Also, this cross-sectional study did not evaluate symptom changes longitudinally. Studying changes over time could provide insight into whether affected carrier females experience progressive visual loss.
What unanswered questions remain for you?
Dr. Gocuk: Whether the MRDQ can be used to detect retinal disease progression is the next area we are interested in investigating. Considering the significant disease impact, we are interested to see whether our findings will affect the inclusion of female carriers in upcoming retinal gene therapy clinical trials.
Dr. Duncan: I would like to know whether affected carrier females experience progressive visual loss over time and whether there are differences between female carriers of RPGR-related retinal degeneration and RP2-related X-linked retinitis pigmentosa and female carriers of choroideremia.
Is there anything else you’d like to mention?
Dr. Gocuk: Clinicians should consider regular, detailed visual assessments for female carriers of X-linked IRDs, with particular attention to age-related changes. Contrary to historical beliefs, these women require psychological support and educational resources to manage the impact of visual impairments and to set realistic expectations regarding the impact of disease. Collaborating with geneticists is crucial for understanding the genetic factors that influence disease severity and progression.
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