Prevalence of inherited retinal diseases in a large Egyptian cohort

A population-based analysis and estimated prevalence of IRDs in Egypt has, to our knowledge, not been reported before. Egypt is still lagging behind in terms of diagnostics and the application of new techniques as the public healthcare system is largely underfunded.

IRDs are rare disease entities where an average general ophthalmologist can see only a few cases during his or her entire career, and this contributes to the difficulty in reaching the correct clinical diagnosis which could direct the genetic testing to be as focused and least expensive as possible. A gap of knowledge exists regarding the prevalence of this group of blinding diseases in Egypt which will be amenable to therapy in the near future.

It is quite challenging to determine the IRDs diagnoses, especially without genetic testing, mainly due to clinical heterogeneity and considerable overlap of phenotypes among the different types of IRDs. These factors explain the large number of undiagnosed cases as well as the lack of conclusive clinical diagnosis in other cases.

Other factors that can hinder definitive diagnoses are lack of information about symptoms and signs of different disease entities, lack of accurate family history and proper pedigree labelling, time of patient evaluation whether early or late in the natural course of the disease, the presence of confounding characteristics, and difficulty of disease progression monitoring. Moreover, the lack of awareness among general ophthalmologists of IRDs as well as the scarcity of IRD experts with special training who can recognize the different subtypes of IRDs, contribute to the missing or delay in identifying the phenotype which is crucial to focus genetic testing.

The overall prevalence of IRDs in our study was 0.2% i.e. 1:500. This was much higher than reported rates from Norway (1:3856), [11]. Denmark (1:3454), [8] and Northern France (1:1490) [12]. Regarding the clinical spectrum, the most common IRD encountered was isolated RP with a prevalence of 0.16% (1:625) confirming as in other studies that it is the most prevalent of all IRDs. This is comparable to the prevalence in South India (1:570) [5] and Beijing Eye Study (1:1000) [7] but lower than that reported in Puerto Rico (1:229) [13]. However, lower prevalence rates were detected in the United States of America (1:3700), [14]. Norway (1:4440), [15]. Birmingham city in the United Kingdom (1:4869), [16]. Slovenia (1:6023), [17] and Switzerland (1:7000) [18]. This could be attributed to less accurate estimation owing to a relatively small studied population as well as diagnoses being largely based only on clinical examination or fundus appearance. Moreover, consanguinity rates vary from one population to another with variable religious, cultural, and geographical factors (urban/rural community, size of area, and population isolation) [19]. High rates of consanguinity are observed in most communities of North Africa and the Middle East as well as South India with high rates of inbreeding accounting for 20–50% of all marriages [20, 21]. Egypt is no stranger to consanguinity, where it is deeply rooted in some communities mainly in Upper Egypt and rural areas. Lastly, the higher prevalence may be related to the fact that the hospitals are tertiary care hospitals with cases referred from all over Egypt.

Among IRDs, the most common syndromic IRD encountered in our study was Usher syndrome accounting for 2.4% of cases, thereby agreeing with previous reports from South Africa [22]. Brazil [23], and Northern France [12]. BBS, the second most common syndromic RP, accounted only for 1.1% of cases, which corresponds roughly to half of those with Usher syndrome. A plausible explanation is the fact that the nine known genes responsible for Usher syndrome are very large genes with a greater probability of mutation occurrence than in diseases caused by smaller genes [24].

As for macular dystrophies, STGD was the most frequently encountered disease entity in our study comprising 6.3% of the cases, this was aligned with most of the other studies [25]. There was a wide range of prevalence rates reported ranging from 5.51% in Southern France [24] up to 20.62% in Brazil [23]. This wide variability could be attributed to the difficulty in ensuring a definite diagnosis based on fundus appearance, and the geographical variability related to underlying gene mutations as seen in North Carolina macular dystrophy (NCMD).

Lastly, 1.5% of cases encountered in our study couldn’t be accurately diagnosed and remain unclassified, this highlights the importance of raising awareness among ophthalmologists about IRDs and the multi-modal imaging as well as functional studies that may be needed to reach a probable diagnosis. Moreover, many cases require referral to an IRD expert who can proceed to do deep phenotyping to reach the clinical diagnosis, which can guide further genetic testing.

As it was expected that the IRD diagnosis will be missed in many patients, the reported prevalence (0.2%) of all IRDs is the minimum prevalence. Likewise, RP is reported to be the most common not just for being so, but also due to its characteristic fundus appearance and striking presenting symptom of night blindness that usually pushes the patient to seek medical advice.

Regarding age, the median age of patients was 35 years which agreed with that reported in Norway (42.7 years), [11]. Korea (44.8 years) [26] and Australia (46 years) [27] yet was less than that reported in South India (53.9) [5] and Beijing eye study (57 years) [7], thus reflecting relative diagnostic delay. The delay in seeking medical advice in children and young adults is not uncommon and may result from the deferment of patients with referring symptoms and/or lack of awareness and expertise in IRDs among ophthalmologists. This is commonplace with any rare disease as per the data from the Survey of the Delay in Diagnosis for Rare Disease in Europe [28]. Moreover, children with unappreciated disabilities who hardly complain along with minimal fundus changes can contribute to this delay significantly.

Our study showed preponderance for males accounting for 59.5%, this could be contributed to men having more access to healthcare services as well as the inclusion of X-linked diseases within the cohort.

Cataract was found in 39.2% of our cohort with 35.3% associated with isolated RP and 1.3% with Usher syndrome, thereby confirming that cataract is an important co-morbidity in RP whether isolated or syndromic and causes a significant impairment of central visual function to patients whose peripheral visual functions are already compromised. The prevalence of cataract found in our study agrees with those reported by Pruett (46.5%) [29] and Fishman et al. (41%) [30]. These findings highlight the importance of monitoring IRD patients for the occurrence of cataract and their proper timely management.

To the best of our knowledge, our study is the first of its kind among the Egyptian population, we were able to include a wide age range of patients coming from different regions of the same country. However, our study had limitations, most notably the discrepancy follow-up between different patients where some had only one visit, and others several ones over a few years. Moreover, the age of diagnosis was elusive, as we couldn’t ensure when exactly the patient received the diagnosis. Some remained undiagnosed till we could review their records, further emphasizing the importance of review by an IRD expert. Lastly, the hospital-based study design may affect the overall population frequency as it limits the data to those only whose data were included in the given hospitals.