The current study presents interesting data about the relative frequencies of inherited retinal diseases and their clinical appearance, inheritance patterns, age at diagnosis, and results of genetic testing in a Spanish region with 2,500,000 inhabitants.
As expected, RP was the most frequently inherited retinal disease found in the current study. The RP frequencies vary little between published studies and range from 34.75–43.06% [8, 15, 16]. Even the group of syndromic RPs as a whole had similar frequencies (Table 4). Usher syndrome was the most frequent form of syndromic pigmentary retinopathy as reported previously [8, 15, 16]. Regarding macular dystrophies, Stargardt’s disease was the most frequently seen entity in the current study and in most studies but with important variations ranging from 5.51% reported by Bocquet et al. in Southern France to 20.62% reported by Motta et al. in Brazil [8, 15]. The reported frequencies of other macular dystrophies vary widely among studies of different populations, and the current study has the higher percentage [8, 15, 16]. Such wide variations can be due to several factors: it is unclear if some macular dystrophies included in the current study also were included in other studies; the definite diagnosis of a particular macular dystrophy can be challenged; moreover, geographic variations in the frequency of some mutations can promote geographic disparities in the frequency of some entities as happens with the higher rate of CACD in the Spanish population compared with others [17, 18]. Although consanguinity can play an important role in the prevalence of IRD in some populations [19], the current study had consanguinity data, including relative consanguinity data (11.11% and 17.46%, respectively), similar to those published in most populations [15, 20].
Concerning the inheritance patterns in the RP group, the rate of AR inheritance in the current sample was high (53.61% vs. 16.0%-39% in other studies), while sporadic cases occurred less frequently than in other studies (24.23% vs. 40%-51% in other studies) [4, 21–24]. Nevertheless, 28 patients in our sample did not provide family history data and thus they were not included in this analysis; if they had been considered as sporadic cases, this figure would have approached 50%.
Within the RP group, the ERG was abolished or diminished in most patients, similar to data reported by Berson et al [20, 25].
With small variations, the clinical presentations of IRDs in the current sample was similar to those already described. Regarding the ocular fundus, most had the classic pattern of pigmentation in the spicules. The percentage of cataract patients (39.42%) was similar to the data provided by Testa et al [24]. and slightly lower than in other studies (45%-52%) [26]; the group of pseudophakic patients among the current cases (31.25%) was greater than that found in the other studies (15.4%-20%).[10, 27–29] The mean age at the time of cataract surgery was similar to those reported previously [27–29]. Finally, the prevalence of macular edema in our RP sample (17.06%) was lower than in other studies (23%-50%) [10, 30–31], although it was similar to that reported by Hirakawa et al [32]. Genetic diagnosis of IRDs is desirable for many reasons because it can provide a definitive diagnosis, which can deliver great relief to patients and families; it also helps physicians to better define the inheritance pattern and the risk for the remaining family members, and it is crucial to identify patients for potential enrollment in clinical trials or new advanced therapies. Besides, 71.6% of the patients in the current series without a genetic study had good remaining vision, so they could be candidates for gene therapy. The first important difficulty for genetic diagnosis of IRDs is that the clinical diagnosis of different phenotypes may be due to the same mutation and vice versa [33]. Thus, the wide variety of IRDs and their relative low frequency make it difficult for the general ophthalmologist and the retinal specialist to establish an accurate diagnose and focus the search on one or a small number of gene mutations. Another important factor is the possibility for ophthalmologists and patients to access a clinical genetic unit. In our case, Castilla y Leon region lacks a genetic unit. These reasons explain the low rates of genetic diagnoses obtained in the current study (22.95%), which was slightly lower than those published in other such studies (30.11% and 32.10%) [8, 15].
Delayed diagnoses are common problems in IRDs and may result from deferral of patients with referring symptoms and/or the inexperience of doctors who first treated them. Data from the Survey of the Delay in Diagnosis for Rare Diseases in Europe confirm that this delay generally occurs in the diagnosis of any rare disease [34]. Moreover, late diagnosis of stable diseases may be due in part to their moderate visual impairment and minimal fundus changes in children who do not complain [35]. Entities with a more characteristic phenotype can be recognized early, but in many cases a conclusive diagnosis of an IRD cannot be made until several visits and electrophysiologic and imaging evaluations are performed and interpreted correctly.
The major strength of the current study was that the patients were part of ordinary specialized practices and the sample size was adequate considering that the diseases are rare. It also emphasizes the need to improve access to genetic testing in our population.
But the current study has important limitations. First, the sample size of each disease was small except for that of RP. However, these are rare diseases and, in this context, relevant findings could be highlighted. Another constraint was the heterogeneity in the follow-up of the patients (some, up to 20 years of follow-up and others, only infrequent visits). In addition, the presence of macular edema may have been underestimated, especially in patients with few visits during the first years in which optical coherence tomography was unavailable, although this happened only in a small number of patients. A major problem was that the vast majority of patients do not have a molecular diagnosis and the state-of-the -art in IRD is based on both clinical and molecular diagnosis. In this context comments about inheritance patterns must be taken with caution. Finally, many of the genetic studies with negative results were very old and patients need to be reassured using NGS techniques. Nevertheless, this is something we wanted to point out to be able to ask regional management for a change in their policy denying test to this group of patients and families.
Knowing the rate of genetic testing in actual clinical practice can be a good starting point to plan future actions such as genetic studies with new diagnostic techniques for as many subjects as possible, which would allow classification of the pathology from the genotypic point of view in our population, to move forward in the search for new mutations and properly diagnose patients with doubtful diagnoses.