It is important to sensitize the ophthalmic community for early changes of RPE65-IRD. Early stages of RPE65-IRD should not be confounded with mild RPE65-IRD. The images in figure 2 of the paper Stingl et al. clearly show distinct pathologies even in the colour fundus image. For more details see [Fig. 1]
[3]. The fovea has a dull macular reflex, the vitreoretinal interface is abnormal, the retinal arteries are narrowed, and outside the macula there are hypopigmented (“blond”) areas with increased mottling of the retinal pigment epithelium (RPE), indicating disturbed RPE with increased visibility of the choroid not related to myopia (the patient is hypermetropic at the time of examination).
Fig. 1 Wide-angle colour fundus images of the right and left eye of P12 [3] at age 9 years. Wide-angle colour images showed clear pathologies that were in line with his visual field constriction to about 200 sum degrees with the kinetic Goldmann perimeter and his visual acuity of 0.4 to 0.6 logMAR in both eyes (RE, LE). Consequently, after informed consent of the parents and the patient, he received VN therapy. The right eye is the same eye presented in fig. 2 of Stingl et al. 2024 [1].
These early findings in young patients with severe forms of EOSRD were reported already in 2000 [4]. Of note, all four patients described in that paper became legally blind later, and received voretigene neparvovec (VN) between 2021 and 2022. Their results are reported in 2024 (P06, 07, 08, and 17) [3]. All four patients had a blond fundus and increased granularity of the RPE in early childhood, the four fundi are shown in the paper with the technology available at that time. [Fig. 2 a] shows the right eye of P17 at age 5.75 years (slight hypermetropia, logMAR 1.0; at age 8 years logMAR 0.5 on binocular testing), and [Fig. 2 b] P08 at age 6.75 years (moderate hypermetropic astigmatism, log MAR 1.0.
Fig. 2 a (left) fundus images of P17 at age 5.75 years. b (right) fundus images of P08 [3] at age 6.75 years [4]. Distinct pathologies are described in the text. Please note that due to differences in illumination the colour images appear much brighter than seen on funduscopy, and brighter than the wide-angle images shown in [Fig. 1] and [Fig. 3].
It is important that ophthalmologists be aware of and recognize such early pathologies on fundoscopy as additional examinations such as OCT will only be ordered in case of suspected pathologies. Early diagnosis has become important, as with the approval of VN (in Europe in 2018), an effective treatment has become available. Intensive information of the professional community about the early phenotype has led to a decrease of missed diagnosis from 17% in 2019 to 5% in 2021 as reported in the two surveys conducted by the European Vision Institute Clinical Research Net EVICR.net in 2019 and 2021 [5].
The authors rightly state that there are also patients with mild RPE65 phenotypes. We described the first case in 2008 and explained it with residual enzyme activity associated with a hypomorphic mutation [6]. [Fig. 3] shows a fundus montage of this first identified patient. Visual acuity maybe full but also reduced to logMAR 0.2 registered at age 8 years in this patient that at follow-up improved to logMAR 0.0. Of note, this patient did not have nystagmus compared to the other patients described in this letter who all had some degree of sensory defect nystagmus including a rotatory component.
Fig. 3 Fundus montage of a patient with hypomorphic mutations in RPE65. The macula has a dull reflex, and the retinal periphery appears hypopigmented. The patient is reported in Lorenz et al. IOVS2008, where a slightly different fundus montage is shown [6].
In very young children, only rough estimates of their visual performance are possible. Therefore, it may be difficult to differentiate between early severe and early mild forms unless enzyme activity studies are performed or comparable tests to estimate the functional consequences of the specific sequence variants in individual patients. Fullfield ERG may also be helpful as in milder forms residual photopic answers maybe seen [6].
My personal concept is not to advise treatment too early but wait until solid subjective functional measurements are possible. Given the relatively slow decline in visual acuity during the first decade of life [7], and in some instances even spontaneous functional improvement to some degree, I do not think that we miss the therapeutic window for successful treatment with such a conservative approach. As in most instances VN mainly induces improved rod function but not cone function, prevention of amblyopia is not a valid argument. Very few data are available on preschool children treated with VN. In a series by Gerhardt et al. [8], one out of the four treated children showed an extreme improvement in visual acuity. The patient did not have nystagmus prior to therapy hence a true mild case cannot be excluded. On the other hand, it has been shown that in the mouse RPE65 plays a role in cone homeostasis of retinoid
pools rather than in chromophore regeneration [9] so that early restoration of the protein could in fact improve cone function.
Enhanced high-resolution imaging and definition of novel biomarkers may help discerning the various phenotypes in the future even in the absence of subjective functional parameters i.e. in very young or non-cooperative children. Sensory defect nystagmus (SDN) may indicate a more severe phenotype. The immediate and long-term retinal complication rates that maybe higher in very young children have to be weighed against theoretical advantages of early treatment.
In summary, given the availability of an effective gene therapy to treat RPE65-IRD, that nevertheless carries a risk of treatment-induced accelerated retinal degeneration of up to 50% [3], it is of utmost importance to differentiate early disease from mild disease and to collect as many data possible on the natural history of the different phenotypes. To this end, recognition of early cases of the extremely rare RPE65-IRD is crucial.
Birgit Lorenz
