According to the researchers, “concept elicitation” is the process of identifying the symptoms experienced and the functions affected as the result of a given disease and how this has an impact on patients’ lives. The study was typically done through semi-structured qualitative interviews with patients.  Among the 14 symptoms reported, poor night vision/night blindness, difficulty seeing in bright light, and difficulty seeing in low/dim light were experienced by all participants. Over 50% of participants in either condition reported difficulty adapting from bright to dark and vice versa, poor peripheral vision, poor contrast sensitivity, poor distance vision, and poor visual acuity. Symptoms had a significant impact on activities of daily living. Most commonly impacted were the ability to navigate and the use of digital screens (n = 17/17, 100%) as well as physical functioning and work/school-related activities (n = 16/17, 94.1%). These impacts were often exacerbated by environmental factors, navigation and on emotional well-being.  In particular, health-related Quality of Life (HRQoL) impacts associated with emotional wellbeing (n = 13/17, 76.5%).  The study showed that patients reported sadness/depression due to their eye condition (n = 6/13, 46.2%),  and this concern was followed by annoyance/frustration (n = 4/13, 30.8%), guilt/burden (n = 3/13, 23.1%), anxiety/stress (n = 2/13, 15.4%), fear (n = 2/13, 15.4%), anger (n = 2/13, 15.4%), powerlessness (n = 2/13, 15.4%), and embarrassment/ self-consciousness (n = 2/13, 15.4%). All impacts on emotional well-being were mentioned spontaneously and not specifically probed upon during the interviews.

Figure 1. Conceptual model of RP and CHM symptom and impact concepts

Table 1.  Number of RP and CHM patients reporting symptoms to cause or exacerbate impacts

[The research work is licensed under the terms  of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), cited by Rometsch et al., entitled by: “Patient experience in retinitis pigmentosa and Choroideremia- a concept elicitation study in 17 patients based on qualitative interviews”, Orphanet J Rare Dis . 2025 Aug 11;20(1):418.  doi: 10.1186/s13023-025-03713-4].

The researchers summarised that the most frequently reported impacts concerned activities of daily living (100%), emotions (90%), reading (81%), driving (71%), chores and cleaning (62%), navigation (52%), sports/ physical activity (52%), and walking into objects (48%). Impacts were reported to be exacerbated by lighting conditions, unfamiliar environments and weather conditions.  The patient interviews provided insight into the patient experience of RP and CHM to develop a combined conceptual model of the RP and CHM disease experience.  Finally, the researchers commented that, “our findings are suitable to inform recommendations for the development of patient-reported outcome (PRO) and performance outcome (PerfO) measures needed to evaluate novel therapies for both RP and CHM.”

The Fight Inherited Retinal Blindness! (FIRB!) Registry is an expanded registry building on previous modules supported by the Save Sight Registries, a non-profit organisation, also supported with the University of Sydney, Australia.   A committee of six members was overseen the construction of the Fight Inherited Retinal Blindness! Module with a further 11 experts all of whom have a clinical and/or research interest in IRDs.  The web-based Fight Inherited Retinal Blindness! registry records baseline demographic, clinical, and genetic data together with follow-up data. The Human Phenotype Ontology and Monarch Disease Ontology nomenclature were incorporated within the Fight Inherited Retinal Blindness! architecture to standardize nomenclature (Mondo: unifying diseases for the world, by the world. medRxiv 2022: 1–12). The registry has developed software that can assign individual diagnoses to one of seven broad phenotypic groups, with minimum datasets dependent on the broad phenotypic group. New patient entries can be completed in 5 minutes, and follow-up data can be entered in 2 minutes.

Figure 1. Screengrab of a data entry/presentation page for a patient with IRD secondary to biallelic RPE65 mutations after retinal gene therapy with voretigene neparvovec. Pertinent clinical data (e.g., best-corrected visual acuity, FST results) can be plotted against time as a means of easily tracking disease progression and treatment effects. [The research work is licensed under the terms  of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), cited by Simunovic et al., entitled by: “THE FIGHT INHERITED RETINAL BLINDNESS! PROJECT A New Treatment Outcome and Natural History Registry for Inherited Retinal Disease”, Retina, 2025; 45:286–295 ].

According to the researchers, The Fight Inherited Retinal Blindness Registry! was conceived for two purposes: “first, to track the natural history of IRDs, and second, to monitor real-world outcomes in patients receiving emerging treatments, such as gene therapy”. The FIRB! registry provides a rapid means of recording outcomes from treatments, for example, following Luxturna gene therapy (voretigene neparvovec). The outcome measures are those “recommended by both regulatory authorities and professional bodies internationally, making the registry a convenient and rapid means of recording outcomes to assess real world outcomes and for drug monitoring by national authorities”. In addition, FIRB! provides a means of “tracking adverse or unanticipated events—such as the development of chorioretinal atrophy—which has only been reported post regulatory approval in a significant minority of patients undergoing voretigene neparvovec gene therapy”.

Figure 1. The spectrum of ABCA4 retinopathy. Representative FAF images are shown for each stage. Individuals with a normal fundus can carry any of these alleles: WT/WT, WT/severe, WT/mild, severe/mildIP, mild/mild, mild/mildIP, or mildIP/mildIP. MildIP, mild with incomplete penetrance; WT, wild type. Images were obtained and modified from Cremers FP et al, Prog Retin Eye Res. 2020;79:100861, (CC-BY license).  [This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, cited by Panneman DM,  et al. Expansion of the ABCA4-associated retinopathy spectrum: Severe variants can be associated with early-onset severe retinal dystrophy. Invest Ophthalmol Vis Sci. 2025;66(6):19. https://doi.org/10.1167/iovs.66.6.19).

As a juvenile form of RP, LCA is a severe congenital or early infant-onset form of non-syndromic retinal disease characterised by severe retinal dystrophy, vision loss, nystagmus, an absence of a normal pupil response and an almost non-recordable ERG. LCA was originally identified by a German clinical ophthalmologist, Theodor von Leber in 1869 and the disorder was primarily based on the early infant-onset form of non-syndromic inherited visual loss.  However, following the original description of the infantile disorder, a subsequent milder form of the same disease presented in the 6th and 7th years of life and led to blindness by the age of 30 years, considered to be on the same spectrum as LCA.  This later-onset disease has been referenced by several different names including juvenile and early-onset retinitis pigmentosa, childhood-onset severe retinal dystrophy, Early Onset Severe Retinal Dystrophy (EOSRD) and Severe Early Childhood Onset Retinal Dystrophy (SECORD). A more recent structure for nomenclature, aiming to define the basis as being on genotype rather than phenotype (e.g., RPE65-related LCA), is preferable.  Currently, the researchers studying in Nijmegen, investigated the genetic cause of disease and clinical characteristics in three probands with EOSRD.

The three patients were seen in various ocular genetics and retinal dystrophy clinics from Chicago, IL, USA, Vancouver, Quebec, Canada, and Auckland, New Zealand.

Table 1. Genetic Findings in ABCA4 for Probands 1, 2, and 3. Severity scores are according to Cornelis et al., Am J Hum Genet. 2022;109:498–507 The protein notation of the c.6729+5_6729+19del variant is based on the midigene assay results from Sangermano et al., Genome Res. 2018;28:100–110. [Open Access, Panneman DM,  et al. Expansion of the ABCA4-associated retinopathy spectrum: Severe variants can be associated with early-onset severe retinal dystrophy. Invest Ophthalmol Vis Sci. 2025;66(6):19. https://doi.org/10.1167/iovs.66.6.19)].

Following their analysis, the researchers described “a new genotype–phenotype correlation identified in three EOSRD probands that carry at least two severe variants in ABCA4”. The data showed that two probands carry the same pathogenic, homozygous splice site variant. In addition, extensive studies of the ABCA4 gene in associated conditions such as Stargardt disease (STGD1) and STGD-like macular diseases have revealed late-onset phenotypes, and they commented that “no link with severe early-onset IRDs such as EOSRD or LCA has been found previously”. Using  whole genome sequencing (WGS), the researchers identified two NBAS (neuroblastoma-amplified sequence) variants and a homozygous CNGB3 (cyclic nucleotide gated channel subunit beta 3) variant in probands 1 and 3, respectively.  In summary, the team’s results “expand the phenotypic spectrum of disorders associated with variants in ABCA4”, spanning ages from birth to old age.

Sensorineural hearing and vision loss occur in a heterogeneous group of conditions arising from a range of causes including genetic defects, infections and autoimmune diseases. Genetic causes affect primary cilia, including Usher syndrome (USH), Bardet-Biedl, Waardenburg, Stickler and Alstrom syndromes.  Usher syndrome (USH) is a rare disease, historically categorised into three groups (USH1, USH2, and USH3), dependent on the severity of hearing loss, onset of retinitis pigmentosa (RP) and presence/absence of vestibular dysfunction.  (A fourth and atypical subgroup (USH4) are further identified with variants in arylsulfatase G (ARSG) centrosomal proteins (CEP78 and CEP250), and abhydrolase domain-containing protein 12).  USH may arise from mutations in at least 9 genes including: MY07A, USH1C, CDH23, PCHD15, USH1G, USH2A, GPR98, WHRN and CLRN.

In the current research from the University of British Columbia, four affected members and four unaffected members of a four-generation Canadian family were evaluated showing a phenotype of hearing loss and RP segregated in an autosomal dominant manner:

Figure 1. Four-generation family tree segregating autosomal dominant hearing loss and RP. The black symbols represent affected individuals and white symbols represent unaffected individuals. The arrow indicates the proband patient. The line above the symbols denotes family members who were examined. The first two generations were reported by proband as deaf-blind but were not examined or genetically tested. [The research work is licensed under a Creative Commons Attribution-Non Commercial-No Derivatives (http://creativecommons.org/licenses/by-nc-nd/3.0/) cited by Gregory-Evans et al., entitled by: “Mutation of beta-tubulin 4B gene (TUBB4B) causes autosomal dominant retinitis pigmentosa with sensorineural hearing loss in a multigenerational family”, Molecular Vision 2025; 31:175-188 <http://www.molvis.org/molvis/v31/175> ].

Following their clinical testing and analysis, results showed that a panel-based genetic test revealed a heterozygous c.1168C>T, p.Arg390Trp variant in the beta-tubulin 4B gene (TUBB4B), only in affected family members.  The researchers commented that, “based on in silico analysis, segregation analysis through the family, and literature evaluation, this variant is likely to be the disease-causing variant inherited in an autosomal dominant manner”, confirmed to be a rare disease variant. To further understand how variants in TUBB4B might cause retinal and hearing loss phenotypes, the researchers used a zebrafish and mouse model and found loss of both rod and cone photoreceptors appeared to be lethal.  The study concluded that, “due to the high level of gene conservation, loss of function of Tubb4b/tubb4b leads to early lethality in both mice and zebrafish and suggests that homozygous variants in TUBB4B in humans might also be embryonic lethal. Since the tubb4b zebrafish model demonstrates an eye phenotype unlike mice, this could become the best model to test potential therapeutic options for the retinal phenotype”.

Rare diseases are a challenge to diagnose and identify the correct pathology, not least of all for the rarity of diagnosticians available in the world. The use of machine learning and AI tools are hugely beneficial to overcome some of these challenges then capable to support clinicians, families and their patients. In a recent study, it was estimated that over 40% of ophthalmic patients in the UK did not obtain a genetic diagnosis, and in many parts of the world where genetic testing is unavailable, showed a further number of undiagnosed cases. To address these concerns, the UCL and Moorfields research teams have developed a deep learning model, (Eye2Gene), now capable to predict the causative IRD gene from the retinal scans of a patient providing a gene-level prediction score for 63 distinct IRD genes. The Eye2Gene model was trained on a total of 58,030 scans from 2,451 patients (4,801 eyes) from Moorfields, split into three different modalities: FAF (n = 16,708), IR (n = 20,659) and SD-OCT volumes (n = 20,663). In addition, the research team asked eight ophthalmologists specializing in inherited retinal degenerations (IRDs), with 5–15 years of experience, to predict the causative gene based on a single FAF image per patient across 50 different patients.

Figure 1. Eye2Gene model. Eye2Gene provides IRD-gene prediction given a retinal scan of one of three imaging modalities (FAF, IR or SD-OCT) for up to 63 gene classes. Images are initially resized to 256 by 256 pixels and rescaled to the range [0,1]. Each image modality-specific predictor block consists of an ensemble of five CoAtNet neural networks. The outputs are averaged to produce a final prediction output. The performance of Eye2Gene is evaluated on a held-out internal test dataset from MEH (Moorfields) consisting of 28,174 images acquired from 524 patients over 9,291 patient visits since 2006. [The research work is licensed under a Creative Commons Attribution-Non Commercial-No Derivatives 4.0 International License, cited by Pontikos N., et al., entitled by: “Next-generation phenotyping of inherited retinal diseases from multimodal imaging with Eye2Gene”, Nature Machine Intelligence, Volume 7, June 2025, 967–978; https://doi.org/10.1038/s42256-025-01040-8].

Table 1. Top-five accuracy represents the proportion of case for which the correct gene appeared in the top-five ranked choices of the model. Anticipated top-five accuracy refers to extrapolated accuracy based on per-gene accuracy at MEH extrapolated to target dataset gene distribution. Note that unspecified ethnicity is not accounted in the ethnicity distribution reported here. Bold indicates summary data across sites.

Following their results, their deep learning algorithm, (with an externally validated dataset provided by five different clinical centres) provided better-than-expert-level top-five accuracy of 83.9% for supporting genetic diagnosis for the 63 most common genetic causes. In their study, the UK researchers commented that, ”Eye2Gene shows that next-generation phenotyping using AI is a promising approach to aid in the genetic diagnosis for individuals with IRDs, something that is not only important for improving patient experience and reducing associated overheads, but is likely to become especially important due to the growing number of potentially treatable IRDs where a rapid genetic diagnosis can lead to an improved outcome for the patient.” However, the team also cautioned the outcomes with some caveats including: (1) the training dataset was established in Moorfields Eye Hospital, London, and other gene distributions can vary between different patient populations and across patients of different ethnic backgrounds’; (2) the current Eye2Gene version is limited to predicting 63 gene classes out of a potential of 281 genes associated with IRDs however, there may be other genes that are yet to be confirmed outside of the 63 classes, and finally; (3) the human ophthalmic experts’ evaluation and diagnosis was based on images only, rather than a wider evaluation of clinical decision making and genetic interpretations. Regardless, the learning aspect of the AI model will likely to improve as fine-tuned iterations become updated in due course.

While drusen is normal with advancing age, and can be seen by small yellow or white accumulations of extracellular material that build up between Bruch’s membrane and the retinal pigment epithelium (RPE), reticular pseudodrusen appears more prominent under blue light. In contrary to drusen which locates below the RPE, reticular pseudodrusen is located superficial to the RPE, more commonly found at the superotemporal quadrant of the macula.  According to the current authors’ GWAS study, “several lines of evidence highlight the distinctions between drusen and RPD, including their anatomic location (below and above the RPE, respectively); differences in biochemical composition; a significantly increased risk of progression in AMD patients with RPD compared to without; and appearance of RPD in conditions where drusen are not part of the main phenotype.”

GWAS have been conducted since 2002 and there have been >4,000 studies conducted worldwide, reporting ~55,000 unique genetic associations across nearly ~5,000 traits and diseases. GWAS aim to identify single-nucleotide polymorphisms (SNPs) that occur more frequently within the genomes of a given disease population than in a control population and the SNPs can infer genomic regions for disease association.  In the current study from Moorefield hospital, their results showed that the primary GWAS analyses on their AMD cohort yielded 4 loci reaching genome-wide significance for pure RPD (ARMS2-HTRA1, PARD3B, ITPR1 and SLN) and 2 loci for pure drusen (CFH and ARMS2-HTRA1), summarized in the figure below:

Figure 1. Manhattan and quantile-quantile plots of GWAS results for number of pure RPD (in the absence of drusen) and number of pure drusen (in the absence of RPD). [The research work is licensed under a Creative Commons Attribution-Non Commercial-No Derivatives 4.0 International License, cited bySchwartz et al., entitled by: “Genetic Distinctions Between Reticular Pseudodrusen and Drusen: A Genome-Wide Association Study”, American Journal of Ophthalmology,  Volume 274, P286-295, June 2025, https://doi.org/10.1016/j.ajo.2025.03.007].

The GWAS analyses reported genetic associations with (i) pure RPD (cases with RPD in at least one eye but no drusen) and (ii) pure drusen (cases with drusen in at least one eye but no RPD).  The study included 1,787 participants: 1,037 controls, 361 pure drusen, 66 pure RPD, and 323 mixed cases. The primary pure RPD GWAS identified four genome-wide significant loci: rs11200630 near ARMS2-HTRA1 (P = 1.9e-09), rs79641866 at PARD3B (P = 1.3e-08), rs143184903 near ITPR1 (P = 8.1e-09), and rs76377757 near SLN (P = 4.3e-08). The latter three are uncommon variants (minor allele frequency <5%) and the authors commented that they should be interpreted with caution pending validation in larger studies and external cohorts. A significant association at the CFH locus was also observed using a candidate approach (P = 1.8e-04). In addition, for pure drusen, two loci reached genome-wide significance: rs10801555 at CFH (P = 6.0e-33) and rs61871744 at ARMS2-HTRA1 (P = 4.2e-20).

In summary, the researchers stated that, “we present the first reported GWAS for RPD, finding a genome-wide significant association at the ARMS2-HTRA1 locus, and potentially novel associations at the PARD3B, ITPR1 and SLN loci. An association at CFH was also observed, though at a lower significance threshold, and this locus colocalized with AMD. Larger studies are needed to clarify the roles of ARMS2-HTRA1 and CFH in RPD development and validate these newly identified RPD-specific genetic associations. Future research should aim to quantify RPD burden to enhance the statistical power of these studies.”

As EURETINA members know, The Lancet, the New England Journal of Medicine (NEJM), and the Journal of the American Medical Association (JAMA) are long-standing medical and scientific journals, originally established in 1823, 1812 and 1883, respectively.  The research journals provide a wide range of medical and clinical publications, including ophthalmology, with significant rankings, or impact factors (IF).  The current impact factor for The Lancet is 98.4, ranked #3, NEJM’s impact factor is 96.2, ranked #4 and JAMA’s impact factor is 63.5, ranked #10.  As of writing, there have been no specific comments to date from Mr. Kennedy’s remarks from representatives of The Lancet, the New England Journal of Medicine (NEJM), or the Journal of the American Medical Association (JAMA).

In the current research environment, the work and efforts are generally authored by multiple affiliations shared across the globe, and such international expertise often strengthens the validity of knowledge that serves patients and the public.  To block such journals (The Lancet, NEJM, JAMA) data will likely impact the value of US research, potentially required to publish in HHS government ‘in-house’ periodicals.  This may be immensely disruptive in an international cross-border current research and clinical trial environment.  Commenting in The Washington Post newspaper (accessed 29/5/2025), Dr. Adam Gaffney, MD, a public health researcher and assistant professor at Harvard Medical School stated that, “banning NIH-funded researchers from publishing in leading medical journals and requiring them to publish only in journals that carry the RFK Jr seal of approval would delegitimize taxpayer-funded research.”  In the podcast with Mr. Kennedy, there appears to be is a disconnect between the blocking of peer reviewed publicly-funded US scientists, due to alleged conflicts-of-interest and corruption on certain journals, on the one hand, while simultaneously issuing government policy through a private podcast advertising wellness products, with little or no peer review or independence. While conflicts-of-interest are not new in any endeavour of society, reform and improvements are likely to be a preferable course, rather than jettison such long-standing journals entirely.  Independent regulation, under-pinned by rigorous evidence-based decision making, should improve research integrity for all stakeholders.  The EURETINA Brief will follow for any updates and follow up in due course.

According to researchers, the average time to diagnosis for an IRD patient in Europe or America is presently 6.4(±9.1) years.  Getting a definitive diagnosis for patients for a recommended 1 year timeframe is challenging due to extreme genetic heterogeneity, phenotypic variability and availability of clinical expertise for IRD many jurisdictions.  In addition, interpreting novel or rare genetic variants can yield an inconclusive result, including “variants of uncertain significance”.  Artificial intelligence (AI) can analyse large volumes of imaging data acquired from patients with IRDs, enabling identification of distinct patterns of genotype-phenotype correlations.  The availability of connected data, formats and jurisdictions now have an opportunity to accelerate a diagnostic process and one example of such AI provides a “tool that is in development to aid genetic diagnosis is Eye2Gene”, an initiative supported by the National Institute for Health Research (NIHR) Biomedical Research Centre (BRC) at Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology, and also funded by a Moorfields Eye Charity Career Development Award. The Eye2Gene work located on https://eye2gene.com/#eye2gene and their summary approach outlines on the patient journey:

Researchers that conducted the survey used an online secure platform through registered charities in the UK, which provided support to patients with IRDs: Retina UK, Moorfields Eye Charity and Stargardt Connected. The survey was answered by 242 respondents, 80.2% of which were patients and the remainder were relatives, friends or caregivers. Following analysis of the data, the researchers confirmed that there was substantial variability in patient diagnostic journeys.  The median (IQR) age of the participants was 53 (36–64) years and 57.4% were women, with the most common conditions were Stargardt disease (44.2%) and retinitis pigmentosa (RP) (43.0%).  In terms of waiting times to see a specialist, the IQR was 1–4 years, the commute required IQR was 10–74 miles and number of visits to reach a diagnosis IQR was 2–4 (visits).

The results indicated that a substantial proportion of patients (35.8%) had a change in diagnosis in the patient journey and “the majority of respondents (>90%) were overwhelmingly in favour of the integration of AI into the IRD pathway to accelerate genetic diagnosis and improve care.”  The researchers concluded that the IRD care pathway may potentially bridge gaps of knowledge using AI and the survey provides a favourable attitude towards incorporating AI into diagnostic testing of IRDs.  According to the researchers, “the majority of the patients, as well as their companions, have a positive attitude towards AI being incorporated to improve their clinical care in the UK. These findings, which reflect the perspectives of patients, are valuable for informing and shaping policy on the integration of AI into the IRD care pathway.”

Figure 1. Associations of the PTPRB missense variant rs113791087 with central serous chorioretinopathy in 4 studies. The association of rs113791087 with central serous chorioretinopathy (CSC) was examined in 4 different studies. In all biobank-based studies (FinnGen, Million Veteran Program [MVP] and All of Us [see Methods in Nature Communications, 2025 16:4127)] included in the meta-analysis, patients with CSC were identified based on International Statistical Classification of Diseases codes, and all participants with age related macular degeneration were excluded from patients and controls following a harmonized study protocol. In the chronic CSC (cCSC) cohort, patients were identified from ophthalmological clinics based on expert review. Odds ratios (OR) and P-values were derived using logistic regression as implemented in Regenie (v2.2.4) in FinnGen, SAIGE (v1.3.0) in MVP, and Regenie (v3.2.2) in All Of Us. Association estimates and two-sided p-values were previously derived in the European cCSC cohort using the firth bias-corrected likelihood ratio test (see Rämö, JT et al Nat Comm, 2025) 16:4127). [This work is an open access content, licensed under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/), authored by Rämö, JT et al., entitled, “Rare genetic variation in PTPRB is associated with central serous chorioretinopathy, varicose veins and glaucoma”, published in Nature Communications ( 2025) 16:4127, https://doi.org/10.1038/s41467-025-58686-6].

Central serous chorioretinopathy (CSC) is a maculopathy with a thickened and dilated choroidal vasculature, retinal pigment epithelium (RPE) detachments and subretinal fluid (SRF) and the disorder may manifest in individuals between 30-50 years of age with decreased visual acuity.  The incidence can range between 5.8:100,000 and 34:100,000 in different populations.  The researchers commented that vascular remodelling in CSC has been “compared most closely to varicose veins, although the changes are on a much smaller scale. Varicose veins are a common disease affecting approximately 20% of the population (females more than males) and represent a weakening of the vessel wall with resultant vascular dilation in the lower extremity (typically in the greater and lesser saphenous veins)”.  In their current study, the researchers identified genotype data from 1,477 patients and 455,449 controls in the FinnGen dataset, showing the association with a missense variant (rs113791087) in PTPRB (odds ratio=2.85, P = 4.5 × 10^-9) and was prioritized as “the likely causal variant by statistical fine-mapping” and “an increased risk of varicose veins and with a reduced risk of glaucoma”.

Following analysis, the researchers have proposed that ocular and systemic vascular diseases highlight a potential role for vascular dysfunction in central serous chorioretinopathy and this may provide an opportunity to identify novel therapeutic options.  Commenting on their paper, the authors stated that a “genetic finding has illuminated the Tie-2 and VE-Cadherin pathways as important in CSC, an area of study that was not under investigation previously but that may be important for therapeutic advancement.”  The same authors published a case series of patients with chronic CSC treated with intravitreal faricimab (an Ang-2 blocker and thus a Tie-2 activator). Fourteen of sixteen treated eyes (14/16) were found “to have reduced disease activity in response to the medication, providing additional evidence that this genetic finding is highly relevant” (see Am. J. Ophthalmol. 269, 246–254 [2024]).

Neuronal ceroid lipofuscinoses (NCL) comprise a group of genetically heterogeneous lysosomal storage disorders are the most common inherited neurodegenerative disorders of childhood, primarily arising from an autosomal recessive pattern of inheritance.  Thirteen (13) causative genes are highly relevant for NCL characterized by the accumulation of auto-fluorescent storage material in neurons, leading to epileptic seizures, progressive psychomotor retardation, and premature death.  Abnormal accumulation of pathology leads to generalized photoreceptor disease and profound visual impairment. In the current study, researchers evaluated 12 subjects with pathogenic, or likely pathogenic variants, in 5 NCL-causing genes (CLN3, TPP1, PPT1, CLN6, and MFSD8). Patients presented with varying phenotypes ranging from severe neurocognitive features (n = 8; 67%), including seizures and developmental delays and regressions, to non-syndromic retinal dystrophies (n = 2; 17%). Visual acuities at presentation ranged from light perception to 20/20. In those with recordable ERGs, the traces were electronegative and suggestive of early cone dysfunction. Fundus imaging and OCTs demonstrated outer retinal loss that varied with underlying genotype.

Figure 1. Genotypic variants of PPT1 can lead to differential retinal phenotypes and progressive features. A, In Subject 9 with classic systemic features of neuronal ceroid lipofuscinoses, the exam was consistent with a bulls eye maculopathy as evidenced on fundus autofluorescence (white arrow). Over the course of 1 year follow-up, OCT findings showed progressive loss of the outer retinal layers which correlated with decline in best-corrected visual acuity. B, In subject 10 with more isolated retinal findings and genotypic findings consistent with granular osmiophilic deposit, the exam was again consistent with a bulls eye maculopathy as evidenced on fundus autofluorescence (white arrow), but OCT findings were most notable for almost total loss of the outer retinal bands with hyperreflective foci in the fovea that progressively enlarged over the course of 12 months (yellow arrows). [This work is an open access content, licensed under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/), authored by Huey, J et al., entitled, “Genetic Reasons for Phenotypic Diversity in Neuronal Ceroid Lipofuscinoses and High-Resolution Imaging as a Marker of Retinal Disease”, published in Ophthalmology Science, Vol. 4, No. 6, Dec 2024, https://doi.org/10.1016/j.xops.2024.100560].

Following their analysis from the cohort, the study “provides new insight into how individual genotypes can influence phenotypic features of retinal disease in different forms of NCL.” The researchers found that subjects had molecular confirmation of either homozygous or compound heterozygous pathogenic, or likely pathogenic variants in PPT1, TPP1, and CLN3. In addition, 5 novel pathogenic or likely pathogenic variants were identified in their cohort, including TPP1 c.837C>G, TPP1 c.508þ4A>G, CLN6 c.247dup, MFSD8 c.1217_1218dup, and MFSD8 exon 11e13 deletion.  The clinicians also commented that, “understanding the genetic contributions to disease can have important retinal implications that can help guide the clinician. In certain cases, it may differentiate between a classic, multisystemic NCL presentation and a more isolated retinal phenotype.” Pre-clinical trials for specific therapies for TTP1-related NCL are in progress in animal models, reportedly preserving retinal function until reached end-stage neurological disease.  Further research are likely to progress on a range of technological strategies to support these NCL patients and their families.