Introduction
Inherited retinal diseases (IRDs) represent a highly heterogenous group of genetic disorders. Although individually rare, they collectively represent a major cause of vision impairment. Many of these diseases are typically characterized by progressive dysfunction, including the loss of photoreceptors and retinal pigment epithelium (RPE), ultimately leading to severe vision impairment or blindness. IRDs are reported to be the leading cause of low vision certification amongst the working-age population in several countries.1–3
A diverse panel of experts was interviewed to share their unique insights and perspectives on IRDs. These discussions covered various topics, including the challenges faced by patients with IRDs, the complexities associated with diagnosing these conditions, and strategies for managing patients in the absence of effective treatments, with the notable exception of RPE65-IRD. The panel was comprised of Dr. Bart Leroy, chair of the EURETINA IRD and paediatric retina subspecialty section; ophthalmologists and retina specialists Dr. Philipp Herrmann and Dr. Omar Mahroo; genetic counselor Hannah L. Scanga; and patient advocate Avril Daly.
Fundamentals of IRDs
Clinical classifications and terminology systems are essential for standardizing patient health information across various healthcare contexts, including clinical care, research, reimbursement, and epidemiological studies. Over time, the naming conventions for IRDs have evolved from simplistic eponyms and descriptive terms to more sophisticated classifications based on electrophysiology and genetics. Despite these advancements, reaching a consensus on standardized terminology remains a significant challenge. This lack of agreement can cause difficulties and insecurities for patients and referring colleagues, Dr. Herrmann notes. However, efforts are actively underway to address this issue, with organizations like EU Rare Diseases and European Reference Network for Rare Eye Diseases (ERN-EYE) playing a pivotal role. Their objectives include supporting the definition, codification, and comprehensive cataloging of rare diseases.
Clinical Classifications and Terminology
Classifying IRDs is particularly challenging due to the influence of numerous factors such as inheritance patterns, age of onset, disease progression rate, primary site of retinal dysfunction, and associated syndromic features.
IRDs can be categorized based on the cell type or area of retina primarily affected. Conditions restricted to the macula are termed macular dystrophies, whilst progressive conditions affecting photoreceptors across the retina are termed retinal dystrophies. If rod photoreceptors are affected earlier than cone photoreceptors, the term rod-cone dystrophy may be used (this is the case in retinitis pigmentosa). Those conditions affecting cone photoreceptors or primarily cone photoreceptors may be termed cone or cone-rod dystrophies. In terms of inheritance patterns, IRDs can follow autosomal dominant, autosomal recessive, X-linked, and mitochondrial (or maternal) modes. Additionally, they can be classified by age of onset, with some manifesting in early childhood (such as Leber congenital amaurosis) and others presenting symptoms in adolescence or later in life. However, IRDs can also be categorized as either stationary or progressive.
Dr. Mahroo acknowledges the advantages of each classification system while noting that none of them is perfect. Despite the growing emphasis on gene-based classification systems, relying solely on genetic information may not be sufficient. Therefore, achieving enhanced diagnostic precision may necessitate integrating additional details such as mode of inheritance and phenotype alongside genetic information.
Dr. Leroy indeed emphasizes the enduring importance of basic clinical classification systems, which prioritize the clinical symptoms reported by patients. Following this initial evaluation, ophthalmologists can then identify the underlying molecular defects, specifically the pathogenic variants in the responsible gene, highlighting the significance of newer molecular classification systems. Ideally, a classification system includes some degree of both genetic and clinical information.
Prevalence
IRDs affect approximately 1 in 3450 individuals.4 The most prevalent IRD, retinitis pigmentosa (RP), affects about 1 in 4500 individuals on average. Stargardt disease follows at 1 in 17,000, Usher syndrome at 1 in 25,000, and Leber congenital amaurosis at 1 in 42,000.4 However, prevalence can vary widely depending on geographic area, population ethnicity (whether heterogeneous or homogeneous), and cultural habits. For example, in populations with high rates of consanguinity, the prevalence of RP can be up to 1 in 500. 5–7
To date, 325 genes have been implicated in IRDs (RetNet, accessed on 13 July 2024). However, the contribution of individual genes to the overall prevalence of the disease is relatively modest, with the majority of identified pathogenic variants being unique to a single individual.8
The ABCA4 gene is among the most common disease-causing genes in IRDs, and biallelic pathogenic variants therein are considered the primary cause of Stargardt disease.9 Some variants in this gene can also lead to Stargardt disease with additional cone or cone-rod dystrophy. The most common causes of X-linked retinitis pigmentosa (XLRP) are variations in the RPGR gene, which account for up to 80% of XLRP cases.10 Pathogenic variants in the USH2A gene represent the most frequent known causes of autosomal recessive RP (the gene is also associated with Type II Usher syndrome).11,12 For autosomal dominant RP, the most commonly associated genes include RHO, PRPF31, and RP1.13,14
It’s important to note that the prevalence of specific genes and variants significantly varies among different ethnicities. However, there is currently a prominent gap in the existing genetic databases regarding diversity of ethnic groups.
Families with a history of IRDs often harbor misconceptions about inheritance patterns, particularly regarding the risk of passing the condition to their children. Understanding this exact pattern is critical for providing accurate information. In the case of recessive diseases, the likelihood of a patient’s child inheriting the condition is very low unless the patient’s partner is genetically related. Whereas dominant, X-linked, or mitochondrial disorders are more prominently displayed in families, since they may be inherited from a single affected individual or female carrier. Some families hold stories that IRDs skip generations or affect specific traits like eye color. While respecting these family narratives and perspectives, it is important to explain that advancements in genetic testing and imaging now offer more accurate ways to identify individuals at risk.
Impact on Overall Quality of Life
Vision is one of our most critical senses, and its impairment or loss can profoundly impact patients. Terms like “blinding disease” can evoke strong emotions and misconceptions, with many patients inaccurately assuming they will have a complete absence of light perception. Therefore, it is crucial to openly discuss and clarify the meaning of “blindness” to address fears and confusion exacerbated by government and disability markers based on visual acuity. Additionally, cultural differences must be considered to ensure that patients fully understand the terminology used. As Dr. Leroy emphasizes, “It’s important that patients understand what I mean.”
Living with IRDs extends beyond physical health, deeply affecting psychological well-being and quality of life. Dr. Mahroo highlights the importance of prioritizing patients’ quality of life in care, recognizing the diverse effects of IRDs and that each individual’s response is unique, influenced by factors like life circumstances, timing of diagnosis, and disease progression pace. Ms. Daly highlights that patients’ reactions vary greatly based on their prior awareness of IRDs; those with a family history often approach their diagnosis with expectations shaped by familial experiences, even though their disease course may differ. For healthcare providers, empathizing with these individual journeys and delivering personalized support are crucial in significantly enhancing patients’ quality of life.
Complementing this focus on quality of life, the emotional impact of an initial IRD diagnosis can be profound, deeply affecting both patients and their families. Regardless of age, individuals are often confronted with feelings of loss, guilt, self-doubt, and uncertainty about their future capabilities. Ms. Scanga stresses the importance of acknowledging and normalizing these emotions as part of coping with such impactful news. Recognizing when patients or families require additional support and referring them to mental health professionals and identifying support services (e.g., support groups, vision support or rehabilitation services) can provide crucial assistance during this difficult time.
Ms. Daly further points out that these psychological challenges associated with living with IRDs are enduring. Fear of the unknown and adapting to a progressive and unpredictable condition are challenging. Healthcare providers should address these concerns by emphasizing the importance of obtaining a clear diagnosis and understanding the genotype, which can help predict the disease’s natural course. This approach aligns patient expectations with accurate information rather than fear.
The hereditary nature of IRDs complicates decisions concerning family planning, career choices, and personal identity, often exacerbating societal stigma and stress related to concealing vision loss. Addressing these complex effects requires healthcare providers to offer tailored support, including empathy, access to mental health services, and strategies aimed at enhancing quality of life and fostering resilience in managing IRDs.
The Intricacies of the Diagnostic Process
Key Elements
Diagnostic testing for IRDs involves a series of comprehensive evaluations. It begins with taking a general medical and ocular history and assessing the patient’s family history. A thorough eye examination follows, including anterior segment and dilated fundus examination and evaluation of best-corrected visual acuity. The extent of vision loss is determined using a visual field test, such as the Goldmann visual field test. Retinal activity is evaluated through a full-field electroretinogram, and imaging techniques such as fundus photography, spectral-domain optical coherence tomography, and fundus autofluorescence are employed to evaluate patterns, structural changes and function of the retina. Dr. Mahroo highlights that, “High-quality retinal imaging has revolutionized our practices, allowing us to see patterns that we could never see before.”
Additionally, full-field stimulus threshold testing serves as a valuable tool for further diagnostic investigation. Establishing the genotype of IRDs is increasingly regarded as essential in the diagnostic workup, complementing clinical findings and aiding in confirming or clarifying the diagnosis, as well as the likely progression of the disease. Dr. Leroy underscores the inseparability of molecular and clinical data, emphasizing the critical need for their integration and synchronization in making important decisions.
Ultimately, achieving a robust diagnosis is a highly intricate process that entails numerous steps and critical decisions. Dr. Mahroo underscores the development of algorithms designed to assist clinicians in navigating this complexity.15
The Challenges
Due to the diverse and overlapping manifestations of different IRDs, achieving a definitive diagnosis is often complex. IRDs exhibit significant variability in visual impairment, impact on daily life, disease progression, and suitability for therapeutic intervention. While assessing the extent of symptoms and visual function is relatively straightforward, identifying IRDs at early stages and pinpointing their underlying causes remains challenging. Patients often experience what is commonly referred to as a “diagnostic odyssey”, where it can take years to obtain a definite genetic diagnosis.
Diagnosing an IRD is relatively straightforward when its presentation aligns with textbook examples. The tools we have today are satisfactory and have significantly improved diagnostic accuracy. However, the real difficulty lies in identifying IRDs at early stages and when cases deviate from classical patterns. A delay in diagnosis can result in significant time loss, as patients might already be symptomatic. Fortunately, advancements in imaging techniques and genetics provide promising avenues for even quicker, easier, and more accurate diagnoses, both phenotypically and genotypically.
An additional challenge in the diagnostic process is accessing genetic testing and then pinpointing the responsible genetic variant. In more than 40% of IRD patients, identifying their genetic variant remains elusive, either due to its novelty in association with retinal disease or challenges in detection with current technology. Another area of potential difficulty is differentiating between genetic diseases and conditions that mimic them, such as inflammatory diseases, drug toxicities, or infections. Misdiagnoses can result in inappropriate treatments, including unnecessary immunosuppression.
In summary, early and precise diagnosis is crucial for patients with IRDs and their families. It not only facilitates timely management and intervention but also enables early access to social and psychological support. Furthermore, early diagnosis can guide life planning, helping to mitigate the impact of the disease on education and professional pursuits.
Navigating IRD Clinical Cases
Case#1: A Complex Family
This is an intriguing clinical case involving an exceptionally complex family that included four members remarkably affected by four different IRDs, each linked to distinct mutations and inheritance modes (Figure 1).16 Dr. Herrmann notes that achieving a conclusive disease classification was challenging at the time of presentation, necessitating molecular genetic testing for precise classification. The quest for an accurate diagnosis and prognosis demanded a comprehensive approach integrating clinical characterization with extensive molecular diagnostics.
Figure 1. For each patient (IV.3, IV.4, V.1, and V.2) is shown, fundus color image (first column), fundus autofluorescence imaging with 488 nm excitation (second column), and horizontal spectral-domain optical coherence tomography line scan (third column) for one eye. Courtesy of Philipp Herrmann.
The diagnoses of the two unrelated parents (IV.3, IV.4), with autosomal dominant RP (mutation in the RHO gene) and autosomal recessive ABCA4-related retinopathy, respectively, were straightforward. However, the molecular genetic findings for their two children (V.1, V.2) yielded unexpected results. Both sons exhibited features within the phenotypic spectrum of ocular albinism, achromatopsia, and congenital stationary night blindness (CSNB), despite distinct differences. Molecular genetic testing revealed a novel mutation in the X-linked CACNA1F gene in the eldest son (V.1), commonly associated with incomplete CSNB,17,18 and a mutation in the MITF gene in the youngest son (V.2), known to cause two overlapping disorders: the Waardenburg syndrome type 2A and the Tietz albinism-deafness syndrome.19 These molecular genetic findings were consistent with their respective phenotypes, indicating distinct retinal dystrophies with an autosomal dominant de novo variant in one son and an X-linked variant in the other.
Diagnosing IRD cases like this is akin to what Dr. Herrmann describes as “engaging in detective-like work, digging into family details to make sense of the information we have.”
Case#2: A Negative Whole Genome Sequencing Result
In this case, Dr. Mahroo encountered an 18-year-old male who has experienced lifelong night blindness and mildly subnormal visual acuity despite refractive correction, along with high myopia. The anterior segment examination was unremarkable, and fundus findings were consistent with high myopia (Figure 2, top). His family history indicated a similar problem in a maternal cousin (Figure 2, bottom), suggesting a genetic condition. Both were recruited to the 100,000 Genomes Project in the UK and underwent whole-genome sequencing, which initially did not identify a potential underlying genetic cause.
Figure 2. Top) Color fundus photography from right and left eyes of an 18-year-old patient consistent with high myopia. Bottom) Family tree indicating a maternal cousin with similar problems. Courtesy of Omar Mahroo.
Upon reviewing their family tree, X-linked inheritance was strongly suggested. Electrophysiology, although less commonly used today, played a crucial role in establishing the diagnosis. Examination of electrophysiology data from when the patient was five years old revealed features consistent with incomplete congenital stationary night blindness. This information directed attention to the CACNA1F gene, the only X-linked gene known to cause this condition, guiding re-interrogation of the whole-genome sequencing data. A causative variant was then discovered in that gene that was initially missed, having been classified as a filter failure in the bioinformatics pipeline.
This example illustrates a common misconception: people assume that obtaining all genetic data will automatically provide answers. However, comprehensive testing often yields negative results or identifies variations in multiple genes that are not pathogenic. Expertise is crucial to interpret these results. Careful examination of the family history, phenotype, and electrophysiology is essential to pinpoint specific genes for detailed investigation. When encountering variations in multiple genes, it is vital to prioritize those that align with the phenotype.
Case#3: Isolated Rod-Cone Dystrophy Due to Mutations in Genes for Syndromic IRDs
Dr. Leroy sheds light on a case involving two siblings, a brother and a sister, who experienced night blindness for several years and were eventually diagnosed with RP. The other sister and parents did not have the disease. The brother, now in a stable relationship and wanting to start a family, sought to understand the recurrence risk for his children. To find answers, he underwent whole-exome sequencing targeting known IRD genes (RetNet-WES). The test revealed several genetic variants (Figure 3), some of which raised significant concerns upon closer investigation.
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Figure 3. Results from whole-exome sequencing targeting known inherited retinal disease genes (RetNet-WES) for the brother and sister. Courtesy of Bart Leroy.
One of the identified variants, CLN3: c1213C>T, p.(Arg405Trp), heterozygous, class 3, has been previously associated with isolated retinal degeneration. In one case, this variant was linked to adult-onset neurodegeneration following an initial presentation of isolated retinal degeneration. Furthermore, bi-allelic mutations in CLN3 mutations are associated with autosomal recessive neuronal ceroid lipofuscinosis or Batten disease, a fatal neurodegenerative disorder that typically begins in childhood. Children with this condition progressively lose their vision within months, and over a few years, they lose all their bodily functions, eventually leading to death. Understandably, this information caused considerable distress for the proband and his partner.
Additionally, the presence of bi-allelic mutations in EYS is known to be associated with autosomal recessive RP, while heterozygous mutations in PRPH2 are linked to autosomal dominant RP. The variant detected in the RPL1 gene has been previously described in affected family members of three Japanese families with occult macular dystrophy and in three apparently unaffected individuals from two families, suggesting reduced or age-related penetrance.
Given the complexity and potential implications of these findings, genetic counseling was strongly recommended. Molecular results were interpreted in the context of clinical presentation, and further workup was requested, including segregation analysis of the variants identified in CLN3, EYS, and PRPH2 in first-degree relatives. The molecular results from the affected sister confirmed that compound heterozygosity for the CLN3 variant, now upgraded to class 4, and a deletion of exons 8-9 of CLN3 was the cause of isolated autosomal recessive retinitis pigmentosa (ARRP) in both siblings. Dr. Leroy stresses the importance of distinguishing between a class 3 variant, which has an uncertain relationship with a disease, and class 4 or 5 variants, which are likely pathogenic or pathogenic, respectively. Class 4 and 5 variants are actionable, allowing for prenatal or preimplantation genetic testing, and potentially gene therapy.
Dr. Leroy also emphasizes that while certain genes are often associated with the worst-case scenarios, they can also be linked to milder forms of diseases. In this case, the patients were reassured that although CLN3 is typically associated with a severe paediatric disease, as adults, they likely have non-syndromic ARRP caused by bi-allelic mutations in CLN3 (missense and deletion of exons 8-9). This diagnosis provided closure to the patients. They were also informed about the possibility of preconceptual partner carrier screening and advised that neurological evaluation should be based solely on the presence of symptoms.
Genetic Testing: Understanding the Options
The decision to conduct genetic testing is driven by various motivations, primarily to better understand the prognosis, recurrence risk, and/or learn about future or current treatment options for the patient’s condition.20 Additionally, patients often seek genetic testing to gain a deeper understanding of their own or a family member’s condition. Other reasons include eligibility for clinical trials and confirmation that the condition does have a genetic, rather than non-genetic, cause.
However, to undergo genetic testing, patients typically face significant delays and consult multiple physicians, including family doctors, optometrists, ophthalmologists, and retinal specialists, from the time they first notice a vision problem until they are tested. According to a recent global survey,20 it can take three or more years for most IRD patients to undergo genetic testing. Ms. Daly points out that people are simply not being referred to Centers of Expertise, often due to a lack of education or for financial reasons. These delays underscore the importance of informed and timely referrals to qualified professionals.
In the United States, genetic counselling is primarily provided by specifically trained genetic counsellors, whereas in Europe, medical geneticists or genetic specialists often take on this role.20 Ms. Scanga, an experienced genetic counselor, emphasizes that “No patient should go through a genetic test without having some pre-test counseling and education, because they may not know what they’re agreeing to undergo and the implications of the result.”
For patients suspected of having an IRD, genetic counselors start by meticulously evaluating the patient’s medical and family history. This assessment includes the age of symptom onset, the progression and nature of symptoms, any pertinent extraocular medical history, and the construction of a detailed family pedigree. This comprehensive approach allows genetic counselors to tailor an appropriate testing plan that aligns with the patient’s unique circumstances.
Throughout this process, genetic counselors play a pivotal role as educators, simplifying intricate medical terminology and relating it to the patient’s personal health journey. They provide comprehensive information about available genetic tests, the test’s purpose, possible results (positive, negative or inconclusive; Figure 4), and associated costs. It is crucial that patients fully understand and consent to the test before proceeding. This approach establishes a solid framework, ensuring that patients are well-prepared to receive and understand their genetic test results. Furthermore, if a patient is satisfied knowing they have an IRD but is not ready to explore the underlying reasons, they should also be empowered to make that decision.
Figure 4. Step-by-step actions to consider when looking into genetic testing. Courtesy of Hannah L. Scanga.
Available Genetic Tests
Various genetic tests are available (Figure 5), each presenting challenges in selection. The goal is to balance comprehensiveness for a high detection rate, while minimizing difficult-to-interpret incidental findings. Broader tests increase the likelihood of finding answers but also increase the risk of incidental findings.
Targeted testing for known mutations is optimal when the cause has been previously identified through genetic testing of an affected relative and the patient’s clinical diagnosis aligns with the family diagnosis. This can be done pre- or post-symptomatically. Pre-symptomatic testing requires counseling on “the right to know” and “the right not to know” principles. When clinical features deviate from family patterns, broader testing is necessary to avoid false reassurance from negative results.
Single-gene testing is less common due to the gene overlap in IRDs but remains useful for specific single-gene phenotypes like Choroideremia (CHM gene) or gyrate atrophy (OAT gene). Phenotype-driven gene panels, testing a large group of IRD-related genes, are the most common approach and should ideally include about 325 genes to cover all IRD phenotypes, along with mitochondrial DNA to capture these types of mutations. Whole-exome or whole-genome sequencing is another option, often chosen first due to its availability and support from various programs. In the UK, for instance, Dr. Mahroo notes that most patients have already transitioned to whole-genome sequencing. Looking ahead, Dr. Leroy anticipates the emergence of the clinical genome era, with comprehensive sequencing becoming readily accessible in clinic settings. This will support “the right to know your gene” principle for all genetic conditions.
More extensive testing may also be necessary if previous tests are negative. It is important to note, however, that these tests can identify conditions beyond IRDs, such as hereditary cancer syndromes or cardiomyopathy. Patients must be informed and decide whether they want information about these potential findings. While these tests generate a large amount of data, which can be challenging to interpret immediately, having this data allows for future re-evaluation as our understanding of genetic influences on IRDs evolves, offering a secondary benefit.
Ms. Daly strongly advocates for genetic testing as crucial for patients to make informed decisions about their future. Technological advancements have simplified genetic testing and increased support, despite ongoing debates on sequencing methods and ethical concerns.
Understanding Genetic Test Results
An effective approach to reviewing a genetic test result begins with thorough pre-test discussions. When delivering the test result, it is crucial to get straight to the point. Start by stating the test result category (Figure 6) without using technical jargon, as this is what the patient is most eager to hear. Then delve into the details, reminding them that it’s a lot of information and that you can be as detailed as they want. Some patients seek all the information, while others prefer just the highlights. Counselors should check in with their patients regularly, providing opportunities to revisit and clarify the information.
A positive test result can bring relief to patients who have lived with a diagnosis for years. These patients may expect or even hope for a positive result, as it provides precise information and may open doors for therapies or targeted management of their condition. On the other hand, for newly diagnosed patients, especially children, a positive test result can often be distressing. The impact of the diagnosis can be emotionally overwhelming, as they might have had doubts and clung to the hope that the diagnosis wasn’t real or that there was another explanation for the symptoms besides IRD.
Negative test results can surprise patients who were expecting answers, particularly if they have symptoms or a known condition. Many patients believe genetic tests will provide conclusive results, especially if they know others who received clear answers and expect a similar outcome. It’s crucial to inform patients before testing that not all genetic test results are positive and there is no guarantee of receiving a definitive answer. Preparing patients for a negative result is important, as they may feel confused or disappointed if they were expecting a way for them to move forward. It is also critical to acknowledge that a negative test result does not conclude that there is no genetic cause for the condition. The knowledge of the underlying genes for IRDs is continuing to expand, and patients who previously received negative results may benefit from repeated or expanded testing in the future.
The inconclusive result is the most difficult category for providers, who must decide if additional information can clarify the interpretation. Patients may remain in this inconclusive category for an extended period, prompting considerations for more imaging or testing, including testing other family members. Often, patients fall into this category due to unique genetic variations known as private mutations or variants, which are specific to their family.
It’s important to emphasize that our interpretation of genetic test results as positive, negative, or inconclusive relies on data from disease and population databases. When a genetic change is unique to a family and not found in these databases, it complicates interpretation and can cause confusion within the family.
It’s crucial to understand that one genetic test is not the end of the road. Regular follow-up appointments can be appropriate for patients with negative or inconclusive genetic test results, as these allow for reassessment and consideration of additional testing as our knowledge of genetics evolves.
As of 2024, not all genetic causes for IRDs have been identified. Therefore, a negative result does not definitively rule out a genetic basis or the possibility of familial recurrence, except in cases of conclusive familial variant testing. Even for patients with positive results, ongoing research may uncover new insights into specific mutations within their families that could impact future generations.
Access to Genetic Testing
Access to genetic testing often depends on the clinician consulted by the patient. “Seeing a retinal specialist who values genetic testing is advantageous, whereas clinicians who only consider it when treatment options are available present challenges”, says Ms. Daly. Genetic tests are often limited and costly, with hospital budgets in Ireland frequently unable to cover expenses, leading to referrals and causing uncertainty for patients due to lengthy waiting lists. Dr. Herrmann also points out the significant disparities in the accessibility of genetic testing across countries.
In response to these challenges, organizations such as Fighting Blindness in Ireland established the Target 5000 initiative, offering free genetic testing for individuals affected by IRDs. In Germany and Belgium, on the other hand, genetic testing is covered by basic national health insurance, ensuring accessibility for all individuals regardless of their insurance provider. In the UK, whole-genome sequencing is available for IRDs and is nationally funded. Ms. Daly advocates for establishing a standardized care protocol for IRD patients and underscores the importance of aligning with European standards.
Managing IRDs
Currently, voretigene neparvovec (VN) gene therapy stands as the sole approved treatment for patients with bi-allelic RPE65-mediated inherited retinal dystrophy who have sufficient viable retinal cells. VN was approved by the FDA in 2017 and later by EMA in 2018. This therapy uses a viral vector to deliver the RPE65 gene into RPE cells, effectively compensating for the underlying mutations and positioning itself as the most advanced treatment option available for these conditions.21
Dr. Herrmann emphasizes continuous development efforts in the field, albeit sometimes slower than hoped for by the patients. Ongoing clinical trials are exploring new gene therapies. For Stargardt disease, various pharmacological approaches that modulate the visual cycle are also under clinical investigation. These treatments, however, remain experimental and are not yet widely accessible to most patients.
Dr. Leroy highlights a critical point regarding the challenges faced by current clinical trials in demonstrating success for IRD therapies. These therapies often target individuals with very low vision, who, early in life, did not develop normal neural visual pathways between the eyes and the brain. Consequently, improving vision function is challenging, and these therapies may only stabilize the disease or slow degeneration rather than significantly enhance vision.
Regulatory bodies such as the FDA and EMA have high standards, mainly based on results from treatments of common retinal diseases, such as diabetic retinopathy, where anti-VEGF treatments can significantly improve visual acuity. However, applying these standards to IRD therapies is problematic and often unattainable. There is a pressing need for a paradigm shift in how novel therapies for IRDs are developed, approved, and brought to market. This shift would help navigate the complex and challenging pathway from therapy development to patient access.
The Importance of Continuous Monitoring
In the absence of widely available treatments for most IRDs, follow-up appointments play a crucial role in assessing prognosis and monitoring disease progression. Given the field’s relative newness and historical lack of clear diagnostics, understanding disease evolution is pivotal for advancing research, conducting clinical trials, and developing effective treatments.
Appointment intervals are typically adjusted based on disease progression rates: faster-progressing cases may necessitate shorter intervals, whereas slower progression may allow for appointments spaced over several years. Generally, due to the slow progression of the majority of IRDs, standard practice involves scheduling appointments at intervals of approximately one to two years.
Patients with certain conditions may need more frequent follow-ups due to associated vascular issues. For instance, mutations in the CRB1 gene can in some cases lead to abnormal blood vessel development (Coats-like vasculopathy), requiring vigilant monitoring and prompt laser treatment if needed. Similarly, in cases of macular dystrophies, new blood vessels may develop, requiring anti-VEGF treatment and more frequent follow-ups.
Understandably, patients with IRDs often perceive healthcare visits as merely validating what they already know, regardless of whether there are changes or not. However, as our understanding of IRDs and their management advances, healthcare providers are assuming greater responsibilities. A notable trend is the establishment of dedicated clinics and specific days exclusively for IRD patients at many centers. This model ensures comprehensive care, including necessary imaging, detailed discussions about any developments since their last visit, addressing questions, and attending to patients' emotional needs. These specialized clinics also prioritize updating patients on the latest treatments and research, aspects often overlooked in general clinics due to time constraints.
“Despite these advancements, accessing specialized centers remains a significant challenge for patients”, as highlighted by Dr. Herrmann. Swift access across Europe is crucial, particularly with one treatment currently available and the potential for future therapies. Improving access is a top priority to facilitate timely interventions that could potentially slow or halt disease progression and prevent advanced stages. The ERN-EYE is one organization focused on improving cross-border care for IRD patients.
Healthcare Coverage & Resources
In the US, patients with IRDs often face considerable coverage disparities. While medical insurance typically covers essential services in ophthalmology, vision-related needs such as glasses, optical devices, and low-vision aids are often inadequately covered or entirely excluded by vision insurance. As patients’ vision deteriorates, the need for new aids escalates, leading to significant out-of-pocket expenses as they strive to maintain their independence. Fortunately, there are foundations and programs offering resources and discounts to assist patients. Ms. Scanga emphasizes the importance of consistently connecting patients with these resources, including local bureaus specialized in blindness and vision services, as well as national foundations.
In contrast, the approach in the UK differs significantly. Dr. Mahroo explains that most eye departments integrate low-vision assessment or aid clinics. These clinics are staffed by optometrists specialized in optimizing vision for individuals with IRDs or other causes of impaired vision that cannot be fully corrected with standard glasses. They provide a variety of aids, including magnifiers, and advice on digital magnification tools tailored to each person’s specific needs. The advent of smartphone applications like SeeingAI have revolutionized the lives of many patients. Similarly, reimbursed services are available in most continental European countries.
Ms. Daly points out that while support services like adaptive software or long cane training are available if needed in Ireland, they are not always immediately necessary after diagnosis when a patient’s vision is often still functional. It is essential to understanding the patients’ evolving needs as the disease progresses, with a primary focus on psychological support.
Dr. Mahroo also underscores the critical roles of eye clinic liaison officers, who offer advice and support to patients facing visual impairment challenges. Similarly, in Ireland, certain clinics provide liaison officers who guide patients to organizations such as the Vision Ireland, Fighting Blindness Ireland, Guide Dogs, or ChildVision. The Certificate of Vision Impairment (CVI) serves as another crucial resource in the UK, providing formal recognition and facilitating access to financial and practical assistance for eligible individuals.
Luckily, dedicated support groups for IRDs are widely available across Europe, complemented by continent-wide groups accessible online. Patients also find valuable support through social media communities. It’s important for patients to engage with both general IRD support groups, providing broad insights into vision loss, and specific support groups tailored to their particular IRD. General groups provide diverse support and ideas, especially beneficial for those with rare conditions seeking peer connections. Conversely, specific diagnosis support groups foster a strong sense of community, where members share experiences and knowledge about their unique conditions.
Both patients and healthcare providers are encouraged to actively seek out these support groups and foundational organizations like the Foundation Fighting Blindness, which is actively involved in the United States and internationally. These organizations typically offer patient registries, email lists, and regular updates on research and news, ensuring patients stay well-informed and connected. Engaging with these resources not only provides a sense of community and belonging, but also empowers patients by staying abreast of advancements in their condition, rather than waiting for updates only during medical appointments.
Ultimately, it’s about actively engaging with patients to learn about their feelings and challenges, so healthcare providers can effectively identify and connect patients with pertinent resources and support networks throughout their healthcare journey.
Conclusion
Moving IRD research and care forward requires a collaborative effort involving ophthalmologists, researchers, patients, and families. Breaking down barriers and fostering genuine collaboration through interdisciplinary meetings, workshops, webinars, and inclusive conferences is crucial. This cross-talk enhances understanding, improves patient care, and strengthens the community.
Patients play a pivotal role and should have a voice in shaping research and care strategies. Their insights into symptoms and challenges are invaluable and often provide new perspectives for clinicians. Research driven by patient input is already yielding significant insights, emphasizing the need to integrate patient experiences into treatment development.
Over the past six to seven years, substantial progress has been made in Europe through structured collaboration and the development of care pathways and guidelines. The ERN-EYE is instrumental in this evolution. This shift towards open discussion and innovation is creating exciting opportunities for advancing diagnostics, care, and treatment. Continued cooperation and a proactive approach are essential to maintain this momentum and achieve future goals.
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