Diagnosis of Inherited Retinal Diseases

Abstract

Inherited retinal diseases are a frequent cause of severe visual impairment or blindness in children and adults of working age. Across this group of diseases, there is great variability in the degree of visual impairment, the impact on everyday life, disease progression, and the suitability to therapeutic intervention. Therefore, an early and precise diagnosis is crucial for patients and their families. Characterizing inherited retinal diseases involves a detailed medical history, clinical examination with testing of visual function, multimodal retinal imaging as well as molecular genetic testing. This may facilitate a distinction between different inherited retinal diseases, as well as a differentiation from monogenic systemic diseases with retinal involvement, and from mimicking diseases.

Key words

inherited retinal diseases - retinitis pigmentosa - cone-rod dystrophy - diagnosis - imaging - genetic testing

Inherited retinal diseases are among the most frequent causes of severe visual impairment and blindness in children and adults of working age. They result from mutations in genes that, in the most part, play an essential role in the structure, function or metabolism of the outer retinal layers. An early, accurate diagnosis not only facilitates therapeutic measures and the provision of visual support, but also enables social and psychological support to be sought at an early stage and may guide life planning (i. e. help to minimize the effects of the disease on education and professional choices).

The diagnosis of an inherited retinal disease is often complex due to pronounced heterogeneity [1], [2], [3], [4], [5], [6]. While it is relatively straightforward to determine the extent of symptoms and visual function, accurate identification of the underlying disease cause often depends on various investigations including molecular genetic testing, and on the experience of the clinician.

Many patients with inherited retinal diseases experience a diagnostic odyssey before receiving an accurate diagnosis and comprehensive disease counseling. To prevent this, it is essential to suspect or recognize an inherited retinal disease at an early stage and to initiate further investigations in a specialized center. This may require the expertise of a multidisciplinary team (i. e. including geneticists and genetic counsellors). Even comprehensively characterized patients sometimes seek advice from several centers as they feel they are missing therapeutic opportunities. Therefore, it is essential not only to examine patients, but also to provide comprehensive patient counseling, follow-up examinations, and to connect them to patient advocacy groups.

Core elements of the characterization of inherited retinal diseases, which may serve as a cornerstone for thorough patient and family counseling, include:

• Detailed ocular history

• Comprehensive general medical history to reveal comorbidities and/or systemic disorders

• Comprehensive family history

• Clinical examinations

• Determination of visual function (including electrophysiology, if indicated)

• Multimodal retinal imaging

• Molecular genetic testing

For patients and their families, the following may be of particular importance:

• Classification of visual function (whether the individual satisfies the legal visual criteria for driving, workplace design), advice regarding current limitations, and some indication of the likelihood, and rate, of future visual loss

• Information on (novel) therapeutic approaches and clinical studies

• Differentiation from non-genetic diseases

• Investigation of suspected syndromal or systemic manifestations

• Information regarding likelihood of heritability

• Information regarding patient organizations and disease-specific patient groups

• Information regarding patient registers, for example the patient register of PRO RETINA in Germany (www.pro-retina.de/patientenregister), MyEyeSite in the UK (https://myeyesite.health) or My Retina Tracker Registry by the Foundation Fighting Blindness in the USA (www.myretinatracker.org)

Medical History

In a routine clinical setting, a variety of symptoms may signify an inherited retinal disease, particularly when symptoms cannot be explained by other diseases or anomalies. Examples include difficulties seeing in the dark, visual field restriction or delayed adaptation to a change between different light environments. Although the development of symptoms in the first 2 – 3 decades of life and progressive visual difficulties are characteristic of most inherited retinal diseases, neither advanced age nor stationary findings can exclude a diagnosis. A detailed medical history can substantiate an initial suspicion of inherited retinal disease and may guide further examinations. The age of onset and nature of the initial symptoms can also guide disease classification, especially when advanced degenerative changes do not allow a morphology-based classification.

Patients with inherited retinal diseases often are accustomed to (some of) the symptoms and develop specific coping strategies. Accordingly, detailed questioning may be required to obtain relevant information, which is particularly the case in patients with functional limitations since birth or early childhood. Specific questions, when phrased in different ways, often succeed in revealing such changes in visual function. It may, for instance, be the case that scotopic vision is compromised if the patient feels uncomfortable in unfamiliar surroundings but is quite comfortable in familiar surroundings. Glare may be a problem if the patient prefers being indoors, and/or wears sunglasses or tinted glasses more frequently than others. However, such glasses are also worn by some patients to improve contrast in their vision.

The general medical history is also important. Retinal changes may be associated with systemic syndromes (e.g. Usher or Bardet-Biedl syndrome) or may be a manifestation of a systemic disease which involves various organ systems. Examples of such systemic diseases include pseudoxanthoma elasticum (PXE) with an increased cardiovascular risk, primary hyperoxaluria type 1 with renal dysfunction, and mitochondrial diseases such as Kearns-Sayre syndrome, or McArdle disease with muscle problems [7], [8], [9], [10], [11]. A precise medication history is also essential, so that, for instance, retinopathy due to hydroxychloroquine or pentosan polysulfate can be differentiated [12], [13], [14], [15], [16], [17], [18]. Immunomodulatory therapies, whether for tumour therapy (melanoma, basal cell carcinoma), rheumatological conditions or ophthalmic diseases, may not only have ocular side-effects, but may also point to systemic conditions associated with vision problems (e. g. vitamin A deficiency associated with ulcerative colitis). Dietary and lifestyle factors should also be considered: For example, there are indications of possible negative effects on the disease course when patients with variants in the ABCA4 gene take high-dose vitamin A, or when patients with retinitis pigmentosa smoke [19], [20].

A family history of (eye) diseases can also suggest the underlying disease. Inherited retinal diseases can be passed on to descendants via autosomal-dominant, autosomal-recessive, X-chromosomal or mitochondrial inheritance. Whenever possible, documentation of a pedigree should encompass at least 3 generations and 2nd-degree relatives, which may reveal X-chromosomal inheritance patterns or dominant inherited diseases with reduced penetrance (i. e. that not every carrier develops the disease). Even if no other family members are affected, a pedigree should be recorded. It may, for instance, document consanguinuity, which is often associated with autosomal-recessive disorders, and may identify other family members in whom examination may be contributory. Furthermore, detailed enquiries of medical history is worthwhile: If the parents are not known to be related, this does not exclude consanguinuity, e. g. if they are from the same village or neighbouring villages, or met at a family celebration. Furthermore, it is important to document the age at death of deceased family members: For example, if one parent died at an age at which the disease may not yet have been symptomatic, this person cannot be considered healthy with certainty (especially in case of late-onset symptoms/disease). Comprehensive documentation of other systemic diseases of family members may also be important. For instance, diabetes mellitus in the mother and hearing impairment in her sister may point to a mitochondrial disease, even if each affected person develops different organ manifestations. Furthermore, apparently separate eye diseases may sometimes point to the genetic cause: Family members with a mutation in the KIF11 gene, for example, may manifest different retinal changes (familial exudative vitreoretinopathy, cone-rod dystrophy or congenital chorioretinal atrophies) [21], [22]. Documentation of ethnicity may help in interpreting differences in regional incidence of genetic variants and disease.

Examination of Visual Function

Refraction and best corrected visual acuity are important parameters that may provide useful information for differential diagnosis. Visual acuity testing and refraction is usually reliable in adults, but it can take several visits to obtain accurate visual acuity and refraction in children under the age of 2. Under this age, refraction should be determined in cycloplegia. The established method for determination of near vision is to measure line vision, e.g. with LEA symbols or Landolt rings. Another important aspect is to differentiate/exclude amblyopia. Besides visual acuity, symptoms such as nystagmus may indirectly allow conclusions regarding visual function. Reduced visual acuity in children is, however, not restricted to the spectrum of inherited retinal diseases. Differential diagnosis may, for instance, include delayed visual maturation, central visual disorders or optic nerve hypoplasia [23], [24]. In young patients with mild visual impairment and subtle changes on retinal imaging, colour vision examination can also be helpful, for instance in differentiating inherited retinal diseases from optic neuritis.

The refraction may also be considered in the differential diagnostic workup. For example, patients with mutations in the bestrophin gene are often hyperopic, whereas patients with retinitis pigmentosa or congenital stationary night blindness are often myopic.

Visual field examinations provide information regarding peripheral and central visual field defects and may support the diagnosis as well as classification of inherited retinal diseases. Particularly in advanced disease stages, Goldmann perimetry often provides more information than static computer perimetry as it better depicts residual visual field “islands” [25]. In addition to its value in diagnosis and follow-up examinations, Goldmann perimetry may provide valuable information regarding insurance, liability and social security assessments such as reduced earning capacity, ability to operate vehicles, workplace risks or disability allowances for the blind and visually handicapped [25], [26].

Historically, electrophysiology was often critical in diagnosing retinal diseases, but recent developments in retinal imaging and molecular genetic testing have reduced its importance. Electroretinography (ERG), however, is still useful in the differentiation of panretinal from macular dystrophies, for diagnosing generalized retinal dysfunction such as CSNB or achromatopsia, and to identify characteristic gene-specific patterns, for example in patients with variants in the KCNV2 or NR2E3 gene. Electrophysiological examination can also be useful when interpreting genetic variants of undetermined significance, or in differentiating mimicking diseases (see below). The importance of electrooculography (EOG) has also decreased due to developments in imaging and molecular genetics, and even in Best disease EOG readings are not necessarily abnormal [27]. Furthermore, there is no benefit in performing an EOG if ERG responses are severely reduced or absent.

Retinal Imaging

Retinal imaging facilitates the detection of retinal pathologies including changes that are barely visible or cannot be detected on fundus examination alone. In addition to conventional colour fundus photography, used to document funduscopic findings, established technologies include high-resolution optical coherence tomography (OCT) and fundus autofluorescence (AF) ([Fig. 1]) [3], [4], [5], [6]. Changes over the course of a disease can often be precisely tracked and measured using AF and OCT imaging. This is particularly important for clinical studies, since visual acuity often does not change significantly within the timeframe of a study, whereas disease progression may be traceable in the images.

Fig. 1 Representative inherited retinal diseases using widefield color imaging, fundus autofluorescence (AF) and optical coherence tomography (OCT) (from left to right). Rows 1 and 2: ABCA4-associated retinopathy (Stargardt disease) with spots of increased and reduced autofluorescence as well as a central chorioretinal atrophy. Row 3: Retinitis pigmentosa (RP) sine pigmento with characteristic RP findings on AF (ring of increased autofluorescence) as well as on OCT (central photoreceptor band retained with adjacent thinning and atrophy of outer retina). Row 4: “Classic” retinitis pigmentosa. Row 5: Autosomal-recessive bestrophinopathy with spots of increased AF as well as serous subretinal fluid in OCT imaging.

OCT generates “quasi histological” cross-sectional images of the retina with rapid image acquisition. In retinal dystrophies, important aspects include assessment of the integrity of the retinal pigment epithelium (RPE) and the photoreceptor layers (e.g. ellipsoid zone, outer nuclear layer). Most patients with retinitis pigmentosa (RP) initially show peripheral thinning and atrophy of the outer retina due to a primary or predominant rod degeneration [28], [29]. By contrast, patients with cone-rod dystrophies (CRD) with primary macular degeneration show mainly central atrophic changes in the outer retina ([Fig. 1]). Furthermore, using OCT examinations, these two disease entities can be differentiated from stationary diseases that typically show little or no changes on OCT imaging such as congenital stationary night blindness or achromatopsia [30], [31], [32]. OCT can also detect macular oedema that occurs frequently in RP patients, which is hardly noticeable on fluorescein angiography. The strength of OCT imaging lies in the documentation of detailed follow-up examinations, and OCT imaging is particularly useful when it is combined with additional imaging modalities, such as blue or near-infrared AF.

AF visualizes the distribution of ocular fundus fluorophores, commonly using short-wavelength excitation light in the blue or green spectrum. This can reveal valuable diagnostic information regarding the topographic distribution and extent of retinal disease, and may often allow conclusions regarding retinal function [33], [34], [35], [36]. RP provides a good example: At the transition between mainly intact central retina and degenerated peripheral retina a concentric ring of increased autofluorescence with no visible funduscopic correlate is typically found [37], [38], [39]. Even if the exact origin of this phenomenon is not completely understood, OCT examinations have demonstrated that the ring corresponds to loss of the ellipsoid band and pronounced thinning or even loss of the photoreceptor layer. In keeping with this interpretation, a correlation was also found between the diameter of the ring and the size of the remaining visual field [40]. Thus a ring of increased autofluorescence is not only diagnostically valuable, it also provides information on the extent of retinal dysfunction [38], [41]. Rings of increased autofluorescence can also be found at the edges of degenerative retina in other diseases, confirming the necessity of detailed disease characterization (see section on mimicking retinal diseases). Further characteristic findings include spots of increased autofluorescence, e.g. in patients with ABCA4-associated retinopathy, or a vitelliform lesion with increased autofluorescence in patients with autosomal-dominant Best disease or in cases with IMPG2 mutations [42]. AF is also valuable in the early stages of retinal dystrophies. AF-alterations may be apparent even though funduscopy does not detect obvious abnormalities and patients have no, minimal or non-specific symptoms. Furthermore, in carriers of X-linked diseases (e.g. RPGR-associated RP or choroideremia), characteristic changes may appear in AF imaging ([Fig. 2]) that may facilitate a reliable diagnosis even before genetic testing is performed [43], [44], [45], [46], [47].

Fig. 2 Fundus color image (left), fundus autofluorescence (middle) and optical coherence tomography (right) of female carriers of X-linked retinal dystrophies. The upper row shows a carrier for RPGR-associated retinitis pigmentosa and the lower row for choroideremia.

Near-infrared fundus autofluorescence (NIR-AF) is an alternative imaging modality to conventional AF using longer wavelength excitation light (787 nm) [48]. Even though the NIR-AF signal is less intense and this imaging modality is used less frequently, it has numerous advantages over conventional AF: The image acquisition process is more comfortable for patients due to reduced glare, cataract has less impact on the images, and interpretation of the central retina is not compromised by macular pigment, allowing even minor changes to be analyzed. Due to the lower energy, there is also less concern of retinal light toxicity. Assuming good image quality, similar changes may be observed in patients with inherited retinal diseases in these two imaging modalities, although precise analysis can certainly detect qualitative differences ([Fig. 3]) [36], [49], [50], [51], [52]. A further benefit of NIR-AF may lie in the differential diagnosis of non-inherited retinal changes [26], [53], [54].

Fig. 3 Exemplary images using blue-light fundus autofluorescence (left) and near-infrared fundus autofluorescence (right). Good image quality often reveals similar changes with these imaging modalities, although precise analysis does detect qualitative differences. From top to bottom a healthy control and patients with retinitis pigmentosa, ABCA4-associated retinopathy, macular dystrophy as well as choroideremia are shown, respectively.

Along with these established retinal imaging modalities, new developments include quantitative autofluorescence [55], [56], which provides an indirect measure of RPE lipofuscin content, adaptive optics, allowing visualization of the retina at a cellular level [57], [58] and OCT angiography enabling non-invasive visualization of vessels of the ocular fundus [59], [60], [61]. However, the value and feasibility of these modalities have yet to be established. The relevance of angiography in inherited retinal diseases is practically nil, with applications still useful in special cases only, such as suspected choroidal neovascularization or retinal vascular changes with exudation.

Classification and Terminology of Inherited Retinal Diseases

The terminology used in the description of inherited retinal diseases is inconsistent. This may result in a patient receiving apparently different diagnoses from different ophthalmologists, and communicating the reason for apparent inconsistencies to patients may be appropriate to ensure trust.

An initial clinical classification is often based on the medical history and disease course. Inherited retinal diseases are predominantly progressive, as seen in cone-rod dystrophies and retinitis pigmentosa, although stationary findings are also possible as in congenital stationary night blindness or achromatopsia.

Subsequently, a classification can be established based on the retinal cell types primarily involved. Historically, this was based mainly on the results of full-field ERG testing: A macular dystrophy is characterized by normal photopic and scotopic responses with a reduced-pattern ERG and cone dystrophy by reduced photopic responses. In cone-rod dystrophies, the photopic readings are more affected than the scotopic readings, which is the opposite in rod-cone dystrophies (retinitis pigmentosa). In routine clinical practice, this terminology is also used frequently even if the required ERG testing has not been performed. However, the approach of using electrophysiological terminology to describe structural observations may be incorrect or occasionally inadequate.

Proper names have been established for numerous inherited retinal diseases, where first describers summarized observations or a constellation of symptoms into one disease. Although this may be appropriate in diseases with distinct phenotype-genotype correlations, such as Best disease, choroideremia or Biettiʼs crystalline dystrophy, it is often inaccurate for diseases with a broad genetic and/or phenotypic heterogeneity.

The use of proper names can result in morphological-functional as well as molecular inaccuracies. For example, “Stargardt disease” is also called – occasionally depending on the presentation – Stargardt disease type 1 (STGD1), fundus flavimaculatus, macular dystrophy, cone-rod dystrophy, cone dystrophy or ABCA4-associated retinal dystrophy. Despite this Babylonian confusion, whereby different terms evoke different associations, “Stargardt disease” usually refers to the autosomal-recessive disease due to mutations in the ABCA4 gene (STGD1). Historically, however, three additional conditions with a similar retinal phenotype were designated as Stargardt disease (STGD2–4). It turned out that both STGD2 and STGD3 are caused by mutations of the ELOVL4 gene (“STGD2” is no longer in use), and that STGD4 is caused by mutations of the PROM1 gene. The consecutive numeration of Stargardt disease was no longer used to describe patients with similar retinal features. This would, for example, also include patients with particular mutations in the PRPH2 gene. Autosomal-dominant mutations in ELOVL4, PROM1 and PRPH2 result in a retinal phenotype that may be similar to “true” Stargardtʼs disease patients, but these conditions are clinically, genetically and pathophysiologically different [62]. In addition, autosomal-recessive mutations in ELOVL4 and PROM1 also cause other conditions: ELOVL4 mutations may also lead to spinocerebellar ataxia as well as to ichthyosis, spastic quadriplegia, and learning difficulties [63], [64]; autosomal-recessive PROM1 mutations may cause an RP phenotype [65], [66], [67], [68], [69]. Some variants in the PRPH2 gene may also lead to central areolar choroidal dystrophy (CACD) or retinitis pigmentosa [70], [71], [72].

Thus, the nosology of inherited retinal diseases is complicated since mutations in the same gene may cause multiple retinal diseases (phenotypic heterogeneity) [73]. Furthermore, mutations in different genes may cause a similar phenotype (genotypic heterogeneity), and there may be other (as yet largely unknown) genetic and/or environmental factors that may have an influence on the disease manifestation [19], [74], [75], [76], [77].

The use of proper names may also confound the distinction between syndromal and non-syndromal conditions. For instance, variants in USH2A are typically associated with Usher syndrome, in which patients exhibit RP in addition to mild to severe hearing loss [78]. With increased frequency of molecular genetic testing, however, it became evident that many RP patients with USH2A mutations do not exhibit hearing impairment and that these patients do not show a syndromic disease [2], [79], [80]. If these patients are described as patients with Usher syndrome, this may imply hearing impairment, which, however, is not present. Likewise, mutations in Bardet-Biedl syndrome-associated genes may also be present in patients with non-syndromic RP [81], [82] or mutations in CEP290, classically associated with Senior-Løken, Joubert or Meckel-Gruber syndrome, may also be identified in non-syndromic Leberʼs congenital amaurosis (LCA) or RP [2], [83], [84], [85], [86]. Monogenic systemic diseases with retinal involvement should also be considered in the differential diagnosis. The transition from “classic” retinal dystrophies to systemic diseases with a retinal phenotype may be indistinct, as it is the case in PXE, some ciliopathies, or mitochondrial diseases [10], [87], [88], [89], [90], [91], [92].

Until a generally accepted, consensus-based terminology is established, the following pragmatic principle can be applied: be as precise as possible and as vague as necessary. With increasing diagnostic certainty, this can be modified: For example, a “retinal dystrophy” can be diagnosed at first non-specifically, followed by more precise specification once the results of electrophysiological and molecular genetic testing are known (e.g. “ABCA4 associated macular dystrophy”). If a stationary (e.g. CSNB) or mimicking disease cannot be excluded, this should be mentioned early in the differential diagnostics process. In order to not unsettle the patient, it is often worth providing a brief explanation of uncertainties in the diagnostic workflow. The diagnostic efficiency also depends on the experience and expertise of the clinician: a reliable diagnosis can often be established at the first consultation when characteristic disease features are present. However, a previously made diagnosis should always be reassessed and confirmed or rejected in the context of additional information or current findings/disease progression.

It may also be helpful to use terminology that links retinal alterations with monogenic systemic diseases. Examples include “PXE-associated retinopathy” or “mitochondrial retinopathy”. It may also be reasonable to indicate the affected gene or subtype of a disease, especially if (gene-)specific therapies are in development or available.

Differentiation from Mimicking Retinal Diseases

There are many diseases that can mimic an inherited retinal disease (mimicking diseases). This includes post-inflammatory retinal conditions (e.g. rubella retinopathy or post-uveitic conditions), adverse drug effects (e.g. of hydroxychloroquine, deferoxamine or pentosan retinopathy) and the spectrum of autoimmune retinopathies. Vitelliform macular lesions may also be observed occasionally associated with age-dependent macular degeneration, chronic vitreomacular traction or central serious chorioretinopathy (to name only a few) ([Fig. 4]). The diagnosis of a mimicking disease is of great relevance. For example, rubella retinopathy does not show significant progression, and in cases of adverse drug effects the causative therapeutic should be discontinued. In autoimmune processes, tumor screening may be indicated or, if necessary, immunosuppression may be considered.

Fig. 4 Exemplary retinal diseases that may mimic inherited retinal diseases. From top to bottom, patients with deferoxamine, rubella and hydroxychloroquine retinopathies, as well as a vitelliform macular lesion and autoimmune retinopathy. Fundus photography (left), blue-light fundus autofluorescence (middle) and optical coherence tomography (right).

This may also be relevant for family counselling, since the risk for family members is often less direct. Diagnosing a mimicking disease requires a detailed medical history and recognition of characteristic morphological features. Post-inflammation and autoimmune retinopathies in particular present with less symmetry compared to inherited diseases, although asymmetry may also be observed in retinal dystrophies, particularly in the early stages. Negative molecular testing may support but not confirm the diagnosis of a mimicking disease, as the causative mutation(s) are also not always identified in monogenic diseases [1], [2], [93], [94], [95], [96], [97].

Genetic Testing

A cornerstone in the diagnosis of inherited retinal dystrophies is molecular genetic testing [1], [2], [96], [97], [98], [99], [100], [101], [102], [103], [104], [105]. Identification of the molecular cause can not only provide information regarding the potential disease course or inheritance, but is also essential in light of (potential) disease-specific therapeutic options, including gene therapy, dietetic measures (e.g. a diet low in phytanic acid in Refsum disease) and pharmacotherapies (e.g. deuterated vitamin A [106] or visual cycle inhibitors in ABCA4-associated retinopathy/Stargardt disease). The approval of the first gene therapy (voretigene neparvovec) for patients with Leberʼs congenital amaurosis, due to mutations in the RPE65 gene, is likely just the beginning as it is expected that further novel therapies will become available [107]. For instance, gene therapies for choroideremia and X-linked RP (RPGR mutations) are currently in the late stages of clinical development [108], [109], [110], [111]. In advanced cases of inherited retinal diseases, where the exact phenotype cannot be determined due to widespread retinal degeneration, molecular testing may still enable a specific diagnosis.

Molecular testing can also result in the correction of an initial clinical diagnosis, may uncover an unexpected diagnosis, and may guide further investigations (e. g. hearing impairment, renal dysfunction, dyslipidemia, cardiomyopathy, diabetes) if the retinal disease suggests a syndromal condition [21]. Overall, a multidisciplinary approach involving geneticists, ophthalmologists, and potentially additional disciplines is essential in the interpretation of clinical ophthalmologic and molecular results. This sometimes includes a phenotypic re-evaluation following identification of a (potentially) causative molecular variant. After an interdisciplinary interpretation of the molecular results, comprehensive genetic counseling should be offered to patients and their families. If family members without disease signs or symptoms consider predictive genetic testing, counseling by a clinical geneticists or specialists qualified for this purpose is required beforehand.

Although detection of the molecular disease cause has become more accessible, the clinical diagnosis cannot be supported by genetic testing in all patients. However, a “negative” molecular result (no variant explaining the clinical findings detected) does not exclude the diagnosis of an inherited retinal disease – the clinical diagnosis remains in these cases. Furthermore, the detection of variant(s) in genes associated with retinal diseases does not exclude the possibility that mutations in other gene(s) are responsible for the phenotype.

Summary

Inherited retinal diseases may cause severe challenges in everyday life, physically as well as emotionally. For patients and their families, an accurate and comprehensive diagnosis is critical to prepare for the lifelong interpersonal, social and occupational impact of the diagnosis as well as for the potential loss of vision. A multidisciplinary approach is often essential, involving ophthalmologists, geneticists and other medical specialists.

Conflict of Interest/Interessenkonflikt

The authors declare that they have no conflict of interest./Die Autorinnen/Autoren geben an, dass kein Interessenkonflikt besteht.

Acknowledgements

This work was supported by the Dr. Werner Jackstädt Foundation, Wuppertal, Germany (Grant S0134-10.22), the National Institute for Health Research (NIHR) Oxford Biomedical Research Centre (BRC) and the Medical Research Council, UK (Grant MR/R000735/1). The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health.

• References/Literatur

• 1 Birtel J, Eisenberger T, Gliem M. et al. Clinical and genetic characteristics of 251 consecutive patients with macular and cone/cone-rod dystrophy. Sci Rep 2018; 8: 4824
• 2 Birtel J, Gliem M, Mangold E. et al. Next-generation sequencing identifies unexpected genotype-phenotype correlations in patients with retinitis pigmentosa. PLoS One 2018; 13: e0207958
• 3 Birtel J, Gliem M, Holz FG. et al. [Imaging and molecular genetic diagnostics for the characterization of retinal dystrophies]. Ophthalmologe 2018; 115: 1021-1027
• 4 Kellner U, Tillack H, Renner AB. Hereditäre Netzhaut-Aderhaut-Dystrophien Teil 1: Pathogenese, Diagnostik, Therapie, Patientenbetreuung. Ophthalmologe 2004; 101: 307-319
• 5 Renner AB, Kellner U. [Hereditary Macular Dystrophies]. Klin Monbl Augenheilkd 2016; 233: 1124-1141
• 6 Kellner U, Kellner S, Saleh M. et al. [Congenital Retinal Dystrophies: Combining Ophthalmological Techniques to Improve the Read-out]. Klin Monbl Augenheilkd 2020; 237: 275-287
• 7 Birtel J, Herrmann P, Garrelfs SF. et al. The Ocular Phenotype in Primary Hyperoxaluria Type 1. Am J Ophthalmol 2019; 206: 184-191
• 8 Birtel J, Charbel Issa P, Herrmann P. et al. Examination of the eye and retinal alterations in primary hyperoxaluria type 1. Nephrol Dial Transplant 2020; DOI: 10.1093/ndt/gfaa101.
• 9 Gliem M, Müller PL, Birtel J. et al. Frequency, Phenotypic Characteristics and Progression of Atrophy Associated With a Diseased Bruchʼs Membrane in Pseudoxanthoma Elasticum. Invest Ophthalmol Vis Sci 2016; 57: 3323-3330
• 10 Gliem M, Zaeytijd JD, Finger RP. et al. An update on the ocular phenotype in patients with pseudoxanthoma elasticum. Front Genet 2013; 4: 14
• 11 Shalaby AK, Charbel Issa P. Retinopathy in McArdle Disease. Ophthalmol Retina 2021; 2: 117
• 12 Kellner U, Kellner S, Weinitz S. et al. [Toxic retinopathies]. Ophthalmologe 2020; 117: 1247-1266
• 13 Marmor MF, Kellner U, Lai TY. et al. Revised recommendations on screening for chloroquine and hydroxychloroquine retinopathy. Ophthalmology 2011; 118: 415-422
• 14 Yusuf IH, Charbel Issa P, Lotery AJ. Pentosan Polysulfate Maculopathy-Prescribers Should Be Aware. JAMA Ophthalmol 2020; 138: 900-902 doi:10.1001/jamaophthalmol.2020.2364
• 15 Melles RB, Marmor MF. The risk of toxic retinopathy in patients on long-term hydroxychloroquine therapy. JAMA Ophthalmol 2014; 132: 1453-1460
• 16 Wang D, Au A, Gunnemann F. et al. Pentosan-associated maculopathy: prevalence, screening guidelines, and spectrum of findings based on prospective multimodal analysis. Can J Ophthalmol 2020; 55: 116-125
• 17 Shah R, Simonett JM, Lyons RJ. et al. Disease Course in Patients With Pentosan Polysulfate Sodium-Associated Maculopathy After Drug Cessation. JAMA Ophthalmol 2020; 138: 894-900 doi:10.1001/jamaophthalmol.2020.2349
• 18 Yusuf IH, Ledingham JM, MacPhie E. et al. Monitoring for retinal toxicity in patients taking hydroxychloroquine and chloroquine. Rheumatology (Oxford) 2019; 58: 3-4
• 19 Oishi A, Noda K, Birtel J. et al. Effect of smoking on macular function and retinal structure in retinitis pigmentosa. Brain Commun 2020; 2: fcaa117 doi:10.1093/braincomms/fcaa117
• 20 Radu RA, Yuan Q, Hu J. et al. Accelerated accumulation of lipofuscin pigments in the RPE of a mouse model for ABCA4-mediated retinal dystrophies following Vitamin A supplementation. Invest Ophthalmol Vis Sci 2008; 49: 3821-3829
• 21 Birtel J, Gliem M, Mangold E. et al. Novel Insights Into the Phenotypical Spectrum of KIF11-Associated Retinopathy, Including a New Form of Retinal Ciliopathy. Invest Ophthalmol Vis Sci 2017; 58: 3950-3959
• 22 Jones GE, Ostergaard P, Moore AT. et al. Microcephaly with or without chorioretinopathy, lymphoedema, or mental retardation (MCLMR): review of phenotype associated with KIF11 mutations. Eur J Hum Genet 2014; 22: 881-887
• 23 Garcia-Filion P, Borchert M. Optic nerve hypoplasia syndrome: a review of the epidemiology and clinical associations. Curr Treat Options Neurol 2013; 15: 78-89
• 24 Weber P, John R, Konrad K. et al. Visuelle Wahrnehmungsstörungen. Monatsschr Kinderheilkd 2018; 166: 437-444
• 25 Kellner U, Renner AB, Herbst SM. et al. [Hereditary retinal dystrophies]. Klin Monbl Augenheilkd 2012; 229: 171-193 quiz 194–196
• 26 Kellner U, Kellner S, Renner AB. et al. [Evidence-based diagnostic approach to inherited retinal dystrophies 2009]. Klin Monbl Augenheilkd 2009; 226: 999-1011
• 27 Wabbels B, Preising MN, Kretschmann U. et al. Genotype-phenotype correlation and longitudinal course in ten families with Best vitelliform macular dystrophy. Graefes Arch Clin Exp Ophthalmol 2006; 244: 1453-1466
• 28 Hood DC, Lazow MA, Locke KG. et al. The transition zone between healthy and diseased retina in patients with retinitis pigmentosa. Invest Ophthalmol Vis Sci 2011; 52: 101-108
• 29 Jacobson SG, Aleman TS, Sumaroka A. et al. Disease boundaries in the retina of patients with Usher syndrome caused by MYO7A gene mutations. Invest Ophthalmol Vis Sci 2009; 50: 1886-1894
• 30 Greenberg JP, Sherman J, Zweifel SA. et al. Spectral-domain optical coherence tomography staging and autofluorescence imaging in achromatopsia. JAMA Ophthalmol 2014; 132: 437-445
• 31 Chen RW, Greenberg JP, Lazow MA. et al. Autofluorescence imaging and spectral-domain optical coherence tomography in incomplete congenital stationary night blindness and comparison with retinitis pigmentosa. Am J Ophthalmol 2012; 153: 143-154.e2
• 32 Zeitz C, Robson AG, Audo I. Congenital stationary night blindness: an analysis and update of genotype-phenotype correlations and pathogenic mechanisms. Prog Retin Eye Res 2015; 45: 58-110
• 33 Schmitz-Valckenberg S, Pfau M, Fleckenstein M. et al. Fundus autofluorescence imaging. Prog Retin Eye Res 2020; DOI: 10.1016/j.preteyeres.2020.100893.
• 34 Birtel J, Gliem M, Herrmann P. et al. Peripapillary Sparing in Autosomal Recessive Bestrophinopathy. Ophthalmol Retina 2020; 4: 523-529
• 35 Charbel Issa P, Gliem M, Yusuf IH. et al. A Specific Macula-Predominant Retinal Phenotype Is Associated With the CDHR1 Variant c.783G>A, a Silent Mutation Leading to In-Frame Exon Skipping. Invest Ophthalmol Vis Sci 2019; 60: 3388-3397
• 36 Müller PL, Birtel J, Herrmann P. et al. Functional Relevance and Structural Correlates of Near Infrared and Short Wavelength Fundus Autofluorescence Imaging in ABCA4-Related Retinopathy. Transl Vis Sci Technol 2019; 8: 46
• 37 Robson AG, Tufail A, Fitzke F. et al. Serial imaging and structure-function correlates of high-density rings of fundus autofluorescence in retinitis pigmentosa. Retina 2011; 31: 1670-1679
• 38 Robson AG, Michaelides M, Saihan Z. et al. Functional characteristics of patients with retinal dystrophy that manifest abnormal parafoveal annuli of high density fundus autofluorescence; a review and update. Doc Ophthalmol 2008; 116: 79-89
• 39 Lima LH, Burke T, Greenstein VC. et al. Progressive constriction of the hyperautofluorescent ring in retinitis pigmentosa. Am J Ophthalmol 2012; 153: 718-727 727.e1–727.e2 doi:10.1016/j.ajo.2011.08.043
• 40 Popovic P, Jarc-Vidmar M, Hawlina M. Abnormal fundus autofluorescence in relation to retinal function in patients with retinitis pigmentosa. Graefes Arch Clin Exp Ophthalmol 2005; 243: 1018-1027
• 41 Aizawa S, Mitamura Y, Hagiwara A. et al. Changes of fundus autofluorescence, photoreceptor inner and outer segment junction line, and visual function in patients with retinitis pigmentosa. Clin Exp Ophthalmol 2010; 38: 597-604
• 42 Brandl C, Schulz HL, Charbel Issa P. et al. Mutations in the Genes for Interphotoreceptor Matrix Proteoglycans, IMPG1 and IMPG2, in Patients with Vitelliform Macular Lesions. Genes (Basel) 2017; 8: 170
• 43 Wegscheider E, Preising MN, Lorenz B. Fundus autofluorescence in carriers of X-linked recessive retinitis pigmentosa associated with mutations in RPGR, and correlation with electrophysiological and psychophysical data. Graefes Arch Clin Exp Ophthalmol 2004; 242: 501-511
• 44 Nanda A, Salvetti AP, Clouston P. et al. Exploring the Variable Phenotypes of RPGR Carrier Females in Assessing their Potential for Retinal Gene Therapy. Genes (Basel) 2018; 9: 643
• 45 Huang AS, Kim LA, Fawzi AA. Clinical characteristics of a large choroideremia pedigree carrying a novel CHM mutation. Arch Ophthalmol 2012; 130: 1184-1189
• 46 Edwards TL, Groppe M, Jolly JK. et al. Correlation of retinal structure and function in choroideremia carriers. Ophthalmology 2015; 122: 1274-1276
• 47 Renner AB, Fiebig BS, Cropp E. et al. Progression of retinal pigment epithelial alterations during long-term follow-up in female carriers of choroideremia and report of a novel CHM mutation. Arch Ophthalmol 2009; 127: 907-912
• 48 Piccolino FC, Borgia L, Zinicola E. et al. Pre-injection fluorescence in indocyanine green angiography. Ophthalmology 1996; 103: 1837-1845
• 49 Birtel J, Salvetti AP, Jolly JK. et al. Near-Infrared Autofluorescence in Choroideremia: Anatomic and Functional Correlations. Am J Ophthalmol 2019; 199: 19-27
• 50 Kellner S, Kellner U, Weber BH. et al. Lipofuscin- and melanin-related fundus autofluorescence in patients with ABCA4-associated retinal dystrophies. Am J Ophthalmol 2009; 147: 895-902 902.e1
• 51 Duncker T, Tabacaru MR, Lee W. et al. Comparison of near-infrared and short-wavelength autofluorescence in retinitis pigmentosa. Invest Ophthalmol Vis Sci 2013; 54: 585-591
• 52 Kellner U, Kellner S, Weber BH. et al. Lipofuscin- and melanin-related fundus autofluorescence visualize different retinal pigment epithelial alterations in patients with retinitis pigmentosa. Eye (Lond) 2009; 23: 1349-1359
• 53 De Silva SR, Neffendorf JE, Birtel J. et al. Improved Diagnosis of Retinal Laser Injuries Using Near-Infrared Autofluorescence. Am J Ophthalmol 2019; 208: 87-93
• 54 Birtel J, Hildebrand GD, Charbel Issa P. Laser Pointer: A Possible Risk for the Retina. Klin Monbl Augenheilkd 2020; 237: 1187-1193
• 55 Gliem M, Muller PL, Birtel J. et al. Quantitative Fundus Autofluorescence and Genetic Associations in Macular, Cone, and Cone-Rod Dystrophies. Ophthalmol Retina 2020; 4: 737-749
• 56 Müller PL, Gliem M, McGuinnes M. et al. Quantitative Fundus Autofluorescence in ABCA4-Related Retinopathy-Functional Relevance and Genotype-Phenotype Correlation. Am J Ophthalmol 2020; 222: 340-350
• 57 Reiniger JL, Domdei N, Pfau M. et al. [Potential of Adaptive Optics for the Diagnostic Evaluation of Hereditary Retinal Diseases]. Klin Monbl Augenheilkd 2017; 234: 311-319
• 58 Harmening WM, Sincich LC. Adaptive Optics for Photoreceptor-targeted Psychophysics. In: Bille JF. ed. High Resolution Imaging in Microscopy and Ophthalmology: New Frontiers in biomedical Optics. Cham: Springer International Publishing; 2019: 359-375
• 59 Birtel J, Lindner M, Mishra DK. et al. Retinal imaging including optical coherence tomography angiography for detecting active choroidal neovascularization in pseudoxanthoma elasticum. Clin Exp Ophthalmol 2019; 47: 240-249
• 60 Spaide RF, Fujimoto JG, Waheed NK. et al. Optical coherence tomography angiography. Prog Retin Eye Res 2018; 64: 1-55
• 61 Arrigo A, Romano F, Parodi MB. et al. Br J Ophthalmol 2020; DOI: 10.1136/bjophthalmol-2020-316528.
• 62 Cremers FPM, Lee W, Collin RWJ. et al. Clinical spectrum, genetic complexity and therapeutic approaches for retinal disease caused by ABCA4 mutations. Prog Retin Eye Res 2020; 79: 100861 doi:10.1016/j.preteyeres.2020.100861
• 63 Giroux JM, Barbeau A. Erythrokeratodermia with ataxia. Arch Dermatol 1972; 106: 183-188
• 64 Aldahmesh MA, Mohamed JY, Alkuraya HS. et al. Recessive mutations in ELOVL4 cause ichthyosis, intellectual disability, and spastic quadriplegia. Am J Hum Genet 2011; 89: 745-750
• 65 Kniazeva M, Chiang MF, Morgan B. et al. A new locus for autosomal dominant stargardt-like disease maps to chromosome 4. Am J Hum Genet 1999; 64: 1394-1399
• 66 Wolock CJ, Stong N, Ma CJ. et al. A case-control collapsing analysis identifies retinal dystrophy genes associated with ophthalmic disease in patients with no pathogenic ABCA4 variants. Genet Med 2019; 21: 2336-2344
• 67 Maw MA, Corbeil D, Koch J. et al. A frameshift mutation in prominin (mouse)-like 1 causes human retinal degeneration. Hum Mol Genet 2000; 9: 27-34
• 68 Zhang Q, Zulfiqar F, Xiao X. et al. Severe retinitis pigmentosa mapped to 4p15 and associated with a novel mutation in the PROM1 gene. Hum Genet 2007; 122: 293-299
• 69 Cehajic-Kapetanovic J, Birtel J, McClements ME. et al. Clinical and Molecular Characterization of PROM1-Related Retinal Degeneration. JAMA Netw Open 2019; 2: e195752
• 70 Weleber RG, Carr RE, Murphey WH. et al. Phenotypic variation including retinitis pigmentosa, pattern dystrophy, and fundus flavimaculatus in a single family with a deletion of codon 153 or 154 of the peripherin/RDS gene. Arch Ophthalmol 1993; 111: 1531-1542
• 71 Wells J, Wroblewski J, Keen J. et al. Mutations in the human retinal degeneration slow (RDS) gene can cause either retinitis pigmentosa or macular dystrophy. Nat Genet 1993; 3: 213-218
• 72 Leroy BP, Kailasanathan A, De Laey JJ. et al. Intrafamilial phenotypic variability in families with RDS mutations: exclusion of ROM1 as a genetic modifier for those with retinitis pigmentosa. Br J Ophthalmol 2007; 91: 89-93
• 73 Sharon D, Sandberg MA, Caruso RC. et al. Shared mutations in NR2E3 in enhanced S-cone syndrome, Goldmann-Favre syndrome, and many cases of clumped pigmentary retinal degeneration. Arch Ophthalmol 2003; 121: 1316-1323
• 74 Samardzija M, Wenzel A, Naash M. et al. Rpe65 as a modifier gene for inherited retinal degeneration. Eur J Neurosci 2006; 23: 1028-1034
• 75 Barone I, Novelli E, Piano I. et al. Environmental enrichment extends photoreceptor survival and visual function in a mouse model of retinitis pigmentosa. PLoS One 2012; 7: e50726
• 76 German OL, Insua MF, Gentili C. et al. Docosahexaenoic acid prevents apoptosis of retina photoreceptors by activating the ERK/MAPK pathway. J Neurochem 2006; 98: 1507-1520
• 77 Komeima K, Rogers BS, Lu L. et al. Antioxidants reduce cone cell death in a model of retinitis pigmentosa. Proc Natl Acad Sci U S A 2006; 103: 11300-11305
• 78 Smith RJ, Berlin CI, Hejtmancik JF. et al. Clinical diagnosis of the Usher syndromes. Usher Syndrome Consortium. Am J Med Genet 1994; 50: 32-38
• 79 Rivolta C, Sweklo EA, Berson EL. et al. Missense mutation in the USH2A gene: association with recessive retinitis pigmentosa without hearing loss. Am J Hum Genet 2000; 66: 1975-1978
• 80 Verbakel SK, van Huet RAC, Boon CJF. et al. Non-syndromic retinitis pigmentosa. Prog Retin Eye Res 2018; 66: 157-186
• 81 Estrada-Cuzcano A, Koenekoop RK, Senechal A. et al. BBS1 mutations in a wide spectrum of phenotypes ranging from nonsyndromic retinitis pigmentosa to Bardet-Biedl syndrome. Arch Ophthalmol 2012; 130: 1425-1432
• 82 Mockel A, Perdomo Y, Stutzmann F. et al. Retinal dystrophy in Bardet-Biedl syndrome and related syndromic ciliopathies. Prog Retin Eye Res 2011; 30: 258-274
• 83 den Hollander AI, Koenekoop RK, Yzer S. et al. Mutations in the CEP290 (NPHP6) gene are a frequent cause of Leber congenital amaurosis. Am J Hum Genet 2006; 79: 556-561
• 84 Sayer JA, Otto EA, OʼToole JF. et al. The centrosomal protein nephrocystin-6 is mutated in Joubert syndrome and activates transcription factor ATF4. Nat Genet 2006; 38: 674-681
• 85 Valente EM, Silhavy JL, Brancati F. et al. Mutations in CEP290, which encodes a centrosomal protein, cause pleiotropic forms of Joubert syndrome. Nat Genet 2006; 38: 623-625
• 86 Frank V, den Hollander AI, Bruchle NO. et al. Mutations of the CEP290 gene encoding a centrosomal protein cause Meckel-Gruber syndrome. Hum Mutat 2008; 29: 45-52
• 87 Le Saux O, Martin L, Aherrahrou Z. et al. The molecular and physiological roles of ABCC6: more than meets the eye. Front Genet 2012; 3: 289
• 88 Chinnery PF. Mitochondrial disease in adults: whatʼs old and whatʼs new?. EMBO Mol Med 2015; 7: 1503-1512
• 89 de Laat P, Smeitink JAM, Janssen MCH. et al. Mitochondrial retinal dystrophy associated with the m.3243A>G mutation. Ophthalmology 2013; 120: 2684-2696
• 90 Birtel J, Von Landenberg C, Gliem M. et al. Ophthalmol Retina 2021; DOI: 10.1016/j.oret.2021.02.017. [in press]
• 91 Gorman GS, Chinnery PF, DiMauro S. et al. Mitochondrial diseases. Nat Rev Dis Primers 2016; 2: 16080
• 92 Gliem M, Birtel J, Müller PL. et al. Acute Retinopathy in Pseudoxanthoma Elasticum. JAMA Ophthalmol 2019; 137: 1165-1173 doi:10.1001/jamaophthalmol.2019.2910
• 93 Shah M, Shanks M, Packham E. et al. Next generation sequencing using phenotype-based panels for genetic testing in inherited retinal diseases. Ophthalmic Genet 2020; 41: 331-337
• 94 Stone EM, Andorf JL, Whitmore SS. et al. Clinically Focused Molecular Investigation of 1000 Consecutive Families with Inherited Retinal Disease. Ophthalmology 2017; 124: 1314-1331
• 95 Boulanger-Scemama E, El Shamieh S, Demontant V. et al. Next-generation sequencing applied to a large French cone and cone-rod dystrophy cohort: mutation spectrum and new genotype-phenotype correlation. Orphanet J Rare Dis 2015; 10: 85
• 96 Oishi M, Oishi A, Gotoh N. et al. Next-generation sequencing-based comprehensive molecular analysis of 43 Japanese patients with cone and cone-rod dystrophies. Mol Vis 2016; 22: 150-160
• 97 Glockle N, Kohl S, Mohr J. et al. Panel-based next generation sequencing as a reliable and efficient technique to detect mutations in unselected patients with retinal dystrophies. Eur J Hum Genet 2014; 22: 99-104
• 98 Bolz HJ. Genetische Diagnostik von Netzhautdystrophien. Ophthalmologe 2018; 115: 1028-1034 doi:10.1007/s00347-018-0762-5
• 99 Bolz HJ. [Next-Generation Sequencing: A Quantum Leap in Ophthalmology Research and Diagnostics]. Klin Monbl Augenheilkd 2017; 234: 280-288
• 100 Birtel J, Gliem M, Hess K. et al. Comprehensive Geno- and Phenotyping in a Complex Pedigree Including Four Different Inherited Retinal Dystrophies. Genes (Basel) 2020; 11: 137 doi:10.3390/genes11020137
• 101 Yusuf IH, Birtel J, Shanks ME. et al. Clinical Characterization of Retinitis Pigmentosa Associated With Variants in SNRNP200. JAMA Ophthalmol 2019; 137: 1295-1300 doi:10.1001/jamaophthalmol.2019.3298
• 102 Oishi M, Oishi A, Gotoh N. et al. Comprehensive molecular diagnosis of a large cohort of Japanese retinitis pigmentosa and Usher syndrome patients by next-generation sequencing. Invest Ophthalmol Vis Sci 2014; 55: 7369-7375
• 103 Birtel J, Gliem M, Oishi A. et al. Genetic testing in patients with retinitis pigmentosa: Features of unsolved cases. Clin Exp Ophthalmol 2019; 47: 779-786
• 104 Bravo-Gil N, Gonzalez-Del Pozo M, Martin-Sanchez M. et al. Unravelling the genetic basis of simplex Retinitis Pigmentosa cases. Sci Rep 2017; 7: 41937
• 105 Preising MN, Gorg B, Friedburg C. et al. Biallelic mutation of human SLC6A6 encoding the taurine transporter TAUT is linked to early retinal degeneration. FASEB J 2019; 33: 11507-11527
• 106 Charbel Issa P, Barnard AR, Herrmann P. et al. Rescue of the Stargardt phenotype in Abca4 knockout mice through inhibition of vitamin A dimerization. Proc Natl Acad Sci U S A 2015; 112: 8415-8420
• 107 Scholl HP, Strauss RW, Singh MS. et al. Emerging therapies for inherited retinal degeneration. Sci Transl Med 2016; 8: 368rv6 doi:10.1126/scitranslmed.aaf2838
• 108 Cehajic-Kapetanovic J, Xue K, Martinez-Fernandez de la Camara C. et al. Initial results from a first-in-human gene therapy trial on X-linked retinitis pigmentosa caused by mutations in RPGR. Nat Med 2020; 26: 354-359
• 109 Cehajic Kapetanovic J, McClements ME, Martinez-Fernandez de la Camara C. et al. Molecular Strategies for RPGR Gene Therapy. Genes (Basel) 2019; 10: 674
• 110 Cehajic Kapetanovic J, Barnard AR, MacLaren RE. Molecular Therapies for Choroideremia. Genes (Basel) 2019; 10: 738
• 111 MacLaren RE, Groppe M, Barnard AR. et al. Retinal gene therapy in patients with choroideremia: initial findings from a phase 1/2 clinical trial. Lancet 2014; 383: 1129-1137

Correspondence/Korrespondenzadresse

Oxford Eye Hospital

Oxford University Hospitals NHS Foundation Trust, John Radcliffe Hospital

Oxford OX3 9DU

United Kingdom   

Email: [e-mail]

Publication History

Received: 13 October 2020

Accepted: 09 February 2021

Article published online:
30 March 2021