|Year : 2013 | Volume
| Issue : 4 | Page : 18-25
Hereditary retinal eye diseases in childhood and youth affecting the central retina
Martin M Nentwich, Guenther Rudolph
Department of Ophthalmology, Ludwig Maximilians-University, Munich, Germany
|Date of Web Publication||30-Nov-2013|
Martin M Nentwich
Department of Ophthalmology, Ludwig Maximilians University, Mathildenstr 8, 80336 Munich
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Hereditary dystrophies affecting the central retina represent a heterogeneous group of diseases. Mutations in different genes may be responsible for changes of the choroid (choroideremia), of the retinal pigment epithelium [RPE] (Best's disease), of the photoreceptor outer segments (Stargardt's disease) and of the bipolar and Mueller cells (x-linked retinoschisis).
The correct diagnosis of hereditary retinal dystrophies is important, even though therapeutic options are limited at the moment, as every patient should get a diagnosis and be informed about the expected prognosis. Furthermore, specific gene therapy of a number of diseases such as Leber congenital amaurosis, choroideremia, Stargardt's disease, Usher Syndrome and achromatopsia is being evaluated at present.
Classic examinations for patients suffering from hereditary retinal dystrophies of the central retina are funduscopy - also using red-free light - visual-field tests, electrophysiologic tests as electro-retinogram [ERG] and multifocal ERG and tests evaluating color vision. Recently, new imaging modalities have been introduced into the clinical practice. The significance of these new methods such as high-resolution spectral-domain optic coherence tomography [SD-OCT] and fundus autofluorescence will be discussed as well as "next generation sequencing" as a new method for the analysis of genetic mutations in a larger number of patients.
Keywords: Autofluorescence, Hereditary macular dystrophies, Macular dystrophy, Next generation sequencing, OCT
|How to cite this article:|
Nentwich MM, Rudolph G. Hereditary retinal eye diseases in childhood and youth affecting the central retina. Oman J Ophthalmol 2013;6, Suppl S1:18-25
|How to cite this URL:|
Nentwich MM, Rudolph G. Hereditary retinal eye diseases in childhood and youth affecting the central retina. Oman J Ophthalmol [serial online] 2013 [cited 2022 Aug 8];6, Suppl S1:18-25. Available from: https://www.ojoonline.org/text.asp?2013/6/4/18/122290
| Introduction|| |
Hereditary dystrophies affecting the central retina in children and adolescents represent a heterogeneous group of diseases. Genetic alterations may be responsible for changes of the choroid (choroideremia), of the retinal pigment epithelium [RPE] (Best's disease), of the photoreceptor outer segments (Stargardt's disease), and of the bipolar and Mueller cells (x-linked retinoschisis).
Within the retina 60-125 million rods and 3.2-6.5 million cones are distributed. While no rods are present in the fovea itself, the highest density of rods is found at a distance of about 20° from the fovea. The cones, on the other hand are mainly concentrated in the fovea. They are most densely packed within the foveola (100000-200000 per mm 2 ) and as soon as 3 mm distant from the fovea, their number decreases to 7000 per mm 2 . Therefore, diseases affecting rods mainly cause visual problems at night and in situations with reduced light density as well as peripheral visual-field defects. In case of impaired function of cones, patients complain about increased sensitivity to light, loss of central vision, impaired color vision and central visual-field defects. 
Genetics and genetic testing
Understanding the basic principles of genetics (autosomal-dominant, autosomal-recessive, x-chromosomal, mitochondrial) is essential for the comprehension of any hereditary disease and for genetic counseling of affected patients. Family history is of utmost importance in any patient with symmetric retinal changes, for obtaining additional information on possible underlying hereditary diseases.
Best's vitelliform macular dystrophy is a classic example of an autosomal-dominant hereditary disorder of the macula, while achromatopsia and most cases of Stargardt's disease are autosomal-recessive retinal dystrophies. X-linked retinoschisis and choroideremia are x-linked disorders.
Up to now, genetic loci of a number of retinal dystrophies [Table 1] and more than 200 different genes have been identified in retinal dystrophies ( http://www.retina-international.org/sci-news/databases/mutation-database/ ).
Hereditary retinal dystrophies include many different potentially blinding diseases with variable clinical presentations, which may be genetically heterogeneous such as retinopathia pigmentosa [RP]. Therefore, conventional, sequential gene sequencing for genetic testing would be expensive and work-intensive, as mutations in more than 200 genes are responsible for the diversity of disease phenotypes. ,
Next generation sequencing
Recently, new methods of genetic testing offering the possibility of analyzing multiple genes or the entire genome in parallel have been developed. These new methods have been named "next generation sequencing" [NGS] and exome-sequencing.  NGS allows to analyze several DNA templates in one reaction at the same time and therefore enables much faster and more cost-effective analyses than conventional sequential gene sequencing.  Also genetically heterogeneous diseases, which could hardly be studied on a genetic level before the advent of NGS, have recently been studied.
The technology of NGS is available at a number of laboratories. Gloeckle et al. ( http://cegat.de ) recently published results applying NGS for the identification of 170 genetically and clinically unselected patients with hereditary retinal dystrophies. While NGS was used in the analysis of 105 genes associated with hereditary retinal dystrophies, conventional Sanger sequencing was applied in order to examine underrepresented regions. Depending on the initial clinical diagnosis, this group was successful in identifying likely causative mutations in 80% of Bardet-Biedl or Usher syndrome and 55% of retinitis pigmentosa cases. Additionally, 71 new mutations in 40 genes were found to be associated with hereditary retinal dystrophies. Based on their results, the authors concluded that NGS may be used as a reliable and cost-efficient method for genetic testing of genetically heterogeneous diseases such as hereditary retinal dystrophies.  This positive evaluation of NGS is supported by the results published by other groups. ,,
[Table 2] compares conventional Sanger Sequencing and NGS adapted from Gillespie et al.  .
Recently, analysis of specific mutations has become more relevant, as gene therapy of diseases such as Leber congenital amaurosis, choroidermia, Stargardt's disease, Usher Syndrome and achromatopsia is being evaluated at present.
In Leber congenital amaurosis, which is associated with RPE65 mutations and dysfunction and degeneration of photoreceptors, studies have shown some positive effects of gene therapy. , Also in Stargardt's disease (mutation in ABCA4 gene), first results have been published showing that an equine infectious anemia virus (EIAV)-based lentiviral vector, which expresses the photoreceptor-specific adenosine triphosphate (ATP)-binding cassette transporter (ABCA4) protein, is well-tolerated and remains localized to the eye in an animal model.  Clinical evaluations of patients are ongoing at present in order to acquire data for possible gene therapy concepts (e.g. characterization of patients with achromatopsia due to CNGA3 mutations and patients with retinitis pigmentosa due to PDE6A mutations).
Diagnostic tools in hereditary diseases of the central retina
Even though visual acuity is reduced to a great extent in many patients suffering from hereditary diseases of the central retina, tests evaluating general retinal function such as electro-retinogram [ERG] usually do not show any pathologic findings due to the limited number of photoreceptors within the fovea compared to the entire retina.
Test evaluating the central retina more specifically, such as multifocal ERG [mfERG], high-resolution spectral-domain optic coherence tomography [SD-OCT], fundus autofluorescence [FAF] and the examination of color vision (e.g., Chroma-Test), however, will show pathologic findings which are helpful in characterizing a specific hereditary phenotype. Visual field testing is another important functional examination.
Multifocal ERG analyses cone function and offers topographic information, which is not available in full-field ERG.  It can evaluate functional changes limited to the central retina, which cannot be detected by full-field ERG. 
FAF of the retinal pigment epithelium [RPE] shows changes of the distribution of lipofuscin. FAF may be increased in patients with active dystrophic processes and is decreased if RPE cells are lost or autofluorescence is blocked.  According to recent studies, FAF is helpful not only in the differential diagnosis of retinal dystrophies but also to monitor the clinical course over time. ,,,,
The introduction of SD-OCT probably represents the most striking development in the field of imaging of the macula within the past few years. Even though first OCT devices were used in the clinical practice in the end of 1990s, the advent of high-resolution SD-OCT nowadays enables ophthalmologist to gain new insights into the morphologic changes associated with retinal dystrophies. ,
| Classification of Hereditary Retinal Dystrophies|| |
Hereditary retinal dystrophies can be classified according to the time of onset of symptoms, genetics and patient's symptoms.
Hereditary dystrophies of the central retina are associated with loss of vision, (para-) central visual field defects, dyschromatopsia and increased glare sensitivity (especially in case of cone dystrophies). Peripheral visual fields are not affected in early stages of disease. While full-field ERG usually shows unremarkable results in patients with hereditary dystrophies of the central retina, mfERG, FAF and SD-OCT are useful tools in the diagnosis of these conditions.
Stargardt's disease, Best's disease, x-linked retinoschisis are more commonly found hereditary dystrophies of the central retina, while achromatopsia is a rare condition. 
| Selected Hereditary Dystrophies of the Central Retina|| |
Stargardt's disease, with or without fundus flavimaculatus, is the most common hereditary dystrophy affecting the central retina. In most patients, Stargardt's disease is inherited as an autosomal recessive trait and mutations of the ABCA4 gene are identified. Because of the missing ABCA4 protein, all-trans-retinal accumulates, reacts with ethanolamine and forms the fluorophore A2E, the hydrophobic part of lipofuscin. This dystrophy was first described by the German ophthalmologist Karl Stargardt in 1909 as a progressive, bilateral atrophic macular dystrophy characterized by perimacular and peripheral "dirty grey-yellow spots". Most patients experience rapid deterioration of vision during the first two decades of life. However, symptoms may also appear later in life and progress more slowly. It is estimated that Stargardt's disease occurs in one of 8000-10000 people. 
In early disease, changes of the foveal reflex can be seen. Later RPE changes become more easily visible and bull's eye maculopathy may develop. End-stage disease is characterized by extensive RPE defects and geographic atrophy ([Table 3] summarizes possible differential diagnoses of "bull's eye" maculopathy). Fundus flavimaculatus is variable and distribution and number of the yellowish spots may change over the course of time [Figure 1].
|Figure 1: Stargardt's disease Color fundus photograph of female patient with late-onset Stargardt's disease and multiple yellowish lesions consisting of lipofuscin-like material at the posterior pole, which change in quantity, autofl uorescent characteristics and location over the course of time. (a) 30 years of age: fundus photo, (b) 30 years of age: fundus autofl uorescence, (c) 33 years of age: Fundus photo, (d) 33 years of age: Fundus autofl uorescence|
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FAF is helpful in the detection of RPE changes, as it is sometimes difficult to evaluate these on funduscopy in the early stages of disease, and FAF often visualizes loss of autofluorescence with increased autofluorescence at the margin of the affected area. Kinetic visual field tests show central scotomas with normal outer limits. While full-field ERG often does not detect any pathology, amplitudes from the central retina are reduced in mfERG even in early disease and cases of unremarkable findings on funduscopy. As both autosomal-recessive Stargardt's disease and the autosomal-recessive form of cone rod dystrophies are related to a mutation of the ABCA4 gene, both dystrophies may share the same clinical features. , Vitamin A supplementation is contraindicated in patients with Stargardt's disease as the ABCA4 gene interferes with the vitamin A metabolism.  Gene therapy is being evaluated at present. ,
Case report of stargardt's disease
A female patient noted a rapid decline of visual acuity at the age of eight years and presented with 20/200 vision on her right eye and 20/100 vision on her left eye. Chroma-Test showed pathologic protan color contrast threshold (right eye: 18.2%; left eye: 16.2%; norm <6%), while tritan threshold was normal (right eye: 8.5%; left eye: 7.5%; norm <8%). Microperimetry revealed a complete central scotoma on both eyes. Full-field ERG was normal under scotopic conditions, while photopic ERG showed reduced amplitudes in both eyes. Genetic testing confirmed two mutations of the ABCA4 gene and verified the suspected diagnosis of Stargardt's disease [Figure 2], [Figure 3] and [Figure 4].
|Figure 2: Patient #1 – Stargardt's disease Color fundus photograph of an 11-year-old girl with Stargardt's disease: On both eyes, atrophy of the retinal pigment epithelium can be seen, while yellowish lesions are missing|
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|Figure 3: Patient #1 – Stargardt's disease: Fundus autofl uorescence (FAF) is markedly reduced at the posterior pole, while at the margin of the lesion, FAF is increased|
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|Figure 4: Patient #1 – Stargardt's disease: In SD-OCT multiple highly refl ective dots can be seen at the level of the retinal pigment epithelium, while the inner/outer segment junction and the outer retinal layers are no longer visible, suggesting loss of photoreceptors in the fovea|
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Two years later, visual acuity was 20/200 in both eyes and both protan and tritan color threshold had deteriorated.
Up to now, this patient has been followed-up for six years. While visual acuity stabilized at 20/200, color contrast threshold deteriorated over time.
Best's disease or Best's vitelliform macular dystrophy is the second most common hereditary dystrophy of the macula characterized by an abnormal accumulation of lipofuscin at the level of the retinal pigment epithelium.  It is a progressive autosomal-dominant hereditary disease with variable penetrance among different members of the same family, which was identified by Friedrich Best in 1906. The mutation has been localized to the BEST1 (VMD2) gene on chromosome 11. , Symptoms start within the first two decades of life.  Visual acuity deteriorates when the "egg-yolk" lesion ruptures. However, symptoms may also develop later in life. It is one of the vitelliform macular dystrophies, which share the common aspect of an "egg-yolk" appearance of the central retina. 
Clinically, five stages of Best's disease can be discriminated:
Stage 1: Asymptomatic, no visible retinal changes, but electrooculogram [EOG] pathologic
Stage 2: "Egg-yolk" lesion: One or more yellow spots at the posterior pole, usually between 0.5 and 3 optic disc parameter in size;  visual acuity often unaffected
Stage 3: "Pseudohypopyon": Partial liquefaction of the material; superior part of the lesion hyperfluorescent, inferior part hypofluorescent due to persisting blockage of fluorescence due to the accumulated material; visual acuity often still good
Stage 4: "scrambled-egg": Lesion ruptures; deterioration of visual acuity
Stage 5: "Scar": Development of a chorioretinal scar as the material is being resorbed; often severe loss of central vision
The accumulated material shows increased autofluorescence and blocks fluorescence in fluorescein angiography, while in scarred areas autofluorescence is diminished and early hyperfluorescence can be seen.  At present, Best's disease is the only indication for EOG, which usually shows a reduced Arden ratio. However, a dominant pedigree and the possibility of genetic testing has limited the clinical application of EOG also in Best's disease as genetic testing is more accurate than EOG in case of borderline EOG results. 
Case report of Best's disease
In routine ophthalmic exam at a private ophthalmologist's office, vitelliform macular lesions were seen in a 10 year-old boy [Figure 5]. At time of first presentation at our institution, full-field ERG was normal, while FAF revealed an increased autofluorescence within the whole, centrally located lesion in both eyes [Figure 6]. SD-OCT showed accumulation of material at the level of the RPE [Figure 7]. Genetic analysis confirmed the clinical diagnosis by the identification of a mutation of the BEST1 gene.
|Figure 5: Patient #2 – Best's disease: Fundus photography shows the "egg-yolk" appearance in a 10-year-old boy|
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|Figure 6: Patient #2 – Best's disease: Changes of FAF over three years. (a) First presentation, (b) One year later c. Two years after fi rst presentation|
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|Figure 7: Patient #2 – Best's disease: SD-OCT scans of the foveal region of both eyes corresponding to the FAF pictures of Figure 6c. In both eyes, a detachment of the pigment epithelium and accumulation of subretinal material can be seen|
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Until today, the clinical course of this patient has been followed for three years. During follow-up visual acuity remained stable at 20/20 on the right eye and 20/40 on the left eye, while the subretinal accumulation of lipofuscin increased over time. However, the lesion has not ruptured, yet and the patient is still in the vitelliform stage of Best's disease (stage 2).
Congenital achromatopsia is a genetic disease, which is transmitted in an autosomal-recessive trait and causes complete loss of cone function, while rod function is normal throughout the course of disease.  Its prevalence is estimated to be about 1:30000. Clinically, complete achromatopsia and incomplete achromatopsia can be distinguished.  Symptoms include reduced visual acuity to a level of less than 20/200, congenital nystagmus, photophobia and complete color blindness present from birth on.
Fundoscopy is unremarkable and rarely changes of the foveal reflex can be seen. Visual fields show a relative central scotoma.  ERG is the most essential tool in assessing function in patients with achromatopsia. In ERG cone function is missing represented by loss of 30 Hz flicker response, while rod function is normal. On post-mortem histologic examination of eyes of affected patients, loss of cones and abnormal cone morphology was found. 
Until today, mutations in five genes have been detected which cause achromatopsia. These genes are responsible for the encoding of major factors of the phototransduction cascade of cones. Commonly mutations in the CNGA3, KCNV2 or - most common and found in about 50% of patients - CNGB3 gene can be identified in affected patients. ,
Case report of achromatopsia
A female patient with complete achromatopsia and visual impairment since birth has been followed at different eye clinics for 33 years. Diagnosis of achromatopsia was made at the age of six. Over time, visual acuity remained stable on both eyes at 20/200. Clinical examination showed nystagmus and slight changes of the retinal pigment epithelium in the fovea, while FAF was normal during follow-up [Figure 8]. In SD-OCT, loss of structure in the photoreceptor layer in the foveal region was clearly visible [Figure 9]. While dark-adapted (scotopic) ERG was normal, the 30 Hz flicker response during photopic ERG was absent [Figure 10]a and b.
|Figure 8: Patient #3 – Achromatopsia: FAF is unremarkable in this 33-year-old female patient with known achromatopsia|
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|Figure 9: Patient #3 – Achromatopsia: SD-OCT scans of the foveal region of both eyes corresponding to the FAF pictures of Figure 8. In both eyes subfoveal loss of photoreceptors is clearly visible|
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|Figure 10: Patient #3 – Achromatopsia: (a) Scotopic ERG: normal amplitudes (b) Photopic ERG: 30 Hz fl icker (the upper two lines) extinct, all other amplitudes reduced|
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X-linked retinoschisis is an x-linked recessive disease, caused by mutations of the RS1-gene, which encodes the protein retinoschisin. A defect of retinoschisin results in retinoschisis.  It almost exclusively affects young males. The prevalence is estimated to be about 1:15000-1:30000.  On funduscopy, foveal retinoschisis, which is present in almost all patients with x-linked retinoschisis, may be difficult to detect. Therefore, before the use of SD-OCT, this condition might have been mistaken as visual impairment of unknown origin in some patients. Hyperopia is common in affected patients as is peripheral retinoschisis, which is seen in about half of patients. , Visual acuity is reduced to a variable extent but usually remains stable over the years. SD-OCT is a very useful tool for the detection of foveal retinoschisis and visualizes cystic spaces within the retina, mainly at the level of the inner nuclear and outer plexiform layers.  Recently, the topical administration of carbonic anhydrase inhibitors dorzolamide and brinzolamide was shown to be effective in reducing the macular cysts in patients with x-linked retinoschisis. ,
Case report of x-linked retinoschisis
A 7-year-old patient with x-linked retinoschisis and a mutation in exon 5 of the RS1 gene has been followed for several years. Comparing the clinical findings at the time of first presentation and at last follow-up, visual acuity was stable at about 20/100 on the right eye and 20/200 on the left eye. On funduscopy, slight retinal changes could be seen in the fovea, while clinically the diagnosis of foveal retinoschisis was hard to confirm [Figure 11]. Because of nystagmus since early childhood, MRI imaging had been performed at the age 1.5 years of age, which did not show any pathologic findings. SD-OCT revealed the cystic spaces within the central retina and showed symmetrical findings in both eyes [Figure 12]. Magnifying vision aids were prescribed in order to obtain best visual acuity possible.
|Figure 11: Patient #4 – x-linked retinoschisis: Fundus photograph of a 7-year-old boy with x-linked retinoschisis with minimal spoke wheel appearance of the fovea|
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|Figure 12: Patient #4 – x-linked retinoschisis: IR-SLO image and SD-OCT show the spoke wheel appearance of the macula and impressive cystic spaces within the retina|
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| Summary|| |
Hereditary dystrophies of the central retina have a major impact on visual function and constitute a significant challenge for affected patients in activities of daily life, as they interfere with central vision.
Some of these dystrophies such as Best's disease or Stargardt's disease can be recognized by funduscopy, while other disease such as x-linked retinoschisis or achromatopsia are easily overlooked during clinical examination. Electrophysiology, FAF and SD-OCT are essential tools in the diagnosis of central retinal disorders. Genetic testing is a prerequisite for understanding genetically caused dystrophies and gene therapy for some of these diseases is being evaluated at present.
As long as no causative treatments are available for hereditary retinal dystrophies, there is a need for genetic counseling regarding transmission to descendants, the expected visual prognosis and occupational choices.
| References|| |
|1.||Augustin AJ. Augenheilkunde. In: Augustin AJ, Editor. Berlin: Springer; 2007. p. 402-63. |
|2.||Glöckle N, Kohl S, Mohr J, Scheurenbrand T, Sprecher A, Weisschuh N, 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 2013. [In press]. |
|3.||Audo I, Bujakowska KM, Léveillard T, Mohand-Saïd S, Lancelot ME, Germain A, et al. Development and application of a next-generation-sequencing (NGS) approach to detect known and novel gene defects underlying retinal diseases. Orphanet JRare Dis 2012;7:8. |
|4.||O'Sullivan J, Mullaney BG, Bhaskar SS, Dickerson JE, Hall G, O'Grady A, et al. A paradigm shift in the delivery of services for diagnosis of inherited retinal disease. JMed Genet 2012;49:322-6. |
|5.||Gillespie RL, Hall G, Black GC. Genetic testing for inherited ocular disease: Delivering on the promise at last? Clin Experiment Ophthalmol 2013 [In press] |
|6.||Verma A, Perumalsamy V, Shetty S, Kulm M, Sundaresan P. Mutational screening of LCA genes emphasizing RPE65 in South Indian cohort of patients. PloS One 2013;8:e73172. |
|7.||Chen X, Zhao K, Sheng X, Li Y, Gao X, Zhang X, et al. Targeted sequencing of 179 genes associated with hereditary retinal dystrophies and 10 candidate genes identifies novel and known mutations in patients with various retinal diseases. Invest OphthalmolVis Sci 2013;54:2186-97. |
|8.||Annear MJ, Mowat FM, Bartoe JT, Querubin J, Azam SA, Basche M, et al. Successful gene therapy in older RPE65-deficient dogs following subretinal injection of an adeno-associated vector expressing RPE65. Hum Gene Ther 2013;24:883-93. |
|9.||Cideciyan AV, Jacobson SG, Beltran WA, Sumaroka A, Swider M, Iwabe S, et al. Human retinal gene therapy for Leber congenital amaurosis shows advancing retinal degeneration despite enduring visual improvement. Proc Natl Acad Sci U S A 2013;110:E517-25. |
|10.||Binley K, Widdowson P, Loader J, Kelleher M, Iqball S, Ferrige G, et al. Transduction of photoreceptors with equine infectious anemia virus lentiviral vectors: safety and biodistribution of StarGen for Stargardt disease. InvestOphthalmolVis Sci 2013;54:4061-71. |
|11.||Prokofyeva E, Troeger E, Zrenner E. The special electrophysiological signs of inherited retinal dystrophies. Open Ophthalmol J 2012;6:86-97. |
|12.||Praidou A, Hagan R, Newman W, Chandna A. Early diagnosis of Stargardt disease with multifocal electroretinogram in children. Int Ophthalmol 2013. [In press]. |
|13.||Ritter M, Zotter S, Schmidt WM, Bittner RE, Deak GG, Pircher M, et al. Characterization of stargardt disease using polarization-sensitive optical coherence tomography and fundus autofluorescence imaging. Invest Ophthalmol Vis Sci 2013;54:6416-25. |
|14.||Fakin A, Jarc-Vidmar M, Glavac D, Bonnet C, Petit C, Hawlina M. Fundus autofluorescence and optical coherence tomography in relation to visual function in Usher syndrome type 1 and 2. VisRes 2012;75:60-70. |
|15.||Robson AG, Tufail A, Fitzke F, Bird AC, Moore AT, Holder GE, et al. Serial imaging and structure-function correlates of high-density rings of fundus autofluorescence in retinitis pigmentosa. Retina 2011;31:1670-9. |
|16.||Maurizio BP, Pierluigi I, Stelios K, Stefano V, Marialucia C, Ilaria Z, et al. Retro-mode imaging and fundus autofluorescence with scanning laser ophthalmoscope of retinal dystrophies. BMC Ophthalmol 2012;12:8. |
|17.||Zhang Q, Small KW, Grossniklaus HE. Clinicopathologic findings in Best vitelliform macular dystrophy. Graefes Arch Clin Exp Ophthalmol 2011;249:745-51. |
|18.||Thumann G. Prospectives for gene therapy of retinal degenerations. CurrGenomics 2012;13:350-62. |
|19.||Kitiratschky VB, Grau T, Bernd A, Zrenner E, Jägle H, Renner AB, et al. ABCA4 gene analysis in patients with autosomal recessive cone and cone rod dystrophies. Eur J Hum Genet 2008;16:812-9. |
|20.||Rudolph G, Kalpadakis P, Haritoglou C, Rivera A, Weber BH. Mutations in the ABCA4 gene in a family with Stargardt's disease and retinitis pigmentosa (STGD1/RP19). Klin Monbl Augenheilkd 2002;219:590-6. |
|21.||Liu MM, Tuo J, Chan CC. Gene therapy for ocular diseases. Br JOphthalmol 2011;95:604-12. |
|22.||Petrukhin K, Koisti MJ, Bakall B, Li W, Xie G, Marknell T, et al. Identification of the gene responsible for Best macular dystrophy. NatGenet 1998;19:241-7. |
|23.||White K, Marquardt A, Weber BH. VMD2 mutations in vitelliform macular dystrophy (Best disease) and other maculopathies. HumMutat 2000;15:301-8. |
|24.||Kortum K, Kernt M, Reznicek L. Significance of ophthalmological imaging in common hereditary retinal diseases. Klin Monbl Augenheilkd 2013;230:223-31. |
|25.||Yeh CY, Goldstein O, Kukekova AV, Holley D, Knollinger AM, Huson HJ, et al. Genomic deletion of CNGB3 is identical by descent in multiple canine breeds and causes achromatopsia. BMC Genet 2013;14:27. |
|26.||Poloschek CM, Kohl S. Achromatopsia. Ophthalmologe2010;107:571-80; quiz 81-2. |
|27.||Kohl S, Varsanyi B, Antunes GA, Baumann B, Hoyng CB, Jägle H, et al. CNGB3 mutations account for 50% of all cases with autosomal recessive achromatopsia. EurJHumGenet 2005;13:302-8. |
|28.||Meier P. Paediatric retinal detachment and hereditary vitreoretinal disorders. Klin Monbl Augenheilkd 2013;230:914-9. |
|29.||Walia S, Fishman GA, Molday RS, Dyka FM, Kumar NM, Ehlinger MA, et al. Relation of response to treatment with dorzolamide in X-linked retinoschisis to the mechanism of functional loss in retinoschisin. AmJOphthalmol 2009;147:111-5 e1. |
|30.||Yang FP, Willyasti K, Leo SW. Topical brinzolamide for foveal schisis in juvenile retinoschisis. JAAPOS 2013;17:225-7. |
| Authors|| |
[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7], [Figure 8], [Figure 9], [Figure 10], [Figure 11], [Figure 12]
[Table 1], [Table 2], [Table 3]