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SummaryPurpose To discuss the current status of gene therapy for inherited retinal disease. Methods Data from the literature on gene therapy trials for several inherited retinopathies will be combined with those of the Phase 1, Phase 1 follow-on and Phase 3 trials for RPE65-related inherited retinal disease at The Children's Hospital of Philadelphia, Philadelphia, PA, USA. Results Gene therapy is capable of improving or stabilizing visual function. According to some recent reports, there is progression of disease in RPE65-related IRD trial participants despite successful subretinal delivery of RPE65 using an AAV2 vector. Other data suggest that there may at least be a decrease in the speed of retinal degeneration, if not stabilization. Conclusions Gene therapy for inherited retinal disease using viral vectors has demonstrated safety and improvement or stabilization of visual function in some diseases. Whereas disease progression is noted in some RPE65-related IRD trial participants, despite successful application of subretinal gene therapy, others may even have either a stable or slower disease course after treatment.

Objective Most industrialized countries have introduced some form of universal newborn hearing screening program. Both identification and rehabilitation of hearing loss in newborns have evolved to an acceptable standard and the need for a standardized etiological protocol is emerging. Methods Extensive literature search to determine which investigations can help identifying the cause of congenital hearing loss and how to limit extensive testing in these children by taking into account the most prevalent causes. Findings A stepwise approach to detect the cause of hearing loss in children with congenital sensorineural hearing loss was developed. Conclusion In general it is advised to first rule out Cx26 / Cx30 and infectious causes (cytomegalovirus and, if indicated, toxoplasmosis and rubella), and to preserve more extensive investigations for those children in whom these causes do not explain the hearing loss.

Purpose To investigate the accuracy of recognizing female heterozygotes for X-linked retinitis pigmentosa (XLRP) and choroideraemia (CHM) using fundoscopy and blue-light fundus autofluorescence (FAF). Methods Retrospective analysis revealed 26 female XLRP heterozygotes from 17 different families (age 3–77 years) and 8 CHM heterozygotes from 5 families (age 14–65 years). Molecular diagnosis has been obtained for all subjects. Results In XLRP, 17 of 26 patients (65.4%) mentioned nyctalopia. RPGR mutations were identified in 18 subjects – 9 of which in ORF15 – whereas a causative mutation was found in RP2 in the remaining 8 subjects. Dilated fundoscopy showed no abnormalities in 8 subjects, a tapetoid reflex in 2, regional pigmentary changes in 16 and full-blown RP features in 2 patients. An abnormal FAF pattern was found in 18 of 26 patients (69.2%). Of the 26 molecularly proven heterozygotes, 23 (88.5%) showed abnormalities on fundoscopy and/or FAF. In CHM, only 1 of 8 patients – aged 40 – mentioned visual difficulties at night. In each of the 8 subjects, equatorial mottled pigmentary changes were evident. FAF revealed multiple hyper- and hypoautofluorescent flecks in all 8 patients. In both XLRP and CHM, clinical findings were independent of age or specific mutation. Conclusions Female heterozygotes of XLRP show abnormalities on dilated fundoscopy and/or blue-light fundus autofluorescence in 88.5% of cases with a molecularly proven diagnosis. The most characteristic feature is a radial pattern of alternating areas of hyper- and hypoautofluorescence. In CHM, all carriers exhibit pigmentary changes in the retinal midperiphery and scattered autofluorescence changes, despite a lack of visual symptoms.

Purpose To study the different genotypes and phenotypes in Belgian patients with albinism. Methods Phenotypes and genotypes in a cohort of 89 patients were studied in detail. These patients were then grouped according to genotype. Results A total of 40 patients with isolated oculocutaneous (OCA), and 11 with XL ocular albinism (XLOA) were molecularly confirmed. Nine syndromic OCA patients were identified. Genotypes of 29 patients were unknown at the time of study. Although not statistically significant due to small sample size, patients with a proper TYR mutation in combination with a temperature sensitive variant (TS) generally showed milder characteristics. A study of one specific family showed 3 affected siblings with this genotype. However, 2 normal children, each of a different patient, also had this genotype. There was perfect concordance between fundoscopic identification of lyonization in 15 female carriers of XLOA, and molecular confirmation of heterozygosity. Two adult patients with Chediak-Higashi syndrome showed OCA in combination with neurodegeneration. Systemic abnormalities in 7 Hermansky-Pudlak syndrome patients were very variable. Conclusions Molecular analysis is essential to confirm clinical phenotyping in albinism. A causal relationship between a combination of a TYR mutation and the TS variant is as yet uncertain and requires more in depth analysis.

Purpose: To illustrate the different types of clinical subtypes of albinism. Methods: A systematic overview of the different clinical subtypes of albinism will be given. The relationship between the different phenotypes and their respective genotypes will be explained. Results: In general, a distinction is made between ocular albinism and oculocutaneous albinism. The latter can be isolated or syndromic. Examples of syndromic albinism include the Hermansky-Pudlak and Chediak-Higashi syndromes. Conclusions: Ocular and oculocutaneous types of albinism exist. The latter can isolated or can be part of syndromic oculocutaneous albinism.

To functionally study the effect of cis-acting splice site mutations of ABCA4 found in Stargardt patients in vitro and in vivo. To increase our insights into the role of pre-mRNA splicing in the pathogenesis of Stargardt disease. To explore antisense oligonucleotide-mediated treatment in patient-derived cells. To uncover novel treatment strategies for Stargardt disease.

Purpose Central serous chorioretinopathy (CSC) is characterized by a serous detachment of the neurosensory retina caused by focal or diffuse dysfunction of the retinal pigment epithelium. A patient with a leopard-spot pattern of yellow-orange subretinal deposits as a rare dramatic form of CSC is described. Methods A 65 year-old man with severe chronic obstructive pulmonary disease and congestive heart failure noticed a poor visual acuity after waking up from a coma elicited by an acute exacerbation of COPD and need for ventilation treatment. He underwent a full ophthalmic exam and extensive imaging including fluorescein-angiography, OCT and the use of infrared and auto-fluorescent light. Results In the ocular history there was prior cataract surgery because of severe subcapsular posterior cataract in both eyes. Visual acuity (VA) was reduced to counting fingers in the right eye and perception of light in the left eye. Fundoscopy showed a leopard-spot pattern of yellow-orange subretinal deposits in the posterior pole more pronounced in the right eye compared to the left. On FFA, the deposits were hypofluorescent with additional multiple pinpoint areas of hyperfluorescence spread over the posterior pole. Spectral OCT demonstrated a shallow detachment of the neurosensory retina with extensive intraretinal fluid and alternating atrophic areas and deposits at the level of the RPE which corresponded with hypo- and hyperfluorescent areas with autofluorescent light. Conclusion Coarsely mottled or leopard-spot hyperpigmentation and secondary retinal detachment may develop as a rare dramatic complication in patients with CSC.

Purpose Nonarteritic anterior ischemic optic neuropathy (NAION) is a common, visually disabling disease. It is usually due to a hypotensive perfusion insufficiency leading to infarction of the optic nerve. Only very rarely, NAION has a thromboembolic etiology. A transgender patient with a sequential bilateral NAION related to excessive use of transdermal estrogen is described. Methods A 44 year-old male to female transgender patient developed acute painless visual loss in the right eye (RE) followed by the left eye (LE) 2 months later. She underwent a full ophthalmic exam and an extensive etiological work-up. Results Visual acuity (VA) dropped to perception of light in the RE and, 2 months later, to 3/10 in the left eye. Fundoscopy showed a swollen disc in both eyes in the acute phase, which evolved into pallor later. CT-brain revealed old ischemic areas unrelated to VA loss. A diagnosis of bilateral sequential NAION was made. Predisposing risk factors, though both well controlled, were diabetes and arterial hypertension. Thrombophilia screening and cardiac work-up were negative. When estrogen levels of 60 times the normal value were measured, the patient admitted to overdose with transdermal estrogen to enhance her female characteristics. Such high estrogen levels are very thrombogenic. It is highly likely that it caused the cerebrovascular accidents and also triggered the bilateral sequential NAION. Conclusion NAION only rarely has a thromboembolic etiology. However, careful history taking is warranted to exclude modifiable risk factors in the poorly treatable NAION to prevent affection of the second eye and/or the central nervous system.

Purpose To illustrate different mechanisms which lead to vitamin A deficiency and result in retinal dysfunction. To show how a diagnosis can be made, and how, and to which degree, in such cases, retinal function can be recovered. Methods A case presentation format will be used to illustrate different mechanisms of retinal dysfunctions due to vitamin A deficiency. Patient history taking, clinical and electrophysiological phenotypes and therapeutic approaches will be addressed. Results Mechanisms of vitamin A deficiency are very different, but all have fat malabsorption in common. Often, other concomitant vitamin deficiencies exist. With vitamin A repletion therapy, either partial or complete restoration of retinal function can be attained. Conclusion Causes of vitamin A deficiency are very diverse. Thorough history taking, in combination with an extensive clinical examination and psychophysical and electrophysiological tests, most often allows making a more specific diagnosis of an underlying malabsorption. Vitamin A repletion therapy is effective in such cases.

Purpose To investigate the type and severity of colour vision deficiencies (CVDs) in Stargardt disease (STD). And, to establish how the degree of CVD relates to best-corrected visual acuity (BCVA), full field ERG (ffERG) and duration of disease. Methods A retrospective, cross-sectional study of 97 patients with a clinical diagnosis of STD included a comprehensive medical history and a full clinical work-up, with extensive colour vision testing. Eight patients underwent anomaloscopy. ABCA4 was screened in 92 patients. Results Patients were allocated to 5 BCVA groups and to 3 ffERG groups. Normal colour vision was found in almost 30% of patients. R/G CVDs increased as BCVA declined. More than 50% had a deutan type R/G CVD, although protan R/G CVDs became progressively apparent as BCVA decreased. A predominance of pseudoprotanomaly was evident only on anomaloscopy. Additional Blue/Yellow (B/Y) CVDs were noted in 25% of patients. B/Y CVDs and BCVA higher than 0.75 were seen in adult-onset STD. CVDs evolve to scotopization in patients with low BCVA and/or longstanding disease. Duration of disease did not correlate well with CVDs. Also, no statistically significant differences in ERG results were found between groups with or without a CVD. Conclusion Since colour vision function is better correlated to BCVA than either disease duration or ffERG, it is a rather reliable indicator of disease severity. The presence of CVDs may help to establish an early diagnosis of STD.

Purpose To describe the causes of both genetically determined and acquired night blindness. Methods A case presentation format will be used to illustrate different genetically determined and acquired conditions leading to night blindness. Both clinical and electrophysiological phenotypes as well as genotypes will be discussed. Results Phenotypes and genotypes of genetically determined diseases leading to night blindness are very different. An important distinction to be made is the one between stationary and progressive diseases. Indeed, other than night blindness the visual outcome differs considerably between different conditions. Conclusion The causes of night blindness are diverse. Taking a thorough history in combination with an extensive clinical examination and psychophysical and electrophysiological tests most often allows a to make a specific diagnosis. Acquired conditions are generally treatable, and should be differentiated from those that are inherited. For genetic disease, it is important to distinguish between progressive and stationary conditions.

Purpose To describe the presentation, ophthalmic features and electrophysiological findings in 4 patients with disulfiram (Antabuse) related optic neuropathy. Methods Observational case series involving 4 patients. All patients underwent an extensive ophthalmological work-up, including psychophysical and electrophysiological testing. Results All patients took disulfiram (Antabuse) tablets in varying doses and length of time before developing profound, bilateral visual loss. Three patients were smokers and one patient suffered from schizophrenia. Ophthalmic examination in combination with automated and manual perimetry showed reduction of visual acuity, disturbed colour vision and visual field defects consistent with bilateral optic neuropathy. Electrophysiological testing revealed delayed and reduced amplitudes on pattern VEP. After cessation of disulfiram, visual acuity, perimetry and electrophysiological testing gradually returned to normal or near-normal levels. Conclusion Disulfiram is a rare cause of reversible toxic optic neuropathy. Patients who take disulfiram are more likely to abuse tobacco and possibly other drugs, or have psychiatric or psychological comorbidity. These patients may also be labelled as cases of malingering. Careful history and examination should alert the clinician to the possibility of disulfiram optic neuropathy.

Purpose To describe the retinal conditions that need to be excluded when non-organic visual loss is suspected, and the investigations required to either confirm or exclude them. Methods A case presentation format will be used to illustrate those conditions which can be discovered using psychophysical and electrophysiological tests as well as special imaging including autofluorescence, infrared and red free imaging and spectral-domain optical coherence tomography, in patients in whom a non-organic origin for visual loss is suspected. Results Inherited retinal diseases such as Stargardt macular dystrophy, X-linked retinoschisis and cone dystrophy as well as Batten disease in their early stages all need to be excluded when visual loss is thought to be non-organic. In addition, several acquired retinal conditions such as acute acular neuroretinopathy need to be taken into account. visual field testing, ISCEV-standard full-field flash electroretinography, pattern electroretinography and visual evoked potentials and specialised imaging techniques contribute significantly to making the correct diagnosis. Conclusion Visual loss in a list of organic conditions may mimic non-organic visual loss. Functional testing as well as specialised imaging techniques are essential in differentiating true organic from non-organic visual loss.

Purpose To provide an overview of the recent developments in genetics of inherited retinal dystrophies and dysfunctions. Methods A systematic approach, supported by case presentations, will be used to illustrate an overview of new insights into genotypes and phenotypes of generalised dystrophies and dysfunctions of the retina. Results Much progress has been made in recent years in unravelling the molecular mechanisms underlying generalised retinal dystrophies and dysfunctions, with a wide variety of functions attributed to proteins encoded by causative genes. Identification of new genes such as PDE6C in achromatopsia and TRPM1 in autosomal recessive cCSNB provide further insight in retinal function. In addition, proven and confirmed success of gene therapy for Leber congenital amaurosis in man is leading the way for further treatment trials in humans suffering from different inherited retinal diseases. Conclusion Rapid progress is being made in the field of genetic retinal disease, with novel developments both in genotyping and improved detailed phenotyping. In addition, gene therapy is becoming a potentially feasible treatment option for several inherited retinal conditions.

Purpose Angioid streaks (AS) are funduscopic findings, caused by crack-like dehiscences in elastic portions of Bruch membrane. AS are a manifestation of underlying systemic conditions, such as pseudoxanthoma elasticum (PXE), Paget disease, sickle cell anemia, other blood dyscrasias and, rarely, Ehlers-Danlos syndrome. By far the commonest association is PXE. Differences and similarities of AS in β-thalassemia minor, PXE-like syndrome and Savanna haemoglobinopathy with AS seen in PXE are discussed. The description of AS in Savanna haemoglobinopathy is a first. Methods Angioid streaks were detected in one patient with β-thalassemia minor, one with PXE-like syndrome and one with Savanna haemoglobinopathy. They underwent a full ophthalmic work-up. Molecular analysis of the ABCC6 gene to exclude PXE was performed by dHPLC (denaturing high-performance liquid chromatography) and direct sequencing. Results A 34 year old lady with β-thalassemia minor had a fundus appearance which was an exact phenocopy of PXE retinopathy, including angioid streaks, peau d’orange and comets. In contrast, a 51 year old lady with PXE-like syndrome and a 55 year old man with Savanna haemoglobinopathy had a limited number of short, thick, feathered, white streaks around the optic disc. Conclusion AS differ in aspect depending on the underlying condition. The exact etiology of AS in these systemic conditions has not yet been elucidated. However, it is tempting to suggest that distinct pathogenetic mechanisms underlying very different blood dyscrasias as well as PXE, meet at a final common pathway, leading to breaks in Bruch membrane.

Purpose: To report a previously undescribed autosomal recessive retinal dystrophy Methods: Seven patients from five families in two countries were ascertained with progressive visual loss and punctate retinal flecks. All patients received full ophthalmic examination, ERGs, PERG, EOG and fundus autofluorescence imaging, and gave DNA for mutational screening. They had previously received a variety of diagnoses, including “Goldmann-Favre syndrome”, “fundus flavimaculatus” and “unrecognised dystrophy”. Results: All patients had reduced visual acuity, were hyperopic and had irregularity of the RPE reflex with widespread subretinal deposits. A maculopathy was associated with intra-retinal or subretinal fluid in four cases. Autofluorescence imaging was particularly useful in demonstrating these signs. Angle-closure glaucoma was present in two cases. All patients had abnormality of both rod and cone full-field ERG responses, with delay in the cone flicker ERG. All had abnormal EOG light-rise. Progression in ERG abnormality was documented in three families. The results of genetic analysis will be discussed. Conclusions: A novel retinal disorder is described. The distinctive clinical and electrophysiological features enable directed mutational screening.

To report chorioretinal vasoconstriction as a potential pathogenic mechanism in acute macular neuroretinopathy (AMNR). To describe a time lag between the onset of functional deficits and that of fundoscopically visible lesions and illustrate the superior value of infrared (IR) compared to red-free or white light imaging in AMNR. Two young female patients (30 and 19 years old) with AMNR are described. Both underwent detailed clinical examination with additional imaging using IR, blue, and red-free light. Functional evaluation with pattern and multifocal electroretinography, Goldmann manual, and automated Humphrey visual fields (VFs) was also performed. The first patient was diagnosed with AMNR after a caesarian section during and after which she received treatment with vasoconstrictive drugs. She was followed up for 28 months, after which time she still suffered from bilateral U-shaped paracentral scotomata associated with macular lesions. The second patient complained of central scotomata prior to the onset of any visible fundoscopic lesions, following a bout of flu. VFs confirmed a central scotoma and pattern electroretinography was consistent with loss of macular function. Bilateral petaloid lesions became visible after 3 days when function began to improve. In both patients IR imaging was superior to standard red-free and white light in identifying macular lesions. Vasoconstriction in the chorioretina may be pathogenic in AMNR. Functional complaints precede fundus lesions in AMNR. And, IR light is superior to red-free or white light imaging in detecting typical fundus lesions in AMNR both early and late in the course of the disease.