Unusual OCT findings in a patient with CABP4-associated cone-rod synaptic disorder.

PURPOSE: Bi-allelic variants in CABP4 are associated with congenital cone-rod synaptic disorder, which has also been classified, electrophysiologically, as incomplete congenital stationary night blindness (iCSNB). We describe clinical findings in a patient who demonstrated an unusual macular optical coherence tomography (OCT) phenotype, not previously reported in this condition. METHODS: Our patient underwent multimodal retinal imaging, international standard full-field ERG testing and whole genome sequencing. RESULTS: The patient was a 60-year-old woman with non-progressive visual impairment since birth, nystagmus and preference for dim lighting. Clinical fundus examination was unremarkable. OCT imaging revealed a hypo-reflective zone under an elevated fovea in both eyes. ERGs showed an electronegative DA10 response, with severely abnormal light-adapted responses. Whole genome sequencing revealed homozygosity for a known pathogenic variant in CABP4. No variants were found in other genes that could explain the patient's phenotype. CONCLUSIONS: OCT findings of foveal elevation and an underlying hypo-reflective zone are novel in this condition. Whilst the clinical history was similar to achromatopsia and other cone dysfunction syndromes, ERG findings suggested disease associated with CACNA1F or CABP4. As CACNA1F is X-linked, CABP4 was more likely, and confirmed on genetic testing. The patient saw better in dim light, confirming that night blindness is not a feature of CABP4-associated disease. Our case highlights the value of ERGs in discriminating between causes of cone dysfunction, and extends the range of retinal imaging phenotypes reported in this disorder.

Novel homozygous mutations in the transcription factor NRL cause non-syndromic retinitis pigmentosa.

Purpose: To describe the clinical phenotype and genetic basis of non-syndromic retinitis pigmentosa (RP) in one family and two sporadic cases with biallelic mutations in the transcription factor neural retina leucine zipper (NRL). Methods: Exome sequencing was performed in one affected family member. Microsatellite genotyping was used for haplotype analysis. PCR and Sanger sequencing were used to confirm mutations in and screen other family members where they were available. The SMART tool for domain prediction helped us build the protein schematic diagram. Results: For family MM1 of Pakistani origin, whole-exome sequencing and microsatellite genotyping revealed homozygosity on chromosome 14 and identified a homozygous stop-loss mutation in NRL, NM_006177.5: c.713G>T, p.*238Lext57, which is predicted to add an extra 57 amino acids to the normal protein chain. The variant segregated with disease symptoms in the family. For case RP-3051 of Spanish ancestry, clinical exome sequencing focusing on the morbid genome highlighted a homozygous nonsense mutation in NRL, c.238C>T, p.Gln80*, as the most likely disease candidate. For case RP-1553 of Romanian ethnicity, targeted-exome sequencing of 73 RP/LCA genes identified a homozygous nonsense mutation in NRL, c.544C>T, p.Gln182*. The variants were either rare or absent in the gnomAD database. Conclusions: NRL mutations predominantly cause dominant retinal disease, but there have been five published reports of mutations causing recessive disease. Here, we present three further examples of recessive RP due to NRL mutations. The phenotypes observed are consistent with those in the previous reports, and the observed mutation types and distribution further confirm distinct patterns for variants in NRL causing recessive and dominant diseases.

The X-linked retinopathies: Physiological insights, pathogenic mechanisms, phenotypic features and novel therapies.

X-linked retinopathies represent a significant proportion of monogenic retinal disease. They include progressive and stationary conditions, with and without syndromic features. Many are X-linked recessive, but several exhibit a phenotype in female carriers, which can help establish diagnosis and yield insights into disease mechanisms. The presence of affected carriers can misleadingly suggest autosomal dominant inheritance. Some disorders (such as RPGR-associated retinopathy) show diverse phenotypes from variants in the same gene and also highlight limitations of current genetic sequencing methods. X-linked disease frequently arises from loss of function, implying potential for benefit from gene replacement strategies. We review X-inactivation and X-linked inheritance, and explore burden of disease attributable to X-linked genes in our clinically and genetically characterised retinal disease cohort, finding correlation between gene transcript length and numbers of families. We list relevant genes and discuss key clinical features, disease mechanisms, carrier phenotypes and novel experimental therapies. We consider in detail the following: RPGR (associated with retinitis pigmentosa, cone and cone-rod dystrophy), RP2 (retinitis pigmentosa), CHM (choroideremia), RS1 (X-linked retinoschisis), NYX (complete congenital stationary night blindness (CSNB)), CACNA1F (incomplete CSNB), OPN1LW/OPN1MW (blue cone monochromacy, Bornholm eye disease, cone dystrophy), GPR143 (ocular albinism), COL4A5 (Alport syndrome), and NDP (Norrie disease and X-linked familial exudative vitreoretinopathy (FEVR)). We use a recently published transcriptome analysis to explore expression by cell-type and discuss insights from electrophysiology. In the final section, we present an algorithm for genes to consider in diagnosing males with non-syndromic X-linked retinopathy, summarise current experimental therapeutic approaches, and consider questions for future research.

Clinical Features of a Retinopathy Associated With a Dominant Allele of the RGR Gene.

Purpose: We describe the clinical features in two pedigrees with dominantly inherited retinopathy segregating the previously reported frameshifting mutation, c.836dupG (p.Ile280Asn*78) in the terminal exon of the RGR gene, and compare their haplotypes to that of the previously reported pedigree. Methods: The probands were ascertained at West Virginia University Eye Institute (WVU) and Moorfields Eye Hospital (MEH) through next generation sequencing (NGS) and whole genome sequencing (WGS) respectively. Clinical data included visual acuity (VA), visual fields, fundus autofluorescence (FAF), optical coherence tomography (OCT), and electroretinography (ERG). Haplotype analysis was performed using Sanger sequencing of the DNA from the molecularly ascertained individuals from the three pedigrees. Results: Nine heterozygous mutation carriers were identified in two families. Four carriers were asymptomatic; five carriers had variable VA reduction, visual field constriction, and experienced difficulty under dim illumination. Fundus examination of the asymptomatic carriers showed diffuse or reticular pigmentation of the retina; the symptomatic carriers had chorioretinal atrophy. FAF imaging showed widespread signal loss in advanced retinopathy, and reticular hyperautofluorescence in mild cases. OCT showed loss of outer retinal lamina in advanced disease. ERG showed moderate-to-severe rod-cone dysfunction in two symptomatic carriers; and was normal in three asymptomatic carriers. A shared haplotype flanking the mutation of up to 6.67 Mb was identified in both families. Within this region, 1.27 Mb were shared with the first family reported with this retinopathy. Conclusions: The clinical data suggest a variable and slow degeneration of the RPE. A shared chromosomal segment surrounding the RGR gene suggests a single ancestral mutational event underlying all three families.

Retinal thickness measurements in sickle cell patients with HbSS and HbSC genotype.

OBJECTIVE: Temporal macula thinning has been reported in sickle cell patients, but it remains unclear if there is a difference between HbSS and HbSC genotypes. We aimed to quantitatively compare macular thickness between eyes with HbSS and HbSC genotype. DESIGN: Retrospective descriptive study. METHODS: Consecutive patients seen over a 5.5-year period in the Ophthalmology Department at St Thomas' Hospital, London, were identified. Macular optical coherence tomography images were retrospectively analyzed. The retinal thickness in all 9 subfields of the Early Treatment Diabetic Retinopathy Study (ETDRS) grid was compared between HbSS and HbSC eyes. Right eyes and left eyes were analyzed independently, as well as averaged measurements from both eyes. Comparison was made between the 2 genotypes, adjusting for age and sex, and for multiple testing. Scans were excluded in cases of poor fixation or ocular comorbidity affecting retinal thickness. RESULTS: 132 HbSC and 120 HbSS patients were identified. Scans from 166 right and 153 left eyes were included (with approximately equal numbers of HbSS and HbSC genotypes). Mean retinal thickness was lower in HbSS eyes compared with HbSC eyes in all subfields of the ETDRS grid, but in most subfields the difference was <10 microns. Differences reached statistical significance for outer superior, inferior, and temporal subfields and the inner temporal subfield (p < 0.05). CONCLUSION: Although the HbSC genotype is more strongly associated with proliferative retinopathy, HbSS patients had on average more macular thinning.

A twin study of cilioretinal arteries, tilted discs and situs inversus.

PURPOSE: To establish the prevalence and heritability of cilioretinal arteries (CRAs), tilted discs (TDs) and situs inversus (SI). METHODS: Fundus photos from the Twins UK Adult Twin registry twin database were analyzed: 1812 individuals, 526 complete monozygotic (MZ) twin pairs and 336 complete dizygotic (DZ) pairs. Images were assessed non-stereoscopically on a computer screen by the same ophthalmologist for presence of CRAs, TDs or SI. Prevalence figures, probandwise concordances and heritabilities were calculated. RESULTS: Prevalence of a CRA in subjects' right eyes was 28.6% (26.5-30.8). Prevalence of subjects with a CRA in at least one eye was 45.0% (42.6-47.5), with a TD in at least one eye was 1.2% (0.8-1.9), and with SI at least one eye was 0.5% (0.3-1.0). There was no association between birth weight and presence of CRA. Concordance for CRA in at least one eye (MZ twins) was 60% (95% CI 55-64), and (DZ) was 45% (95% CI 39-51). Heritability for CRAs in at least one eye was 49.4% (95% CI 38.1-59.7) and for both eyes was 32.9% (95% CI 10.4-53.3). We were unable to calculate meaningful heritabilities or concordances for TDs and situs SI, due to insufficient numbers. CONCLUSIONS: The presence of CRAs appears to be moderately heritable, with greater variance explained by individual environmental factors or even stochastic events. They were not associated with low birth weight. Future genetic research and studies of birth/lifecourse cohorts may offer further insights into the etiology of congenital papillovascular abnormalities.

Differentiating drusen: Drusen and drusen-like appearances associated with ageing, age-related macular degeneration, inherited eye disease and other pathological processes.

Drusen are discussed frequently in the context of their association with age-related macular degeneration (AMD). Some types may, however, be regarded as a normal consequence of ageing; others may be observed in young age groups. They also occur in a number of inherited disorders and some systemic conditions. Whilst drusen are classically located external (sclerad) to the retinal pigment epithelium, accumulations of material internal (vitread to) this layer can display a drusen-like appearance, having been variously termed pseudodrusen or subretinal drusenoid deposits. This review first briefly presents an overview of drusen biogenesis and subclinical deposit. The (frequently overlapping) subtypes of clinically detectable deposit, seen usually in the context of ageing or AMD, are then described in more detail, together with appearance on imaging modalities: these include hard and soft drusen, cuticular drusen, reticular pseudodrusen and "ghost drusen". Eye disorders other than AMD which may exhibit drusen or drusen-like features are subsequently discussed: these include monogenic conditions as well as conditions with undefined inheritance, the latter including some types of early onset drusen such as large colloid drusen. A number of systemic conditions in which drusen-like deposits may be seen are also considered. Throughout this review, high resolution images are presented for most of the conditions discussed, particularly the rarer ones, providing a useful reference library for images of the range of conditions associated with drusen-like appearances. In the final section, some common themes are highlighted, as well as a brief discussion of some future avenues for research.

Risk factors for visual impairment in patients with sickle cell disease in London.

PURPOSE: Dramatically improved health care in recent years has increased the life expectancy of patients with sickle cell disease (SCD) as well as the prognosis for its ocular complications. We sought to identify risk factors for visual impairment in patients with SCD in London 4 decades after Goldberg's seminal studies. METHODS: Patients 16 years and older with SCD (genotypes HbSS, HbSC, HbSß-thalassemia) attending hematology and ophthalmology services were offered ocular examination. Retinopathy was graded according to the Goldberg classification. Visual impairment was defined as corrected distance visual acuity of 20/40 or poorer. RESULTS: In total, 182 eyes of 182 patients (mean ± SD age, 37.2 ± 12.8 years; female, 65.9%) were included. Women were significantly older than men (mean ± SD age, 38.8 ± 13.1 vs 34.2 ± 11.8 years; p = 0.0174). There was no difference in mean age of each genotype group (p>0.15). Risk factors for sight-threatening proliferative sickle retinopathy (PSR) were age over 35 years (odds ratio [OR] 2.01; 95% confidence interval [CI] 1.05-3.89; p = 0.0359) and HbSC genotype (OR 4.06; 95% CI 2.07-7.98; p<0.0001). Although visual impairment was related to the presence of sight-threatening PSR (OR 7.23; 95% CI 1.50-35.0; p = 0.0138), it was not related to hemoglobin genotype (p>0.50). CONCLUSIONS: We present the largest study of ocular findings in SCD in the United Kingdom. Sight-threatening PSR is a risk factor for visual impairment, but hemoglobin genotype status is not.

Cilioretinal Artery Territory Infarction Associated With Papilledema in a Patient With Neurofibromatosis Type 2.

Cilioretinal artery territory infarction can occur in isolation or in association with other vascular compromise of the retinal circulation. Our patient, an 18-year-old woman with neurofibromatosis type 2, developed a cilioretinal artery territory infarction in the setting of papilledema. Our case, together with one previous report, suggests that cilioretinal artery territory infarction in the context of papilledema, although rare, is a real entity.

Spectral domain optical coherence tomography findings in long-term silicone oil-related visual loss.

PURPOSE: To investigate spectral domain optical coherence tomography findings in long-term silicone oil-related visual loss. METHODS: Four symptomatic patients were reviewed 4 years to 9 years after vitrectomy with silicone oil tamponade for macula-on retinal detachment. Three lost vision with oil in situ, with one at the time of oil removal. Eleven control eyes with good vision were included. Patients underwent assessment of best-corrected visual acuity, contrast sensitivity, Farnsworth-Munsell 100 Hue testing, static perimetry, and spectral domain optical coherence tomography imaging of the macula and disk. RESULTS: Long-term best-corrected visual acuity was significantly reduced in affected eyes (range, 0.44-1.02), as was contrast sensitivity (0.75-1.35) and color discrimination (Farnsworth-Munsell-100 Hue score, 151-390). Static perimetry showed a central scotoma in all affected eyes. Optical coherence tomography revealed microcystic macular changes in the inner nuclear layer of all affected eyes associated with severe loss of the papillofoveal retinal nerve fiber layer. In one patient, serial optical coherence tomography images showed development of microcystic macular changes 18 months after oil removal. Control eyes lacked these features, except two asymptomatic eyes that showed microcystic changes on optical coherence tomography with a corresponding paracentral scotoma. CONCLUSION: We have demonstrated microcystic macular changes in the inner nuclear layer of affected eyes, as well as focal severe loss of the papillofoveal projection. These changes share significant morphologic features reported in multiple sclerosis-associated optic neuritis and Leber hereditary optic neuropathy.

Anti-vascular endothelial growth factor therapies in ophthalmology: current use, controversies and the future.

Use of anti-vascular endothelial growth factor (VEGF) therapies was introduced for the treatment of ocular disorders in 2005. In the UK, the current licensed and NICE approved indications are for the treatment of neovascular age-related macular degeneration (nAMD), diabetic macular oedema (DMO), macular oedema secondary to a retinal vein occlusion (RVO) and choroidal neovascularization in pathological myopia. These diagnoses alone account for two-thirds of the main causes of legally registrable visual impairment and blindness. Ranibizumab (Lucentis®; Genentech/Novartis), a drug specifically designed for intraocular use, is the primary licensed medication. Controversially however, clinicians have been using an unlicensed cheaper drug, bevacizumab (Avastin®; Genentech/Roche), originally designed for systemic administration, with a similar mode of action and shown to have a similar efficacy. However, there are fears of greater side effects with bevacizumab though studies have not been sufficiently powered to show statistical difference. In the current global economic climate, anti-VEGF treatment places huge financial and logistical pressure on already strained health care systems. Bevacizumab is considerably more cost effective than ranibizumab, and thus using bevacizumab would widen access to treatment particularly in developing countries. This licensing issue also places clinicians in a difficult medico-legal position especially in Europe, where doctors are duty bound to use a licensed drug for a particular indication if this is available. As the indications of anti-VEGF therapies expand and the cost of health care provision becomes more expensive, the controversies surrounding their use will inevitably become more important.

Recessive mutations in SLC38A8 cause foveal hypoplasia and optic nerve misrouting without albinism.

Foveal hypoplasia and optic nerve misrouting are developmental defects of the visual pathway and only co-occur in connection with albinism; to date, they have only been associated with defects in the melanin-biosynthesis pathway. Here, we report that these defects can occur independently of albinism in people with recessive mutations in the putative glutamine transporter gene SLC38A8. Nine different mutations were identified in seven Asian and European families. Using morpholino-mediated ablation of Slc38a8 in medaka fish, we confirmed that pigmentation is unaffected by loss of SLC38A8. Furthermore, by undertaking an association study with SNPs at the SLC38A8 locus, we showed that common variants within this gene modestly affect foveal thickness in the general population. This study reveals a melanin-independent component underpinning the development of the visual pathway that requires a functional role for SLC38A8.

A new recessively inherited disorder composed of foveal hypoplasia, optic nerve decussation defects and anterior segment dysgenesis maps to chromosome 16q23.3-24.1.

PURPOSE: We have previously described two families with unique phenotypes involving foveal hypoplasia. The first family (F1) presented with foveal hypoplasia and anterior segment dysgenesis, and the second family (F2) presented with foveal hypoplasia and chiasmal misrouting in the absence of albinism. A genome-wide linkage search in family F1 identified a 6.5 Mb locus for this disorder on chromosome 16q23.2-24.1. The aim of this study was to determine if both families have the same disorder and to see if family F2 is also linked to the 16q locus. METHODS: Family members underwent routine clinical examination. Linkage was determined by genotyping microsatellite makers and calculating logarithm of the odds (LOD) scores. Locus refinement was undertaken with single nucleotide polymorphism (SNP) microarray analysis. RESULTS: The identification of chiasmal misrouting in family F1 and anterior segment abnormalities in family F2 suggested that the families have the same clinical phenotype. This was confirmed when linkage analysis showed that family F2 also mapped to the 16q locus. The single nucleotide polymorphism microarray analysis excluded a shared founder haplotype between the families and refined the locus to 3.1 Mb. CONCLUSIONS: We report a new recessively inherited syndrome consisting of foveal hypoplasia, optic nerve decussation defects and anterior segment dysgenesis, which we have abbreviated to FHONDA syndrome. The gene mutated in this disorder lies within a 3.1 Mb interval containing 33 genes on chromosome 16q23.3-24.1 (chr16:83639061 - 86716445, hg19).