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Restoring vision in inherited retinal degenerations remains an unmet medical need. In mice exhibiting a genetically engineered block of the visual cycle, vision was recently successfully restored by oral administration of 9-cis-retinyl acetate (QLT091001). Safety and visual outcomes of a once-daily oral dose of 40 mg/m2/day QLT091001 for 7 consecutive days was investigated in an international, multi-center, open-label, proof-of-concept study in 18 patients with RPE65- or LRAT-related retinitis pigmentosa. Eight of 18 patients (44%) showed a ≥20% increase and 4 of 18 (22%) showed a ≥40% increase in functional retinal area determined from Goldmann visual fields; 12 (67%) and 5 (28%) of 18 patients showed a ≥5 and ≥10 ETDRS letter score increase of visual acuity, respectively, in one or both eyes at two or more visits within 2 months of treatment. In two patients who underwent fMRI, a significant positive response was measured to stimuli of medium contrast, moving, pattern targets in both left and right hemispheres of the occipital cortex. There were no serious adverse events. Treatment-related adverse events were transient and the most common included headache, photophobia, nausea, vomiting, and minor biochemical abnormalities. Measuring the outer segment length of the photoreceptor layer with high-definition optical coherence tomography was highly predictive of treatment responses with responders having a significantly larger baseline outer segment thickness (11.7 ± 4.8 μm, mean ± 95% CI) than non-responders (3.5 ± 1.2 μm). This structure-function relationship suggests that treatment with QLT091001 is more likely to be efficacious if there is sufficient photoreceptor integrity. ClinicalTrials.gov NCT01014052.

Progressive cone and cone-rod dystrophies are a clinically and genetically heterogeneous group of inherited retinal diseases characterised by cone photoreceptor degeneration, which may be followed by subsequent rod photoreceptor loss. These disorders typically present with progressive loss of central vision, colour vision disturbance and photophobia. Considerable progress has been made in elucidating the molecular genetics and genotype–phenotype correlations associated with these dystrophies, with mutations in at least 30 genes implicated in this group of disorders. We discuss the genetics, and clinical, psychophysical, electrophysiological and retinal imaging characteristics of cone and cone-rod dystrophies, focusing particularly on four of the most common disease-associated genes: GUCA1A, PRPH2, ABCA4 and RPGR. Additionally, we briefly review the current management of these disorders and the prospects for novel therapies.

Background/AimsTo report the prevalence of treatable complications (cystoid macular oedema, CME; epiretinal membrane, ERM and cataract) in patients with retinitis pigmentosa (RP).MethodsConsecutive patients with RP attending a tertiary eye clinic in 2012. Spectral domain-optical coherence tomography was used to determine presence of CME and ERM. Clinic records were reviewed to identify cataract and pseudophakia. Multivariable analyses adjusted for age, gender and other confounders.ResultsData are presented for 338 eyes from 169 patients. CME was present in 58.6% of patients and 50.9% of eyes and was bilateral in 73.7%. ERM, cataract and pseudophakia were present in 22.8%, 23.4% and 11.2% eyes, respectively. In multivariable analyses, CME was associated with younger age (OR 0.81, 95% CI 0.67 to 0.98) but not with gender. Patients with ERM and cataract/pseudophakia were less likely to also have CME (OR 0.19, 95% CI 0.09 to 0.40 and OR 0.37, 95% CI 0.16 to 0.84, respectively). CME was most prevalent in patients with autosomal-dominant inheritance (71.4%), followed by autosomal recessive/sporadic inheritance (58.9%) and least likely in persons with X linked inheritance (12.5%, p<0.001).ConclusionsThe prevalence of treatable RP complications is high and suggests it may be clinically beneficial to screen patients with RP to identify those who may benefit from current or future interventions.

Age-related macular degeneration (AMD) is a leading cause of blindness. Genetic variants at the chromosome 1q31.3 encompassing the complement factor H ( CFH , FH) and CFH related genes ( CFHR1-5 ) are major determinants of AMD susceptibility, but their molecular consequences remain unclear. Here we demonstrate that FHR-4 plays a prominent role in AMD pathogenesis. We show that systemic FHR-4 levels are elevated in AMD ( P -value = 7.1 × 10 −6 ), whereas no difference is seen for FH. Furthermore, FHR-4 accumulates in the choriocapillaris, Bruch’s membrane and drusen, and can compete with FH/FHL-1 for C3b binding, preventing FI-mediated C3b cleavage. Critically, the protective allele of the strongest AMD-associated CFH locus variant rs10922109 has the highest association with reduced FHR-4 levels ( P -value = 2.2 × 10 −56 ), independently of the AMD-protective CFHR1–3 deletion, and even in those individuals that carry the high-risk allele of rs1061170 (Y402H). Our findings identify FHR-4 as a key molecular player contributing to complement dysregulation in AMD. A locus on chromosome 1 encompassing the CFHR genes is highly associated with AMD risk. Here, Cipriani and colleagues investigate the role of CFHR4 , encoding FHR-4, and demonstrate a relationship between AMD risk, circulating FHR-4 levels and genetic variants at this locus.

Susanne Kohl and colleagues report mutations in ATF6 , a regulator of the unfolded protein response pathway, that cause a familial form of achromatopsia. Their results indicate a role for ATF6 in foveal development rather than a direct role in the cone phototransduction pathway. Achromatopsia (ACHM) is an autosomal recessive disorder characterized by color blindness, photophobia, nystagmus and severely reduced visual acuity. Using homozygosity mapping and whole-exome and candidate gene sequencing, we identified ten families carrying six homozygous and two compound-heterozygous mutations in the ATF6 gene (encoding activating transcription factor 6A), a key regulator of the unfolded protein response (UPR) and cellular endoplasmic reticulum (ER) homeostasis. Patients had evidence of foveal hypoplasia and disruption of the cone photoreceptor layer. The ACHM-associated ATF6 mutations attenuate ATF6 transcriptional activity in response to ER stress. Atf6 −/− mice have normal retinal morphology and function at a young age but develop rod and cone dysfunction with increasing age. This new ACHM-related gene suggests a crucial and unexpected role for ATF6A in human foveal development and cone function and adds to the list of genes that, despite ubiquitous expression, when mutated can result in an isolated retinal photoreceptor phenotype.

A form of Leber's congenital amaurosis is caused by mutant RPE65 , a critical component of the visual cycle. Two early clinical trials to assess subretinal injection of a viral vector containing RPE65 in young adults with advanced retinal degeneration show that this approach is generally safe in the short term, although one group reported an adverse event: macular hole. The authors observed improvement in some measures of visual function. Two early clinical trials to assess subretinal injection of a viral vector containing RPE65 in young adults with advanced retinal degeneration show that this approach is generally safe in the short term, although one group reported an adverse event: macular hole. The authors observed improvement in some measures of visual function. Leber's congenital amaurosis is a term used to describe a group of recessively inherited, severe, infantile-onset rod–cone dystrophies. 1 Mutation of one of several genes, including RPE65 , causes disease that involves impaired vision from birth 2 , 3 and typically progresses to blindness in the third decade of life. There is no effective treatment. RPE65 is expressed in the retinal pigment epithelium and encodes a 65-kD protein that is a key component of the visual cycle, 1 , 4 – 8 a biochemical pathway that regenerates the visual pigment after exposure to light. 9 – 14 A lack of functional RPE65 results in deficiency of 11- cis . . .

BackgroundLens development is orchestrated by transcription factors. Disease-causing variants in transcription factors and their developmental target genes are associated with congenital cataracts and other eye anomalies.MethodsUsing whole exome sequencing, we identified disease-causing variants in two large British families and one isolated case with autosomal dominant congenital cataract. Bioinformatics analysis confirmed these disease-causing mutations as rare or novel variants, with a moderate to damaging pathogenicity score, with testing for segregation within the families using direct Sanger sequencing.ResultsFamily A had a missense variant (c.184 G>A; p.V62M) in PAX6 and affected individuals presented with nuclear cataract. Family B had a frameshift variant (c.470–477dup; p.A160R*) in PITX3 that was also associated with nuclear cataract. A recurrent missense variant in HSF4 (c.341 T>C; p.L114P) was associated with congenital cataract in a single isolated case.ConclusionsWe have therefore identified novel variants in PAX6 and PITX3 that cause autosomal dominant congenital cataract.

Background/AimsA subset of patients with X linked retinoschisis (XLRS) have bullous schisis cavities in the peripheral retina. This study describes the characteristics and prognosis of the bullous form of XLRS.MethodsA retrospective case series was performed of nine patients with molecularly proven bullous XLRS seen at a single tertiary centre.ResultsAll cases of bullous peripheral schisis were bilateral, with one unilateral case at presentation which developed into bilateral bullous schisis over time. The mean age of onset was 1.9 years (range: 1 month–7 years, SD: 2.1 years) and at clinical diagnosis was 5.9 years (range: 1 month–27 years, SD: 9.0 years). Mean follow-up was 11 years (range: 6 months–36 years, SD: 10.8 years). Strabismus was the most common presentation (n=7). Other presenting complaints included decreased vision, floaters and an irregularly shaped pupil. The most frequently associated ocular features were strabismus (100%), vitreous haemorrhage (4/18 eyes, 22%), nystagmus (2/9, 22%) and persistent fetal vasculature (1/18, 6%). Localised tractional detachment was seen in 2/18 (11%) eyes, total detachment that underwent surgical repair in 1/18 (6%) and pigmented demarcation lines in a further 22% of the eyes. There was one eye with exudative retinal detachment.ConclusionIn XLRS, bullous schisis may be congenital or develop soon after birth and most commonly presents with strabismus. Cases may be complicated by some form of retinal detachment, which may be tractional or a Coats-like exudative detachment.

Background Oliver–McFarlane syndrome is characterised by trichomegaly, congenital hypopituitarism and retinal degeneration with choroidal atrophy. Laurence–Moon syndrome presents similarly, though with progressive spinocerebellar ataxia and spastic paraplegia and without trichomegaly. Both recessively inherited disorders have no known genetic cause. Methods Whole-exome sequencing was performed to identify the genetic causes of these disorders. Mutations were functionally validated in zebrafish pnpla6 morphants. Embryonic expression was evaluated via in situ hybridisation in human embryonic sections. Human neurohistopathology was performed to characterise cerebellar degeneration. Enzymatic activities were measured in patient-derived fibroblast cell lines. Results Eight mutations in six families with Oliver–McFarlane or Laurence–Moon syndrome were identified in the PNPLA6 gene, which encodes neuropathy target esterase (NTE). PNPLA6 expression was found in the developing human eye, pituitary and brain. In zebrafish, the pnpla6 curly-tailed morphant phenotype was fully rescued by wild-type human PNPLA6 mRNA and not by mutation-harbouring mRNAs. NTE enzymatic activity was significantly reduced in fibroblast cells derived from individuals with Oliver–McFarlane syndrome. Intriguingly, adult brain histology from a patient with highly overlapping features of Oliver–McFarlane and Laurence–Moon syndromes revealed extensive cerebellar degeneration and atrophy. Conclusions Previously, PNPLA6 mutations have been associated with spastic paraplegia type 39, Gordon–Holmes syndrome and Boucher–Neuhäuser syndromes. Discovery of these additional PNPLA6-opathies further elucidates a spectrum of neurodevelopmental and neurodegenerative disorders associated with NTE impairment and suggests a unifying mechanism with diagnostic and prognostic importance.

A variant on complement factor 3 is associated with age-related macular degeneration, with a population attributable risk of 22%. This finding underlines the importance of complement activation in the pathogenesis of the disease. A variant on complement factor 3 is associated with age-related macular degeneration, with a population attributable risk of 22%. Age-related macular degeneration is the leading cause of visual impairment in the elderly and the most common cause of blindness in Western countries. 1 It affects the macular region of the retina. The macula has a high density of photoreceptors and provides detailed central vision. In the early stages of the disease (referred to as age-related maculopathy), deposits called drusen develop between the retinal pigment epithelium and underlying choroid. 1 Later, the disease is manifested as either extensive atrophy of the retinal pigment epithelium and overlying photoreceptor cells (geographic atrophy) or aberrant choroidal angiogenesis (choroidal neovascularization). 1 Both of these conditions can lead . . .