Inherited retinal diseases are the most common cause of blindness in the working-age population in Australia.

Background: This study examined the frequency of inherited retinal diseases (IRDs) as the reason for blindness registrations over the last two decades and the demographic and clinical phenotypes of inherited retinal disease (IRD)-related registrations.Materials and methods: Retrospective, observational study of individuals registered with a state-wide blind and vision-impaired registry. Low-vision or blindness-only (≤20/200 or ≤20°) certificates issued to children (0-15 years), working-age (16-64 years) and older-age (65 and older) adults were assessed. Sex and age distributions were examined for the top 20 reasons for certification. Demographic and clinical features of specific phenotypes of IRDs listed in the registry were examined.Results: Amongst 11824 low-vision certificates issued between July 1995 and January 2017, 679 (5.7%) listed an IRD as the reason for registration. In individuals with blindness-only certification (N=4919), IRDs was the second most common diagnosis (8.3%), overtaking glaucoma (8.1%) and diabetic retinopathy (5.4%). IRD was the second most common reason for low-vision certification amongst children (11.6%) and the most common reason amongst working-age population (23.3%). The mean±SD age for IRD-related blindness-only certification was 46±20 years. The top three phenotypes of IRD-related low-vision certification were non-syndromic retinitis pigmentosa (54%), Stargardt disease (12%) and macular dystrophy (8%).Conclusion: Our findings of IRDs as a common cause of blindness in all ages justify continued funding for providing low-vision services and developing treatments for these conditions.

Genetic causes of nystagmus, foveal hypoplasia and subnormal visual acuity- other than albinism.

Background: To describe genetic molecular findings in individuals with congenital nystagmus, foveal hypoplasia, and subnormal vision, with normal ocular pigmentation (absence of diffuse transillumination or transparent retinal pigment typical for albinism).Methods: This is a retrospective, multicenter study of ophthalmic, systemic, and genetic features, as collected from medical records of patients diagnosed with infantile nystagmus and foveal hypoplasia. Ophthalmic findings include best-corrected visual acuity (BCVA), biomicroscopic examination, cycloplegic refraction, retinal examination, macular optical coherence tomography, and electroretinography. Genetic information was retrieved from the participating genetic clinics and included ethnicity and molecular diagnosis.Results: Thirty-one individuals met the inclusion criteria and had a secure molecular diagnosis. Mutations in two genes predominated, constituting 77.4% of all the represented genes: SLC38A8 (45.1%) and PAX6 (32.3%). Seventy-eight percent of the subjects who had a measurable BCVA had moderate and severe visual impairment (range 20/80 to 20/270). Most patients with a mutation in SLC38A8 had mild to moderate astigmatism, while most patients with PAX6 mutation had moderate and severe myopia. Patients in the PAX6 group had variable degrees of anterior segment manifestations.Conclusion: In our cohort, the main causative genes for congenital nystagmus and foveal hypoplasia in normally pigmented eyes were SLC38A8 and PAX6. A mild phenotype in PAX6 mutations may be an under-diagnosed cause of nystagmus and foveal hypoplasia. Reaching an accurate genetic diagnosis is essential for both the patients and their family members. This enables predicting disease prognosis, tailoring correct follow-up, and providing genetic counseling and family planning to affected families.

Targeted panel sequencing identifies a novel NR2F1 mutations in a patient with Bosch-Boonstra-Schaaf optic atrophy syndrome.

Background: Nuclear hormone receptor gene, NR2F1, plays a key role in brain and eye development. Bosch-Boonstra-Schaaf optic atrophy syndrome (BBSOAS, MIM #615772) is an autosomal dominant hereditary disorder caused by mutations in this gene. However, there have been few studies describing fundus and optical coherence tomography findings on BBSOAS. Materials and methods: The patient underwent a detailed clinical evaluation and ophthalmic imaging followed by targeted panel next-generation sequencing analysis. Results: A 7-year-old Korean boy, with a history of delayed development and borderline intellectual functioning, was referred to our clinic for evaluation of low vision. He was born full-term with no perinatal insults. Best-corrected visual acuity was 20/100 in both eyes, and latent nystagmus was noted. Dilated fundus examinations revealed optic atrophy in both eyes, and optical coherence tomography showed diffuse thinning of retinal nerve fiber layers. Targeted panel next-generation sequencing showed novel c.513C>G; p.Tyr171Ter (NM_005654.4) in NR2F1 gene. This stop-gain mutation was predicted to be deleterious by in silico prediction programs, and was absent in the current population genomic database. Conclusions: We highlighted the value of genetic testing in definite diagnosis of BBSOAS in patients with unexplained optic atrophy.

Ophthalmic manifestations in patients with Leigh syndrome, French Canadian type.

BACKGROUND: Leigh syndrome, French Canadian type is a rare neurodegenerative disease. To our knowledge, there have been no studies based on ocular findings published for this disease. The purpose of this study is to describe ophthalmic findings in these patients. PATIENTS: Six patients genetically identified as having the syndrome were included in this study. METHODS: Four patients had an ophthalmic examination with an ophthalmologist including evaluation of visual acuity, extraocular motility and lid position, orthoptic workup, evaluation of stereopsis, refraction, evaluation of pupils, color vision, slit-lamp biomicroscopy, measurement of intraocular pressure, and fundoscopy. Two patients had a chart review. RESULTS: Visual acuity ranged from 0.00 logmar to 1.55 logmar. Extraocular motility abnormalities and ptosis were noted in half of the patients. Strabismus was present in the entire cohort, and stereopsis was absent in half of these patients. Amblyopia was noted in 83% of individuals and suppression in 33%. Only one patient had nystagmus. Refraction varied throughout patients. It included severe hyperopia, myopia, astigmatism, and significant anisometropia. Pupils, anterior segment, fundus, and color vision were normal in all patients. Intraocular pressure was slightly elevated in one patient. CONCLUSION: Patients with Leigh syndrome, French Canadian type display a variety of ophthalmic findings, and screening at a young age is recommended.

Mild aniridia phenotype: an under-recognized diagnosis of a severe inherited ocular disease.

PURPOSE: Aniridia is a rare panocular disorder caused by mutations in the PAX6 gene and characterized mainly by iris hypoplasia. Here, we present six families with a history of low vision/blindness with a previously undiagnosed mild aniridia phenotype with minimal iris changes. METHODS: Retrospective case series of patients diagnosed with a subtle aniridia phenotype characterized by minimal iris abnormalities, foveal hypoplasia, and an identified mutation in PAX6. Data collection from patient's charts included ocular examination findings, visual acuity, refraction, and clinical pictures when available. Genetic analysis was performed by isolation of genomic DNA from peripheral blood. The main outcome was the identification of patients with mild aniridia harboring a PAX6 mutation. RESULTS: In all six families, the phenotype included minimal corectopia and foveal hypoplasia; nystagmus was present in 10 out of 11 patients. A PAX6 mutation was identified in all six families; three of these mutations were identified previously, and three are novel mutations. All the mutations are located within the conventional 128-residue paired domain of PAX6. CONCLUSIONS: A mild form of aniridia should be considered in the differential diagnosis of patients with low vision associated with mild iris abnormalities, nystagmus, and foveal hypoplasia. To ensure an accurate diagnosis of aniridia, minimal pupillary changes and/or incipient keratopathy should be examined. The broad phenotypic heterogeneity among aniridia leads to the fact that eye care clinicians must have a high index of suspicion for the disease when seeing undiagnosed low vision patients, because proper diagnosis can improve management as well as facilitate genetic testing and counselling.

Novel truncating mutation in CACNA1F in a young male patient diagnosed with optic atrophy.

BACKGROUND: Low vision in children can be accompanied by pallor of the optic disc with little or no characteristic morphologic changes of the retina. A variety of diseases can be the underlying cause, including hereditary optic atrophy, Leber's congenital amaurosis (LCA), achromatopsia, and calcium channel, voltage-dependent, L-type, alpha-1F subunit gene (CACNA1F)-associated retinopathy (most widely known as incomplete congenital stationary night blindness: iCSNB). Differentiation at early age is desirable due to large differences in prognosis, but may be difficult because phenotypes overlap and electrophysiological testing is challenging in young patients. We present the case of a 6-year-old boy with unexplained low vision and pallor of the optic disc who originally had been diagnosed with hereditary optic atrophy in the absence of recordable full-field electroretinography (ERG) due to poor patient cooperation. MATERIALS AND METHODS: Standard Sanger sequencing excluded mutations in the OPA1 gene (autosomal-dominant optic atrophy). To identify the underlying genetic cause, whole-exome sequencing was performed on patient's DNA. Recording of the full-field ERG was successfully performed 6 months later. RESULTS: We identified a novel truncating mutation in CACNA1F gene (NM_001256789: c.3895C > T in exon 33) which led to the correct diagnosis of CACNA1F-associated retinopathy in the young boy. ERG recordings showed a negative scotopic mixed response with preserved oscillatory potentials and a flicker ERG with reduced amplitude and biphasic waveform, compatible with a CACNA1F-asssociated phenotype. CONCLUSIONS: We show that genetic testing may help to differentiate between optic atrophy, LCA, and CACNA1F-associated retinopathy at a much earlier age, in absence of electrophysiological examination and by widely overlapping phenotypes.

CCDC102B confers risk of low vision and blindness in high myopia.

The incidence of high myopia is increasing worldwide with myopic maculopathy, a complication of myopia, often progressing to blindness. Our two-stage genome-wide association study of myopic maculopathy identifies a susceptibility locus at rs11873439 in an intron of CCDC102B (P = 1.77 × 10-12 and Pcorr = 1.61 × 10-10). In contrast, this SNP is not significantly associated with myopia itself. The association between rs11873439 and myopic maculopathy is further confirmed in 2317 highly myopic patients (P = 2.40 × 10-6 and Pcorr = 1.72 × 10-4). CCDC102B is strongly expressed in the retinal pigment epithelium and choroids, where atrophic changes initially occur in myopic maculopathy. The development of myopic maculopathy thus likely exhibits a unique background apart from the development of myopia itself; elucidation of the roles of CCDC102B in myopic maculopathy development may thus provide insights into preventive methods for blindness in patients with high myopia.

OPA1 gene therapy prevents retinal ganglion cell loss in a Dominant Optic Atrophy mouse model.

Dominant optic atrophy (DOA) is a rare progressive and irreversible blinding disease which is one of the most frequent forms of hereditary optic neuropathy. DOA is mainly caused by dominant mutation in the OPA1 gene encoding a large mitochondrial GTPase with crucial roles in membrane dynamics and cell survival. Hereditary optic neuropathies are commonly characterized by the degeneration of retinal ganglion cells, leading to the optic nerve atrophy and the progressive loss of visual acuity. Up to now, despite increasing advances in the understanding of the pathological mechanisms, DOA remains intractable. Here, we tested the efficiency of gene therapy on a genetically-modified mouse model reproducing DOA vision loss. We performed intravitreal injections of an Adeno-Associated Virus carrying the human OPA1 cDNA under the control of the cytomegalovirus promotor. Our results provide the first evidence that gene therapy is efficient on a mouse model of DOA as the wild-type OPA1 expression is able to alleviate the OPA1-induced retinal ganglion cell degeneration, the hallmark of the disease. These results displayed encouraging effects of gene therapy for Dominant Optic Atrophy, fostering future investigations aiming at clinical trials in patients.

A case with 46,XX,del(11)(q23.2) karyotype and poor vision with literature review.

Here we describe clinical and cytogenetic data on a female child whom had been referred to our laboratory suspected to have Turner syndrome since she had webbed neck. Cytogenetic analysis revealed that she had deletion at 11q23.2 to 11q terminal so her karyotype was ascertained as 46,XX,del(11)(q23.2). Her parents had normal karyotypes. In addition to many clinical features of del(11q ) syndrome the case had poor vision which is not common for this syndrome. Clinical features of this case and a few published cases will be reviewed briefly.

Bevacizumab intravítreo en neovascularización coroidea asociada a enfermedad de Best / Intravitreal bevacizumab for choroidal neovascularization associated with Best's disease

CASO CLÍNICO: Mujer de 27 años que presentaba disminución de visión en ojo derecho (20/200). El examen funduscópico reveló una hemorragia intrarretiniana macular con desprendimiento neurosensorial en ojo derecho, y un depósito de material viteliforme en el ojo izquierdo. La angiografía fluoresceínica y el electrooculograma confirmaron el diagnóstico de neovascularización coroidea asociada a enfermedad de Best. Cuatro semanas después de una única inyección de bevacizumab intravítreo, la agudeza visual a la normalidad (20/25) y se mantuvo estable tras 12 meses de seguimiento. DISCUSIÓN: El bevacizumab intravítreo puede ser una opción terapéutica eficaz en la neovascularización coroidea secundaria a enfermedad de Best

CASE REPORT: A 27-year old woman presented with loss of vision in the right eye (20/200). Ophthalmoscopic examination showed intrarretinal hemorrhage in the macular region with neurosensory detachment in the right eye, and viteliform deposit on the left eye. Fluorescein angiography and the electrooculogram confirmed the diagnosis of choroidal neovascularization associated with Best's disease. Four weeks after a single bevacizumab intravitreal injection, visual acuity was restored (20/25) and remained stable after a 12 month follow-up. DISCUSSION: Intravitreal bevacizumab appears to be an effective treatment for choroidal neovascularization associated to Best's disease

Rationale, design, and demographic characteristics of the Handan Offspring Myopia Study.

PURPOSE: The Handan Offspring Myopia Study (HOMS) aims to investigate the familial associations of myopia between parents and their offspring. METHODS: Children aged 6-18 years, residing in 6 villages where all people aged ≥30 years had participated in The Handan Eye Study in 2006-2007, were selected for the current eye study between March and June 2010. A mobile clinic was set up in the 6 villages for comprehensive eye examinations, including visual acuity, ocular biometry, cycloplegic autorefraction and retinal photography. RESULTS: Of 1238 eligible individuals, 878 children (70.2%; 52.6% male) from 541 families were recruited. Mean age of the children was 10.5 ± 2.5 years. The prevalence of myopia (spherical equivalent refraction <-0.5 diopter) was 23.5% (males 16.8%, females 30.8%). The prevalence of low vision (presenting visual acuity ≥20/400 but <20/60) in the better eye was 7.1%. A higher number of females had low vision at the time of presentation (9.2%) compared to males (5.2%, p = 0.02). The prevalence of low vision in the worse eye was 10.6% (males 6.7%, females 14.9%, p < 0.001). The majority of visual impairment in the better-seeing (56/62, 90.3%) as well as the worse-seeing (84/93, 90.3%) eye was correctable. CONCLUSIONS: The HOMS examined about 70% of eligible Han Chinese offspring of Handan Eye Study participants in a rural region of northern China. Results from the HOMS will provide key information about the prevalence of refractive errors and eye diseases in rural Chinese children.

Congenital macular dystrophy, corpus callosum agenesis, hippocampi hypoplasia--a novel neuro-ophthalmic syndrome: case report.

INTRODUCTION: Macular dystrophy is a cause of childhood and adult visual handicap and has been associated with multiple gene defects. Syndromic macular dystrophy is rare and a novel congenital form of syndromic macular dystrophy is presented. The authors report on a consanguineous family in which the 5-year-old female proband presented with nystagmus and low vision due to congenital macular dystrophy visible on fundus examination associated with complete corpus callosum agenesis, hippocampi hypoplasia and recurrent illnesses. MATERIALS AND METHODS: Patients signed informed consent forms to participate in the research. Proband was screened for 18 recessive macular dystrophy genes and ABCA4 and had a G banded karyotype on peripheral blood lymphocytes. Patients were evaluated using ocular biomicrosopy, fluorescein retinal angiograms, electroretinograms, visual evoked potentials, retinal optical coherence tomography, brain MRI and multifocal electroretinograms. RESULTS: The older brother presented with subclinical findings of bilateral absence of foveal macular peak on multifocal electroretinograms and minimal corpus callosum hypoplasia. The younger sister was recently discovered to have a similar macular dystrophy. The father showed subclinical unilateral decreased foveal macular peak and the mother showed a granular-appearing fundus. No mutations were identified in the RP and macular dystrophy genes screened. DISCUSSION: A review of the literature confirms that this is the first report of a congenital and possibly developmental macular dystrophy, with neurologic syndromic features and possible autosomal recessive inheritance but varying penetrance.

Bilateral macular holes in X-linked retinoschisis: now the spectrum is wider.

Bilateral occurrence of macular hole in X-linked retinoschisis is an extremely rare event. Spectral domain optical coherence tomography (OCT) findings revealed that formation of a macular hole is secondary to the retinoschisis process alone. Bilateral macular holes should be added to the spectrum of X-linked retinoschisis variations and the retinoschisis process alone should be accounted for their formation.

Prevalence of chronic ocular diseases in a genetic isolate: the Norfolk Island Eye Study (NIES).

PURPOSE: Over 40% of the permanent population of Norfolk Island possesses a unique genetic admixture dating to Pitcairn Island in the late 18(th) century, with descendents having varying degrees of combined Polynesian and European ancestry. We conducted a population-based study to determine the prevalence and causes of blindness and low vision on Norfolk Island. METHODS: All permanent residents of Norfolk Island aged ≥ 15 years were invited to participate. Participants completed a structured questionnaire/interview and underwent a comprehensive ophthalmic examination including slit-lamp biomicroscopy. RESULTS: We recruited 781 people aged ≥ 15, equal to 62% of the permanent population, 44% of whom could trace their ancestry to Pitcairn Island. No one was bilaterally blind. Prevalence of unilateral blindness (visual acuity [VA] < 6/60) in those aged ≥ 40 was 1.5%. Blindness was more common in females (P=0.049) and less common in people with Pitcairn Island ancestry (P<0.001). The most common causes of unilateral blindness were age-related macular degeneration (AMD), amblyopia, and glaucoma. Five people had low vision (Best-Corrected VA < 6/18 in better eye), with 4 (80%) due to AMD. People with Pitcairn Island ancestry had a lower prevalence of AMD (P<0.001) but a similar prevalence of glaucoma to those without Pitcairn Island ancestry. CONCLUSIONS: The prevalence of blindness and visual impairment in this isolated Australian territory is low, especially amongst those with Pitcairn Island ancestry. AMD was the most common cause of unilateral blindness and low vision. The distribution of chronic ocular diseases on Norfolk Island is similar to mainland Australian estimates.

Mitochondrial haplogroup M9a specific variant ND1 T3394C may have a modifying role in the phenotypic expression of the LHON-associated ND4 G11778A mutation.

We report here the clinical, genetic and molecular characterization of four Han Chinese families with Leber's hereditary optic neuropathy (LHON). The penetrances of optic neuropathy in these Chinese pedigrees were 38%, 38%, 44% and 56%. This observation is in contrast with the previously identified 14 Chinese families with very low penetrance of LHON. The age-at-onset for visual impairment in matrilineal relatives in these Chinese families varied from 18 to 30years. Furthermore, the ratios between affected male and female matrilineal relatives in these families were 3:0, 3:0, 3:1 and 2:3, respectively. Molecular analysis of mitochondrial genomes identified the known ND4 G11778A mutation and distinct sets of variants belonging to the Asian haplogroups M9a. Of these, the ND1 T3394C mutation caused the substitution of a highly conserved histidine for tyrosine (Y30H) at amino acid position 30. This mutation was associated with LHON in other families with low penetrance of optic neuropathy and other clinical abnormalities. The presence of both G11778A and T3394C mutations appears to contribute to higher penetrance of optic neuropathy in these four Chinese families than other Chinese families carrying only the G11778A mutation. Therefore, the mitochondrial haplogroup M9a specific variant T3394C may modulate the phenotypic manifestation of LHON-associated G11778A mutation in these Chinese pedigrees.

Very low penetrance of Leber's hereditary optic neuropathy in five Han Chinese families carrying the ND1 G3460A mutation.

We report here the clinical, genetic, and molecular characterization of five Han Chinese families with Leber's hereditary optic neuropathy (LHON). Strikingly, there were very low penetrances of visual impairment in these Chinese families, ranging from 4.2% to 22.2%, with an average of 10.2%. In particular, only 7 (4 males/3 females) of 106 matrilineal relatives in these families exhibited the variable severity and age-at-onset in visual dysfunction. The age-at-onset for visual impairment in matrilineal relatives in these families, varied from 20 to 25 years, with an average of 21.8 years old. Molecular analysis of mitochondrial genomes identified the homoplasmic ND1 G3460A mutation and distinct sets of variants, belonging to the Asian haplogroups B5b, C4a1, D5, F1, and R9, respectively. This suggests that the G3640A mutation occurred sporadically and multiplied through evolution of the mtDNA in China. However, there was the absence of known secondary LHON-associated mtDNA mutations in these Chinese families. Very low penetrance of visual loss in these five Chinese pedigrees strongly indicated that the G3640A mutation was itself insufficient to develop the optic neuropathy. The absence of secondary LHON mtDNA mutations suggest that these mtDNA haplogroup-specific variants may not play an important role in the phenotypic expression of the G3640A mutation in those Chinese families with low penetrance of vision loss. However, nuclear modifier genes, epigenetic and environmental factors appear to be modifier factors for the phenotypic manifestation of the G3640A mutation in these Chinese families.

Impaired cone function and cone degeneration resulting from CNGB3 deficiency: down-regulation of CNGA3 biosynthesis as a potential mechanism.

The cone cyclic nucleotide-gated (CNG) channel is essential for central and color vision and visual acuity. This channel is composed of two structurally related subunits, CNGA3 and CNGB3; CNGA3 is the ion-conducting subunit, whereas CNGB3 is a modulatory subunit. Mutations in both subunits are associated with achromatopsia and progressive cone dystrophy, with mutations in CNGB3 alone accounting for 50% of all known cases of achromatopsia. However, the molecular mechanisms underlying cone diseases that result from CNGB3 deficiency are unknown. This study investigated the role of CNGB3 in cones, using CNGB3(-/-) mice. Cone dysfunction was apparent at the earliest time point examined (post-natal day 30) in CNGB3(-/-) mice. When compared with wild-type (WT) controls: photopic electroretingraphic (ERG) responses were decreased by approximately 75%, whereas scotopic ERG responses were unchanged; visual acuity was decreased by approximately 20%, whereas contrast sensitivity was unchanged; cone density was reduced by approximately 40%; photoreceptor apoptosis was detected; and outer segment disorganization was observed in some cones. Notably, CNGA3 protein and mRNA levels were significantly decreased in CNGB3(-/-) mice; in contrast, mRNA levels of S-opsin, Gnat2 and Pde6c were unchanged, relative to WT mice. Hence, we show that loss of CNGB3 reduces biosynthesis of CNGA3 and impairs cone CNG channel function. We suggest that down-regulation of CNGA3 contributes to the pathogenic mechanism by which CNGB3 mutations lead to human cone disease.

Ophthalmic features of spinocerebellar ataxia type 7.

BACKGROUND: Patients with spinocerebellar ataxia 7 (SCA7) are known to develop ocular abnormalities. The purpose of this study was to characterize these abnormalities in greater detail and with the aid of newer quantitative technologies. METHODS: Seven patients with SCA7 diagnosed by genetic analysis at La Paz Hospital (Madrid, Spain), a country-wide referral center for ataxias, were included in the study. Demographic data and ocular features were recorded from a complete ophthalmologic examination, specular microscopy, corneal topography (Pentacam), and optical coherence tomography (OCT). RESULTS: All 7 patients had decreased visual acuity associated with varying degrees of macular pigmentary changes on ophthalmoscopy. All 7 had lower corneal endothelial cell densities than expected for their age, and 5 had increased corneal volume, although none had corneal edema. Patients with mild disease showed retinal thinning at the fovea. In patients with more advanced disease, retinal thinning was present also in the outer zone of the macula. Mean peripapillary retinal nerve fiber layer thickness was decreased in all patients; however, the temporal quadrant was spared except in advanced disease. CONCLUSIONS: This study of 7 patients with SCA7 amplifies previous reports of ophthalmic abnormalities in this condition by providing data from specular microscopy, corneal topography, and OCT. Abnormalities were present in the anterior and posterior ocular segments, as well as in eye movements and pupillary reactions. Visual dysfunction, present in all patients, was associated with retinal thinning. Decreased endothelial cell density and increased corneal thickness were common.