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Autosomal Dominant Optic Atrophy (ADOA) is the most common inherited optic atrophy where vision impairment results from specific loss of retinal ganglion cells of the optic nerve. Around 60% of ADOA cases are linked to mutations in the OPA1 gene. OPA1 is a fission-fusion protein involved in mitochondrial inner membrane remodelling. ADOA presents with marked variation in clinical phenotype and varying degrees of vision loss, even among siblings carrying identical mutations in OPA1. To determine whether the degree of vision loss is associated with the level of mitochondrial impairment, we examined mitochondrial function in lymphoblast cell lines obtained from six large Australian OPA1-linked ADOA pedigrees. Comparing patients with severe vision loss (visual acuity [VA]<6/36) and patients with relatively preserved vision (VA>6/9) a clear defect in mitochondrial ATP synthesis and reduced respiration rates were observed in patients with poor vision. In addition, oxidative phosphorylation (OXPHOS) enzymology in ADOA patients with normal vision revealed increased complex II+III activity and levels of complex IV protein. These data suggest that OPA1 deficiency impairs OXPHOS efficiency, but compensation through increases in the distal complexes of the respiratory chain may preserve mitochondrial ATP production in patients who maintain normal vision. Identification of genetic variants that enable this response may provide novel therapeutic insights into OXPHOS compensation for preventing vision loss in optic neuropathies. [ABSTRACT FROM AUTHOR]

PAX6 is a key regulator of eye development and there are many well recognized ophthalmic sequelae of mutations at this locus. The 14 exon PAX6 gene is well conserved across species and phyla. Coding region mutations manifest in a variety of phenotypes. Predicted premature protein truncations are generally associated with classical aniridia. Missense mutations are often found in cases with variant phenotypes such as ectopia pupillae; isolated foveal hypoplasia; nystagmus and hyaloid vessel proliferation. The locus has also been implicated, through a genome-wide sib-pair scan, to be important in the normal variation of myopia. We investigated the association between identified PAX6 mutations and refractive error in Australian patients from four pedigrees. Two of eight subjects with a 1410delC PAX6 mutation had a mean spherical equivalence < -9D, whilst a mean spherical equivalence ≤ -5D was recorded in two from four subjects with an Arg240Stop PAX6 mutation and one of two subjects with a Glu93Stop mutation. One individual identified with a Pro346Ala PAX6 mutation had a mean spherical equivalence of +2.8 D. Thus, our observations generally support other incidental findings, that PAX6 mutation, particularly predicted haploinsufficiency, may be associated with extreme refractive error, although the mechanism by which this occurs is not clear. [ABSTRACT FROM AUTHOR]

AimMethodResultsConclusionLeber hereditary optic neuropathy (LHON) predominantly manifests during adolescence or young adulthood, resulting in sudden and profound vision loss in individuals who previously had normal vision. This abrupt change significantly impacts daily life, necessitating emotional support, counseling and low-vision rehabilitative services to help affected individuals cope with the shock and adapt to their residual vision. The psychosocial burden of dealing with vision loss extends beyond the individuals directly affected by LHON, affecting matrilineal relatives who face the dual challenges of grieving for their loved one’s vision loss and managing their own uncertainty about potential vision loss and its familial implications.We reviewed key information that needs to be obtained prior to genetic counseling for LHON. We reviewed key counseling issues within LHON-affected families and the issues pending several subgroups of family members with distinct and varying genetic counseling needs.Family subgroups requiring specific counseling issues include the individuals affected by LHON, their mother, siblings, father, partner, and children. Genetic counseling plays an integral part of clinical care in families affected by LHON, providing tailored support and information to each subgroup.To provide accurate information to families and guide them toward potential supports, treatments and preventive measures, health professionals need to be aware of the factors influencing visual recovery and individual risk of vision loss. [ABSTRACT FROM AUTHOR]

With the increased availability of genetic testing and the addition of mitochondrial genetic variants on disease panels, accurate genetic counselling for individuals and families affected by, or at risk of, Leber hereditary optic neuropathy (LHON) is becoming increasingly relevant. Challenges in providing genetic counselling for LHON include its mitochondrial inheritance pattern, different haplogroups, incomplete penetrance and that it predominantly affects males. Accurate genetic counselling aims to avoid incorrect disease-risk assessment and delays in either diagnosis or implementation of psychosocial support. Families are also empowered to make autonomous health decisions regarding potential trigger factors for LHON vision loss and informed reproductive choices. Using clinical vignettes, this review demonstrates that an increased awareness of LHON amongst eye care, general and genetic health professionals can address challenges and misconceptions., (© 2025 The Author(s). Clinical & Experimental Ophthalmology published by John Wiley & Sons Australia, Ltd on behalf of Royal Australian and New Zealand College of Ophthalmologists.)

Background: Conducting ethically grounded research is a fundamental facet of all investigations. Nevertheless, the administrative burdens of current ethics review are substantial, and calls have been made for a reduction in research waste., Aims: To describe the heterogeneity in administration and documentation required by Human Research Ethics Committees (HRECs) and Research Governance Offices (RGOs) across Australia., Methods: In establishing a nationwide study to investigate the molecular aetiology of Giant Cell Arteritis (GCA), for which archived pathological specimens from around Australia are being recruited, we identified variation across separate HREC and RGO requirements. Submission paperwork and correspondence from each collaborating site and its representative office for research were reviewed. This data was interrogated to evaluate differences in current guidelines., Results: Twenty-five pathology departments across seven Australian States collaborated in this study. All states, except Victoria, employed a single ethics review model. There was discrepancy amongst HRECs as to which application process applied to our study: seven requested completion of a "National Ethics Application Form" and three a "Low Negligible Risk" form. Noticeable differences in guidelines included whether electronic submission was sufficient. There was variability in the total number of documents submitted (range five to 22) and panel review turnaround time (range nine to 136 days)., Conclusion: We demonstrate the challenges and illustrate the heavy workload involved in receiving widespread ethics and governance approval across Australia. We highlight the need to simplify, homogenise, and nationalise human ethics for non-clinical trial studies. Reducing unnecessary administration will enable investigators to achieve research aims more efficiently.

Purpose: Corneal astigmatism is a common eye disorder characterized by irregularities in corneal curvature. Recently, the rs7677751 single nucleotide polymorphism (SNP) at the platelet-derived growth factor receptor alpha (PDGFRA) locus was found to be associated with corneal astigmatism in people of Asian ancestry. In the present study, we sought to replicate this finding and identify other genetic markers of corneal astigmatism in an Australian population of Northern European ancestry., Methods: Data from two cohorts were included in this study. The first cohort consisted of 1,013 individuals who were part of the Western Australian Pregnancy Cohort (Raine) Study: 20-year follow-up Eye Study. The second cohort comprised 1,788 individuals of 857 twin families who were recruited through the Twins Eye Study in Tasmania and the Brisbane Adolescent Twin Study. Corneal astigmatism was calculated as the absolute difference between the keratometry readings in two meridians, and genotype data were extracted from genome-wide arrays. Initially, each cohort was analyzed separately, before being combined for meta- and subsequent genome-wide pathway analysis., Results: Following meta-analysis, SNP rs7677751 at the PDGFRA locus had a combined p=0.32. No variant was found to be statistically significantly associated with corneal astigmatism at the genome-wide level (p<5.0×10(-8)). The SNP with strongest association was rs1164064 (p=1.86×10(-6)) on chromosome 3q13. Gene-based pathway analysis identified a significant association between the Gene Ontology "segmentation" (GO:0035282) pathway, corrected p=0.009., Conclusions: Our data suggest that the PDGFRA locus does not transfer a major risk of corneal astigmatism in people of Northern European ancestry. Better-powered studies are required to validate the novel putative findings of our study.

Purpose: To describe the phenotype of ocular hypertension and primary open-angle glaucoma in a family with individuals compound heterozygote for Gln368STOP and Thr377Met myocilin (MYOC) mutations., Methods: Family members of the proband underwent comprehensive ocular clinical examination and DNA sequencing for MYOC mutations., Results: A 34-year-old woman with marked ocular hypertension was found to carry Gln368STOP and Thr377Met MYOC mutations. Three other siblings carried both mutations, while one carried Gln368STOP alone. Three of five siblings had received treatment for ocular hypertension or early glaucoma, with the average age of diagnosis 28 years; one required trabeculectomy at age 27. The mother of the proband was found to be a carrier for Gln368STOP alone, which indicates that her offspring with both Gln368STOP and Thr377Met carry variants on opposing alleles., Conclusions: This pedigree is the first report with individuals compound heterozygote for the two most common glaucoma-causing MYOC variants. The combination of mutations manifests a more severe phenotype than either alone. Identification of gene changes associated with glaucoma within the family has enabled unaffected members to stratify their risk of future disease and institute closer monitoring and early treatment.

Purpose: Acute anterior uveitis (AAU) is the most common form of uveitis; however, while it is presumed to have an immunological basis, the precise underlying etiology remains elusive. Toll-like receptors (TLRs) have a key role in linking innate and adaptive immunity, thereby forming a molecular bridge between microbial triggers and the development of AAU. The purpose of this study was to investigate the role of TLR2 and TLR4 gene polymorphisms in the pathogenesis of AAU., Methods: The study comprised 225 confirmed cases of idiopathic or human leukocyte antigen (HLA) B27 (subtypes B*2701-2759; HLA-B27)-related AAU and 2,534 population-based controls from the Blue Mountains Eye Study. All participants were of Anglo-Celtic descent. Blood samples were collected for DNA extraction and genotyping. A total of 16 single nucleotide polymorphisms (SNPs) were selected for analysis and either directly genotyped or imputed to cover the common variations within the TLR genes. Data were analyzed at the allelic, genotypic and haplotypic levels., Results: Control subjects were significantly older than case subjects (p<0.0001). There was no significant difference in the gender composition between the case and control cohorts (p=0.18). One TLR2 SNP (rs11938228) was found to be associated with AAU at the allelic level (OR=1.28; p=0.017); however this association did not remain following adjustment for age and sex (p=0.067). None of the SNPs at the TLR4 locus were found to differ significantly between cases or controls, irrespective of adjustment for age and gender., Conclusions: This study has confirmed that common TLR variants of moderate effect size do not predispose to AAU, undermining the implication of reported mutations in the selective perturbations of TLR expression and function evident in AAU.