John R. Grigg

Description:PROM1 inherited retinal diseases (IRDs) result in significant phenotypic heterogeneity ranging from macular dystrophy to severe rod-cone dystrophy. This study examined a cohort of patients with autosomal recessive (AR) PROM1-associated IRD to determine important potential biomarkers of disease progression on multimodal imaging. Ophthalmic phenotyping included clinical examination, OCT, fundus autofluorescence and electrophysiology. The cohort included six patients with bi-allelic variants, including two novel variants, and a median of 11.8 years of follow-up. Best-corrected visual acuity (BCVA) was maintained until a steep decline around 15 years of age. This was preceded by contraction of the subfoveal ellipsoid zone length (EZL), measured on OCT. Review of the literature demonstrated that cone or cone-rod dystrophy was the most frequently identified clinical phenotype. Loss of function variants including nonsense, frameshift and splice variants were particularly common. This study provides detailed insights into the natural history of AR PROM1 IRD and current understanding in the published literature. Contraction of the subfoveal EZL appears to be a potential biomarker for disease progression and occurs earlier than reduction in BCVA.

Description:Background: Inherited eye disorders, though individually rare, are a collectively common cause of paediatric vision impairment. Many occur as part of a syndrome, in association with congenital anomalies and/or growth/developmental disorders. Paediatricians are well placed to recognise ocular disorders and syndromic associations, and help facilitate appropriate investigations and referrals, including genetic testing. Timely recognition of these conditions may allow patients to capitalise on the recent advances in ocular genetic therapy and clinical trials which are progressing for both non-syndromic and syndromic ocular conditions. Objective: This review provides a practical guide for paediatricians on recognising genetic eye conditions in children, initiating appropriate investigations, and referring for genetic testing. Methods: An overview of the most common Mendelian paediatric eye conditions and their syndromic associations is provided, encompassing disorders which affect the anterior and/or posterior segments. A suggested framework including a flowchart for recognising potentially inherited ocular conditions and recognising syndromic diagnoses is included. Finally, a discussion regarding the utility of a genetic diagnosis, including information about inheritance, genetic counselling, and current gene therapy and clinical trials is provided. Conclusions: Genetic eye conditions are an important cause of ocular morbidity in children. These conditions may be isolated to the eye or have multisystem syndromic associations. Additionally, in an era where genetic testing is increasingly being mainstreamed and given the availability of gene therapy, it is relevant for paediatricians to be familiar with genetic eye conditions. This review provides a practical approach for paediatricians to help navigate these conditions.

Description:Objective: The electronegative electroretinogram (ERG) is a specific clinical finding usually indicating inner retinal dysfunction occurring post-phototransduction. X-linked retinoschisis (XLRS) and complete and incomplete congenital stationary night blindness (cCSNB, iCSNB) are inherited retinal dystrophies classically associated with electronegative ERGs. Comparing the full-field ERG b:a ratio expands current ERG diagnostic criteria and aids in localising physiological sites and pathological mechanisms. Methods: A retrospective review of patients with a clinical diagnosis of iCSNB, cCSNB and XLRS was conducted. ERG and genetic results were analysed. Average b:a ratios between groups were compared, and prevalence of electropositivity was assessed using thresholds of b:a > 1.0 and b:a > 1.50. Results: 53 patients were included, and genetic confirmation was available in 7/24 iCSNB, 3/14 cCSNB and 11/15 XLRS patients respectively. In genetically proven cases, mean b:a ratio in XLRS patients (b:a = 1.04) was significantly higher than cCSNB (b:a = 0.60, p < 0.001) and iCSNB (b:a = 0.60, p < 0.001). An electropositive ERG was significantly more likely to be associated with RS1 than iCSNB (p < 0.001) or cCSNB (p = 0.001) at b:a > 1.0 threshold, and more likely RS1 than iCSNB (p = 0.040) at b:a > 1.5 threshold. Conclusions: Our study highlights the distinct ERG findings between these typically electronegative inner retinal dystrophies. In a clinical setting, the traditional electronegative definition of b:a < 1.0 appears very insensitive to detect XLRS patients. Our data suggests clinical suspicion should remain even in patients with a b:a ratio > 1.50, and highlights the importance of genetic testing in these cases.

Description:Objective: We present the protocol of a prospective scoping review which aims to understand how multi-channel visual evoked potentials (mcVEPs) are used to investigate congenital chiasmal misrouting and what outcomes are measured, interpreted and reported. Background: mcVEPs are used for the objective evaluation of chiasmal misrouting, which is characterized by a crossed asymmetry in the distribution of cortical responses over each hemisphere during monocular stimulation, and is often observed in patients with albinism. The application and analysis of mcVEPs varies across centers, creating a need to explore the range of practice regarding their conduct and reporting and to identify potential areas for adaptation or optimization or guidelines for specific populations. Methods: Peer reviewed and grey literature on the use of mcVEP to detect chiasmal misrouting in humans with non-acquired pathologies will be considered. All literature providing details of mcVEP methodology for replication and specification of chiasmal misrouting will be included for review. Methods: Searches will be conducted using MEDLINE, Embase, Cochrane and Web of Science with the expertise of a librarian. The search will be conducted with no limitation on time period, but will be restricted to the Latin alphabet. Titles and abstracts will be screened by two investigators with conflicts resolved by a third investigator. Included articles will proceed with data extraction on study details including methodology, design, and outcomes. The results will be synthesized and mapped for logical understanding.