Driving with retinitis pigmentosa

Background: To establish the proportion of patients with retinitis pigmentosa (RP) meeting the Australian fitness to drive (FTD) visual standards. Methodology: A prospective consecutive case series of patients with a clinical or genetic diagnosis of RP. Data on age at symptom onset, current driving status, inheritance pattern, better eye visual acuity (BEVA), binocular Esterman visual field (BEVF) parameters, genotype and ability to meet the driving standards based on BEVA and BEVF were collected. Outcome measures included the proportion of RP patients overall meeting the standards and clinical predictors for passing. A sub-analysis was performed on those RP patients who reported to drive. Change in BEVA and BEVF parameters across age in specific genotype groups was assessed. Results: Overall, 228 patients with RP had a BEVF assessment. Only 39% (89/228) met the driving standards. Younger age at the time of testing was the only significant predictor (p \u3c 0.01) for passing. Of the 55% of RP patients who reported to drive, 52% (65/125) met the standards, decreasing to 14% in the 56- to 65-year-old age group. RP patients harbouring mutations in HK1 or RHO genes may have slower rates of decline in their VF parameters. Conclusion: Nearly 40% of RP patients met the driving standards. However, almost 50% of RP drivers were unaware of their failure to meet the current standards. BEVF testing is essential in the assessment of RP patients who are still driving. Phenotype and genotype predictors for passing the standards warrant further investigation. Abbreviation: FTD, fitness to drive; IRD, inherited retinal disease; RP, retinitis pigmentosa; RHO, rhodopsin; HK1, hexokinase 1; PRPF31 pre-mRNA processing factor 31; RPGR, retinitis pigmentosa GTPase regulator; VF, visual field; BEVA, better eye visual acuity; BEVF, binocular Esterman visual field

Genotype-specific lesion growth rates in stargardt disease

Reported growth rates (GR) of atrophic lesions in Stargardt disease (STGD1) vary widely. In the present study, we report the longitudinal natural history of patients with confirmed bial-lelic ABCA4 mutations from five genotype groups: c.6079C \u3e T, c.[2588G \u3e C;5603A \u3e T], c.3113C \u3e T, c.5882G \u3e A and c.5603A \u3e T. Fundus autofluorescence (AF) 30◦ × 30◦ images were manually seg-mented for boundaries of definitely decreased autofluorescence (DDAF). The primary outcome was the effective radius GR across five genotype groups. The age of DDAF formation in each eye was calculated using the x-intercept of the DDAF effective radius against age. Discordance between age at DDAF formation and symptom onset was compared. A total of 75 eyes from 39 STGD1 patients (17 male [44%]; mean ± SD age 45 ± 19 years; range 21–86) were recruited. Patients with c.3113C \u3e T or c.6079C \u3e T had a significantly faster effective radius GR at 0.17 mm/year (95% CI 0.12 to 0.22; p \u3c 0.001 and 0.14 to 0.21; p \u3c 0.001) respectively, as compared to those patients harbouring c.5882G \u3e A at 0.06 mm/year (95% CI 0.03–0.09), respectively. Future clinical trial design should consider the effect of genotype on the effective radius GR and the timing of DDAF formation relative to symptom onset

Sibling concordance in symptom onset and atrophy growth rates in Stargardt disease using ultra-widefield fundus autofluorescence

Purpose: To investigate concordance in symptom onset, area of dark autofluorescence (DAF), and growth rate (GR) between Stargardt disease siblings at an age-matched time point. Methods: In this retrospective longitudinal study of sibling pairs with identical biallelic ABCA4 variants, age at symptom onset, best-corrected visual acuity, atrophy area, and effective radius of DAF on ultra-widefield fundus autofluorescence were recorded. Absolute intersibling differences for both eyes were compared with absolute interocular differences using the Mann-Whitney test. Results: Overall 39 patients from 19 families were recruited. In 16 families, age-matched best-corrected visual acuity and DAF were compared between siblings. In 8 families, DAF GR was compared. The median (range) absolute difference in age at symptom onset between siblings was 3 (0-35) years. Absolute intersibling differences in age-matched best-corrected visual acuity were greater than interocular differences (P = 0.01). Similarly, absolute intersibling differences in DAF area and radius were greater than interocular differences (P = 0.04 for area and P = 0.001 for radius). Differences between absolute interocular and intersibling GR were not statistically significant (P = 0.44 for area GR and P = 0.61 for radius GR). Conclusion: There was significant discordance in age-matched best-corrected visual acuity and DAF beyond the expected limits of interocular asymmetry. Lack of significant intersibling differences in GR warrants further investigation

Maternal uniparental isodisomy of chromosome 6 unmasks a novel variant in TULP1 in a patient with early onset retinal dystrophy

Per the publisher's policy, "This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited, used for non-commercial purposes, and is not altered or transformed."Purpose Inherited retinal dystrophies are a clinically and genetically heterogeneous group of disorders. Molecular diagnosis has proven utility for affected individuals. In this study, we report an individual enrolled in the Australian Inherited Retinal Disease Registry and DNA Bank diagnosed with clinical features overlapping between Leber congenital amaurosis and retinitis pigmentosa. Methods DNA from the proband was sequenced using a gene panel for inherited retinal disorders, and a single nucleotide polymorphism (SNP) array was conducted to detect the presence of deletions and uniparental disomy. Results We identified a novel homozygous variant (c.524dupC, p.(Pro176ThrfsTer7)) in TULP1 resulting from maternal uniparental isodisomy of chromosome 6. The patient had clinical features consistent with biallelic pathogenic variants in TULP1, including congenital nystagmus, night blindness, non-recordable electroretinogram, mild myopia, and mild peripheral pigmentary changes in the fundus. Conclusions This is the first report of uniparental disomy 6 and a homozygous variant in TULP1 associated with a rod-cone dystrophy. Molecular diagnosis of inherited retinal dystrophies is essential to inform the mode of transmission and clinical management, and to identify potential candidates for future gene-specific therapies

Clinical and molecular characterization of females affected by X-linked retinoschisis

Background: X-linked retinoschisis (XLRS) is a leading cause of juvenile macular degeneration associated with mutations in the RS1 gene. XLRS has a variable expressivity in males and shows no clinical phenotype in carrier females. Design: Clinical and molecular characterization of male and female individuals affected with XLRS in a consanguineous family. Participants: Consanguineous Eastern European-Australian family Methods: Four clinically affected and nine unaffected family members were genetically and clinically characterized. Deoxyribonucleic acid (DNA) analysis was conducted by the Australian Inherited Retinal Disease Register and DNA Bank. Main Outcome Measures: Clinical and molecular characterization of the causative mutation in a consanguineous family with XLRS. Results: By direct sequencing of the RS1 gene, one pathogenic variant, NM_000330.3: c.304C > T, p. R102W, was identified in all clinically diagnosed individuals analysed. The two females were homozygous for the variant, and the males were hemizygous. Conclusion: Clinical and genetic characterization of affected homozygous females in XLRS affords the rare opportunity to explore the molecular mechanisms of XLRS and the manifestation of these mutations as disease in humans.5 page(s

Generation of two induced pluripotent stem cell lines from a retinitis pigmentosa patient with compound heterozygous mutations in CRB1

Two human iPSC lines were generated from dermal fibroblasts derived from a patient with retinitis pigmentosa caused by CRB1 mutation using episomal plasmids containing OCT4, SOX2, LIN28, KLF4, L-MYC and mp53DD. These clonal iPSC lines carry compound heterozygous mutations in CRB1 (c.2555 T > C and c.3014A > T). Both lines expressed pluripotency markers, displayed a normal karyotype and demonstrated the ability to differentiate into the three primary germ layers, as well as retinal organoids

Enhanced Visualization of Subtle Outer Retinal Pathology by <i>En Face</i> Optical Coherence Tomography and Correlation with Multi-Modal Imaging - Fig 1

<p><i>En face</i> optical coherence tomography images of the ellipsoid zone (A-I:V), interdigitation zone (B-I:V), retinal pigment epithelium (C-I:V) and Bruch’s membrane (D-I:V). Images from the first 3 columns are from a normal subject and the last column is from a patient with Bietti crystalline dystrophy. The scanning protocol covers a 15° (horizontal) × 10° (vertical) field of view on the retina. Each row (I:V) corresponds to increasing separation between consecutive B-scans: 11, 30, 60, 120 and 240 μm.</p

Genotype-Specific Lesion Growth Rates in Stargardt Disease

Reported growth rates (GR) of atrophic lesions in Stargardt disease (STGD1) vary widely. In the present study, we report the longitudinal natural history of patients with confirmed biallelic ABCA4 mutations from five genotype groups: c.6079C&gt;T, c.[2588G&gt;C;5603A&gt;T], c.3113C&gt;T, c.5882G&gt;A and c.5603A&gt;T. Fundus autofluorescence (AF) 30&deg; &times; 30&deg; images were manually segmented for boundaries of definitely decreased autofluorescence (DDAF). The primary outcome was the effective radius GR across five genotype groups. The age of DDAF formation in each eye was calculated using the x-intercept of the DDAF effective radius against age. Discordance between age at DDAF formation and symptom onset was compared. A total of 75 eyes from 39 STGD1 patients (17 male [44%]; mean &plusmn; SD age 45 &plusmn; 19 years; range 21&ndash;86) were recruited. Patients with c.3113C&gt;T or c.6079C&gt;T had a significantly faster effective radius GR at 0.17 mm/year (95% CI 0.12 to 0.22; p &lt; 0.001 and 0.14 to 0.21; p &lt; 0.001) respectively, as compared to those patients harbouring c.5882G&gt;A at 0.06 mm/year (95% CI 0.03&ndash;0.09), respectively. Future clinical trial design should consider the effect of genotype on the effective radius GR and the timing of DDAF formation relative to symptom onset

Characterization of CRB1 splicing in retinal organoids derived from a patient with adult‐onset rod‐cone dystrophy caused by the c.1892A>G and c.2548G>A variants

Abstract Background Mutations in the human crumbs homologue 1 (CRB1) gene are associated with a spectrum of inherited retinal diseases. However, functional studies demonstrating the impact of individual CRB1 mutations on gene expression are lacking for most variants. Here, we investigated the effect of two CRB1 variants on pre‐mRNA splicing using neural retinal organoids (NRO) derived from a patient with recessive rod‐cone dystrophy caused by compound heterozygous mutations in CRB1 (c.1892A>G and c.2548G>A). Methods The patient received ophthalmological examinations including multimodal imaging. NRO were differentiated from induced pluripotent stem cells (iPSCs) derived from the patient and a control subject. CRB1 transcripts were characterized by RT‐PCR and Sanger sequencing. Results The Patient displayed retinal thickening with disorganization of retinal layers and preservation of para‐arteriolar retinal pigment epithelium. Both patient and control iPSC produced NRO containing photoreceptor progenitor cells expressing CRB1 mRNA. Patient NRO expressed a novel CRB1 transcript displaying skipping of exon 6. CRB1 transcripts containing the c.2548G>A substitution in exon 7 were expressed in patient NRO. Conclusions Together, these results confirm the pathogenicity of the c.1892A>G and c.2548G>A CRB1 variants in a family with recessive adult‐onset rod‐cone dystrophy and further demonstrate the effects of these variants on pre‐mRNA splicing. This data provide important insights into the pathogenic mechanisms associated with these variants