CDH23-Associated Usher Syndrome: Clinical Features, Retinal Imaging, and Natural History.

Purpose: The purpose of this study was to analyze the clinical spectrum and natural history of CDH23-associated Usher syndrome type ID (USH1D). Methods: Molecularly-confirmed individuals had data extracted from medical records. Retinal imaging was extracted from an in-house database. The main outcome measurements were retinal imaging and electroretinography (ERG) and clinical findings, including age of onset, symptoms, best-corrected visual acuity (BCVA), outer nuclear layer (ONL) thickness, ellipsoid zone width (EZW), and hyperautofluorescent ring area. Results: Thirty-one patients were identified, harboring 40 variants in CDH23 (10 being novel). The mean (range, ±SD) age of symptom onset was 10.1 years (range = 1-18, SD = ±4.1). The most common visual symptoms at presentation were nyctalopia (93.5%) and peripheral vision difficulties (61.3%). The mean BCVA at baseline was 0.25 ± 0.22 in the right eyes and 0.35 ± 0.58 LogMAR in the left eyes. The mean annual loss rate in BCVA was 0.018 LogMAR/year over a mean follow-up of 9.5 years. Individuals harboring the c.5237G>A p.(Arg1746Gln) allele had retinitis pigmentosa (RP) sparing the superior retina. Seventy-seven percent of patients had hyperautofluorescent rings in fundus autofluorescence. Full-field and pattern ERGs indicated moderate-severe rod-cone or photoreceptor dysfunction with relative sparing of macular function in most patients tested. Optical coherence tomography (OCT) revealed intraretinal cysts in the transfoveal B-scan of 13 individuals (43.3%). The rate of EZW and ONL thickness loss was mild and suggestive of a wide window of macular preservation. Conclusions: Despite the early onset of symptoms, USH1D has a slowly progressive phenotype. There is high interocular symmetry across all parameters, making it an attractive target for novel therapies.

Cone-driven strong flash electroretinograms in healthy adults: Prevalence of negative waveforms.

PURPOSE: Both rod and cone-driven signals contribute to the electroretinogram (ERG) elicited by a standard strong flash in the dark. Negative ERGs usually reflect inner retinal dysfunction. However, in diseases where rod photoreceptor function is selectively lost, a negative waveform might represent the response of the dark-adapted cone system. To investigate the dark-adapted cone-driven waveform in healthy individuals, we delivered flashes on a dim blue background, designed to saturate the rods, but minimally adapt the cones. METHODS: ERGs were recorded, using conductive fibre electrodes, in adults from the TwinsUK cohort. Responses to 13 cd m-2 s white xenon flashes (similar to the standard DA 10 flash), delivered on a blue background, were analysed. Photopic and scotopic strengths of the background were 1.3 and 30 cd m-2, respectively; through a dilated pupil, this is expected to largely saturate the rods, but adapt the cones much less than the standard ISCEV background. RESULTS: Mean (SD) participant age was 62.5 (11.3) years (93% female). ERGs from 203 right and 204 left eyes were included, with mean (SD) b/a ratios of 1.22 (0.28) and 1.18 (0.28), respectively (medians, 1.19 and 1.17). Proportions with negative waveforms were 23 and 26%, respectively. Right and left eye b/a ratios were strongly correlated (correlation coefficient 0.74, p < 0.0001). We found no significant correlation of b/a ratio with age. CONCLUSIONS: Over 20% of eyes showed b/a ratios less than 1, consistent with the notion that dark-adapted cone-driven responses to standard bright flashes can have negative waveforms. The majority had ratios greater than 1. Thus, whilst selective loss of rod function can yield a negative waveform (with reduced a-wave) in some, our findings also suggest that loss of rod function can occur without necessarily yielding a negative ERG. One potential limitation is possible mild cone system adaptation by the background.

Prospective study of pediatric patients presenting with idiopathic infantile nystagmus-Management and molecular diagnostics.

Idiopathic infantile nystagmus (IIN) is an inherited disorder occurring in the first 6 months of life, with no underlying retinal or neurological etiologies and is predominantly caused by mutations in the FRMD7 gene. IIN poses a diagnostic challenge as underlying pre-symptomatic "multisystem" disorders varying from benign to life-threatening should first be ruled out before nystagmus can be labeled as idiopathic. A multidisciplinary approach including multimodal ocular investigations and next-generation sequencing with whole-genome sequencing (WGS) or targeted gene panel testing is required to delineate the exact etiology. We report the clinical and genetic outcomes of 22 patients, from 22 unrelated families of diverse ethnicities, with IIN seen in the ocular genetics service at Moorfields Eye Hospital NHS Foundation Trust between 2016 and 2022. Thirty-six percent (8/22) received a confirmed molecular diagnosis with eight mutations identified in two genes (seven in FRMD7 including one novel variant c.706_707del; p. [Lys236Alafs*66], and one in GPR143). This study expands the mutational spectrum of IIN and highlights the significant role of an integrated care pathway and broader panel testing in excluding underlying pathologies.

Variability of retinopathy consequent upon novel mutations in LAMA1.

PURPOSE: Bi-allelic mutations in LAMA1 (laminin 1) (OMIM # 150320) cause Poretti-Boltshauser Syndrome (PTBHS), a rare non-progressive cerebellar dysplasia disorder with ophthalmic manifestations including oculomotor apraxia, high myopia, and retinal dystrophy. Only 38 variants, nearly all loss of function have been reported. Here, we describe novel LAMA1 variants and detailed retinal manifestations in two unrelated families. METHODS: Whole-genome sequencing was conducted on three siblings of a consanguineous family with myopia and retinal dystrophy and on a child from an unrelated non-consanguineous couple. Clinical evaluation included full ophthalmic examination, detailed colour, autofluorescence retinal imaging, retinal optical coherence tomography (OCT), fluorescein angiography under anesthesia, and pattern and full-field electroretinography. RESULTS: Genetic analysis revealed a novel homozygous LAMA1 frameshift variant, c.1492del p.(Arg498Glyfs *25), in the affected siblings in family 1 and a novel frameshift c.3065del p.(Gly1022Valfs *2) and a deletion spanning exons 17-23 in an unrelated individual in family 2. Two of the three siblings and the unrelated child had oculomotor apraxia in childhood; none of the siblings had symptoms of other neurological dysfunction as adults. All four had myopia. The affected siblings had a qualitatively similar retinopathy of wide-ranging severity. The unrelated patient had a severe abnormality of retinal vascular development, which resulted in vitreous haemorrhage and neovascular glaucoma in the left eye and a rhegmatogenous retinal detachment in the right eye. CONCLUSIONS: This report describes the detailed retinal structural and functional consequences of LAMA1 deficiency in four patients from two families, and these exhibit significant variability with evidence of both retinal dystrophy and abnormal and incomplete retinal vascularisation.

Influence of multifocal intraocular lenses on standard automated perimetry test results.

IMPORTANCE: A multifocal intraocular lens (MFIOL) allows for spectacle independence after cataract surgery and is thus a seemingly attractive option. However, several optical limitations have been reported or can be hypothesized. OBJECTIVE: To evaluate the influence of an MFIOL on standard automated perimetry (SAP) size III and size V test results. DESIGN: Cross-sectional case-control. SETTING: The University Medical Center Groningen and the Nij Smellinghe Hospital Drachten, the Netherlands. PARTICIPANTS: Sixteen eyes of 16 patients with a diffractive MFIOL (median age, 64 years), 18 phakic eyes of 18 healthy individuals serving as controls (median age, 62 years), and 12 eyes of 12 patients with a monofocal IOL (median age, 64 years) were included. INTERVENTIONS: All participants underwent (1) SAP using a 30-2 grid and the Swedish Interactive Threshold Algorithm standard strategy with stimulus size III and (2) a full threshold test with stimulus size V. MAIN OUTCOME MEASURES: Primary outcome measures were the mean deviation (MD) for size III and the mean sensitivity (MS) for size V. Comparisons between groups were adjusted for age and pupil size. RESULTS For SAP size III, the average difference in MD between patients in the MFIOL group and phakic controls was -2.40 dB (P < .001) and between patients in the monofocal IOL group and phakic controls was -0.32 dB (P = .52). For SAP size V, the corresponding differences in MS were -1.61 dB (P = .002) and -0.80 dB (P = .09), respectively. The differences were essentially independent of eccentricity for both SAP size III and SAP size V. CONCLUSIONS AND RELEVANCE: Patients with a diffractive MFIOL have a clinically relevant reduction of the visual sensitivity as assessed with SAP size III and size V. The reduction seems to be related to the multifocal design of the IOL rather than to pseudophakia. The reduction interferes with the assessment of common eye diseases such as glaucoma and comes on top of the decline of visual sensitivity due to normal aging or age-related eye diseases, thus potentially accelerating visual impairment.