Advances in gene therapy and genome editing give hope that new treatments will soon be available for inherited eye diseases that together affect a significant proportion of the adult population. New solutions are needed to make genetic diagnosis fast and affordable. This is the first study of such a large group of patients with inherited retinal dystrophies (IRD) and inherited optic neuropathies (ION) in the Polish population. It is based on four years of diagnostic analysis using a broad, targeted NGS approach. The results include the most common pathogenic variants, as well as 91 novel causative variants, including frameshifts in the cumbersome RPGR ORF15 region. The high frequency of the ABCA4 complex haplotype p.(Leu541Pro;Ala1038Val) was confirmed. Additionally, a deletion of exons 22-24 in USH2A, probably specific to the Polish population, was uncovered as the most frequent copy number variation. The diagnostic yield of the broad NGS panel reached 64.3% and is comparable to the results reported for genetic studies of IRD and ION performed for other populations with more extensive WES or WGS methods. A combined approach to identify genetic causes of all known diseases manifesting in the posterior eye segment appears to be the optimal choice given the currently available treatment options and advanced clinical trials.

UNASSIGNED: Acyl-CoA binding domain containing 5 (ACBD5) deficiency is a newly defined inborn peroxisomal disorder with only 7 patients reported to date. Herein, we report a patient with ACBD5 deficiency who was diagnosed after a complicated diagnostic process.
UNASSIGNED: A 6-year-old male patient was admitted with complaints of neuromotor regression and visual disturbances. He had spastic paraparesis dominated with axial hypotonic posturing and horizontal nystagmus. His very-long-chain fatty acid levels were within normal ranges with a slightly elevated C26:0/C22:0 ratio. Brain magnetic resonance imaging revealed white matter involvement. Clinical exome sequencing displayed a novel homozygous intronic splice site variant (c.936 + 2T>G) in the ACBD5 (NM_145698.5) gene.
UNASSIGNED: With this report, a novel variant in ACBD5 deficiency was described. Macular dystrophy was demonstrated with optical coherence tomography imaging for the first time in the literature in ACBD5 deficiency. In order to contribute to the knowledge about the clinical, biochemical, and genetic spectrum of ACBD5 deficiency, new patients need to be defined.

The canonical visual cycle employing RPE65 as the retinoid isomerase regenerates 11-cis-retinal to support both rod- and cone-mediated vision. Mutations of RPE65 are associated with Leber congenital amaurosis that results in rod and cone photoreceptor degeneration and vision loss of affected patients at an early age. Dark-reared Rpe65-/- mouse has been known to form isorhodopsin that employs 9-cis-retinal as the photosensitive chromophore. The mechanism regulating 9-cis-retinal synthesis and the role of the endogenous 9-cis-retinal in cone survival and function remain largely unknown. In this study, we found that ablation of fatty acid transport protein-4 (FATP4), a negative regulator of 11-cis-retinol synthesis catalyzed by RPE65, increased the formation of 9-cis-retinal, but not 11-cis-retinal, in a light-independent mechanism in both sexes of RPE65-null rd12 mice. Both rd12 and rd12;Fatp4-/- mice contained a massive amount of all-trans-retinyl esters in the eyes, exhibiting comparable scotopic vision and rod degeneration. However, expression levels of M- and S-opsins as well as numbers of M- and S-cones surviving in the superior retinas of rd12;Fatp4-/ - mice were at least twofold greater than those in age-matched rd12 mice. Moreover, FATP4 deficiency significantly shortened photopic b-wave implicit time, improved M-cone visual function, and substantially deaccelerated the progression of cone degeneration in rd12 mice, whereas FATP4 deficiency in mice with wild-type Rpe65 alleles neither induced 9-cis-retinal formation nor influenced cone survival and function. These results identify FATP4 as a new regulator of synthesis of 9-cis-retinal, which is a \"cone-tropic\" chromophore supporting cone survival and function in the retinas with defective RPE65.

Purpose: Advancements in retinal imaging have augmented our understanding of the pathology and structure-function relationships of retinal disease. No single diagnostic test is sufficient; rather, diagnostic and management strategies increasingly involve the synthesis of multiple imaging modalities. Methods: This literature review and editorial offer practical clinical guidelines for how the retina specialist can use multimodal imaging to manage retinal conditions. Results: Various imaging modalities offer information on different aspects of retinal structure and function. For example, optical coherence tomography (OCT) and B-scan ultrasonography can provide insights into the microstructural anatomy; fluorescein angiography (FA), indocyanine green angiography (ICGA), and OCT angiography (OCTA) can reveal vascular integrity and perfusion status; and near-infrared reflectance and fundus autofluorescence (FAF) can characterize molecular components within tissues. Managing retinal vascular diseases often includes fundus photography, OCT, OCTA, and FA to evaluate for macular edema, retinal ischemia, and the secondary complications of neovascularization (NV). OCT and FAF play a key role in diagnosing and treating maculopathies. FA, OCTA, and ICGA can help identify macular NV, posterior uveitis, and choroidal venous insufficiency, which guides treatment strategies. Finally, OCT and B-scan ultrasonography can help with preoperative planning and prognostication in vitreoretinal surgical conditions. Conclusions: Today, the retina specialist has access to numerous retinal imaging modalities that can augment the clinical examination to help diagnose and manage retinal conditions. Understanding the capabilities and limitations of each modality is critical to maximizing its clinical utility.

Alstrom\'s syndrome (AS) is an autosomal recessively inherited multisystemic disorder that falls under the umbrella of ciliopathy. It is characterized by poor vision, hearing impairment, cardiomyopathy, childhood obesity, diabetes mellitus type 2, dyslipidemia, pulmonary, hepatic, and renal failure besides systemic fibrosis. Biallelic pathogenic variants in ALMS1 gene cause AS. Retrospective study (1990-2017) included 12 Saudi patients with AS based on their phenotype, biochemical markers, and genotype. The study was approved by Fisal Specialist Hospital and Research Centre, Riyadh (RAC number 2131129) on October 2, 2012. This study showed clinical and genetic heterogeneity; six patients showed a founder mutation (IVS18-2A > T in exon 19), whereas six others showed private mutations. AS in Saudi Arabia is underdiagnosed probably because of its variable clinical manifestations. We report 12 Saudi patients with AS to enhance the awareness about this syndrome.

A precise diagnosis in medicine allows appropriate disease-specific management. Kidney failure of unknown aetiology remains a frequent diagnostic label within the haemodialysis unit and kidney transplant clinic, accounting for 15-20% of these patients. Approximately 10% of such cases may have an underlying monogenic cause of kidney failure. Modern genetic approaches can provide a precise diagnosis for patients and their families. A search for extra-renal disease manifestations is also important as this may point to a specific genetic diagnosis. Here, we present two patients where molecular genetic testing was performed because of kidney failure of unknown aetiology and associated retinal phenotypes. The first patient reached kidney failure at 16 years of age but only presented with a retinal phenotype at 59 years of age and was found to have evidence of rod-cone dystrophy. The second patient presented with childhood kidney failure at the age of 15 years and developed visual difficulties and photophobia at the age of 32 years and was diagnosed with cone dystrophy. In both cases, genetic tests were performed which revealed a homozygous whole-gene deletion of NPHP1-encoding nephrocystin-1, providing the unifying diagnosis of Senior-Løken syndrome type 1. We conclude that reviewing kidney and extra-renal phenotypes together with targeted genetic testing was informative in these cases of kidney failure of unknown aetiology and associated retinal phenotypes. The involvement of an interdisciplinary team is advisable when managing such patients and allows referral to other relevant specialities. The long time lag and lack of diagnostic clarity and clinical evaluation in our cases should encourage genetic investigations for every young patient with unexplained kidney failure. For these and similar patients, a more timely genetic diagnosis would allow for improved management, a risk assessment of kidney disease in relatives, and the earlier identification of extra-renal disease manifestations.
UNASSIGNED: The online version contains supplementary material available at 10.1007/s44162-024-00031-4.

UNASSIGNED: To evaluate adult-onset neuronal intranuclear inclusion disease (NIID)-related retinopathy with guanine-guanine-cytosine repeat expansions in NOTCH2NLC.
UNASSIGNED: Neuro-ophthalmic evaluations, including best-corrected visual acuity, slit-lamp biomicroscopy, intraocular pressure (IOP), ultrasound biomicroscopy, pupillometry, fundus photography, fundus autofluorescence (FAF), optical coherence tomography (OCT), Humphrey visual field, full-field electroretinography (ERG), and multifocal ERG (mf-ERG) were performed in patients with gene-proven NIID.
UNASSIGNED: Nine patients (18 eyes) were evaluated, with a median age of 62 years (55-68) and only one man was included in our study. Six patients presented with decreased visual acuity or night blindness, whereas the other three were asymptomatic. The visual acuity was measured from 20/200 to 20/20. Miosis was present in eight patients, four of whom had ciliary process hypertrophy and pronation, and three of whom had shallow anterior chambers. Fundus photography, FAF, and OCT showed consistent structural abnormalities mainly started from peripapillary areas and localized in the outer layer of photoreceptors and inner ganglion cell layer. ERG and mf-ERG also revealed retinal dysfunction in the corresponding regions.
UNASSIGNED: Patients with NIID showed both structural and functional retinopathies which were unique and different from common cone-rod dystrophy or retinitis pigmentosa. Patients with miosis may have a potential risk of an angle-closure glaucoma attack. Neuro-ophthalmic evaluations is essential for evaluating patients with NIID, even without visual symptom.

A patient who had been diagnosed with infantile retinal dystrophy developed renal failure in his twenties, at which time the diagnosis was revised to Senior-Loken syndrome. He was poorly compliant. At 36 years old, he experienced a sudden drop in visual acuity in the setting of cramping and fatigue and was found to be in uremic crisis. Six months after the event and its treatment, his vision failed to improved. Optic nerve pallor was out of proportion to the retinal dystrophy, and the presumed reason for his new visual loss was uremic optic neuropathy. The patient\'s younger sister also had been diagnosed with infantile retinal dystrophy, and metabolic screening confirmed subclinical renal dysfunction that was to be carefully followed going forward. Infantile retinal dystrophy can be associated with later systemic disease. Early detection of such disease can potentially decrease morbidity. Patients with retinal dystrophy can develop new visual loss from causes other than the retinopathy itself.

Multimodal imaging and genetic testing allow sophisticated assessment of suspected inherited retinal disease. Given the availability of such technology, some question whether the full-field electrogram (ffERG) is needed anymore. In fact, a ffERG remains essential for certain clinical scenarios. The goal of this case-based review is to provide a clear understanding of what clinical situations warrant a ffERG. All practicing ophthalmologists should be familiar with this information.

Chorioretinal atrophy with pigmentation along the retinal veins was observed in the right fundus of a 49-year-old patient. Extensive retinitis pigmentosa (RP) was observed in the left eye. Dynamic quantitative visual field testing revealed a scotoma in the right eye that corresponded to the area of ​​retinochoroidal atrophy and afferent visual field constriction was observed on the left eye. An electroretinogram test revealed that the right eye showed attenuated type and the left eye showed negative type. Thus, the conditions of his right eye and left eye were diagnosed as pigmented paravenous retinochoroidal atrophy (PPRCA) and RP, respectively. Thus, there may be a higher proportion of PPRCA patients with unilateral RP than expected.