Multidisciplinary approach to inherited causes of dual sensory impairment.

PURPOSE: This article presents a review of the main causes of inherited dual sensory impairment (DSI) with an emphasis on the multidisciplinary approach. METHODS: A narrative review of English literature published before January 2023 was conducted using PubMed, Medline, and Scopus databases. The different causes of inherited DSI are discussed from a multidisciplinary perspective. RESULTS: There are a wide range of dual sensory impairment (DSI), commonly referred to as blindness and deafness. While Usher syndrome is the most frequent genetic cause, other genetic syndromes such as Alport syndrome or Stickler syndrome can also lead to DSI. Various retinal phenotypes, including pigmentary retinopathy as seen in Usher syndrome, vitreoretinopathy as in Stickler syndrome, and macular dystrophy as in Alport syndrome, along with type of hearing loss (sensorineural or conductive) and additional systemic symptoms can aid in diagnostic suspicion. A thorough ophthalmologic and otorhinolaryngologic examination can help guide diagnosis, which can then be confirmed with genetic studies, crucial for determining prognosis. Effective hearing rehabilitation measures, such as hearing implants, and visual rehabilitation measures, such as low vision optical devices, are crucial for maintaining social interaction and proper development in these patients. CONCLUSIONS: While Usher syndrome is the primary cause of inherited dual sensory impairment (DSI), other genetic syndromes can also lead to this condition. A proper diagnostic approach based on retinal phenotypes and types of hearing loss can aid in ruling out alternative causes. Multidisciplinary approaches can assist in reaching a definitive diagnosis, which has significant prognostic implications.

Expanding the phenotype of THRB: a range of macular dystrophies as the major clinical manifestations in patients with a dominant splicing variant.

Inherited retinal dystrophies (IRDs) are a clinically and genetically heterogeneous group of disorders that often severely impair vision. Some patients manifest poor central vision as the first symptom due to cone-dysfunction, which is consistent with cone dystrophy (COD), Stargardt disease (STGD), or macular dystrophy (MD) among others. Here, we aimed to identify the genetic cause of autosomal dominant COD in one family. WGS was performed in 3 affected and 1 unaffected individual using the TruSeq Nano DNA library kit and the NovaSeq 6,000 platform (Illumina). Data analysis identified a novel spliceogenic variant (c.283 + 1G>A) in the thyroid hormone receptor beta gene (THRB) as the candidate disease-associated variant. Further genetic analysis revealed the presence of the same heterozygous variant segregating in two additional unrelated dominant pedigrees including 9 affected individuals with a diagnosis of COD (1), STGD (4), MD (3) and unclear phenotype (1). THRB has been previously reported as a causal gene for autosomal dominant and recessive thyroid hormone resistance syndrome beta (RTHß); however, none of the IRD patients exhibited RTHß. Genotype-phenotype correlations showed that RTHß can be caused by both truncating and missense variants, which are mainly located at the 3' (C-terminal/ligand-binding) region, which is common to both THRB isoforms (TRß1 and TRß2). In contrast, the c.283 + 1G>A variant is predicted to disrupt a splice site in the 5'-region of the gene that encodes the N-terminal domain of the TRß1 isoform protein, leaving the TRß2 isoform intact, which would explain the phenotypic variability observed between RTHß and IRD patients. Interestingly, although monochromacy or cone response alterations have already been described in a few RTHß patients, herein we report the first genetic association between a pathogenic variant in THRB and non-syndromic IRDs. We thereby expand the phenotype of THRB pathogenic variants including COD, STGD, or MD as the main clinical manifestation, which also reflects the extraordinary complexity of retinal functions mediated by the different THRB isoforms.

A comprehensive WGS-based pipeline for the identification of new candidate genes in inherited retinal dystrophies.

To enhance the use of Whole Genome Sequencing (WGS) in clinical practice, it is still necessary to standardize data analysis pipelines. Herein, we aimed to define a WGS-based algorithm for the accurate interpretation of variants in inherited retinal dystrophies (IRD). This study comprised 429 phenotyped individuals divided into three cohorts. A comparison of 14 pathogenicity predictors, and the re-definition of its cutoffs, were performed using panel-sequencing curated data from 209 genetically diagnosed individuals with IRD (training cohort). The optimal tool combinations, previously validated in 50 additional IRD individuals, were also tested in patients with hereditary cancer (n = 109), and with neurological diseases (n = 47) to evaluate the translational value of this approach (validation cohort). Then, our workflow was applied for the WGS-data analysis of 14 individuals from genetically undiagnosed IRD families (discovery cohort). The statistical analysis showed that the optimal filtering combination included CADDv1.6, MAPP, Grantham, and SIFT tools. Our pipeline allowed the identification of one homozygous variant in the candidate gene CFAP20 (c.337 C > T; p.Arg113Trp), a conserved ciliary gene, which was abundantly expressed in human retina and was located in the photoreceptors layer. Although further studies are needed, we propose CFAP20 as a candidate gene for autosomal recessive retinitis pigmentosa. Moreover, we offer a translational strategy for accurate WGS-data prioritization, which is essential for the advancement of personalized medicine.

Novel BEST1 mutations and clinical characteristics of autosomal recessive bestrophinopathy in a Spanish patient.

PURPOSE: To describe the clinical and genetic characteristics (novel mutation in BEST1 gene) of a Spanish patient with autosomal recessive bestrophinopathy (ARB). METHODS: The detailed ophthalmological examination included best corrected visual acuity (BCVA), color and autofluorescence photography, fluorescein angiography, optical coherence tomography, and electrophysiology tests. A next-generation sequencing (NGS) strategy was applied to the index patient, and then sequenced in an Illumina NextSeq500 system. RESULTS: A 55-year-old male presented with a BCVA of 20/25 in the right eye and 20/20 in the left eye. Fundoscopy revealed perifoveal yellow flecked-like lesions. Fluorescein angiography and fundus autofluorescence results were consistent with pattern dystrophy. A homozygous frameshift mutation in BEST1 (c.341_342del; p.(Leu114Glnfs*57)) was identified as the cause of the disease. CONCLUSION: ARB is a genetic disease that leads to irreversible visual loss. In this report we found a novel mutation responsible for this disease.

Unusual clinical phenotype of Stargardt disease / Fenótipo clínico incomum da doença de Stargardt

ABSTRACT Mutations in the ABCA4 gene are a common cause of Stargardt disease; however, other retinal phenotypes have also been associated with mutations in this gene. We describe an observational case report of an unusual clinical phenotype of Stargardt disease. The ophthalmological examination included best corrected visual acuity, color and autofluorescence photography, fluorescein angiography, optical coherence tomography, and electrophysiology tests. Targeted next-generation sequencing of 99 genes associated with inherited retinal dystrophies was performed in the index patient. A 48-year-old woman presented with a best corrected visual acuity of 20/25 and 20/20. Fundoscopy revealed perifoveal yellow flecked-like lesions. Fluorescein angiography and fundus autofluorescence findings were consistent with pattern dystrophy. Pattern electroretinogram demonstrated bilateral decrease of p50 values. Genetic testing identified two heterozygous missense mutations, c.428C>T, p.(Pro143Leu) and c.3113C>T, p.(Ala.1038Val), in the ABCA4 gene. Based on our results, we believe that these particular mutations in the ABCA4 gene could be associated with a specific disease phenotype characterized by funduscopic appearance similar to pattern dystrophy. A detailed characterization of the retinal phenotype in patients carrying specific mutations in ABCA4 is crucial to understand disease expression and ensure optimal clinical care for patients with inherited retinal dystrophies.

RESUMO Mutações no gene ABCA4 são causa comum da doença de Stargardt, mas outros fenótipos da retina também foram associados a mutações nesse gene. Apresentamos um relato de caso observacional de um fenótipo clínico incomum da doença de Stargardt. O exame oftalmológico incluiu a acuidade visual com melhor correção, fotografia em cores e com autofluorescência, angiofluoresceinografia, tomografia de coerência óptica e testes de eletrofisiologia. Na paciente em questão, realizou-se o sequenciamento de próxima geração de 99 genes associados a distrofias retinais hereditárias. Tratava-se de uma mulher de 48 anos com melhor acuidade visual corrigida de 20/25 e 20/20. A fundoscopia revelou lesões puntiformes amarelas perifoveais. Os resultados da angiofluoresceinografia e da autofluorescência do fundo de olho foram consistentes com distrofia em padrão. A eletrorretinografia por padrões mostrou diminuição bilateral dos valores de p50. Os testes genéticos revelaram duas mutações missense heterozigóticas, c.428C>T, p. (Pro143Leu) e c.3113C>T, p. (Ala.1038Val), no gene ABCA4. Nossos resultados nos fazem pensar que essas mutações específicas em ABCA4 talvez possam estar associadas a um fenótipo específico da doença, caracterizado por uma aparência fundoscópica semelhante à da distrofia em padrão. Uma caracterização detalhada do fenótipo da retina em pacientes portadores de mutações específicas em ABCA4 é crucial para compreender a expressão da doença e para garantir o tratamento clínico ideal para pacientes com distrofias retinais hereditárias.

Unusual clinical phenotype of Stargardt disease.

Mutations in the ABCA4 gene are a common cause of Stargardt disease; however, other retinal phenotypes have also been associated with mutations in this gene. We describe an observational case report of an unusual clinical phenotype of Stargardt disease. The ophthalmological examination included best corrected visual acuity, color and autofluorescence photography, fluorescein angiography, optical coherence tomography, and electrophysiology tests. Targeted next-generation sequencing of 99 genes associated with inherited retinal dystrophies was performed in the index patient. A 48-year-old woman presented with a best corrected visual acuity of 20/25 and 20/20. Fundoscopy revealed perifoveal yellow flecked-like lesions. Fluorescein angiography and fundus autofluorescence findings were consistent with pattern dystrophy. Pattern electroretinogram demonstrated bilateral decrease of p50 values. Genetic testing identified two heterozygous missense mutations, c.428C>T, p.(Pro143Leu) and c.3113C>T, p.(Ala.1038Val), in the ABCA4 gene. Based on our results, we believe that these particular mutations in the ABCA4 gene could be associated with a specific disease phenotype characterized by funduscopic appearance similar to pattern dystrophy. A detailed characterization of the retinal phenotype in patients carrying specific mutations in ABCA4 is crucial to understand disease expression and ensure optimal clinical care for patients with inherited retinal dystrophies.

Dissecting the role of EYS in retinal degeneration: clinical and molecular aspects and its implications for future therapy.

Mutations in the EYS gene are one of the major causes of autosomal recessive retinitis pigmentosa. EYS-retinopathy presents a severe clinical phenotype, and patients currently have no therapeutic options. The progress in personalised medicine and gene and cell therapies hold promise for treating this degenerative disease. However, lack of understanding and incomplete comprehension of disease's mechanism and the role of EYS in the healthy retina are critical limitations for the translation of current technical advances into real therapeutic possibilities. This review recapitulates the present knowledge about EYS-retinopathies, their clinical presentations and proposed genotype-phenotype correlations. Molecular details of the gene and the protein, mainly based on animal model data, are analysed. The proposed cellular localisation and roles of this large multi-domain protein are detailed. Future therapeutic approaches for EYS-retinopathies are discussed.

Macular choroidal thickness in patients with pseudoxanthoma elasticum measured by enhanced-depth imaging spectral-domain optical coherence tomography.

BACKGROUND/OBJECTIVES: To analyze macular choroidal thickness in patients with pseudoxanthoma elasticum (PXE) by enhanced depth imaging optical coherence tomography (EDI-OCT). SUBJECTS/METHODS: This is a prospective cross-sectional study. Sixty-eight eyes of 34 patients with PXE and 68 normal eyes of 34 controls were included to study the macular area with enhanced depth imaging spectral-domain optical coherence tomography (EDI-OCT). Eyes with PXE were classified in three groups: those without choroidal neovascularization (CNV) or chorioretinal macular atrophy macular (Group 1); those with active CNV (Group 2) and those with macular atrophy secondary to inactive CNV (Group 3). RESULTS: Mean subfoveal choroidal thickness (CT) was 266.70 ± 46.93 µm in control group, 304.24 ± 65.52 µm in group 1, 198.55 ± 66.33 µm in group 2, and 119.45 ± 63.89 µm in group 3 (p = 0.00). Comparison between PXE subgroups showed that subfoveal CT was significantly decreased in group 2 and 3 compared to group 1 (p < 0.0001 for both groups). The CT in the different quadrants (superior, inferior, temporal and nasal) was significantly thinner in group 3, followed by group 2 and 1 in ascendant order. Group 1 showed significant increased thickness compared to the other groups. CONCLUSION: To the best of our knowledge, this is the first report suggesting thicker macular choroid in patients with PXE without active or inactive CNV than in normal eyes. Initial changes in Bruch membrane (MB) and choroid, in addition to the increased oxidative stress, would lead to hyperpermeability of the choroid and alterations of the barrier BM-RPE causing a thick choroid in early stages.

Posterior microphthalmos, retinitis pigmentosa, and foveoschisis caused by a mutation in the MFRP gene: a familial study.

Background: To characterize the phenotype and genotype of a rare syndrome associating posterior microphthalmos (PM), retinitis pigmentosa (RP), and foveoschisis in a consanguineous Spanish family. Methods: The study involved five family members, consisting of three siblings and their parents. All members underwent comprehensive eye examinations for best corrected visual acuity, axial length and refractive error, electroretinography (ERG), fundus photography, retinal fluorescein angiography (FA), and optical coherence tomography (OCT). Clinical exome sequencing of more than 6,000 clinically relevant genes (SureSelect Focused Exome, Agilent) was performed using the Illumina HiSeq 3000 system. Candidate variants were validated and segregated by Sanger sequencing. Results: The affected siblings had bilateral shortening of the posterior ocular segment and normal anterior segment dimensions. The fundoscopy, ERG, and FA results were compatible with RP. Macular OCT analysis revealed schisis of the outer retinal layer. Our data analysis pipeline identified a homozygous frameshift mutation in exon 5 of the membrane frizzled-related protein (MFRP) gene (c.498delC; p.Asn167Thrfs*25). Conclusion: Our study confirmed the association of PM with RP as an autosomal recessive syndrome. Although this has previously been described, it seems that there are some constant (i.e., PM and RP) and some variable features (i.e., optic nerve drusen and foveoschisis). The MFRP mutation has also been detected in other studies associating PM with RP. Analysis of a larger series of cases at the clinical and genetic levels would certainly help us to better understand the phenotype-genotype correlations of this syndrome.

Comparison of long-term clinical evolution in highly myopic eyes with vertical oval-shaped dome with or without untreated serous retinal detachment.

BACKGROUND: To compare the long-term clinical evolution of highly myopic eyes with vertical oval-shaped dome associated with or without untreated serous retinal detachment. METHODS: Twenty-eight patients with high myopia (40 eyes) with smooth macular elevations related to a vertical oval-shaped dome were recruited. Serous retinal detachment was investigated; 11 eyes had persistent submacular fluid (study group) and 29 eyes lacked submacular fluid (control group). All patients underwent complete ophthalmological examinations, including optical coherence tomography at baseline every 6 months for 2 years. Fluorescein angiographies were performed in cases with serous retinal detachment to rule out choroidal neovascularisation. RESULTS: There were no statistical differences in baseline age, sex, spherical equivalence or axial length between the two groups. Serous retinal detachment always occurred at the top of the inward macular incurvation. Moreover, no statistically significant differences in mean best-corrected visual acuity were observed during the 24-month follow-up period in the study and control groups and between the two groups at all time points. The mean central foveal thickness was significantly higher in the study group at each visit (p=0.001, in all cases). At the final follow-up visit, complete resolution of the serous retinal detachment was achieved in 1 of the 11 study group's eyes. CONCLUSIONS: Serous retinal detachment is a complication associated with vertical oval-shaped domes that seems to remain stable in terms of visual function over time without treatment.

Two- and three-dimensional topographic analysis of pathologically myopic eyes with dome-shaped macula and inferior staphyloma by spectral domain optical coherence tomography.

PURPOSE: To investigate the posterior anatomical structure of pathologically myopic eyes with dome-shaped macula and inferior staphyloma using spectral domain optical coherence tomography (SD-OCT). METHODS: Our database of 260 pathologically myopic eyes was analyzed retrospectively to identify patients with dome-shaped macula and inferior staphyloma. All patients underwent vertical and horizontal SD-OCT scans across the central fovea, with three-dimensional macular map reconstruction. Best-corrected visual acuity, axial length, and choroidal thickness measurements were recorded. The macular bulge height was also analyzed in eyes with dome-shaped macula. In the three-dimensional images, the symmetry and orientation of the main plane of the inward incurvation of the macula were examined. RESULTS: Twenty-eight (10.7%) of the 260 pathologically myopic eyes had dome-shaped macula of one of three different types: a round radially symmetrical dome (eight eyes, 28.5%), a horizontal axially symmetrical oval-shaped dome (15 eyes, 53.5%), or a vertical axially symmetrical oval-shaped dome (five eyes, 17.8%). The macular bulge height was significantly greater in horizontal oval-shaped dome eyes (p = 0.01, for each comparison). Inferior posterior staphylomas were observed in ten (3.8%) of the 260 pathologically myopic eyes with asymmetrical macular bends. CONCLUSIONS: Vertical and horizontal OCT sectional scanning in combination with three-dimensional macular map reconstruction provides important information for understanding the posterior anatomical structure of dome-shaped macula and inferior staphyloma in pathologically myopic eyes.

The Effect of Peripapillary Detachment on Retinal Nerve Fiber Layer Measurement by Spectral Domain Optical Coherence Tomography in High Myopia.

PURPOSE: The aim of this study was to investigate the repercussions of peripapillary detachment on retinal nerve fiber layer (RNFL) measurements in patients with highly myopic eyes. METHODS: A total of 244 highly myopic eyes underwent a complete ophthalmologic examination that included optical coherence tomography (OCT) to analyze the peripapillary retina and RNFL thickness. Based on the OCT findings, patients were grouped as follows: group A: eyes with a peripapillary intrachoroidal cavitation (PIC); group B: eyes with a peripapillary neurosensory retinal detachment (PNRD), and group C: eyes without a peripapillary detachment. RESULTS: The OCT scans identified a peripapillary detachment in 42 eyes (17.21%). Out of these 42 eyes, 22 showed PIC (52.38%; group A) and 20 had a PNRD (47.62%; group B). The average overall RNFL thickness in groups A, B and C was 74.11 ± 10.88, 88.26 ± 25.72 and 72.75 ± 16.24 µm, respectively (ANOVA test, p = 0.00). CONCLUSION: Eyes with a PNRD had a significantly greater average RFNL thickness than those without peripapillary detachment in pathologic myopia due to a misidentification of the outer profile of the RFNL. This fact makes the interpretation of RNFL thickness in highly myopic eyes more challenging.

Chorioretinal atrophy after spontaneous resolution of myopic foveoschisis.

Myopic foveoschisis is one of the major complications of pathologic myopia, and it was most recently identified by new imaging modalities. During the natural evolution of this complication, anatomical and visual improvement without surgical intervention is an unusual course, and most of these eyes remain stable or progressively worsen. The authors report a case of a highly myopic eye that developed patchy chorioretinal atrophy after spontaneous resolution of myopic foveoschisis, which to the best of our knowledge has not been reported previously in the medical literature.