The influence of variations in ocular biometric and optical parameters on differences in refractive error.

PURPOSE: To present a paraxial method to estimate the influence of variations in ocular biometry on changes in refractive error (S) at a population level and apply this method to literature data. METHODS: Error propagation was applied to two methods of eye modelling, referred to as the simple method and the matrix method. The simple method defines S as the difference between the axial power and the whole-eye power, while the matrix method uses more accurate ray transfer matrices. These methods were applied to literature data, containing the mean ocular biometry data from the SyntEyes model, as well as populations of premature infants with or without retinopathy, full-term infants, school children and healthy and diabetic adults. RESULTS: Applying these equations to 1000 SyntEyes showed that changes in axial length provided the most important contribution to the variations in refractive error (57%-64%), followed by lens power/gradient index power (16%-31%) and the anterior corneal radius of curvature (10%-13%). All other components of the eye contributed <4%. For young children, the largest contributions were made by variations in axial length, lens and corneal power for the simple method (67%, 23% and 8%, respectively) and by variations in axial length, gradient lens power and anterior corneal curvature for the matrix method (55%, 21% and 14%, respectively). During myopisation, the influence of variations in axial length increased from 54.5% to 73.4%, while changes in corneal power decreased from 9.82% to 6.32%. Similarly, for the other data sets, the largest contribution was related to axial length. CONCLUSIONS: This analysis confirms that the changes in ocular refraction were mostly associated with variations in axial length, lens and corneal power. The relative contributions of the latter two varied, depending on the particular population.

Oncological outcomes of intraperitoneal chemotherapy in advanced ovarian cancer: BRCA mutation role.

INTRODUCTION: The knowledge of BRCA status offers a chance to evaluate the role of the intraperitoneal route in patients selected by biomolecular profiles after primary cytoreduction surgery in advanced ovarian cancer. MATERIALS AND METHODS: We performed a retrospective, multicenter study to assess oncological outcomes depending on adjuvant treatment (intraperitoneal [IP] vs intravenous [IV]) and BRCA status (BRCA1/2 mutated vs. BRCA wild type [WT]). The primary endpoint was to determine progression-free survival. The secondary objectives were overall survival and toxicity. RESULTS: A total of 288 women from eight centers were included: 177 in the IP arm and 111 in the IV arm, grouped into four arms according to BRCA1/2 status. Significantly better PFS was observed in BRCA1/2-mutated patients with IP chemotherapy (HR: 0.35; 95% CI, 0.16-0.75, p = 0.007), which was not present in BRCA1/2-mutated patients with IV chemotherapy (HR: 0.65; 95% CI, 0.37-1.12, p = 0.14). Significantly better OS was also observed in IP chemotherapy (HR: 0.17; 95% CI, 0.06-043, p < 0.0001), but was not present in IV chemotherapy in relation with BRCA mutation (HR: 0.52; 95% CI, 0.22-1.27, p = 0.15). For BRCA WT patients, worse survival was observed regardless of the adjuvant route used. The IP route was more toxic compared to the IV route, but toxicity was equivalent at the long-term follow-up. CONCLUSION: This retrospective study suggests that BRCA status can help to offer an individualized, systematic treatment after optimal primary surgery for advanced ovarian cancer, but is limited by the small sample size. Prospective trials are essential to confirm these results.

Simultaneous Pigmented Paravenous Retinochoroidal Atrophy and Retinitis Pigmentosa in the Contralateral Eye.

This case report describes a simultaneous diagnosis of paravenous retinochoroidal atrophy and retinitis pigmentosa in the same patient.

Intracapsular accommodation mechanism in terms of lens curvature gradient.

The intracapsular accommodation mechanism (IAM) may be understood as an increase in the lens equivalent refractive index as the eye accommodates. Our goal was to evaluate the existence of an IAM by analysing observed changes in the inner curvature gradient of the lens. To this end, we fitted a gradient index and curvature lens model to published experimental data on external and nucleus geometry changes during accommodation. For each case analysed, we computed the refractive power and equivalent index for each accommodative state using a ray transfer matrix. All data sets showed an increase in the effective refractive index, indicating a positive IAM, which was stronger for older lenses. These results suggest a strong dependence of the lens equivalent refractive index on the inner curvature gradient.

Predictive factors of therapeutic response according to craniofacial skeletal biotype in patients with sleep apnea syndrome using mandibular advancement devices: a pilot study.

OBJECTIVES: To evaluate the influence of facial biotype in the therapeutic effect of mandibular advancement devices (MADs) according to polysomnographic records in patients diagnosed with sleep apnea-hypopnea syndrome (SAHS). MATERIALS AND METHODS: A total of 46 patients were recruited. Patients were classified according to facial biotype (mesofacial, brachyfacial, or dolichofacial). The quantitative variables were described as the arithmetic mean and standard deviation or the median and interquartile range. Hypothesis tests used were Pearson's chi-square, paired-sample Student's t- test, the Wilcoxon test, one-way analysis of variance, Kruskal-Wallis test, and Mann-Whitney U-test. P < .05 was considered statistically significant. RESULTS: A total of 46 patients were categorized into three facial biotype subgroups with no significant differences among them in age, body mass index, neck circumference, and sex. The respiratory disturbance index (RDI) results were as follows: brachyfacial patients had a reduction to 15 events/h (P < .001), the mesofacial patients had a reduction to 14 events/h (P < .001), and the dolichofacial patients did not show a significant reduction. The oxygen desaturation index (ODI) results were as follows: brachyfacial patients had a reduction in ODI episodes to 45 episodes/h (P = .001), mesofacial patients had a reduction to 18 episodes/h (P = .001). In the brachyfacial group, the number of awakenings with MAD therapy was reduced to 23 events/h (P = .003), while, in the mesofacial group, it was reduced to 37 episodes/h (P = .012). CONCLUSIONS: The facial biotype influences the effectiveness of MAD therapy and is considered a good predictive factor.

Optical and motor changes associated with lighting and near vision tasks in electronic devices.

Purpose: To assess optical and motor changes associated with near vision reading under different controlled lighting conditions performed with two different types of electronic screens. Methods: Twenty-four healthy subjects with a mean age of 22.9±2.3 years (18- 33) participated in this study. An iPad and an e-ink reader were chosen to present calibrated text, and each task lasted 5 minutes evaluating both ambient illuminance level and luminance of the screens. Results: Eye-tracker data revealed a higher number of saccadic eye movements under minimum luminance than under maximum luminance. The results showed statistically significant differences between the iPad (p=0.016) and the e-ink reader (p=0.002). The length of saccades was also higher for the minimum luminance level for both devices: 6.2±2.8 mm and 8.2±4.2 mm (e-ink max vs min), 6.8±2.9 mm and 7.6±3.6 mm (iPad max vs min), and blinking rate increased significantly for lower lighting conditions. Conclusions: Performing reading tasks on electronic devices is highly influenced by both the configuration of the screens and the ambient lighting, meanwhile, low differences in visual quality that are transient in healthy young people, were found.

A Holistic Vision of the Academic and Sports Development of Elite Spanish Track and Field Athletes.

BACKGROUND: Combining sports and studies could be stressful, but beneficial for the athletes' career development. This study explores resources and barriers in the combination of the sports and academic life spheres during the lifespan of elite Spanish track-and-field athletes. METHODS: Seven elite Spanish track-and-field athletes participated in a semistructured interview about their experiences to establish a dual career combining sports and studies/work. Interpretive phenomenological analysis (IPA) followed to analyze data. RESULTS: Findings show that elite Spanish track-and-field athletes face educational and institutional barriers to developing a dual career. Time management, social support, and additional resources could play a key role in the success or failure to develop a dual career. CONCLUSIONS: This study shows that, to overcome dual-career barriers, athletes are resourceful if social support is provided at both the micro (coaches, families, etc.) and macro (political and educational institutions) levels. It also shows that pursuing an academic career can help in alleviating inherent tensions to athletic life and in finding personal balance.

Physical Demands during Official Competitions in Elite Handball: A Systematic Review.

An understanding of physical demands during official competitions is essential to achieving the highest performance in handball. The aim of this systematic review was to summarise the available scientific evidence associated with physical demands during official competitions in elite handball according to playing positions, competition level and gender. Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, 17 studies were selected after a systematic search and selection process of three digital databases: PubMed, Web of Science and Sport Discus. The quality of the selected studies was evaluated using the Strengthening the Reporting of Observational Studies in Epidemiology checklist; the average score was 18.47 points. The sample consisted of 1175 handball players, of whom 1042 were men (88.68%) and 133 were women (11.32%). The results show that an elite handball player covered on average 3664.4 ± 1121.6 m during a match. The average running pace was 84.8 ± 17.2 m∙min-1. The total distance covered was largely greater in national competitions (4506.7 ± 647.9 m) compared with international competitions (2190.3 ± 1950.5 m) (effect size (ES) = 1.2); however, the running pace did not present any significant difference between the international or national level (ES = 0.06). In regard to gender, the total distance covered was moderately greater in female competitions (4549.1 ± 758.6 m) compared with male competitions (3332.6 ± 1257.7 m) (ES = 0.9), and the running pace was largely greater in female competitions (110.5 ± 7.2 m∙min-1) compared with male competitions (78.4 ± 19.7 m∙min-1) (ES = 1.6). In relation to playing position, backs and wings covered a moderately greater total distance (ES = 0.7 and 0.6) and slightly more meters per minute (ES = 0.4 and 0.2) than pivots. Moreover, the technical activity profile differed between playing positions. Backs performed moderately more throws than pivots and wings (ES = 1.2 and 0.9), pivots exhibited largely more body contact than backs and wings, and wings performed moderately more fast breaks (6.7 ± 3.0) than backs (2.2 ± 2.3) (ES = 1.8). Therefore, this research study provides practical applications for handball coaches and strength and conditioning professionals with respect to designing and implementing more individualised training programmes to maximise performance and reduce injury risk.

OxyR Positively Influences Phaseolotoxin Synthesis and Pyoverdin Production in Pseudomonas savastanoi pv. phaseolicola NPS3121.

Phaseolotoxin is a major virulence factor of the bean pathogen bacterium P. savastanoi pv. phaseolicola. This toxin plays a key role in the development of the halo blight disease in bean plants. So far, the signal transduction pathways involved in the synthesis of phaseolotoxin have not been elucidated. The influence of regulation mechanisms related to the oxidative stress response, in particular the OxyR protein, it has been suggested to be involved in this process.. In this study we evaluated the role of OxyR in P. savastanoi pv. phaseolicola, mainly compared to the synthesis of phaseolotoxin and the virulence of this phytopathogen. Generation of the oxyR-mutant, pathogenicity and virulence tests, and analyses of gene expression by RT-PCR assays were performed. The results showed that OxyR exerts an effect on the synthesis of phaseolotoxin and positively influences the expression of the Pht and Pbo cluster genes. Likewise, OxyR influences the production of pyoverdine by the control of the expression of the genes encoding the PvdS sigma factor, involved in the synthesis of this pigment. This study is the first report on members of the OxyR regulon of P. savastanoi pv. phaseolicola NPS3121.

DMRT Transcription Factors in the Control of Nervous System Sexual Differentiation.

Sexual phenotypic differences in the nervous system are one of the most prevalent features across the animal kingdom. The molecular mechanisms responsible for sexual dimorphism throughout metazoan nervous systems are extremely diverse, ranging from intrinsic cell autonomous mechanisms to gonad-dependent endocrine control of sexual traits, or even extrinsic environmental cues. In recent years, the DMRT ancient family of transcription factors has emerged as being central in the development of sex-specific differentiation in all animals in which they have been studied. In this review, we provide an overview of the function of Dmrt genes in nervous system sexual regulation from an evolutionary perspective.

Impaired Bestrophin Channel Activity in an iPSC-RPE Model of Best Vitelliform Macular Dystrophy (BVMD) from an Early Onset Patient Carrying the P77S Dominant Mutation.

Best Vitelliform Macular dystrophy (BVMD) is the most prevalent of the distinctive retinal dystrophies caused by mutations in the BEST1 gene. This gene, which encodes for a homopentameric calcium-activated ion channel, is crucial for the homeostasis and function of the retinal pigment epithelia (RPE), the cell type responsible for recycling the visual pigments generated by photoreceptor cells. In BVMD patients, mutations in this gene induce functional problems in the RPE cell layer with an accumulation of lipofucsin that evolves into cell death and loss of sight. In this work, we employ iPSC-RPE cells derived from a patient with the p.Pro77Ser dominant mutation to determine the correlation between this variant and the ocular phenotype. To this purpose, gene and protein expression and localization are evaluated in iPSC-RPE cells along with functional assays like phagocytosis and anion channel activity. Our cell model shows no differences in gene expression, protein expression/localization, or phagocytosis capacity, but presents an increased chloride entrance, indicating that the p.Pro77Ser variant might be a gain-of-function mutation. We hypothesize that this variant disturbs the neck region of the BEST1 channel, affecting channel function but maintaining cell homeostasis in the short term. This data shed new light on the different phenotypes of dominant mutations in BEST1, and emphasize the importance of understanding its molecular mechanisms. Furthermore, the data widen the knowledge of this pathology and open the door for a better diagnosis and prognosis of the disease.

Analytical ray transfer matrix for the crystalline lens.

We present the formulation of a paraxial ray transfer or ABCD matrix for onion-type GRIN lenses. In GRIN lenses, each iso-indicial surface (IIS) can be considered a refracting optical surface. If each IIS is a shell or layer, the ABCD matrix of a GRIN lens is computed by multiplying a typically high number of translation and refraction matrices corresponding to the K layers inside the lens. Using a differential approximation for the layer thickness, this matrix product becomes a sum. The elements A, B, C, and D of the approximated GRIN ray transfer matrix can be calculated by integrating the elements of a single-layer matrix. This ABCD matrix differs from a homogeneous lens matrix in only one integration term in element C, corresponding to the GRIN contribution to the lens power. Thus the total GRIN lens power is the sum of the homogeneous lens power and the GRIN contribution, which offers a compact and simple expression for the ABDC matrix. We then apply this formulation to the crystalline lens and implement both numerical and analytical integration procedures to obtain the GRIN lens power. The analytical approximation provides an accurate solution in terms of Gaussian hypergeometric functions. Last, we compare our numerical and analytical procedures with published ABCD matrix methods in the literature, and analyze the effect of the iso-indicial surface's conic constant (Q) and inner curvature gradient (G) on the lens power for different lens models.

GRINCU lens with conicoid iso-indicial surfaces: application for modeling the crystalline lens.

We introduce a new type of lens with two gradients of refractive index (GRIN) and of curvature (GRCU) of iso-indicial surfaces, i.e., GRINCU. The inner structure of the lens resembles that of an onion. Each layer is a meniscus lens with infinitesimal thickness, which coincides with an iso-indicial surface characterized by a conicoid shape and a constant refractive index. The internal distribution automatically adapts to the external geometry. Here, we consider the simplest case of a constant gradient of the curvature radius -G, which indicates a linear decrease as we move along the optical axis. The formulation of this type of lens is presented, including its generalization to nonrotationally symmetric conicoid surfaces. The formulation is then applied to model the crystalline lens; the code corresponding to the numerical computation of the 3D refractive index distribution as well as its gradient is provided as a supplementary file. Finally, we confirmed a refractive power increase of nearly 14% when G changes from 0 to 3.

New Insights on the Genetic Basis Underlying SHILCA Syndrome: Characterization of the NMNAT1 Pathological Alterations Due to Compound Heterozygous Mutations and Identification of a Novel Alternative Isoform.

This study aims to genetically characterize a two-year-old patient suffering from multiple systemic abnormalities, including skeletal, nervous and developmental involvements and Leber congenital amaurosis (LCA). Genetic screening by next-generation sequencing identified two heterozygous pathogenic variants in nicotinamide mononucleotide adenylyltransferase 1 (NMNAT1) as the molecular cause of the disease: c.439+5G>T and c.299+526_*968dup.This splice variant has never been reported to date, whereas pathogenic duplication has recently been associated with cases displaying an autosomal recessive disorder that includes a severe form of spondylo-epiphyseal dysplasia, sensorineural hearing loss, intellectual disability and LCA (SHILCA), as well as some brain anomalies. Our patient presented clinical manifestations which correlated strongly with this reported syndrome. To further study the possible transcriptional alterations resulting from these mutations, mRNA expression assays were performed in the patient and her father. The obtained results detected aberrant alternative transcripts and unbalanced levels of expression, consistent with severe systemic involvement. Moreover, these analyses also detected a novel NMNAT1 isoform, which is variably expressed in healthy human tissues. Altogether, these findings represent new evidence of the correlation of NMNAT1 and SHILCA syndrome, and provide additional insights into the healthy and pathogenic expression of this gene.

Anti-VEGF intravitreal injections in the era of COVID-19: responding to different levels of epidemic pressure.

PURPOSE: Following the first wave of the COVID-19 pandemic in early 2020, the easing of strict measures to reduce its spread has led to a resurgence of cases in many countries at both the national and local level. This article addresses how guidance for ophthalmologists on managing patients with retinal disease receiving intravitreal injections of anti-vascular endothelial growth factor (VEGF) during the pandemic should be adapted to the local epidemic pressure, with more or less stringent measures implemented according to the ebb and flow of the pandemic. METHODS: The Vision Academy's membership of international retinal disease experts analyzed guidance for anti-VEGF intravitreal injections during the COVID-19 pandemic and graded the recommendations according to three levels of increasing epidemic pressure. The revised recommendations were discussed, refined, and voted on by the 14-member Vision Academy Steering Committee for consensus. RESULTS: Protocols to minimize the exposure of patients and healthcare staff to COVID-19, including use of personal protective equipment, physical distancing, and hygiene measures, should be routinely implemented and intensified according to local infection rates and pressure on the hospital/clinic or healthcare system. In areas with many COVID-19-positive clusters, additional measures including pre-screening of patients, postponement of non-urgent appointments, and simplification of complex intravitreal anti-VEGF regimens should be considered. Treatment prioritization for those at greatest risk of irreversible vision loss should be implemented in areas where COVID-19 cases are increasing exponentially and healthcare resources are strained. CONCLUSION: Consistency in monitoring of local infection rates and adjustment of clinical practice accordingly will be required as we move forward through the COVID-19 era. Ophthalmologists must continue to carefully weigh the risk-benefits to minimize the exposure of patients and healthcare staff to COVID-19, ensure that patients receive sight-saving treatment, and avoid the potential long-term impact of prolonged treatment postponement.

Natural occurrence of asbestos in serpentinite quarries from Southern Spain.

The nevado-filábride complex (NFC) (southern Spain) is well known for its widespread mining and quarrying activities. Serpentinite and metabasite rocks are extracted, processed and traded as building and ornamental stones. Due to the possible presence of natural occurrence of asbestos (NOA) in these rocks, the aim of this paper is to conduct an in-depth characterisation of fibrous minerals. To this aim, seven serpentinite rock samples were collected in four quarries located in the Sierra Nevada and Sierra de los Filabres (South-eastern Spain), which were then analysed by X-ray powder diffraction (XRPD), scanning electron microscopy combined with energy-dispersive spectrometry (SEM/EDS), differential scanning calorimetry (DSC), derivative thermogravimetry (DTG) and X-ray synchrotron microtomography (SR-µCT). It is essential to investigate asbestos minerals from both scientific and legal perspective, especially for public health officials that implement occupational health and safety policies, in order to safeguard the health of workers (e.g. quarry excavations, road yards, civil constructions, building stones).

Pachychoroid: current concepts on clinical features and pathogenesis.

PURPOSE: The term "pachychoroid" refers to a newly described phenotype in which functional and structural choroidal changes are thought to play a key pathogenic role in a spectrum of related retinal disorders. A more detailed understanding of how the choroid is involved within this spectrum and a better knowledge of the most relevant clinical signs of the pachychoroid phenotype are important to differentiate these disorders from other retinal conditions. Our objectives are to provide a literature review of pachychoroid and the commonalities that may be present across pathologies included in the spectrum, and to provide details on the examination, monitoring, and management of these disorders. METHODS: We searched the PubMed web platform to identify relevant studies using the following keywords: pachychoroid, pachychoroid pigment epitheliopathy, pachychoroid neovasculopathy, aneurysmal type 1 neovascularization, focal choroidal excavation, peripapillary pachychoroid syndrome, vasculopathy pachysclera, pachychoroid geographic atrophy, and pachydrusen. We selected 157 publications and identified the most important features related to pachychoroid. RESULTS: The presence of hypertrophic or congested vessels in the choroid, not thickened choroid per se, under an area of reduced or absent choriocapillaris in the posterior pole seems to be the most salient feature of pachychoroid. However, other qualitative/quantitative features are needed to differentiate the uncomplicated pachychoroid from the pathological pachychoroid clinical spectrum, which may be associated with exudation, neovascularization, and/or retinal pigment epithelium and photoreceptor atrophy. CONCLUSIONS: The most salient feature of pachychoroid appears to be the presence of large vessels under an area of reduced or absent choriocapillaris. Knowledge of the features and pathogenesis of the different disorders in the pachychoroid spectrum may assist in the management of patients.

Surface Superconductivity Changes of Niobium Sheets by Femtosecond Laser-Induced Periodic Nanostructures.

Irradiation with ultra-short (femtosecond) laser beams enables the generation of sub-wavelength laser-induced periodic surface structures (LIPSS) over large areas with controlled spatial periodicity, orientation, and depths affecting only a material layer on the sub-micrometer scale. This study reports on how fs-laser irradiation of commercially available Nb foil samples affects their superconducting behavior. DC magnetization and AC susceptibility measurements at cryogenic temperatures and with magnetic fields of different amplitude and orientation are thus analyzed and reported. This study pays special attention to the surface superconducting layer that persists above the upper critical magnetic field strength Hc2, and disappears at a higher nucleation field strength Hc3. Characteristic changes were distinguished between the surface properties of the laser-irradiated samples, as compared to the corresponding reference samples (non-irradiated). Clear correlations have been observed between the surface nanostructures and the nucleation field Hc3, which depends on the relative orientation of the magnetic field and the surface patterns developed by the laser irradiation.

Relationship between Aflibercept Efficacy and Genetic Variants of Genes Associated with Neovascular Age-Related Macular Degeneration: The BIOIMAGE Trial.

PURPOSE: To identify the genetic variants of the vascular endothelial growth factor (VEGF) pathway genes and other genes associated with neovascular age-related macular degeneration (nAMD) as possible predictive biomarkers of a favorable treatment response to aflibercept. DESIGN: A 52-week (with extension phase: 104-week), prospective, open-label, single-arm, multicenter, phase IV trial was conducted in Spain. PARTICIPANTS: Patients with nAMD were enrolled. METHODS: Aflibercept was administered every 8 weeks until week 48 (after 1-monthly loading doses over 3 months). After week 48, the interval between visits for aflibercept administration was extended by 2 weeks per visit to a maximum of 12 weeks if no evidence of disease activity was observed. A total of 338 SNPs in 90 genes associated with nAMD were analyzed. MAIN OUTCOME MEASURES: Efficacy was evaluated mainly with best-corrected visual acuity (BCVA), and adverse events (AEs) were reported. Treatment efficacy was defined as an increase in BCVA ≥15 letters versus the baseline visit. Univariate and multivariate logistic regressions were used to associate single-nucleotide polymorphisms (SNPs) and treatment efficacy. RESULTS: 194 nonconsecutive patients were enrolled, 170 completed the 52-week follow-up, and of the 85 patients who started the extension phase, 77 completed this phase. Mean BCVA increased from baseline to weeks 52 and 104 by 9 and 10 letters (p = 0.0001 for both), respectively. The percentages of patients gaining ≥15 letters in weeks 52 and 104 were 33 and 31%, respectively. Multivariate logistic regression showed significant associations of 6 SNPs (in 6 genes) with treatment efficacy: rs12366035 (VEGFB; TT; odds ratio [OR] 217), rs25681 (C5; AA/AG; OR 19.7/8.3), rs17793056 (CX3CR1; CT/CC; OR 8.1/6.2), rs1800775 (CETP; CC; OR 6.6), rs2069845 (IL6; GG/AA; OR 5.6/3.3), and rs13900 (CCL2; CT; OR 4.0). One percent of the patients reported arteriothrombolic events related to aflibercept (cerebrovascular accident) according to the Antiplatelet Trialist Collaboration, and 2% reported serious ocular (retinal pigment epithelial tear, retinal tear, and endophthalmitis) and systemic (cardiac failure, hypersensitivity, and transient ischemic attack) AEs related to aflibercept. CONCLUSIONS: Results suggest strong pharmacogenetic associations between one genetic variant of VEGFB (TT, rs12366035) and C5 (AA, rs12366035) genes and the BCVA response after 52-week aflibercept treatment in patients with nAMD. Likewise, the results support the efficacy of aflibercept observed in phase III studies and a good safety profile.

Identification of a novel homozygous ARSG mutation as the second cause of Usher syndrome type 4.

PURPOSE: Usher syndrome is a genetic disease characterized by combined sensorineural hearing loss, retinitis pigmentosa, and vestibular areflexia, with 15 known causative genes. Depending on the severity and onset of the symptoms, 3 different subtypes of the pathology have been classically established, although an increasing number of rare cases are being accumulated as atypical forms. The present work aims to discover the genetic cause in a patient with atypical Usher syndrome, by performing whole exome sequencing in several family members. OBSERVATIONS: The obtained results identified a novel homozygous missense mutation (p.Asp44Asn) in the ARSG gene as the cause of the disease, which was characterized by late-onset progressive symptoms in the patient. A resembling phenotype, recently defined as the novel Usher syndrome type 4, was described in three families sharing another ARSG mutation. Both mutations affect two contiguous amino acid residues, which appear to be critical for the correct function of the protein. CONCLUSIONS AND IMPORTANCE: These findings support the identification of the second disease mutation in this gene and a new evidence of the implication of ARSG in the genetic basis of Usher syndrome type 4.