Otolith function in Usher type II syndrome.

BACKGROUND: Usher's syndrome type II (USH2) is a rare genetic disorder encompassing hearing loss, vision impairment, and apparent intact vestibular function. Recent research suggests a potential involvement of the otolith vestibular receptors in USH2. AIMS/OBJECTIVES: Evaluate otolith dynamic function in USH2. MATERIAL AND METHODS: Twenty-two USH2 (median age 53.9 ± 2.99) and age-matched controls underwent a complete battery vestibular testing including air conducted cervical and ocular vestibular evoked myogenic potentials (c-VEMPs and o-VEMPs). Vestibular function tests were correlated with Activities Balance Scale (ABC) and Dizziness Handicap Inventory (DHI) scores. RESULTS: Fourteen USH2 reported previous vertigo (vs none control). Among 88 ears, c-VEMPs were absent in 15 USH2 cases and 4 controls (p = 0.034), while o-VEMPs were absent in 22 USH2 cases and 12 controls (p = 0.129). There were significant differences between USH2 vs controls in right ear o-VEMP N1 latencies (median 11.60/10.40, p < 0.010), N1-P1 amplitudes (median 5.15/10.10, p < 0.003) and in o-VEMP N1-P1 asymmetry ratio (median 24.78/40.50, p < 0.014). USH2 showed a strong correlation between o-VEMP amplitude and DHI score (p = 0.003, ρ = 0.769). No association was found between vertigo and VEMPs subgroups. CONCLUSIONS AND SIGNIFICANCE: Our findings suggest the presence of otolith dysfunction in USH2, which is independent from subjectively reported dizziness. Incorporating vestibular testing into USH2 evaluation and monitoring could enhance characterization of this multisensory disease.

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.

Multicentric Longitudinal Prospective Study in a European Cohort of MYO7A Patients: Disease Course and Implications for Gene Therapy.

Purpose: We investigated the natural history of retinal dystrophy owing to variants in the MYO7A gene. Methods: Fifty-three patients (mean age, 33.6 ± 16.7 years) with Usher syndrome owing to biallelic, mostly pathogenic, variants in MYO7A underwent baseline and two annual follow-up visits. Best-corrected visual acuity (BCVA), semiautomatic kinetic visual field, full-field electroretinogram, color fundus imaging, microperimetry, spectral-domain optical coherence tomography, and fundus autofluorescence were assessed. Results: At baseline, all patients presented with decreased BCVA (66.4 ± 17.9 Early Treatment Diabetic Retinopathy score and 59.5 ± 21.7 Early Treatment Diabetic Retinopathy score, in the better- and worse-seeing eyes, respectively), restricted semiautomatic kinetic visual field (III4e area, 3365.8 ± 4142.1°2; 4176.4 ± 4400.3°2) and decreased macular sensitivity (9.7 ± 9.9 dB; 9.0 ± 10.2 dB). Spectral-domain optical coherence tomography revealed reduced central macular thickness (259.6 ± 63.0 µm; 250.7 ± 63.3 µm) and narrowed ellipsoid zone band width (2807.5 ± 2374.6 µm; 2615.5 ± 2370.4 µm). Longitudinal analyses (50 patients) showed a significant decrease of BCVA in better-seeing eyes, whereas no changes were observed in worse-seeing eyes for any parameter. BCVA, semiautomatic kinetic visual field (III4e and V4e) and macular sensitivity were related significantly to age at baseline. Hyperautofluorescent foveal patch (16 eyes [31.4%]) and abnormal central hypoautofluorescence (9 eyes [17.6%]) were significantly associated with worse morphological and functional read-outs compared with the hyperautofluorescent ring pattern (22 eyes [43.1%]). Conclusions: Our European multicentric study offers the first prospective longitudinal analysis in one of the largest cohorts of MYO7A patients described to date, confirming the slow disease progression. More important, this study emphasizes the key role of fundus autofluorescence patterns in retinal impairment staging and advocates its adoption as an objective biomarker in patient selection for future gene therapy clinical trials.

Self-Reported Functional Vision in USH2A-Associated Retinal Degeneration as Measured by the Michigan Retinal Degeneration Questionnaire.

Purpose: The purpose of this study was to evaluate self-reported functional vision (FV) and the impact of vision loss in patients with USH2A-associated retinal degeneration using a patient-reported outcome (PRO) measure, the Michigan Retinal Degeneration Questionnaire (MRDQ), to correlate MRDQ scores with well-established visual function measurements. Design: An observational cross-sectional study (n = 93) of participants who had Usher Syndrome Type 2 (USH2, n = 55) or autosomal recessive non-syndromic retinitis pigmentosa (ARRP; n = 38) associated with biallelic variants in the USH2A gene. Methods: The study protocol was approved by all ethics boards and informed consent was obtained from each participant. Participants completed the MRDQ at the 48-month study follow-up visit. Disease duration was self-reported by participants. One-way ANOVA was used to compare subgroups (clinical diagnosis, age, disease duration, and full-field stimulus threshold [FST] Blue-Red mediation) on mean scores per domain. Spearman correlation coefficients were used to assess associations between MRDQ domains and visual/retinal function assessments. Results: Of the study sample, 58% were female participants and the median disease duration was 13 years. MRDQ domains were sensitive to differences between subgroups of clinical diagnosis, age, disease duration, and FST Blue-Red mediation. MRDQ domains correlated with static perimetry, microperimetry, full-field stimulus testing, and best-corrected visual acuity (BCVA). Conclusions: Self-reported FV measured by the MRDQ, when applied to USH2 and ARRP participants, had good distributional characteristics and correlated well with visual function tests. MRDQ adds a new dimension of understanding on vision-related functioning and establishes this PRO tool as an informative measure in evaluating USH2A outcomes.

Vestibular phenotype-genotype correlation in a cohort of 90 patients with Usher syndrome.

Usher syndrome has been historically categorized into one of three classical types based on the patient phenotype. However, the vestibular phenotype does not infallibly predict which Usher genes are mutated. Conversely, the Usher syndrome genotype is not sufficient to reliably predict vestibular function. Here we present a characterization of the vestibular phenotype of 90 patients with clinical presentation of Usher syndrome (59 females), aged 10.9 to 75.5 years, with genetic variants in eight Usher syndromic genes and expand the description of atypical Usher syndrome. We identified unexpected horizontal semicircular canal reactivity in response to caloric and rotational stimuli in 12.5% (3 of 24) and 41.7% (10 of 24), respectively, of our USH1 cohort. These findings are not consistent with the classical phenotypic definition of vestibular areflexia in USH1. Similarly, 17% (6 of 35) of our cohort with USH2A mutations had saccular dysfunction as evidenced by absent cervical vestibular evoked myogenic potentials in contradiction to the classical assumption of normal vestibular function. The surprising lack of consistent genotypic to vestibular phenotypic findings as well as no clear vestibular phenotypic patterns among atypical USH cases, indicate that even rigorous vestibular phenotyping data will not reliably differentiate the three USH types.

Subjective visual vertical in patients with Usher syndrome.

BACKGROUND: Verticality, or more precisely the ability to perceive spatial orientation with regard to gravity, is based on the integration of visual, vestibular and somesthetic information. OBJECTIVE: The purpose of the present study was to compare the subjective visual vertical (SVV) in patients with Usher (type I and type II) with visual or vestibular impairment, and in healthy participants, in order to explore the importance of the visual and vestibular functions on the vertical's perception. METHODS: We evaluated the SVV using a wall housing which projects on the opposite wall a red-light line of about 2 meters, obtained by laser cannon. The evaluation was carried out under two tilt conditions: clockwise and counter-clockwise randomly performed five times in each direction. The response to the SVV task was quantified by the mean of the absolute values of the SVV. RESULTS: Responses to the SVV were significantly less accurate in patients with Usher with respect to healthy participants while it was similar for the two groups of patients with Usher. CONCLUSIONS: We hypothesize that visual inputs play a very important role in the perception of verticality and that the symmetrical bilateral vestibular deficit in Usher type I does not have a strong impact in perception of verticality.

Living with type I Usher syndrome: insights from patients and their parents.

BACKGROUND: Type 1 Usher syndrome (USH1) is a rare disease and major cause of genetic deaf-blindness. Deafness is present from birth while retinitis pigmentosa (RP) which typically presents during childhood is progressive leading to blindness. The aim of this research was to develop a disease model describing USH1 symptoms and their impact on patients' lives. MATERIALS AND METHODS: Qualitative interviews were conducted with patients (pediatric and adult) and parents of children and adolescents with USH1. Interviewed subjects were enrolled through ophthalmologists from specialized eye centers in the USA and in France. Trained interviewers used semi-structured techniques to elicit concepts relevant to patients and their parents. Thematic analysis of interview transcripts led to the identification of concepts which were organized to generate a disease model. RESULTS: A total of 18 patients (7 in the US; 11 in France)- 9 adults, 4 adolescents, and 5 children- and 9 mothers were interviewed. The most cited ocular symptoms were difficulty seeing at night and loss of peripheral vision. Interviewees reported limitations on Physical (e.g. difficulty moving), Mental (e.g. fear about falling), Social (e.g. difficulty discussing disease with others) and Role (e.g. difficulties at school/work) functioning. These impacts were, when possible, mitigated by coping strategies and support (e.g. using electronic devices, having a positive/proactive attitude). CONCLUSIONS: This research provides an overview of symptoms experienced by patients with USH1 and highlights the dramatic impact these have on patients' lives, allowing the identification of concepts of importance when evaluating therapeutic treatments in development for RP.

Baseline Visual Field Findings in the RUSH2A Study: Associated Factors and Correlation With Other Measures of Disease Severity.

PURPOSE: To report baseline visual fields in the Rate of Progression in USH2A-related Retinal Degeneration (RUSH2A) study. DESIGN: Cross-sectional study within a natural history study. METHODS: Setting: multicenter, international. STUDY POPULATION: Usher syndrome type 2 (USH2) (n = 80) or autosomal recessive nonsyndromic retinitis pigmentosa (ARRP) (n = 47) associated with biallelic disease-causing sequence variants in USH2A. OBSERVATION PROCEDURES: Repeatability of full-field static perimetry (SP) and between-eye symmetry of kinetic perimetry (KP) were evaluated with intraclass correlation coefficients (ICCs). The association of demographic and clinical characteristics with total hill of vision (VTOT) was assessed with general linear models. Associations between VTOT and other functional and morphologic measures were assessed using Spearman correlation coefficients and t tests. MAIN OUTCOME MEASURES: VTOT (SP) and III4e isopter area (KP). RESULTS: USH2 participants had more severe visual field loss than ARRP participants (P < .001, adjusting for disease duration, age of enrollment). Mean VTOT measures among 3 repeat tests were 32.7 ± 24.1, 31.2 ± 23.4, and 31.7 ± 23.9 decibel-steradians (intraclass correlation coefficient [ICC] = 0.96). Better VA, greater photopic ERG 30-Hz flicker amplitudes, higher mean microperimetry sensitivity, higher central subfield thickness, absence of macular cysts, and higher III4e seeing area were associated with higher VTOT (all r > .48; P < .05). Mean III4e isopter areas for left (4561 ± 4426 squared degrees) and right eyes (4215 ± 4300 squared degrees) were concordant (ICC = 0.94). CONCLUSIONS: USH2 participants had more visual field loss than participants with USH2A-related ARRP, adjusting for duration of disease and age of enrollment. VTOT was repeatable and correlated with other functional and structural metrics, suggesting it may be a good summary measure of disease severity in patients with USH2A-related retinal degeneration.

Biomarkers in Usher syndrome: ultra-widefield fundus autofluorescence and optical coherence tomography findings and their correlation with visual acuity and electrophysiology findings.

PURPOSE: To investigate the functional and structural biomarkers and their correlation with Usher syndrome (USH). METHODS: Medical records, imaging and electrophysiology test results of USH patients attending the Save Sight Institute between 2012 and 2017 were reviewed. Best corrected visual acuity (BCVA), ultra-widefield autofluorescence (UW-FAF), spectral-domain optical coherence tomography (SD-OCT), full-field electroretinogram and pattern electroretinogram (pERG) were performed. SD-OCT scans assessed central macular thickness (CMT), greatest linear diameter of preserved outer retinal layers-macular island (MI) and presence of cystoid macular edema (CME). UW-FAF images were qualitatively graded to identify hypo/hyperfluorescence patterns in the peripheral fundus. RESULTS: Thirty-six eyes from 18 subjects were included. Mean BCVA was 0.22 ± 0.3 LogMAR. MI extent was significantly associated with better vision (ß = - 0.175 per 1000 µm; R2 = 0.487; P = 0.002; Fig. 4). A higher pERG P50 was associated with a larger macular island (ß = 782 per µV; R2 = 0.238; P = 0.025), while a higher pERG N95 was associated with a smaller macular island (ß = - 499 per µV; R2 = 0.219; P = 0.030). Mean CMT was 271 ± 35 µm and was significantly associated with better vision (ß = - 0.083 per 10 µm; R2 = 0.612; P < 0.001). CME was diagnosed in 47.2% (n = 17) eyes. There was no significant difference in mean BCVA for those with CME (0.19 ± 0.2 LogMAR) and without CME (0.40 ± 0.5; R2 = 0.081; P = 0.17). All patients had abnormal UW-FAF. Four main patterns of change were identified (granular 55%, annular 11%, bone spicule 17% and patchy 17%). Patients with the patchy pattern demonstrated worse BCVA in comparison with those with granular (P < 0.0001) and bone spicule (P = 0.0179) patterns. CONCLUSIONS: Structural changes identified on OCT and UW-FAF correlated with BCVA and pERG in this cohort representing different stages of the disease. These parameters could represent reliable biomarkers in therapeutic clinical trials on USH.

Mutation screening of the USH2A gene reveals two novel pathogenic variants in Chinese patients causing simplex usher syndrome 2.

BACKGROUND: Usher syndrome (USH) is the most prevalent cause of the human genetic deafness and blindness. USH type II (USH2) is the most common form of USH, and USH2A is the major pathogenic gene for USH2. For expanding the spectrum of USH2A mutations and further revealing the role of USH2A in USH2, we performed the USH2A gene variant screening in Chinese patients with USH2. METHODS: Genomic DNA was extracted from peripheral blood of unrelated Chinese USH2 patients, we designed specific primers for amplifying the coding region (exons 2-72) of the USH2A gene. Sanger sequencing was used to study alleles. Silico prediction tools were used to predict the pathogenicity of the variants identified in these patients. RESULTS: Five heterozygous pathogenic variants were detected in four patients. Two patients were found to have two-mutations and two patients only have one. Two novel variants c.4217C > A (p.Ser1406X) and c.11780A > G (p.Asp3927Gly)) were predicted deleterious by computer prediction algorithms. In addition, three reported mutations (c.8559-2A > G, c.8232G > C and c.11389 + 3A > T) were also found in this study. CONCLUSIONS: We identified five heterozygous pathogenic variants in the USH2A gene in Chinese patients diagnosed with Usher syndrome type 2, two of which were not reported. It expands the spectrum of USH2A variants in USH.

PHENOTYPIC CHARACTERISTICS OF ROD-CONE DYSTROPHY ASSOCIATED WITH MYO7A MUTATIONS IN A LARGE FRENCH COHORT.

PURPOSE: To document the rod-cone dystrophy phenotype of patients with Usher syndrome type 1 (USH1) harboring MYO7A mutations. METHODS: Retrospective cohort study of 53 patients (42 families) with biallelic MYO7A mutations who underwent comprehensive examination, including functional visual tests and multimodal retinal imaging. Genetic analysis was performed either using a multiplex amplicon panel or through direct sequencing. Data were analyzed with IBM SPSS Statistics software v. 21.0. RESULTS: Fifty different genetic variations including 4 novel were identified. Most patients showed a typical rod-cone dystrophy phenotype, with best-corrected visual acuity and central visual field deteriorating linearly with age. At age 29, binocular visual field demonstrated an average preservation of 50 central degrees, constricting by 50% within 5 years. Structural changes based on spectral domain optical coherence tomography, short wavelength autofluorescence, and near-infrared autofluorescence measurements did not however correlate with age. Our study revealed a higher percentage of epiretinal membranes and cystoid macular edema in patients with MYO7A mutations compared with rod-cone dystrophy patients with other mutations. Subgroup analyses did not reveal substantial genotype-phenotype correlations. CONCLUSION: To the best of our knowledge, this is the largest French cohort of patients with MYO7A mutations reported to date. Functional visual characteristics of this subset of patients followed a linear decline as in other typical rod-cone dystrophy, but structural changes were variable indicating the need for a case-by-case evaluation for prognostic prediction and choice of potential therapies.

Double Hyperautofluorescent Rings in Patients with USH2A-Retinopathy.

USH2A mutation is the most common cause of retinitis pigmentosa, with or without hearing impairment. Patients most commonly exhibit hyperautofluorescent ring on fundus autofluorescence imaging (FAF) and rod-cone dystrophy on electrophysiology. A detailed study of three USH2A patients with a rare pattern of double hyperautofluorescent rings was performed. Twenty-four patients with typical single hyperautofluorescent rings were used for comparison of the ages of onset, visual fields, optical coherence tomography, electrophysiology, and audiograms. Double rings delineated the area of pericentral retinal degeneration in all cases. Two patients exhibited rod-cone dystrophy, whereas the third had a cone-rod dystrophy type of dysfunction on electrophysiology. There was minimal progression on follow-up in all three. Patients with double rings had significantly better visual acuity, cone function, and auditory performance than the single ring group. Double rings were associated with combinations of null and missense mutations, none of the latter found in the single ring patients. According to these findings, the double hyperautofluorescent rings indicate a mild subtype of USH2A disease, characterized by pericentral retinal degeneration, mild to moderate hearing loss, and either a rod-cone or cone-rod pattern on electrophysiology, the latter expanding the known clinical spectrum of USH2A-retinopathy.

Full-field electroretinography, visual acuity and visual fields in Usher syndrome: a multicentre European study.

PURPOSE: Usher syndrome (USH) is a multisensory deficiency involving vision, hearing and the vestibular system. The purpose of this study is to report on the functional data (i.e. electroretinography, visual fields, visual acuity) of patients with retinitis pigmentosa (RP) due to Usher syndrome that were collected in a multicentre European study (TREATRUSH). METHODS: A total of 268 genetically confirmed USH patients underwent electrophysiological examinations in the context of multimodal ophthalmological examination in the study (75 USH1, 189 USH2 and four USH3). Full-field electroretinography (ERG) was performed according to ISCEV standards, visual field determination was carried out with either the Octopus or Goldmann perimeters and visual acuity was examined with either ETDRS or Snellen charts. The data were compared between USH subtypes (USH1/USH2/USH3) and correlated with age. RESULTS: Visual acuity decreases significantly with age for both USH1 and USH2 (p < 0.001), without a difference between the two cohorts. When corrected for age, the preserved kinetic visual field was significantly larger in USH2 than in USH1 (p = 0.04). Furthermore, the preserved kinetic visual field area showed a significant decrease with age (based on an exponential fit) in both USH1 and USH2 (p < 0.001). In USH1 patients, however, the visual field was already vastly reduced at an early age. The ERG results were abnormal in all patients. Detectable data for scotopic ERG were obtained from nine patients, and data of photopic ERG were obtained from 24 patients, without a difference between USH1 and USH2 subtypes. CONCLUSIONS: There are differences in the phenotypes of RP in USH subtypes, most visible in the progression of visual fields between USH1 and USH2. The perimetric reduction occurs earlier in USH1 than in USH2. In both subtypes, visual acuity decreases significantly with age and the ERG is not detectable already at early ages.

Usher syndrome and non-syndromic deafness: Functions of different whirlin isoforms in the cochlea, vestibular organs, and retina.

Usher syndrome (USH) is the leading cause of inherited combined vision and hearing loss. However, mutations in most USH causative genes lead to other diseases, such as hearing loss only or vision loss only. The molecular mechanisms underlying the variable disease manifestations associated with USH gene mutations are unclear. This review focuses on an USH type 2 (USH2) gene encoding whirlin (WHRN; previously known as DFNB31), mutations in which have been found to cause either USH2 subtype USH2D or autosomal recessive non-syndromic deafness type 31 (DFNB31). This review summarizes the current knowledge about different whirlin isoforms encoded by WHRN orthologs in animal models, the interactions of different whirlin isoforms with their partners, and the function of whirlin isoforms in different cellular and subcellular locations. The recent findings regarding the function of whirlin isoforms suggest that disruption of different isoforms may be one of the mechanisms underlying the variable disease manifestations caused by USH gene mutations. This review also presents recent findings about the vestibular defects in Whrn mutant mouse models, which suggests that previous assumptions about the normal vestibular function of USH2 patients need to be re-evaluated. Finally, this review describes recent progress in developing therapeutics for diseases caused by WHRN mutations.

Evidence for impaired olfactory function and structural brain integrity in a disorder of ciliary function, Usher syndrome.

Diseases involving cilia dysfunction, such as Usher Syndrome (USH), often involve visual and auditory loss. Psychophysical evidence has suggested that this may also hold true for the peripheral olfactory domain. Here we aimed to go a step further by attempting to establish relations between the integrity of cortical structures and olfactory function in this condition. We investigated olfactory function for USH types 1 (USH1) and 2 (USH2). Bilateral olfactory bulb (OB) volume and olfactory sulcus (OS) depth were also analysed. Thirty-three controls with no previous olfactory deficits were age, sex and handedness-matched to 32 USH patients (11 USH1, 21 USH2). A butanol detection threshold test was performed to measure olfactory function. For OB volume and OS depth, morphometric measurements were performed using magnetic resonance imaging (MRI) based on detailed segmentation by three independent operators. Averaged values across these were used for the statistical analyses. Total intracranial volume was estimated using Freesurfer to account for head size variability. Olfactory threshold was significantly lower in controls when compared to USH, USH1, and USH2. OS depth was found to be shallower in both hemispheres in USH patients when compared with the control group. OB volume was not significantly different between control and USH groups, or respective subgroups. Nevertheless, butanol threshold was negatively correlated with the left OB volume for the USH type 1 subgroup. The main effect of OS depth reduction was found to be mainly due to the comparison between USH2 and controls. Our results provide evidence for morphometric changes and olfactory dysfunction in patients with USH. This correlated with a reduction in left OB volume in the USH1 subgroup, the most severe USH phenotype. The main effect of reduced OS depth was found to stem mainly from USH2 raising questions regarding a possible complex interaction between sensory olfactory loss and central cortical changes in this disease.

Unanticipated prognosis for a patient with type 2 Usher syndrome.

PURPOSE: The Usher syndrome phenotype is comprised of ocular and audiologic anomalies. Patients characteristically experience congenital hearing loss, nyctalopia, reduced visual fields, and ultimately decreased visual acuity. However, diagnosis may initially be more difficult in cases with limited ocular findings. Here, we present a case in which an adult patient had neither subjective visual complaints nor ocular findings at the time of diagnosis aside from a moderate reduction in rod and cone function on electroretinogram testing. Nevertheless, 43 years after his initial examination, he showed severe degenerative changes in the retina. METHODS: A 63-year-old man with Usher syndrome type 2 underwent ophthalmic examination that included visual acuity, optical coherence tomography (OCT), electroretinogram (ERG), fundus photography, and Goldmann visual field testing. The patient also had genetic testing performed. We additionally reviewed the ocular findings on two of his siblings also afflicted with Usher syndrome type 2. RESULTS: Our findings documented the long-term progression of Usher syndrome in this patient. They showed that the patient was asymptomatic with only a moderate reduction on ERG testing at the time of diagnosis, but subsequently progressed to an advanced stage of retinal disease with severe visual loss. CONCLUSIONS: The patient demonstrated that the absence of visual symptoms and favorable findings on functional testing on initial presentation might yet belie a future for austere visual loss. Caution is thus warranted when predicting a visual prognosis in such a patient. Further, the value in electroretinographic testing for diagnosis is demonstrated.

Ciliopathy: Usher Syndrome.

Ciliopathies are a group of disorders caused by a defect in ciliogenesis, ciliary protein trafficking. Because nearly every cell in the body (including the photoreceptors) contains cilia, defects in ciliary proteins typically affect multiple organ systems. Usher syndrome is the most common syndromic cause of retinitis pigmentosa (RP) and accounts for 10-20% of cases of RP Inheritance is autosomal recessive, and the retinal dystrophy is usually rod-cone dystrophy (Figs. 32.1 and 32.2). These patients have RP with sensorineural hearing loss (partial or complete) since birth; some may have vestibular dysfunction. Most patients retain central vision of about 20/40 until about age 40. Usher Syndrome 1 (USH1): Profound congenital sensorineural hearing loss on audiometry, absent vestibular function, and typical RP (onset by 10 years of age); accounts for about 70% of all Usher cases. Patient may benefit from a cochlear implant. The retinitis pigmentosa occurs at an early age (childhood onset) and progress slowly. Usher Syndrome 2 (USH2): Moderate to severe congenital sensorineural hearing loss on audiometry (predominantly for higher frequencies), normal vestibular function, and typical RP (onset by 20 years of age); accounts for about 26% of all Usher cases. Usher Syndrome 3 (USH3): Progressive sensorineural hearing loss and typical RP (onset in second decade); accounts for about 4% of all Usher cases. Vestibular function is normal in about half of patients, but abnormal in the other half.

Knockout of ush2a gene in zebrafish causes hearing impairment and late onset rod-cone dystrophy.

Most cases of Usher syndrome type II (USH2) are due to mutations in the USH2A gene. There are no effective treatments or ideal animal models for this disease, and the pathological mechanisms of USH2 caused by USH2A mutations are still unknown. Here, we constructed a ush2a knockout (ush2a-/-) zebrafish model using TALEN technology to investigate the molecular pathology of USH2. An early onset auditory disorder and abnormal morphology of inner ear stereocilia were identified in the ush2a-/- zebrafish. Consequently, the disruption of Ush2a in zebrafish led to a hearing impairment, like that in mammals. Electroretinography (ERG) test indicated that deletion of Ush2a affected visual function at an early stage, and histological analysis revealed that the photoreceptors progressively degenerated. Rod degeneration occurred prior to cone degeneration in ush2a-/- zebrafish, which is consistent with the classical description of the progression of retinitis pigmentosa (RP). Destruction of the outer segments (OSs) of rods led to the down-regulation of phototransduction cascade proteins at late stage. The expression of Ush1b and Ush1c was up-regulated when Ush2a was null. We also found that disruption of fibronectin assembly at the retinal basement membrane weakened cell adhesion in ush2a-/- mutants. In summary, for the first time, we generated a ush2a knockout zebrafish line with auditory disorder and retinal degeneration which mimicked the symptoms of patients, and revealed that disruption of fibronectin assembly may be one of the factors underlying RP. This model may help us to better understand the pathogenic mechanism and find treatment for USH2 in the future.

Long-term visual outcomes and rehabilitation in Usher syndrome type II after retinal implant Argus II.

BACKGROUND: The aim of this article is to describe visual outcomes and posterior rehabilitation of the first Usher syndrome type II (USH2) patient receiving an Argus II (®) prosthesis. CASE PRESENTATION: We present a case of a USH2 patient who underwent Argus II prosthesis surgery at the age of 53. He had hearing loss from birth and presented a very poor visual field with good light perception. He communicated through sign language translated by his interpreter, who explained all the information regarding the surgical procedure and who assisted in the posterior visual therapy. Sixteen months after surgery, the patient communicates more fluently with sign language and is able to identify letters with high contrast over 6 cm and words up to four letters. CONCLUSIONS: This is the first case described in the literature of a USH2 patient receiving an Argus II prosthesis This is an alternative treatment for USH2 patients, whose interpreters are essential in the selection process and subsequent rehabilitation after surgery.

Central Retina Functional Damage in Usher Syndrome Type 2: 22 Years of Focal Macular ERG Analysis in a Patient Population From Central and Southern Italy.

Purpose: Recent studies show that patients with Usher syndrome type 2 (USH2) have abnormal cone structure and density in the central retina. This occurs in the presence of normal acuity, opening the quest for additional sensitive functional measures of central cone function in USH. We tested here whether focal macular cone electroretinogram (fERG) could be such a tool. Methods: This retrospective study of central cone function loss was based on data from 47 patients with USH2 from the Ophthalmology Department of the Policlinico Gemelli/Catholic University in Rome. The analysis focused on the decrease of the fERG, obtained in response to a 41-Hz sinusoidal modulation of a uniform field presented to the central 18°, generated by red light-emitting diodes (LEDs) and superimposed on an equiluminant steady adapting background. fERG decrease was compared with the decrease of best-corrected visual acuity and Goldmann kinetic perimetry V4E field. Results: fERG follow-up data document a severe and precocious loss of central cone function in USH2 patients, preceding losses in other measures of cone function. fERG is already reduced to 40% of control at the beginning of the second decade of life, and by 25 years of age, all USH2 patients have fERGs less than 30% of control values. Conclusions: fERG represents a sensitive tool to evaluate central cone function in USH2, anticipating the decline of other central cone function measures, such as visual acuity and Goldmann perimetry.