Usher syndrome clinical types I and II: could ocular symptoms and signs differentiate between the two types?

PURPOSE: Usher syndrome types I and II are clinical syndromes with substantial genetic and clinical heterogeneity. We undertook the current study in order to identify ocular symptoms and signs that could differentiate between the two types. METHODS: Sixty-seven patients with Usher syndrome were evaluated. Based on audiologic and vestibular findings, patients were classified as either Usher type I or II. The severity of the ocular signs and symptoms present in each type were compared. RESULTS: Visual acuity, visual field area, electroretinographic amplitude, incidence of cataract and macular lesions were not significantly different between Usher types I and II. However, the ages when night blindness was perceived and retinitis pigmentosa was diagnosed differed significantly between the two types. CONCLUSIONS: There seems to be some overlap between types I and II of Usher syndrome in regard to the ophthalmologic findings. However, night blindness appears earlier in Usher type I (although the difference in age of appearance appears to be less dramatic than previously assumed). Molecular elucidation of Usher syndrome may serve as a key to understanding these differences and, perhaps, provide a better tool for use in clinical diagnosis, prognosis and genetic counseling.     

Screening of the USH1G gene among Spanish patients with Usher syndrome. Lack of mutations and evidence of a minor role in the pathogenesis of the syndrome

The Usher syndrome (USH) is an autosomal recessive hereditary disorder characterized by the association of sensorineural hearing loss, retinitis pigmentosa (RP) and, in some cases, vestibular dysfunction. The USH1G gene, encoding SANS, has been found to cause both Usher syndrome type I and atypical Usher syndrome. 109 Spanish unrelated patients suffering from Usher syndrome type I, type II, type III and unclassified Usher syndrome were screened for mutations in this gene, but only eight different changes without a clear pathogenic effect have been detected. Based on these results as well as previous studies in other populations where mutational analysis of this gene has been carried out, one can conclude that USH1G has a minor involvement in Usher syndrome pathogenesis.     

Visual acuity impairment in patients with retinitis pigmentosa at age 45 years or older.

OBJECTIVE: To determine the severity of visual acuity impairment in patients, age 45 years or older, with either isolated or identifiable genetic subtypes of retinitis pigmentosa (RP) and Usher syndrome. DESIGN: Multicenter, retrospective, cross-sectional analysis. PARTICIPANTS: Visual acuity data were obtained on 999 patients with different genetic subtypes of RP and Usher syndrome, age 45 years or older, from 4 major eye care centers in the United States. INTERVENTION: The best-corrected visual acuity obtained on these patients from the eye with better vision on their most recent visit was used for the analysis. MAIN OUTCOME MEASURE: Best-corrected visual acuity was the main parameter analyzed for the study, and it was obtained with Snellen or Feinbloom low vision charts or with a B-VAT II monitor (Mentor). RESULTS: The final analyses were done on 982 patients (17 patients with a sector form of RP were analyzed separately). Of the 982 patients, 506 (52%) had a visual acuity of 20/40 or better, and 678 (69%) had a visual acuity of 20/70 or better in at least one eye. There were 243 (25%) patients who had a visual acuity of 20/200 or worse in both eyes. Five (0.5%) patients had no light perception in both eyes. The odds ratio for any patient having a visual acuity of 20/200 or worse in this population was 1.4 for each difference of 10 years of age. Similarly, the odds ratio of a patient having a visual acuity of 20/40 or better in at least one eye was 0.95 for a 10-year age difference. CONCLUSIONS: In this large population of patients with RP and Usher syndrome from four centers, it was rare for such patients to lose all vision in both eyes. One fourth of the patients had a visual acuity of 20/200 or worse in both eyes, and more than half of the population had a visual acuity of 20/40 or better in at least one eye. These data can be used to counsel such patients on the extent of potential visual acuity impairment from their disease.     

Kinetics of visual field loss in Usher syndrome Type II

PURPOSE: To characterize the kinetics of visual field decay in Usher syndrome type II. METHODS: The area of 137 Goldmann visual fields (GVFs) delimited with the I4e and V4e targets was measured in each eye of 19 patients with an established diagnosis of Usher syndrome type II, and the average interocular GVF area for each patient at each time point was calculated. The average follow-up was 5.58 years. Symptomatic disease duration was defined as years elapsed after symptoms were first noted. The data set (n = 67 for the I4e target; n = 70 for the V4e target) was analyzed with a random coefficient mixed model to identify the best-fit model describing the decay of visual field size over time. The half-life of the residual visual field area (t(0.5)) was also calculated. RESULTS: The variable that best explained the decay of the GVF area was the duration of symptomatic disease. In an exponential model, the slope estimate for the natural log of the GVF area was -0.172 for the I4e target and -0.136 for the V4e target for each year of symptomatic disease. Accordingly, t(0.5) was approximately 4 years for the I4e target and 5 years for the V4e target. These estimates are very similar to those in previous studies of nonsyndromic retinitis pigmentosa (RP). CONCLUSIONS: This study suggests that the kinetics of GVF decline in Usher syndrome type II are, on average, very similar to other forms of RP and that, once the disease becomes symptomatic, GVF deterioration follows stereotyped kinetics, even in patients with late-onset retinal disease.     

Klinik, Diagnostik und Behandlungsoptionen des Usher-Syndroms

Usher syndrome denotes a clinically and genetically heterogeneous combination of retinitis pigmentosa and sensorineural deafness. The division into subtypes I, II, and III is based on the degree of hearing loss: Type I is characterized by deafness from birth together with ataxia and retarded motor development, type II by a stationary deafness of a moderate degree, and type III by a progressive deafness with adult onset. In Germany, Usher syndrome currently bears particular relevance because in January 2009 a new compulsory screening of auditory function in newborn infants was introduced. Consequently, it can be expected that a higher number of patients with Usher syndrome will be identified in early childhood and referred to ophthalmologists. The focus of this work is to introduce the typical clinical picture of Usher syndrome, summarize diagnostic options, and give an overview of therapeutic strategies.     

Visual Outcomes in Japanese Patients with Retinitis Pigmentosa and Usher Syndrome Caused by USH2A Mutations

Purpose: EYS and USH2A are the most common causative genes for retinitis pigmentosa (RP) in Japan. We determined the clinical outcomes for USH2A-related non-syndromic RP or Usher syndrome type II (USH2). Methods: Two non-syndromic RP and 11 USH2 patients with previously identified USH2A mutations were included. Their complete history and medical records were collected using standard procedures. Visual fields and acuity were compared with those of patients with EYS mutations. Clinical analyses were based on ophthalmic and otolaryngologic examinations. Results: In all patients, the fundus displayed changes typical of RP. Most patients showed relatively well-preserved visual acuity in their thirties or forties, with rapid deterioration in their fifties. Concentric constriction started in the twenties or thirties, and no effective residual visual field was observed after the fifties. Conclusions: The visual outcome for non-syndromic RP or USH2 patients with USH2A mutations is consistent with that for RP patients with EYS mutations.     

Usher syndrome associated with Fuchs’ heterochromic uveitis

Background

The purpose of this study is to report two new cases of Usher syndrome associated with Fuchs’ heterochromic uveitis (FHU), to confirm our previous observation of the association between FHU and retinitis pigmentosa (RP), and to evaluate if FHU is particularly associated with Usher syndrome.

Methods

Retrospective medical record review of all new RP cases at Hadassah Medical Center between the years 2000 and 2007, review of our previously published data, and a meta-analysis of published relevant articles in peer reviewed journals.

Results

During the time frame of the study we diagnosed 58 new cases of RP, of whom one male and one female had the typical findings of FHU, and both had Usher syndrome type II. The difference in the occurrence of FHU between the 616 controls and the patients with RP was significant (p?=?0.0073, Fisher's exact test). In our combined data, FHU occurred only in two types of RP; RP simplex with an incidence of 0.57%, and Usher syndrome with an incidence of 13.5%. This difference between the incidence of FHU in patients with Usher syndrome and other types of RP was significant (p?<?0.0001, Fisher's exact test). Adding up these two cases with what is already published in the literature makes up a total of 17 RP patients with coexisting FHU.

Conclusions

This study confirms the association between FHU and RP; and a particularly stronger association with Usher syndrome type II. Although infectious agents seem to play a role, the cause for this significant correlation is still unclear.     

A genetic analysis of retinitis pigmentosa.

Genetic analysis of 457 patients with retinitis pigmentosa (RP) included categorisation of families by recognised mendelian pattern of inheritance and formal segregation analysis of all informative sibships. Of the 368 probands a surprisingly high 18% (68) had significant congenital loss of hearing and were diagnosed as having Usher syndrome. The RP probands were categorised as: 21.7% autosomal dominant, 9.0% X-linked, 16.0% autosomal recessive, 3.3% genetic type uncertain, and 50.0% simplex. Segregation analysis reflected this high proportion of simplex cases, accounting for reduced penetrance in dominant families; only 20% remain classified as sporadic (possibly nongenetic). In the matings between normal persons estimates of the segregation ratio also indicate lower values than expected. Unlike in RP sibship, segregation in the Usher syndrome is consistent with the hypothesis of recessive inheritance. Therefore RP with significant hearing loss segregates as expected, while even if a proband is classified as a dominant or recessive the recurrence risk for the RP phenotype may be below mendelian expectation.     

Identification of Usher syndrome subtypes by ERG implicit time.

PURPOSE: Usher syndrome (US) is a recessively inherited disorder combining retinitis pigmentosa (RP) and a sensorineural hearing loss. The classification in subtypes is based mainly on auditory tests. The purpose of this study was to analyze implicit time (IT) differences in the electroretinogram (ERG) between RP alone, US I, and US II. METHODS: The data of 15 control subjects and of 15 patients with US I, 15 with US II, and 15 with RP with nonzero 33-Hz flicker ERG responses were analyzed. The ITs of three signal peaks (P1-P3) were evaluated. Sensitivity and specificity of a test to distinguish between US I and II based on timing differences were determined. Multifocal (mf)ERGs were used to assess differences in disease topography. RESULTS: Despite the similar amplitude loss with retinal eccentricity in the mfERG in all three groups, the peak delay in US I was negligible compared with that in US II and RP. In the flicker ERG data, US I and control subjects had almost identical peak times, and the same was true for subjects with US II and RP. Because of the slight overlap between US I and II, the diagnostic test achieved a sensitivity of 100% and a specificity of 93.3%. CONCLUSIONS: Substantial timing differences between US I and II and their usefulness for a diagnostic test were demonstrated. This finding may also be the basis for further investigations regarding the structural differences of retinal impairment between US I and II on a cellular level.     

Molecular updates on Usher syndrome

Usher syndrome (USH) is an autosomal recessive disorder characterized by the association of sensorineural hearing loss and retinitis pigmentosa (RP). Usher syndrome is both clinically and genetically heterogeneous. Three clinical subtypes are defined with respect to vestibular dysfunction and the degree of hearing loss. Type I (USH1) patients have profound hearing loss and vestibular dysfunction from birth. Type II (USH2) is the most frequent and patients tend to have less severe hearing impairment and normal vestibular response. Type III (USH3) is characterized by a progressive loss of hearing and is found more frequently among Finnish patients. Recently, major breakthroughs have been made in the molecular genetics of Usher syndrome as a number of chromosomal loci and causative genes have been identified in each clinical subtype. Twelve loci are known and the corresponding genes have been cloned for six of them. Although their functions are not always clearly established, a common role is emerging for the proteins identified within each subtype. As a result, each subtype could emanate from defects affecting distinct cellular mechanisms.     

Novel RPGR mutations with distinct retinitis pigmentosa phenotypes in French-Canadian families

PURPOSE: To characterize the molecular defects in two x-linked retinitis pigmentosa (RP) families. We hypothesized that different RPGR mutations result in distinct RP phenotypes. DESIGN: Observational case series. METHODS: Fifteen members in family I and three members in family II were evaluated. Full ophthalmic evaluations were done. Linkage analyses were performed and likelihood of odds scores (LOD score) were calculated. For mutation analyses, we used dHPLC and automated sequencing. RESULTS: Two novel RPGR mutations were identified in the two families; a Glu 414 (2-bp del) frameshift mutation in family I and an IVS 2-1 (g to a) splice site mutation in family II. All male family members in family I were severely affected by RP but maintained central visual acuities until their 50s and did not develop a bull's eye maculopathy. The female phenotype was highly variable. Some of the carriers exhibited a severe phenotype, one female displayed an asymmetric phenotype, and other carriers were asymptomatic. All members with the RPGR frameshift mutation exhibited rod-cone electroretinograms abnormalities, whereas five members had hearing loss. Male members of family II were severely affected, with early visual acuity loss, central scotomas, and bull's eye maculopathy. The female family members were asymptomatic but displayed cone-rod electroretinograms changes. There was no hearing loss. CONCLUSIONS: Different RPGR mutations lead to distinct RP phenotypes, with a highly variable inter- and intrafamilial phenotypic spectrum of disease that is associated with the type of mutation in RPGR and nonrandom X chromosome inactivation, respectively.     

Coats-like lesions in Usher syndrome type II

Background An unusual case of Usher syndrome type II associated with bilateral Coats-like exudative retinopathy is described.Methods A 14-year-old boy with congenital sensorineural deafness and normal vestibular functions presented with a recent history of night blindness. He was followed for 3 years with fundus photography, intravenous fluorescein angiography, electroretinography and audiometric testings. His parents refused any form of treatment.Results Fundoscopy showed bilateral retinitis pigmentosa and a single focus of subretinal exudation and overlying telangiectatic retinal vessels inferotemporal to the vascular arcade in the right eye. He had bilateral mild macular edema. A year later, a similar lesion developed inferotemporally in the left fundus. Electroretinography responses, particularly the rod-mediated signals, were significantly reduced. Audiometric studies documented hearing loss in high frequencies. His visual acuity declined from 20/40 to 20/80 RE and from 20/80 to 20/100 LE during follow-up. No new lesions developed.Conclusions Coats-type exudative lesions may develop in patients with Usher syndrome type II. Although left untreated, only a minimal increase in exudation occurred over 3 years.     

The retinal ciliopathies

While the functions of many of the proteins located in or associated with the photoreceptor cilia are poorly understood, disruption of the function of these proteins may result in a wide variety of phenotypes ranging from isolated retinal degeneration to more pleiotropic phenotypes. Systemic findings include neurosensory hearing loss, developmental delay, situs-inversus, infertility, disorders of limb and digit development, obesity, kidney disease, liver disease, and respiratory disease. The concept of "retinal ciliopathies" brings to attention the importance of further molecular analysis of this organelle as well as provides a potential common target for therapies for these disorders. The retinal ciliopathies include retinitis pigmentosa, macular degeneration, cone-dystrophy, cone-rod dystrophy, Leber congenital amaurosis, as well as retinal degenerations associated with Usher syndrome, primary ciliary dyskinesia, Senior-Loken syndrome, Joubert syndrome, Bardet-Biedl syndrome, Laurence-Moon syndrome, McKusick-Kaufman syndrome, and Biemond syndrome. Mutations for these disorders have been found in retinitis pigmentosa-1 (RP1), retinitis pigmentosa GTPase regulator (RPGR), retinitis pigmentosa GTPase regulator interacting protein (RPGR-IP), as well as the Usher, Bardet-Biedl, and nephronophthisis genes. Other systemic disorders associated with retinal degenerations that may also involve ciliary abnormalities include: Alstrom, Edwards-Sethi, Ellis-van Creveld, Jeune, Meckel-Gruber, Orofaciodigital Type 9, and Gurrieri syndromes. Understanding these conditions as ciliopathies may help the ophthalmologist to recognize associations between seemingly unrelated diseases and have a high degree of suspicion that a systemic finding may be present.     

Phenotypes in Defined Genotypes Including Siblings with Usher Syndrome

Objective: To characterize visual function in defined genotypes including siblings with Usher syndrome.

Methods: Thirteen patients with phenotypically different subtypes of Usher syndrome, including 3 families with affected siblings, were selected. Genetic analysis and ophthalmological examinations including visual fields, full-field electroretinography (ERG), multifocal electroretinography (mf ERG), and optical coherence tomography (OCT) were assessed. The patients’ degree of visual handicap was evaluated by a questionnaire (ADL).

Results: Twelve of thirteen patients were genotyped as Usher 1B, 1D, 1F, 2A, 2C or 3A. In 12 of 13 patients examined with ERG the 30 Hz flickering light response revealed remaining cone function. In 3 of the patients with Usher type 1 mf ERG demonstrated a specific pattern, with a sharp distinction between the area with reduced function and the central area with remaining macular function and normal peak time. OCT demonstrated loss of foveal depression with distortion of the foveal architecture in the macula in all patients. The foveal thickness ranged from 159 to 384?µm and was not correlated to retinal function. Three siblings shared the same mutation for Usher 2C but in contrast to previous reports regarding this genotype, 1 of them diverged in phenotype with substantially normal visual fields, almost normal OCT and mf ERG findings, and only moderately reduced rod and cone function according to ERG.

Conclusions: Evaluation of visual function comprising both the severity of the rod cone degeneration and the function in the macular region confirm phenotypical heterogeneity within siblings and between different genotypes of Usher syndrome.     

Charles Bonnet plus syndrome: apropos of a case

Purpose. Charles Bonnet syndrome plus is an exceedingly rare variant of this disorder. The variant has been described in patients with sight impairment and severe hypoacusis, and is usually characterized by complex visual and auditory-musical-hallucinations that the patients recognize as unreal. Method. Case report. Results. A 75-year-old woman diagnosed with Usher syndrome presented with visual acuity of light perception in both eyes, which did not improve with the use of a pinhole occluder. She also had coptosis in right ear and severe hypoacusis in left ear, confirmed through audiometry. Audiometric tests were normal once the implant and the hearing aid were connected. The patient was referred to the Neuro-Ophthalmology Unit after recounting experiencing complex visual hallucinations, as well as auditory (musical) ones at night after disconnecting the hearing aid. She described the latter as a nightly occurrence of hearing "cabaret music." Nevertheless, she was aware of reality and of her sensory impairments. The patient was diagnosed at the interdisciplinary Neuro-Ophthalmology Unit, and began pharmacologic treatment with clear improvement. Conclusions: Knowledge of Charles Bonnet syndrome and in particular of Charles Bonnet syndrome plus-due to its infrequency-on the part of ophthalmologists is fundamental to adequately diagnose and treat this rare disorder.     

Natural course of visual field loss in patients with Type 2 Usher syndrome

PURPOSE: To evaluate the natural course of visual field loss in patients with Type 2 Usher syndrome and different patterns of visual field loss. METHODS: Fifty-eight patients with Type 2 Usher syndrome who had at least three visual field measurements during a period of at least 3 years were studied. Kinetic visual fields measured on a standard calibrated Goldmann perimeter with II4e and V4e targets were analyzed. The visual field areas in both eyes were determined by planimetry with the use of a digitalizing tablet and computer software and expressed in square inches. The data for each visual field area measurement were transformed to a natural log unit. Using a mixed model regression analysis, values for the half-life of field loss (time during which half of the remaining field area is lost) were estimated. Three different patterns of visual field loss were identified, and the half-life time for each pattern of loss was calculated. RESULTS: Of the 58 patients, 11 were classified as having pattern type I, 12 with pattern type II, and 14 with pattern type III. Of 21 patients whose visual field loss was so advanced that they could not be classified, 15 showed only a small residual central field (Group A) and 6 showed a residual central field with a peripheral island (Group B). The average half-life times varied between 3.85 and 7.37 for the II4e test target and 4.59 to 6.42 for the V4e target. There was no statistically significant difference in the half-life times between the various patterns of field loss or for the test targets. CONCLUSION: The average half-life times for visual field loss in patients with Usher syndrome Type 2 were statistically similar among those patients with different patterns of visual field loss. These findings will be useful for counseling patients with Type 2 Usher syndrome as to their prognosis for anticipated visual field loss.     

The ophthalmological course of Usher syndrome type III

Usher syndrome is a recessive hereditary disease group with clinical and genetical heterogeneity leading to handicapped hearing and visual loss until middle age. It is the most common cause for deaf-blindness. Three distinct phenotypes and five distinct genotypes are already known. In Finland the distribution of known Usher types is different than elsewhere. Usher syndrome type III (USH3) is common in Finland and it is thought to include 40% of patients. Progressive hearing loss is characteristic of USH3. Elsewhere USH3 has been regarded as a rarity covering only several percent of the whole Usher population. The aim of this paper is to describe, for the first time, the course of visual handicap and typical refractive errors in USH3 and compare it with other USH types. From a total patient sample consisting of 229 Finnish USH patients, 200 patients' visual findings were analyzed in a multicenter retrospective follow-up study. The average progress rate during a 10-year follow-up period in different USH types was similar. The essential progress occurred below the age of 40 and was continuous up to that age. Visual acuity dropped below 0.05 (severely impaired) at the age of 37 and the visual fields were of tubular shape without any peripheric islands at the average age of 30. Clinically significant hypermetropia with astigmatism seems to be a pathognomonic clinical sign of USH3.     

Evaluation of the Night Vision Spectacles on patients with impaired night vision

· Background: The Night Vision Spectacles (NiViS) were developed by a consortium of European companies to assist individuals who suffer from impaired night vision. They consist of a head-mounted video camera (input) and binocular displays (output) connected to a portable computer processor, which uses an algorithm to enhance the luminance and contrast of the video image. · Methods: Eighteen patients with impaired night vision were tested, including those with retinitis pigmentosa (7), Usher syndrome (2), fundus albipunctatus (1) and complete (4) and incomplete (4) congenital stationary night blindness. Normal trichromats (3) and typical, complete achromats (2) acted as controls. A battery of tests assessed: visual acuity at 5 m (projection unit) and 1 m (chart) and at high and low contrasts; contrast sensitivity; absolute and increment threshold; the influence of glare; contrast motion detection; and hand-eye performance. The tests were performed, with and without the NiViS, at three adaptation levels: low scotopic (10^–3 cd/m²), high scotopic (10^–2 cd/m²) and mesopic (10^–1 cd/m²). · Results: At the low and high scotopic levels, the majority of patients showed improved performance on the visual acuity, contrast sensitivity and motion contrast tests with the NiViS. At the mesopic level, the advantage with the NiViS was greatly reduced, but still present for contrast sensitivity. · Conclusion: Patients with impaired night vision can benefit from the NiViS when performing tasks involving contrast and motion perception. Those with normal visual fields and retaining good photopic vision will benefit more than those with constricted visual fields and impaired cone vision. Recommendations regarding desirable improvements of the NiViS and suitability for the individual patient are given. Received: 31 March 1998 Revised version received: 8 June 1998 Accepted: 9 June 1998     

Combination of retinitis pigmentosa and hearing loss caused by a novel mutation in PRPH2 and a known mutation in GJB2: Importance for differential diagnosis of Usher syndrome

Purpose of this study was to molecularly characterize a family in which two brothers (46 and 36 years) presented with a combination of retinitis pigmentosa (RP) and severe sensorineural hearing loss while father and sister (71 and 41 years) presented with isolated RP. Retinal phenotype was compared with phenotype of 17 patients with Usher syndrome type 1. Ophthalmological examination included assessment of Snellen visual acuity, color vision with Ishihara tables, Goldmann perimetry (targets II/1–4) and microperimetry. Fundus autofluorescence imaging and optical coherence tomography were performed. Direct sequencing of all coding exons and flanking intronic sequences of GJB2 (gap junction protein, beta 2) and PRPH2 (peripherin 2) genes was performed in younger brother. Other family members were analyzed with sequencing (GJB2), high resolution melt analysis (GJB2) or restriction enzymes (PRPH2). Brothers with hearing loss were found to carry a homozygous c.35delG mutation in GJB2, the most common mutation associated with recessive hearing loss. All patients were found to carry a novel heterozygous mutation c.389T > C (p.Leu130Pro) on PRPH2. Age of onset was higher in PRPH2 than USH1 patients, however with some overlap. Differentiation from retinal phenotype of USH1 could only be made in the oldest patient, who retained good central visual function after more than three decades of disease.