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The Usher syndromes are genetically distinct disorders which share specific phenotypic characteristics. This paper describes a set of clinical criteria recommended for the diagnosis of Usher syndrome type I and Usher syndrome type II. These criteria have been adopted by the Usher Syndrome Consortium and are used in studies reported by members of this Consortium.
Usher syndrome is an autosomal-recessive disorder manifested by hearing impairment, retinitis pigmentosa (RP), and variable vestibular deficit. Recent progress in the characterization of the genetics of Usher syndrome has shown that this disorder is phenotypically and genetically complex. This progress impacts the approach of the clinicians in the study of patients who may potentially have Usher syndrome. There are three major phenotypic classes: Usher I, II, and III. Usher I is distinguished from Usher II by having a more severe audiologic involvement and by the presence of vestibular areflexia. Usher III has a progressive hearing loss with variable vestibular involvement. A minimum of three genes have been identified as being responsible for Usher I; two have been identified as being responsible for Usher II. It is not yet clear whether other manifestations such as progressive hearing loss, associated mental retardation, or other physical anomalies are associated with the known Usher genes or whether they represent as yet undiscovered genetic disorders. As progress towards the identification of the Usher genes is made, the clinician will gradually gain new and effective diagnostic procedures for the identification and delineation of the Usher syndromes.
Usher syndrome is a congenital autosomal dominant inherited disease characterised by hearing, balance and vision problems. The aim of the work was an evaluation of hearing and vestibular organ in the chosen group of patients with Usher syndrome diagnosed. Material consisted of 10 persons (5 males and 5 females) aged from 16 to 46 years with Usher syndrome diagnosed. All the patients have been in constant ENT and Ophthalmology Clinics' care. Complex hearing and balance organ, including posturography, as well as complex ophthalmologic examination were performed in each case. Medium or severe perceptive cochlear hearing loss, proper function of vestibular organ and slight elevation of stabilograms parameters were found in 6 cases. In 4 cases there were severe bilateral hearing loss, lack of vestibular function and considerable worsening of stabilograms parameters. In ophthalmologic examination in all the cases there was bilateral symmetrical dystrophy of the retina of various intensification. We concluded that hearing and balance organ examination in Usher syndrome can state accessory diagnostic aspect that might help to distinguish subtypes of the syndrome. In this way audiologic and otoneurologic tests could help to define prognosis of the disease in the individual cases. A necessity of close co-operation of genetics, ophthalmologists and ENT doctors as well as psychologists was stressed.
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.
Usher syndrome is an autosomal recessively inherited disease, characterised by sensorineural hearing loss, tapetoretinal degeneration and in some cases vestibular problems. Based on the clinical heterogeneity, the disease can be classified into three clinical types (I, II and III), which have their own genetic subtypes (Usher 1A-Usher IG, Usher 2A-Usher 2C and Usher 3). The majority of the Usher type I cases are caused by mutations in the MYO7A gene (Usher 1B) while mutations in the USH2A gene (Usher 2A) are the cause of most cases of type II. Usher syndrome type III, caused by mutations in the USH3 gene, is frequently seen only in Finland.
PURPOSE: To evaluate visual impairment in Usher syndrome 1b (USH1b) and Usher syndrome 2a (USH2a). METHODS: We carried out a retrospective study of 19 USH1b patients and 40 USH2a patients. Cross-sectional regression analyses of the functional acuity score (FAS), functional field score (FFS) and functional vision score (FVS) related to age were performed. Statistical tests relating to regression lines and Student's t-test were used to compare between (sub)groups of patients. Parts of the available individual longitudinal data were used to obtain individual estimates of progressive deterioration and compare these to those obtained with cross-sectional analysis. Results were compared between subgroups of USH2a patients pertaining to combinations of different types of mutations. RESULTS: Cross-sectional analyses revealed significant deterioration of the FAS (0.7% per year), FFS (1.0% per year) and FVS (1.5% per year) with advancing age in both patient groups, without a significant difference between the USH1b and USH2a patients. Individual estimates of the deterioration rates were substantially and significantly higher than the cross-sectional estimates in some USH2a cases, including values of about 5% per year (or even higher) for the FAS (age 35-50 years), 3-4% per year for the FFS and 4-5% per year for the FVS (age > 20 years). There was no difference in functional vision score behaviour detected between subgroups of patients pertaining to different biallelic combinations of specific types of mutations. CONCLUSIONS: The FAS, FFS and FVS deteriorated significantly by 0.7-1.5% per year according to cross-sectional linear regression analysis in both USH1b and USH2a patients. Higher deterioration rates (3-5% per year) in any of these scores were attained, according to longitudinal data collected from individual USH2a patients. Score behaviour was similar across the patient groups and across different biallelic combinations of various types of mutations. However, more elaborate studies, preferably covering longitudinal data, are needed to obtain conclusive evidence.
Bardet-Biedl syndrome (BBS) and Usher syndrome (USH) are the most prevalent syndromic forms of retinitis pigmentosa (RP), together they make up almost a quarter of the patients with RP. BBS is defined by the association of retinopathy, obesity, hypogonadism, renal dysfunction, postaxial polydactyly and mental retardation. This clinically complex syndrome is genetically heterogeneous with linkage to more than 6 loci, and 4 genes have been cloned so far. Recent molecular data present evidence that, in some instances, the clinical manifestation of BBS requires recessive mutations in 1 of the 6 BBS loci plus one or two additional mutations in a second BBS locus (tri- or tetra-allelic inheritance). USH is characterized by the combination of congenital or early-onset sensorineural deafness, RP, and variable degrees of vestibular dysfunction. Each of the three clinical types is genetically heterogeneous: 7 loci have been mapped for type 1, three loci for type 2, and two loci for type 3. Currently, 6 USH genes (MYO7A, USH1C, CDH23, PCDH15, USH2A, USH3) have been identified. Pathogenetically, mutations of the USH1 genes seem to result in defects of auditory and retinal sensory cells, the USH 2 phenotype is caused by defects of extracellular matrix or cell surface receptor proteins, and USH3 may be due to synaptic disturbances. The considerable contribution of syndromic forms of RP requires interdisciplinary approaches to the clinical and diagnostic management of RP patients.
Usher Syndrome Type 1 is an autosomal recessive disease characterized by profound congenital hearing impairement and vestibular dysfunction followed by the onset of retinitis pigmentosa in childhood or early adolescence. Members of the Usher Syndrome Consortium, whose objective is to locate and isolate the genes for Usher syndrome, have pooled linkage data from 36 families with 111 affected individuals. We report the analysis of 206 blood group, protein, and DNA marker polymorphisms. No evidence of linkage heterogeneity among families was found for any of the markers studied; the negative lod scores exclude the locus for this disease from about 39% of the genome. Our results indicate the regions of the genome to which our continuing efforts should be directed.
Usher syndrome type I (USH1), the most severe form of this syndrome, is characterized by profound congenital sensorineural deafness, vestibular dysfunction, and retinitis pigmentosa. At least seven USH1 loci, USH1A-G, have been mapped to the chromosome regions 14q32, 11q13.5, 11p15, 10q21-q22, 21q21, 10q21-q22, and 17q24-25, respectively. Mutations in five genes, including MYO7A, USH1C, CDH23, PCDH15 and SANS, have been shown to be the cause of Usher syndrome type 1B, type 1C, type 1D, type 1F and type 1G, respectively. In the present study, we carried out a systematic mutation screening of these genes in USH1 patients from USA and from UK. We identified a total of 27 different mutations; of these, 19 are novel, including nine missense, two nonsense, four deletions, one insertion and three splicing defects. Approximatelly 35-39% of the observed mutations involved the USH1B and USH1D genes, followed by 11% for USH1F and 7% for USH1C in non-Acadian alleles and 7% for USH1G. Two of the 12 MYO7A mutations, R666X and IVS40-1G > T accounted for 38% of the mutations at that locus. A 193delC mutation accounted for 26% of CDH23 (USH1D) mutations, confirming its high frequency. The most common PCDH15 (USH1F) mutation in this study, 5601-5603delAAC, accounts for 33% of mutant alleles. Interestingly, a novel SANS mutation, W38X, was observed only in the USA cohort. The present study suggests that mutations in MYO7A and CDH23 are the two major components of causes for USH1, while PCDH15, USH1C, and SANS are less frequent causes.
BACKGROUND: Usher syndrome, a combination of retinitis pigmentosa (RP) and sensorineural hearing loss with or without vestibular dysfunction, displays a high degree of clinical and genetic heterogeneity. Three clinical subtypes can be distinguished, based on the age of onset and severity of the hearing impairment, and the presence or absence of vestibular abnormalities. Thus far, eight genes have been implicated in the syndrome, together comprising 347 protein-coding exons. METHODS: To improve DNA diagnostics for patients with Usher syndrome, we developed a genotyping microarray based on the arrayed primer extension (APEX) method. Allele-specific oligonucleotides corresponding to all 298 Usher syndrome-associated sequence variants known to date, 76 of which are novel, were arrayed. RESULTS: Approximately half of these variants were validated using original patient DNAs, which yielded an accuracy of >98%. The efficiency of the Usher genotyping microarray was tested using DNAs from 370 unrelated European and American patients with Usher syndrome. Sequence variants were identified in 64/140 (46%) patients with Usher syndrome type I, 45/189 (24%) patients with Usher syndrome type II, 6/21 (29%) patients with Usher syndrome type III and 6/20 (30%) patients with atypical Usher syndrome. The chip also identified two novel sequence variants, c.400C>T (p.R134X) in PCDH15 and c.1606T>C (p.C536S) in USH2A. CONCLUSION: The Usher genotyping microarray is a versatile and affordable screening tool for Usher syndrome. Its efficiency will improve with the addition of novel sequence variants with minimal extra costs, making it a very useful first-pass screening tool.
PURPOSE: Usher syndrome is an autosomal recessive disease associating retinitis pigmentosa and neurosensory deafness. Three clinical types (USH1, USH2, USH3) and 11 mutated genes or loci have been described. Mutations in MYO7A and USH2A are responsible for about 40% and 60% of Usher syndromes type 1 and 2, respectively. These genes were screened in a series of patients suffering from Usher syndrome. METHODS: We performed SSCP screening of MYO7A in 12 unrelated patients suffering from Usher syndrome type 1 (USH1) and USH2A in 28 unrelated patients affected by Usher syndrome type 2 (USH2). RESULTS/CONCLUSIONS: Six mutations in MYO7A were found in five patients, including two novel mutations c.397C > G (His133Asp) and 1244-2A > G (Glu459Stop), accounting for 42% of our USH1 patients. Twelve mutations in USH2A were found in 11 patients, including four new mutations c.850delGA, c.1841-2A > G, c.3129insT, and c.3920C > G (Ser1307Stop), accounting for 39% of our USH2 patients
Usher syndrome type I is the most severe form of Usher syndrome. It is an autosomal recessive disorder characterized by profound congenital sensorineural deafness, retinitis pigmentosa, and vestibular abnormalities. Mutations in the myosin VIIA gene (MYO7A) are responsible for Usher syndrome type 1B (USH1B). This gene is thought to bear greatest responsibility for USH1 and, depending on the study, has been reported to account for between 24% and 59% of USH1 cases. In this report a mutation screening of the MYO7A gene was carried out in a series of 48 unrelated USH1 families using single strand conformation polymorphism analysis (SSCP) and direct sequencing of those fragments showed an abnormal electrophoretic pattern. Twenty-five mutations were identified in 23 out of the 48 families studied (47.9%). Twelve of these mutations were novel, including five missense mutations, three premature stop codons, three frameshift, and one putative splice-site mutation. Based on our results we can conclude there is an absence of hot spot mutations in the MYO7A gene and that this gene plays a major role in Usher syndrome.
Clinical and genetic characteristics are presented of 2 patients from a Dutch Usher syndrome type III family who have a new homozygous USH3 gene mutation: 149-152delCAGG + insTGTCCAAT. One individual (IV:1) is profoundly hearing impaired and has normal vestibular function and retinitis punctata albescens (RPA). The other individual is also profoundly hearing impaired, but has well-developed speech, vestibular areflexia, and retinitis pigmentosa sine pigmento (RPSP). These findings suggest that Usher syndrome type III can be clinically misdiagnosed as either Usher type I or II; that Usher syndrome patients who are profoundly hearing impaired and have normal vestibular function should be tested for USH3 mutations; and that RPA and RPSP can occur as fundoscopic manifestations of pigmentary retinopathy in Usher syndrome.
BACKGROUND: Usher syndrome is a genotypically and phenotypically heterogeneous group of autosomal recessive diseases featuring retinitis pigmentosa (RP) and sensorineural hearing loss. A general ciliary dysfunction has been suspected following reports of a mutated cytoskeletal protein (myosin VIIA) in type IB, and preliminary data has suggested an olfactory deficit. The purpose of this study was to quantitatively assess olfactory function in Usher syndrome patients and to search for a correlation between the degree of impairment of the three sensory systems as indication of an underlying ciliary defect. METHODS: 39 patients with Usher syndrome (8 type I, 31 type II) were examined. The ophthalmologic protocol included patient history, visual acuity, eye morphology, Goldmann perimetry, and electroretinography. The ENT protocol included a thorough examination, speech-recognition test, pure-tone audiometry and an olfactory function test. RESULTS: In both groups, visual acuity was typically 20/40, the remaining visual field area was small, and the ERG responses were low to non-detectable. Average hearing loss was 100% in type I and 40% in type II. Olfactory thresholds were normal [median 9.7 (I) and 8.5 (II) vs. 8.5 in the control group]. There were multiple significant correlations between parameters of the same organ, but no relationship between parameters of different sensory systems. CONCLUSION: Almost all Usher syndrome patients in this study had an advanced form of RP. In contrast, auditory function differed considerably between type I and type II. An impairment of the olfactory system could not be detected, and there was no correlation between parameters representing visual function, hearing ability, and olfactory sense.
The Usher syndrome, an autosomal recessive deafness and blindness, is genetically and clinically heterogeneous. In the past 4 years, genes mutated in Usher syndrome type Ib and type IIa have been described. The Usher Ib gene encodes the motor protein myosin VIIa and was identified as the human homolog of the mouse shaker-1 gene. The Usher type IIa gene was identified by positional cloning and encodes a protein with homology to extracellular matrix proteins and cell adhesion molecules. This review summarizes the current knowledge regarding both the genetic and molecular aspects of Usher syndrome in the context of recent scientific advances in the areas of sensorineural deafness and retinitis pigmentosa.
Usher syndrome type I (US1) is an autosomal recessive condition in which three different genes have been already localised (USH1A, USH1B, and USH1C on chromosomes 14q32, 11q13, and 11p15 respectively). The genetic heterogeneity of US1 has been confirmed in a previous study by linkage analysis of 20 French pedigrees. Here, we report the genetic exclusion of the three previously reported loci in two large multiplex families of Moroccan and Pakistani origin, suggesting the existence of at least a fourth locus in Usher syndrome type I.
The USH2A gene is mutated in patients with Usher syndrome type IIa, which is the most common subtype of Usher syndrome and is characterized by hearing loss and retinitis pigmentosa. Since mutation analysis by DNA sequencing of exons 1-21 revealed only ~63% of the expected USH2A mutations, we searched for so-far-uncharacterized exons of the gene. We identified 51 novel exons at the 3' end of the gene, and we obtained indications for alternative splicing. The putative protein encoded by the longest open reading frame harbors, in addition to the known functional domains, two laminin G and 28 fibronectin type III repeats, as well as a transmembrane region followed by an intracellular domain with a PDZ-binding domain at its C-terminal end. Semiquantitative expression profile analysis suggested a low level of expression for both the long and the short isoform(s) and partial overlap in spatial and temporal expression patterns. Mutation analysis in 12 unrelated patients with Usher syndrome, each with one mutation in exons 1-21, revealed three different truncating mutations in four patients and two missense mutations in one patient. The presence of pathogenic mutations in the novel exons indicates that at least one of the putative long isoforms of the USH2A protein plays a role in both hearing and vision.
Usher syndrome is an autosomal recessive disorder characterised by retinitis pigmentosa and congenital sensorineural hearing loss. A gene for Usher syndrome type II (USH2) has been localised to chromosome 1q32-q41. DNA from a family with four of seven sibs affected with clinical characteristics of Usher syndrome type II was genotyped using markers spanning the 1q32-1q41 region. These included D1S70 and D1S81, which are believed to flank USH2. Genotypic results and subsequent linkage analysis indicated non-linkage of this family to these markers. The A test analysis for heterogeneity with this family and 32 other Usher type II families was statistically significant at p < 0.05. Further clinical evaluation of this family was done in light of the linkage results to determine if any phenotypic characteristics would allow for clinical identification of the unlinked type. No clear phenotypic differences were observed; however, this unlinked family may represent a previously unreported subtype of Usher type II characterised by a milder form of retinitis pigmentosa and mild vestibular abnormalities. Heterogeneity of Usher syndrome type II complicates efforts to isolate and clone Usher syndrome genes using linkage analysis and limits the use of DNA markers in early detection of Usher type II.