Usher syndrome

Usher syndrome (USH) is characterized by hearing impairment, progressive vision loss due to retinitis pigmentosa (RP) and, in some cases, by vestibular dysfunction. It is inherited as an autosomal recessive trait and is the most frequent cause of combined deaf-blindness in humans.

One of the earliest descriptions of this syndrome was given by Dr Albrecht von Graefe who identified the disease among Jewish people in Berlin in 1858. The disease was later named after Dr Charles Usher, a Scottish ophthalmologist who described in 1914 the hereditary nature of the disorder in 19 cases out of 69 patients with retinitis pigmentosa.

Usher syndrome is clinically and genetically heterogeneous. Though the disease is defined by congenital bilateral deafness and a later onset of visual field loss, symptoms vary from person to person and progress at different rates. Balance may also be affected. At least 12 chromosomal loci have been identified so far and assigned to three major clinical types: USH1, USH2 and USH3. Depending on the causative genes, USH1 is further divided into distinct subtypes, designated as types 1B through 1H ( see Table 1). Three genes have been assigned to USH2 (corresponding to three genetic subtypes USH2A, C, D respectively). Recently, a role of PDZD7 as either contributor to digenic disease or modifier of retinal disease expression in Usher syndrome has been suggested. USH3 has at least two genetic forms, but only one causative gene has been identified so far.

Table 1: Usher syndrome subtypes, genes and proteins

Epidemiology

Usher syndrome affects many ethnic groups and has a prevalence of about one in 20,000 in the Caucasian population. It is thought to be responsible for 3-6% of all childhood deafness and about 50% of combined deaf-blindness in adults.

The prevalence of Usher syndrome in persons of Scandinavian descent has been estimated at around 1:29,000. Usher syndrome affects about one in 23,000 in the U.S. and one in 12,500 in Germany. The prevalence of Usher syndrome in Heidelberg (Germany) and its suburbs has been calculated to be 1:16,000, with a ratio of type 1 to type 2 of 1:3.

Usher syndrome types 1 and 2 are the most common forms. Together, they account for approximately 90-95% of all cases. USH 1 is estimated to occur in at least 1 per 25,000 people. As the genetic causes differ, some subtypes are more common than others, e.g. USH 1B is the most common form of USH type 1 accounting for over 40% of all cases, while USH1D appears to be responsible for about 25% of all cases. Subtype 1C seems more common among French Acadians in Louisiana (USA), e.g. the c.216G>A mutation in USH1C accounts for virtually all USH1 cases in this population. Only a few cases of USH 1F and 1G have been reported. A form of USH 1F may be more common among people with Jewish ancestry, e.g. the c.733C>T (p.R254X) mutation in the PCDH15 gene is present in up to 60% of USH1 families of Ashkenazi origin. The exact prevalence of USH type 2 is currently unknown. USH2A mutations (c.2299delG) are involved in 55%-90% of all USH2 cases and account for more than 60% of all pathogenic alleles in Jewish families of non-Ashkenazi descent. A predominant USH2A founder mutation (c.4338_4339delCT) in Quebec French-Canadians has recently been identified. In most populations, type 3 accounts for a very small proportion of all Usher cases (only 1-6% of all Usher syndrome cases). Due to a founder effect, type 3 is more common in the Finnish population and in Ashkenazi Jews where it accounts for about 40% of all cases, as against 2% in most other countries. USH3 was reported to account for 20% of the USH cases in the city of Birmingham (United Kingdom).

Clinical features

Depending on the severity and progression of the hearing impairment, and the age of onset of RP that develops in all types of Usher syndrome, three clinical subtypes are distinguished and designated as types 1, 2, and 3 (Table 2).

Usher syndrome type 1

Usher syndrome type 1 is the most severe form of the disease that is characterized by congenital, bilateral, severe-to-profound sensorineural hearing impairment (Table 2). As patients are typically profoundly deaf from birth, they do not develop speech, unless fitted with a cochlear implant. In some cases the hearing loss becomes profound and severe within the first year of life. Vestibular areflexia affecting the balance is present and results in retarded motor development. Children begin sitting independently later than usual and typically walk later, at age approximately 24 months. Older children experience frequent accidental injuries due to impaired balance or have difficulty with activities and sports requiring balance. Progressive vision loss caused by RP becomes apparent in childhood, almost always by age around 10 years. However, in children older than 4 years who present with association of bilateral hearing impairment and vestibular deficit, the electroretinogram (ERG) may reveal vision abnormalities and serve as a helpful tool for early diagnosis of Usher syndrome. The visual deficit manifests with difficulty seeing at night and progressively constricted visual fields (for detailed information, see the Chapter on retinitis pigmentosa). At age of 30-40 years, patients with USH1 usually have visual field of 5-10 degrees or less. However, "typical" patients with USH1 usually do not become completely blind. Cataracts and macular edema may develop later in life. Histopathologic features of USH type 1 include degeneration of the organ of Corti and cochlear nerve, decrease in cochlear ganglion cell number, and sometimes degeneration of the inferior vestibular nerve.

Further subdivision of Usher syndrome type 1 is based on genetic criteria and some clinical variations, e.g. some USH1 patients exhibit less severe dysfunction of the vestibular system. Usher syndrome type 1 includes the following genetic forms: USH1B, USH1C, USH1D, USH1E, USH1F, USH1G, USH1H (Table 1).

Usher syndrome type 2

Usher syndrome type 2 is the most common subtype and, in general, is less severe (Table 2). It is characterized by congenital bilateral sensorineural hearing loss that predominantly affects high tones (mild-to-moderate in the low frequencies and severe-to-profound in the higher frequencies). Speech perception may decrease over time and the hearing loss may be perceived as progressing, with characteristic 'sloping' audiogram. The degree of hearing loss varies significantly within and among the affected families. Subtle variations within the hearing phenotype of USH type 2 have been reported, mostly regarding the rate of hearing impairment. The latter is considered as stationary and non-progressive, or at least progressing with a much slower rate than that reported for USH type 3. Most of the children with USH type 2 have good oral communication skills. The onset of RP can be during or after puberty, with typical manifestations of night blindness and constricted visual fields (tunnel vision), and eventually decreased central visual acuity. The rate and degree of vision loss vary within and among families but usually tends to progress more slowly than in type 1. Unlike other forms of Usher syndrome, vestibular function is normal and children walk at the normal age of 10 to 14 months. Tooth enamel defects have been reported in some children with USH type 2 (and in single cases of USH type 1).

Usher syndrome type 2 includes the following genetic forms: USH2A (accounting for over 80% of all USH type 2 cases), USH2C, USH2D (Table 1).

Usher syndrome type 3

Unlike the other forms of Usher syndrome, in USH type 3 the hearing and the vestibular function at birth are normal (or near-normal) (Table 2). Hearing loss typically begins during the first two decades of life, after the development of speech, and worsens over time (progressive hearing impairment). By middle age, most affected individuals are profoundly deaf. The onset of RP may vary, but in most cases occurs in late childhood to early adulthood. By mid adulthood, these patients are usually blind. Vestibular function may deteriorate with time and balance may be affected in about half of USH type 3 patients.

Additional features

In some cases, vision is further impaired by cataracts (reported in some USH1 patients), macular edema or central macular atrophy. Several studies indicate that Usher syndrome can also be associated with reduced odor identification (reported in some USH1 and USH2 patients), lower sperm motility, pigmentary glaucoma, mental deficiency, cerebral atrophy and ataxia.

Table 2: Clinical manifestations of Usher syndrome

Etiology & pathogenesis

Causative genes

The first gene for Usher syndrome was discovered in 1995. At present, more than 150 pathogenic mutations for the most common molecular forms USH1B and USH2A have been identified. In all genes implicated in the etiology of Usher syndrome, the disease causing mutations include missense, nonsense, frameshift, splice-site as well as deletions distributed across nearly all exons.

Usher syndrome type 1 is genetically heterogeneous. On the basis of the mutations in genes at five different loci, it is subdivided into USH1B (OMIM 276900), USH1C (OMIM 276904), USH1D (OMIM 601067), USH1F (OMIM 602083), and USH1G (OMIM 606943) (Table 1). Two additional loci associated with Usher syndrome type 1 have been mapped at 21q21 (USH1E, OMIM 602097) and 15q22-q23 (USH1H, OMIM 612632). The USH1A locus does not exist; six of the nine families from the Bressuire region of France originally reported to map at this locus have been found to have mutations in MYO7A (USH1B).

Usher syndrome type 2 is also subdivided into subtypes: USH2A (OMIM 276901), USH2B (it has recently been shown that USH2B locus at chromosome 3p23-24.2 does not exist), USH2C (OMIM 605472, formerly USH2B), and USH2D (OMIM 611383), (Table 1). Mutations in USH2A (USH2A), GPR98/VLGR1 (USH2C) and WHRN (USH2D) account for approximately 80%, 15% and 5% of USH2 cases, respectively.

Mutations in at least two loci have been implicated in Usher syndrome type 3 (OMIM 276902), but USH3A is the only gene identified so far.

Genotype/phenotype correlations

Overlapping and atypical presentations have been described for all three types of Usher syndrome. For example, some mutations in USH2A and USH3 do not give rise to both blindness and deafness, but isolated RP only. Cases of nonsyndromic (isolated) deafness, either recessive or dominant, have been linked to specific (missense or leaky splice site) mutations in some USH1 genes: USH1B, USH1C, USH1D, USH1F. Some mutations in USH2 genes are causative for isolated deafness (WHRN), or isolated RP (USH2A), or atypical USH. Mutations in SANS can also result in atypical Usher syndrome (both missense and deletion mutations). All the mutations in USH genes responsible for isolated deafness or RP reported so far are missense or leaky splice site mutations.

Genotype-phenotype correlations have been found for three of the USH1 genes, USH1G, CDH23 and PCDH15. It has recently been shown that the primary eye defect associated with mutations in MYO7A (USH1B), PCDH15 (USH1F), USH2A (USH2A) and VLGR1 (USH2C) is the photoreceptor degeneration rather than a retinal pigment epithelium or a synaptic defect. Mutations in WHRN have also been reported in several families with recessive nonsyndromic hearing impairment (DFNB31).

Physiological and pathophysiological aspects of the combined hearing and vision loss in Usher syndrome

Pathophysiology of Usher syndrome is complex and still not completely understood. It is, however, well established that the hair cells and photoreceptor cells, which share common structural and functional characteristics, are the primary targets of the hearing and visual deficits, respectively. The cochlear defect of Usher syndrome types 1 and 2 occurs in utero, before the 12th and the 25th week in the inner hair cells (IHC), and the outer hair cells (OHC), respectively. So far, nothing is known on USH3. Conversely, the retinal defect develops in the postnatal development period.

The inner ear consists of two sensory organs: the vestibule (the balance organ) and the cochlea (the hearing organ) (Figure 1).

Structure of human ear (Encyclopedia Britannica Online: www.britannica.com)

The auditory sensory epithelium, termed the organ of Corti, is housed in the membranous labyrinth (known as cochlear duct). The organ Corti contains two types of transducer cells that are involved in the sound processing in the cochlea: IHC, which are responsible for the neurotransmitter release and are considered to be purely sensory, and OHC, which play sensorymotor role and are responsible for the amplification of the sound-evoked vibrations.

Each IHC or OHC is crowned by a unique array of thick and stiff microvilli filled with hundreds of actin crosslinked filaments, termed stereocilia, that project a few micrometres from their apical surface and form the so-called hair bundle. The hair bundle is made up of 20-300 stereocilia and a single genuine cilium, the kinocilium (only transient in the cochlear sensory cells during development). The stereocilia of OHC hair bundles are arranged in three to four rows of increasing heights toward the kinocilium, forming a distinct "V"-shaped (or W-shaped) staircase, where the kinocilium is located at the vertex of the V. IHC hair bundles have a flatter, slightly curved profile. The role of the hair bundle is to capture and convert nanometer stereocilia displacements induced by sound waves into measurable membrane potential changes, a process known as mechanoelectrical transduction.

Two types of links interconnect adjacent stereocilia in the mature hair bundle: tip-links (that connect the tip of each stereocilium to the side of the nearest taller stereocilium) and horizontal top connectors (lateral links that couple adjacent stereocilia both within and between rows). The tip links are oriented along the hair bundle's axis of mechanosensitivity. They are believed to gate the mechanotransducer channels of the hair cells. During development, different lateral links connect the growing stereocilia to each other and the kinocilium to the adjacent stereocilia of the tallest row. They include the transient lateral links (distributed extensively over the entire surface of the emerging stereocilia; disappear after birth), the kinociliary links (they connect the kinocilium to the immediately adjacent stereocilia; disappear after birth) and the ankle links (distributed around the basal region of the hair bundle at postnatal day 2 (P2); persisting up to P9-P11). The horizontal top connectors appear relatively late during development and persist into adulthood. The transient links and top connectors are critically involved in the cohesion of the growing and mature hair bundle.

Usher proteins

The disease-causing genes in Usher syndrome encode proteins of different classes. They are located in the hair bundle and synaptic area of hair cells in the inner ear, and in periciliary and synaptic areas of photoreceptor cells in the retina. Mutations in the different Usher genes can lead to a broad spectrum of phenotypes in the ear and eye. Recent reports provide evidence for the existence of an integrated Usher protein network(s?) in both the inner ear and the retina. Numerous direct interactions between USH proteins have been found in vitro ("USH protein interactome"), many of which are likely to occur also in vivo, within dynamic molecular complexes. These complexes play essential roles in the morphogenesis of the hair bundle, in the catalycal processes of photoreceptor cells and in the synaptic processes of both cell types.

The causative genes for Usher syndrome type 1 have been shown to encode a set of proteins named USH1 proteins: myosin VIIa, cadherin 23, protocadherin 15, harmonin and sans. These proteins are components of different stereocilia links and together form supramolecular complexes.All USH1 proteins are present in the hair bundle during its early development, playing a key role in this process. They are also key components of the mechanoelectrical transduction machinery. At clinical level, the phenotype of USH1 patients caused by mutations in different USH1 genes can not be distinguished, suggesting that the USH1 proteins may be implicated in the same cellular function(s). The early cochlear hair bundle anomalies associated with USH1 gene defects alone account for the congenital deafness of USH1 patients.

Myosin VIIa (molecular motor that uses actin filaments as a substrate to generate force and movements in response to the hydrolysis of ATP) is widely distributed throughout the hair cell and may be concentrated in some particular regions of the hair bundle. Cadherin-23 and protocadherin-15 are transmembrane adhesion proteins, members of the Ca2+-dependent cell-cell adhesion molecule superfamily. These two USH1 proteins form the tip links (that gate the hair cells mechanoelectrical transduction channels) and the transient lateral links (that play a key role in the development of a unitary properly oriented "V"-shaped hair bundle). Harmonin is a PDZ domain-containing scaffolding protein. Harmonin b-isoform most likely mediates the attachement of the tip link protein cadherin-23 to the actin cytoskeleton (Figure 2). The interaction between USH1 proteins suggest that cadherin-23 is anchored to the stereociliary actin filaments via harmonin b and that myosin VIIa exerts tension on the early hair bundle links composed of cadherin-23 and protocadherin-15. Sans is a scaffolding protein with ankyrin repeats that belongs to the tip-link molecular complex and is required for the maintenance of the tip-links.

The USH2A and USH2C genes code for the transmembrane proteins usherin and Vlgr1 (very large G protein-coupled receptor-1), respectively. The USH2D gene encodes whirlin (Figure 3), a PDZ domain-containing protein, which is the closest homolog of harmonin. These three proteins are colocated at the stereocilia base during development, up to almost the final maturation of the hair bundle. Vlgr1, usherin and whirlin have been suggested to be components of the ankle link molecular complex. In cochlear hair cells, usherin has also been detected in the synaptic region. Whirlin is also present at the stereocilia tips, where it persists at mature stages.

In the retina, USH protein network is localized at the interface of the inner segment and the light sensitive outer segment of rod and cone vertebrate photoreceptor cells termed connecting cilium. The connecting cilium has an essential role in the transport of phototransduction proteins and disc membrane lipids from the inner segment (where they are synthesized) to the outer segment. The cooperation of the network members may contribute to the regulation of cargo transfer from inner segment transport carriers to the ciliary transport system. Dysfunction or absence of any of the proteins in the ciliary-periciliary USH protein network may lead to the disruption of the entire network function and cause retinal degeneration.

USH mouse models have shown that hair cells are the primary target cells of the hearing deficit, and that the latter results from abnormal development of the hair bundle (disorganized stereocilia, and in some cases fragmented and misoriented hair bundles). In USH1 mouse models, only the hearing and balance defects typical of the human USH1 have been reproduced, but not the RP; some electrophysiological anomalies of the retina, however, have been reported in some of the mutants, suggesting a defect in the photoreceptor cells. Contrary to earlier studies, shaker-1 mice that have mutant Myo7a (USH1B animal model) was recently shown to possess a robust retinal phenotype. A knock-in mouse containing the human USH1C c.216G>A mutation that reproduce the auditory and visual defects found in Acadian Usher I patients has recently been created. In USH2 mouse models, hearing impairment and photoreceptor degeneration characteristic for human USH2 have been reproduced.

Inheritance and genetic counseling

Usher syndrome is inherited in an autosomal recessive pattern. The parents of a child with this condition each carry one copy of the mutated gene, but they are typically asymptomatic. Each subsequent pregnancy will have a 25% risk of resulting in affected child, a 50% risk for an unaffected child who is a carrier of one copy of the mutated gene, and a 25% chance for unaffected child who is not a carrier of the mutation.

Prenatal testing for pregnancies at increased risk for some forms of Usher syndrome may be available on a clinical basis, if the disease-causing mutations have been identified in the family. The hearing of at-risk sibs should be assessed as soon after birth as possible. Genetic counseling will allow the parents to prepare the child with Usher syndrome for educational and social needs corresponding to the hearing impairment and progressive loss of sight, and focus on communication skills that will be needed.

Diagnosis & differential diagnosis

The diagnosis of Usher syndrome is established on clinical grounds by evaluations of hearing, balance (delayed onset of walking is quite suggestive of a balance defect) and vision. Electrophysiologic and subjective tests of hearing and retinal function, and a family history consistent with autosomal recessive inheritance are part of the diagnosis. Audiology tests may implement otoscopy, pure tone audiometry, assessment of speech perception, and, in some cases, auditory brainstem response (ABR) and distortion product otoacoustic emissions (DPOAE). Examination of the vestibular function includes rotary chair, calorics, electro-nystagmography, and computerized posturography. Fundoscopy, visual acuity, visual field (Goldmann perimetry) and electroretinography (ERG) should detect the onset of visual impairment but should be adjusted to the age of the patient.

When available, molecular testing provides an accurate genetic diagnosis, which is useful for definition of the risks for other family members or future offspring. Clinical genetic testing may be available (depending on the country) for all identified USH genes. Many different mutations have been identified in the USH1 and USH2 genes. Many of these mutations are not recurrent ("private" mutations), and therefore, the best strategy to identify the mutations is currently to sequence all the coding exons and flanking splice sites. However, based on the finding that the R245X mutation in PCDH15 accounts for a large percentage of type I Usher syndrome in the Ashkenazi Jewish population, screening and early diagnosis should be offered to infants from this ethnic group who present with bilateral profound hearing loss and lack other causes of hearing impairment. Prenatal diagnosis and preimplantation genetic diagnosis for at-risk pregnancies require prior identification of the disease-causing mutations in the family. Mutation carrier testing for at-risk family members is possible if the two disease-causing mutations have been identified in the family.

Early clinical and molecular diagnosis of Usher syndrome and improved coordination between ophthalmological and otorhinolaryngological services is of crucial importance for early and adequate management of the patients with this disease.

Follow-up

Routine regular auditory and ophthalmologic evaluation is recommended to detect potentially treatable complications and changes that may require management modifications.

Differential diagnosis

Differential diagnoses include nonsyndromic hearing loss, deafness-dystonia-optic neuronopathy, viral infections, diabetic neuropathy, syndromes involving mitochondrial defects (Kearns-Sayre syndrome, Leber hereditary optic neuropathy) and other multisystemic genetic disorder such as Alström syndrome, Bardet-Biedl syndrome, CHARGE syndrome.

Management

Currently, there is no cure for Usher syndrome and no way to halt the retinal degeneration or to restore normal cochlear function. This is why the early diagnosis is critical for best management of the disease. The earlier the parents know that their child has Usher syndrome, the sooner special educational training programs to manage the hearing and vision loss can begin. Management typically includes hearing aids, auditory training, assistive listening devices, cochlear implants, or other communication methods such as sign language and Braille instruction. Low-vision services, orientation and mobility training, and independent-living training should be offered.

General recommendations

Hearing: Hearing aids are usually ineffective in individuals with USH1 (due to the severity of the hearing impairment), but are helpful in the other types of the disease. Cochlear implantation should be seriously considered, especially for young children. It consists of surgical implantation under the skin behind the ear of a complex electronic device that works as an artificial cochlea. With the use of a highly sensitive speech processor, it can send the sound from the ear to the brain and provide a sense of interpretable sound to individuals with severely impaired hearing. Most often, a single cochlear implant is sufficient to acquire spoken language. The bilateral implantation may improve hearing in noisy rooms and help localization of sound. However, there are still no definitive studies on the benefits of bilateral versus single cochlear implant. Cochlear implantation may also be warranted in older individuals with USH2. Communication skills should be optimized by receiving specialized training from educators of hearing loss and speech training to normalize language.

Vision: Management of progressive sight loss in Usher syndrome should follow the recommendation for management of retinitis pigmentosa.

Balance: Tunnel vision and night blindness, together with vestibular areflexia, can seriously increase the likelihood of accidental injury. Bike riding or ice skating can be dangerous for children with Usher syndrome. At the same time, well-supervised sports may help them to compensate by becoming more adept at using the somatosensory component of the balance system.

Educational programs should begin as soon as possible. They should be tailored depending on the severity of the hearing and vision impairments on the one hand and, on the other hand, on the age and abilities of the individual. Access to low vision services and community support, as well as career counseling may be very helpful.

Therapies under investigation

Gene therapy to replace defective Usher genes is a potential approach to prevent blindness in Usher syndrome. The gene therapy may also be used to treat hearing loss. Retinal degeneration in Usher syndrome seems suitable for treatment by gene therapy because of the monogenic recessive inheritance in most cases. In addition, because of the associated impaired hearing at birth, Usher syndrome patients can be more readily identified prior to the onset of retinal degeneration. At present, real progress with gene therapy for Usher 1B has been achieved. On 20 January 2010, Oxford BioMedica, a U.K. partner of the Foundation Fighting Blindness, has received orphan drug designation from the Committee for Orphan Medicinal Products of the European Medicines Agency (EMEA) for Usher syndrome gene therapy known as UshStat (a gene-based therapy for the treatment of USH1B). UshStat is designed to deliver a corrected version of the MYO7A gene into the retinal cells using the LentiVector® gene delivery technology. Clinical development (Phase I/II) is expected to start in 2011. The adeno-associated virus (AAV)-mediated whirlin replacement as a treatment option is currently under evaluation.

In clinical trials of a gene therapy for Leber congenital amaurosis (a severe retinal degeneration condition) some vision was restored in young adults who were nearly blind. The success with this treatment raises real hopes for development of gene therapies for retinal degenerative diseases, including Usher syndrome.

Encapsulated cell technology (ECT) for delivery to the retina of a therapeutic agent (NT-501) that preserves vision is currently under testing in Phase II/III of human clinical trials (multi-centered, randomized, double-masked, sham-controlled dose ranging studies designed to evaluate the safety and efficacy of NT-501 in patients with retinitis pigmentosa), and the reports from the phase I study were highly encouraging. NT-501 is an intraocular implant that consists of encapsulated human cells genetically modified to secrete ciliary neurotrophic factor (CNTF), a growth factor capable of rescuing dying photoreceptors and protecting them from degeneration.

Similarly to cochlear implants that can restore hearing to some deaf people, retinal implants have been designed and, at present, are under evaluation in preclinical and clinical studies. The implant works with a small camera mounted on glasses that sends a signal to the electrode array implanted on the retina. By electrical stimulation of the nerve cells that normally carry visual signal from the retina to the brain, the retinal prosthesis “takes” the function of lost retinal cells and helps to regain a useful level of vision. This therapeutic approach can be implemented in pathologies leading to severely impaired vision such as retinitis pigmentosa or age-related macular degeneration. An artificial retina, a “second sight” device, is currently under investigation in clinical trials. Versions with 16 and 60 electrodes, Argus I and II respectively, are tested and development of the next generation with a higher electrode count is underway.

Potential future therapies

Retinal cell transplantation to replace the degenerating retinal cells and stem cells to create new retinal cells are areas of growing interest and intensive research.

Prognosis

Children with type I Usher syndrome usually obtain little or no benefit from hearing aids. Unless fitted with a cochlear implant, they do not typically develop speech. Due to the progressive visual loss, communication by sign language and lip reading becomes increasingly difficult over time, thus tactile signing remains a communication option for these patients. Most of the children with type 2 Usher syndrome can benefit from hearing aids. They often communicate through speech assisted by the use of lip-reading and hearing. Individuals with Usher syndrome 3 usually require hearing aids by mid- to late adulthood.

Generally, progressive and permanent loss of visual acuity and visual field became substantial between the second and third decades of life in patients with Usher syndrome, though total vision loss before the age of 60 years is uncommon. This is why visual prognosis is an important issue when counseling Usher syndrome patients and their families.

References

Caberlotto E, Michel V, Foucher I, Bahloul A, Goodyear RJ, Pepermans E, Michalski N, Perfettini I, Alegria-Prévot O, Chardenoux S, Do Cruzeiro M, Hardelin JP, Richardson GP, Avan P, Weil D, Petit C. Usher type 1G protein sans is a critical component of the tip-link complex, a structure controlling actin polymerization in stereocilia. Proc Natl Acad Sci U S A. 2011 Apr 5;108(14):5825-30.

Richardson GP, de Monvel JB, Petit C. How the genetics of deafness illuminates auditory physiology. Annu Rev Physiol. 2011 Mar 17;73:311-34.

Bonnet C, Grati M, Marlin S, Levilliers J, Hardelin JP, Parodi M, Niasme-Grare M, Zelenika D, Delepine M, Feldmann D, Jonard L, El-Amraoui A, Weil D, Delobel B, Vincent C, Dollfus H, Eliot MM, David A, Calais C, Vigneron J, Montaut-Verient B, Bonneau D, Dubin J, Thauvin C, Duvillard A, Francannet C, Mom T, Lacombe D, Duriez F, Drouin-Garraud V, Thuillier-Obstoy MF, Sigaudy S, Frances AM, Collignon P, Challe G, Couderc R, Lathrop M, Sahel JA, Weissenbach J, Petit C, Denoyelle F. Complete exon sequencing of all known Usher syndrome genes greatly improves molecular diagnosis. Orphanet J Rare Dis 2011, 6:21.

Zou J, Luo L, Shen Z, Chiodo VA, Ambati BK, Hauswirth WW, Yang J. Whirlin Replacement Restores the Formation of the USH2 Protein Complex in Whirlin Knockout Photoreceptors. Invest Ophthalmol Vis Sci. 2011 Apr 12;52(5):2343-51. Print 2011 Apr.

Aziz El-Amraoui and Christine Petit. Cadherins as targets for genetic diseases. In: Additional perspectives on cell junctions. Eds. W. James Nelson and Elain Fuchs. Cold Spring Harb Perspect Biol 2010;2:a003095.

Ebermann I, Phillips JB, Liebau MC, Koenekoop RK, Schermer B, Lopez I, Schäfer E, Roux AF, Dafinger C, Bernd A, Zrenner E, Claustres M, Blanco B, Nürnberg G, Nürnberg P, Ruland R, Westerfield M, Benzing T, Bolz HJ. PDZD7 is a modifier of retinal disease and a contributor to digenic Usher syndrome. J Clin Invest. 2010 Jun 1;120(6):1812-23.

Lentz JJ, Gordon WC, Farris HE, MacDonald GH, Cunningham DE, Robbins CA, Tempel BL, Bazan NG, Rubel EW, Oesterle EC, Keats BJ. Deafness and retinal degeneration in a novel USH1C knock-in mouse model. Dev Neurobiol. 2010 Mar;70(4):253-67.

Petit C, Richardson GP. Linking genes underlying deafness to hair-bundle development and function. Nat Neurosci. 2009 Jun;12(6):703-10.

Keats BJB, Lentz J. Usher Syndrome Type I. GeneTests. University of Washington; Seattle: http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=usher1. Accessed May 28, 2009.

Keats BJB, Lentz J. Usher Syndrome Type II. GeneTests. University of Washington; Seattle: http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=usher2. Accessed April 14, 2009.

Ahmed ZM, Riazuddin S, Khan SN, Friedman PL, Riazuddin S, Friedman TB. USH1H, a novel locus for type I Usher syndrome, maps to chromosome 15q22-23. Clin. Genet. 75: 86-91, 2009.

Hmani-Aifa M, Benzina Z, Zulfiqar F, Dhouib H, Shahzadi A, Ghorbel A, Rebaï A, Söderkvist P, Riazuddin S, Kimberling WJ, Ayadi H. Identification of two new mutations in the GPR98 and the PDE6B genes segregating in a Tunisian family. Eur J Hum Genet. 2009 Apr;17(4):474-82.

Saihan Z, Webster AR, Luxon L, Bitner-Glindzicz M. Update on Usher syndrome. Curr Opin Neurol. 2009 Feb;22(1):19-27.

Ebermann I, Koenekoop RK, Lopez I, Bou-Khzam L, Pigeon R, Bolz HJ. An USH2A founder mutation is the major cause of Usher syndrome type 2 in Canadians of French origin and confirms common roots of Quebecois and Acadians. Eur J Hum Genet. 2009 Jan;17(1):80-4. Epub 2008 Jul 30.

Leibovici M, Safieddine S, Petit C. Mouse models for human hereditary deafness. Curr Top Dev Biol. 2008;84:385-429.

Williams DS. Usher syndrome: animal models, retinal function of Usher proteins, and prospects for gene therapy. Vision Res. 2008 Feb;48(3):433-41.

Overlack N, Maerker T, Latz M, Nagel-Wolfrum K, Wolfrum U. SANS (USH1G) expression in developing and mature mammalian retina. Vision Res. 2008 Feb;48(3):400-12

Adams NA, Awadein A, Toma HS. The retinal ciliopathies. Ophthalmic Genet. 2007 Sep;28(3):113-25.

Kremer H, van Wijk E, Märker T, Wolfrum U, Roepman R. Usher syndrome: molecular links of pathogenesis, proteins and pathways. Hum Mol Genet. 2006 Oct 15;15 Spec No 2:R262-70.

Reiners J, Nagel-Wolfrum K, Jürgens K, Märker T, Wolfrum U. Molecular basis of human Usher syndrome: deciphering the meshes of the Usher protein network provides insights into the pathomechanisms of the Usher disease. Exp Eye Res. 2006 Jul;83(1):97-119.

McHugh RK, Friedman RA. Genetics of hearing loss: Allelism and modifier genes produce a phenotypic continuum. Anat Rec A Discov Mol Cell Evol Biol. 2006 Apr;288(4):370-81.

El-Amraoui A, Petit C. Usher I syndrome: unravelling the mechanisms that underlie the cohesion of the growing hair bundle in inner ear sensory cells. J Cell Sci. 2005 Oct 15;118(Pt 20):4593-603.

Contributors & disclaimer

Contributors:
Katia Marazova, PhD, Institut de la Vision (September 2011),
Dr Jean-Pierre Hardelin, MD, PhD (Unité de génétique et physiologie de l'audition, Institut Pasteur, Paris, France),
Dr Crystel Bonnet (Unité de Génétique Médicale, Hôpital d'Enfants Armand-Trousseau/Unité de Génétique et Physiologie de l'Audition, Institut Pasteur, Paris, France).

Disclaimer: This document contains information based on published scientific articles and is for educational purposes only. It is in no way intended as a substitute for qualified medical professional help, advice, diagnosis or treatment.