Viewpoint article - Beyond Clinical Assessments: Advocating for Early Support for Children with Usher Syndrome in Australia

Usher syndrome (USH) is the most common genetic cause of combined deafness and blindness. It is a rare disease, affecting about 400,000 individuals worldwide and 20,000 to 50,000 individuals in the United States.1,2 While there is no cure for this condition, over a century of scientific discovery has resulted in tremendous advances toward the development of treatments. Despite these advances, less than one percent of people with USH is known to researchers, putting future research and clinical trials at risk. Hearing health care professionals can play a critical role in identifying children and adults with USH.Shutterstock/Natali_ Mis. Usher Syndrome, hearing loss, genetics.Table 1: Usher Syndrome Types and Symptoms.Box: The Usher Syndrome CoalitionHISTORY OF USHER SYNDROME Usher syndrome was first described in 1858 by German ophthalmologist Albrecht von Graefe, who studied three siblings with deafness and progressive vision loss caused by retinitis pigmentosa (RP). In 1914, Scottish ophthalmologist Charles Howard Usher studied 69 families and identified an inherited recessive condition that caused deafness and progressive vision loss in a subset of these families.3 This syndrome was later named after Usher. The early years of USH research were focused on identifying the different types of Usher syndrome as well as the prevalence and psychosocial aspects. Before genetic testing of this condition became available, children and adults were diagnosed phenotypically based on a history of early-onset hearing loss, progressive vision loss, and the absence or presence of vestibular involvement. TYPES OF USHER SYNDROME Three types and nine confirmed genetic subtypes of Usher syndrome have been identified to date (Table 14), distinguished by the severity of hearing loss, age of onset of hearing and vision loss, and the presence or absence of vestibular function. In 1995, the first causative gene for Usher syndrome was identified. In subsequent years, additional discoveries located genes for five subtypes within USH1, three for USH2, and in 2001, the gene for USH3A. Historically, a diagnosis of Usher syndrome was devastating, offering few options and resources. Many were told that they would be blind by a certain age, and that the syndrome is so rare they would probably never meet another person with USH. In addition, they had no knowledge of, or access to, researchers around the world who were working to understand Usher syndrome. IMPORTANCE OF EARLY DIAGNOSIS Early diagnosis of Usher syndrome is critical so that individuals and families can find support, make informed decisions about communication, and consider options for education, employment, and beyond. However, finding those with USH remains a challenge. The 2017 National Child Count of Children and Youth Who Are Deaf-Blind5 reported only 329 children with Usher syndrome in the United States. This number represents only a fraction of the thousands of children estimated to have USH.6 The Usher Syndrome Coalition maintains the largest international registry of individuals of all ages and types of Usher syndrome, yet that too has less than one percent of the total population registered. ROLE OF HEARING CARE Universal newborn hearing screenings have dramatically increased the number of babies identified as deaf or hard of hearing.7 Infants who fail this screening are referred to a hearing health care professional for follow-up. These professionals can play a pivotal role in recognizing the early symptoms of Usher syndrome by understanding its functional impact on a child's development and behavior. These include: Type 1: In addition to profound hearing loss, children with Usher type 1 experience vestibular issues that delay the development of their ability to sit upright and walk. Night blindness associated with RP may manifest quite early. Signs of night blindness may include a child appearing to be clumsy or expressing an unusual fear of dimly lit areas. For example, if the audiology booth has low lighting, the child may miss a step or need time for his or her eyes to adjust and get visually oriented to the area. Type 2: Children with Usher type 2 experience moderate to severe hearing loss that is often present at birth. The hearing loss is typically milder in the low frequencies and more severe in the higher ones. Children with this condition often use hearing aids and communicate aurally. Functional implications of Usher type 2 may include a perceived loss of hearing, which may actually be related to the impact of progressive vision loss on the ability to speech-read. Also, as vision loss progresses, individuals may pause and visually scan a room before entering. Type 3: This is the rarest form of Usher syndrome and the most difficult to diagnose because the vision and hearing loss may not express until the teen years or later. Vestibular dysfunction is variable. This type should be considered as a possible cause of late-onset vision and hearing loss, especially in individuals of Ashkenazi Jewish or Finnish heritage. More than a century of scientific discovery has resulted in tremendous advances toward the understanding of USH and the development of treatments for this rare genetic disorder. To ensure that treatment development and clinical trials are not delayed, researchers must have access to their greatest resource—people living with Usher syndrome. As the first point of contact, hearing health care professionals can play a critical role in helping to identify infants, children, and adults with this condition. Together, we can help to find, educate, support, and connect the Usher community, one person at a time.

Usher Syndrome (USH) is a genetically inherited condition characterized by congenital sensorineural hearing loss and progressive vision loss secondary to retinitis pigmentosa. Patients may also display vestibular areflexia and balance issues secondary to inner ear damage. Usher Syndrome is the most commonly diagnosed syndrome within the blind-deaf community, and it accounts for a significant portion of the hearing and visual deficit cases among patients younger than 65 years of age. Due to the reported prevalence of Usher Syndrome in the United States, it appears there is chronic underdiagnosis in clinical settings throughout the country. A possible explanation for this is the visual deficits of Usher syndrome do not appear until later in life and thus inappropriately lower the index of suspicion for this diagnosis in young children with hearing deficits. This case study highlights a healthy newborn who failed the universal newborn hearing screening (UNHS) bilaterally and a follow-up hearing screening in a pediatrician's office. Auditory brainstem response (ABR) later confirmed bilateral severe-to-profound sensorineural hearing loss. Upon genetic testing, an abnormality in the Unconventional Myosin VII-A (MYO7) gene was discovered and consistent with Usher syndrome Type 1B (USH1B). Usher Syndrome should be considered on the differential for patients with congenital hearing loss. Genetic counseling should be used if no other cause of sensorineural hearing loss is identified. Due to the progressive nature of this condition and the physical and developmental deficits that will transpire without treatment, a genetic panel for hearing loss should be prioritized to determine the presence of genetic mutations suggesting Usher syndrome.

Usher syndrome (USH) represents a group of genetically heterogenous autosomal recessive disorders, characterized by combined vision and sensorineural hearing loss, and in some cases vestibular dysfunction.1–3 It primarily affects the light-sensitive photoreceptor cells in the retina and the auditory hair cells in the cochlea. Vision loss in all cases is progressive, and manifests as retinitis pigmentosa (RP), characterized by the gradual degeneration of the photoreceptor cells.4 Peripheral rod function is lost first, leading to night blindness and constricted visual fields, followed by the death of cones and severe visual impairment. There are currently no drugs or biological therapies proven to be effective in treating USH syndrome. Cochlear implantation, which bypasses the damaged hair cells and stimulates the primary auditory neurons directly, is an effective approach to alleviate the hearing impairment in patients. However, there is no remedy for the progressive loss of the photoreceptor neurons in the retina, and thus a critical unmet need exists to develop therapeutic strategies to prevent blindness in USH syndrome. The generation of animal models that faithfully mimic the human USH disorder, the timing of gene therapy interventions, the identification of correct target cells and patient selection are key factors in successfully reaching this goal. USH syndrome was named after Dr Charles Howard Usher, a Scottish ophthalmologist who described 69 patients with the disease in 1914.5 As is commonly the case in medicine, the disease was first described much earlier (1858) in brothers suffering from blindness and deafness by von Grafe6 and was further characterized by his student, Liebreich,7 3 years later in a larger population of patients. From its discovery until recently, USH syndrome and its subgroups were delineated by clinical characteristics.8 Now the disease is recognized by symptomology and classified by genotyping. To date, there are at least 10 causative genes that are associated with USH syndrome, summarized in previous reviews.1,2,9 In general, based on its diverse clinical symptoms, particularly the onset and severity of the sensorineural hearing impairment and the presence of vestibular dysfunction, USH syndrome is grouped into 3 clinical subtypes. Type I disease is associated with severe-to-profound prelingual hearing loss, vestibular abnormalities and prepubescent onset of RP symptoms.10,11 USH1 results from mutations in MYO7A (USH1B), HARMONIN (USH1C), CDH23 (USH1D), PCDH15 (USH1F), SANS (USH1G), and CIB2 (USH1J). Patients with type II disease display moderate-to-severe congenital hearing loss without vestibular dysfunction, and account for >50% of all USH cases. Their RP symptoms generally begin in the second decade.12 USH2 is caused by mutations in USH2A (USH2A), ADGRV1 (USH2C), and WHRN (USH2D). Patients with type III disease caused by mutations in CLRN1 (USH3A) gene have postlingual progressive hearing loss, variable vestibular dysfunction, and variable onset of RP that rapidly progresses to legal blindness by the fourth decade of life.13–17 Mutations in the HARS gene (Histidyl-tRNA synthetase) are associated with the ultra-rare form USH3B.18,19 Other genes have been described in cases of atypical USH, including: CEP250 and CEP78, encoding members of the CEP family of centrosome-associated proteins; ESPN, encoding the F-actin cross-linker espin; ARSG, encoding the arylsulfatase G enzyme.20

An Usher syndrome type 1 patient diagnosed before the appearance of visual symptoms by MYO7A mutation analysis

You have accessThe ASHA LeaderFeature1 Dec 2009Audiologists' Role in Early Diagnosis of Usher Syndrome Josara WallberAuD, CCC-A Josara Wallber Google Scholar , AuD, CCC-A https://doi.org/10.1044/leader.FTR4.14162009.5 SectionsAbout ToolsAdd to favorites ShareFacebookTwitterLinked In Usher syndrome is a frequent cause of deaf-blindness and involves sensorineural hearing loss and retinitis pigmentosa (RP). It occurs in four of every 10,000 births (NIH). The hearing loss is always sensorineural; the vision loss is always progressive; and the etiology of this combination is always genetic, specifically autosomal recessive. Parents are literally "blindsided" by this diagnosis and frequently complain this cannot be genetic because it is "not in their family." Such is the nature of recessive inheritance: both parents are asymptomatic, unknowing carriers of the same gene. RP is a degenerative retinal disease in which initially sighted individuals gradually lose their vision. Although RP occurs in one of every 4,000 persons in the general population, about 14% of all RP cases are caused by Usher syndrome (Hamel, 2006). The pattern of vision loss is quite predictable: night blindness followed by restricted tunnel vision and later loss of acuity and color perception. The onset and rate of progression of RP are, however, highly variable. The delayed onset of expression presents a challenge to the audiologist in assisting families with the diagnosis of Usher syndrome. Although clinical observation and behavioral measures of visual function are possible in older children, the definitive diagnostic test is objective: an electroretinalgram (ERG). Using electrodes placed on the cornea, an ERG measures the responses of retinal photoreceptor cells to light stimulation. There are three recognized clinical types of Usher syndrome, labeled simply Type I, Type II, and Type III. While some atypical expressions have been identified, they are beyond the scope of this article (for a review, see Cohen et al., 2007). The three types are distinguished primarily by severity of hearing loss, presence or absence of vestibular function, and onset of vision loss. All these variables are important, as hearing loss alone cannot diagnose Usher syndrome, nor can it differentiate clearly between the subtypes (Wagenaar et al., 1996). Characteristics Type I presents with congenital, severe-to-profound sensorineural hearing loss, no vestibular function, and noticeable vision involvement in the preteen years. Due to the severity of the hearing loss, hearing aids are generally ineffective. Individuals with Type I are typically identified as deaf during childhood and, prior to cochlear implantation, placed in educational programs that focus on visual communication. Because of the lack of vestibular function these children demonstrate delays in sitting and walking, with the latter being reported at older than 18 months of age (Moller et al., 1989). Night blindness typically appears by age 10. These children may be afraid of the dark and are often described as clumsy because they bump into or trip over objects in the environment. Significant deterioration of visual field and acuity begins between the second and third decade of life, with cataracts being a common complication (Piazza et al., 1986; Edwards et al., 1998; Sadeghi, 2006). Most individuals with Type II exhibit a stable, moderate sensorineural hearing loss (Reisser et al., 2002) and often respond well to amplification. The sub-Type IIa, however, may demonstrate progressive hearing loss not found in other Type II expressions (Sadeghi et al., 2004). Balance is unaffected and vision loss is unnoticed until late teens. Although the sequence of RP progression is similar to that of other types of RP (Iannaccone et al., 2004), visual field and acuity impairments are somewhat less severe compared to Type I during the third and fourth decades of life (Piazza et al., 1986; Edwards et al., 1998; Sadeghi, 2006). Type III has the most variable onset and presentation. Hearing loss is progressive and vestibular function may or may not be affected (Sadeghi et al., 2005). This clinical type, although common in Finland, is rare in the United States and has vision outcomes more similar to Type I (Plantinga, 2006). Type III represents 40% of all cases in Finland but only 2%–4% of all cases in the United States. The National Center for Hearing Assessment and Management (NCHAM) reports that 95% of infants born in the United States are evaluated prior to discharge by early hearing detection and intervention programs (EHDI), which have lowered the average age of identification of hearing loss from 12–18 months to 6 months or younger (Harrison & Roush, 1996). Sininger and colleagues (2009) demonstrated that newborns screened through EHDI are diagnosed more than 24 months earlier than those babies who were not screened. Despite these achievements, a diagnosis of Usher syndrome, with its devastating vision prognosis, typically lags five or 10 years behind the identification of the hearing loss (Kimberling & Lindenmuth, 2007). Although parents learn of their child's hearing loss relatively early, without a differential diagnosis they make critical decisions related to intervention, communication, and educational options without knowing their child eventually will be blind. Parents rely upon audiologists for information and support in working with their children who have hearing loss. ASHA's Guidelines for the Audiologic Assessment of Children From Birth to 5 Years of Age recommend that audiologists should "as appropriate, discuss additional specialty evaluations (e.g., genetics, ophthalmology, child development) with parents/caregivers and the infants' primary care provider" (ASHA, 2004, p. 13). This recommendation requires that the audiologist be familiar with genetic epidemiology of hearing loss and resources for referral and information. Once a child is identified, intervention services require a multi-disciplinary team, but audiologists are often the first—and primary—health care provider for individuals with Usher syndrome, and they must recognize and refer for proper and timely diagnosis those individuals who present with clinical signs and symptoms that may suggest the presence of Usher syndrome. Access Audiology Focuses on Usher Syndrome For more information on Usher syndrome, visit the November/December issue of Access Audiology, the bi-monthly clinical e-newsletter that highlights topics of relevance to audiologists. This issue includes Usher syndrome-related resources on the ASHA Web site as well as other Web resources. Anyone may subscribe to Access Audiology by sending a blank e-mail with "subscribe" in the subject line to [email protected]. References American Speech-Language-Hearing Association (2004) Guidelines for the audiologic assessment of children from birth to 5 years of age. Available from www.asha.org/policy. Google Scholar Cohen M., Bitner-Glindziez M., & Luxon L. (2007). The changing face of Usher syndrome: Clinical implications.International Journal of Audiology, 46, 82–93. Google Scholar Edwards A., Fishman G., Anderson R., Grove S., & Derlackie D. (1998). Visual acuity and visual field impairment in usher syndrome.Archives of Ophthalmology, 116(2), 165–168. Google Scholar Hamel C. (2006). Retinitis pigmentosa.Orphanet Journal of Rare Diseases, 1(40), 1–12. Google Scholar Harrison S., & Rousch J. (1996). Age of suspicion, identificaton, and intervention for infants and young children with hearing loss: a national study.Ear and Hearing, 17, 55–62. Google Scholar Innaccone A., Kritchevsky S., Ciccarelli M., Tedesco S., Macahuso C., Kimberling W., & Somes G. (2004). Kinetics of visual field loss in usher syndrome type II.Investigative Ophthalmology & Visual Science, 45(3), 784–792. Google Scholar Kimberling W., & Lindenmuth A. (2007). Genetics, hereditary hearing loss, and ethics.Seminars in Hearing, 28(3), 216–225. Google Scholar Moller C., Kimberling W., Davenport S., Priluck L., & White V. (1989). Usher syndrome: An otoneurologic study.Laryngoscope, 99, 73–79. Google Scholar National Institute of Health. (2008, February). Usher Syndrome, National Institute on Deafness and Other Communication Disorders athttp://www.nidcd.nih.gov/health/hearing/usher.asp Accessed October 2009. Google Scholar National Center for Hearing Assessment and Management. (2009). Available athttp://www.infanthearing.org. Google Scholar Piazza L., Fishman G., Farer M., Derlacki D., & Anderson R. (1986). Visual acuity loss in patients with usher's syndrome.Archives of Ophthalmology, 104(9), 1336–1339. Google Scholar Plantinga R., Pennings R., Huygen P., Sankila E., Tuppurainen K., Kleemola L., Cremer C., & Deutman A. (2006). Visual impairment in Finnnish usher syndrome type III.Aca Ophthalmologica Scandinavica, 84(1), 36–41. Google Scholar Reisser C., Kimberling W., & Otterstedde C. (2002). Hearing loss in usher syndrome type II is nonprogressive. Annals of Otology, Rhinology, and Laryngology, 111, 1108–111. Google Scholar Sadeghi M, Cohn E., Kelly W., Kimberling W., Tranebjarg L., & Moller C. (2004). Audiological findings in usher syndrome types IIa and II (non-IIa).International Journal of Audiology, 43, 136–143. Google Scholar Sadeghi M., Cohn E., Kimberling W., Tranebjarg L., & Moller C. (2005). Audiological and vestibular features in affected subject with USH3: a genotype/phenotype correlation.International Journal of Audiology, 44, 307–316. Google Scholar Sadeghi A., Eriksson K., Kimberling W., Sjostrom A., & Moller C. (2006). Longterm visual prognosis in usher syndorme types 1 and 2.Aca Ophthalmologica Scandinavica, 84(4), 537–544. Google Scholar Sininger Y., Martinez A., Eisenberg L., Christensen E., Grimes A., & Hu J. (2009). Newborn hearing screening speeds diagnosis and access to intervention by 20–25 months.Journal of the American Academy of Audiology, 20, 49–57. CrossrefGoogle Scholar Wagenaar M., Snik A., Kimberling W., & Cremers C. (1996). Carriers of usher syndrome type IB: is audiometric identification possible?.The American Journal of Otology, 17, 853–858. Google Scholar Author Notes Josara Wallber, AuD, CCC-A, spent 25 years at the National Technical Institute for the Deaf, where in addition to her work with aural rehabilitation, amplification, and cochlear implants for college students, she taught in the deaf education program and was a certified ophthalmic assistant working closely with the deaf-blind community. She is an associate clinical professor at Idaho State University, where she teaches and supervises clinical activities with an emphasis on cochlear implants. Contact her at [email protected]. Advertising Disclaimer | Advertise With Us Advertising Disclaimer | Advertise With Us Additional Resources FiguresSourcesRelatedDetails Volume 14Issue 16December 2009 Get Permissions Add to your Mendeley library History Published in print: Dec 1, 2009 Metrics Current downloads: 567 Topicsasha-topicsleader_do_tagasha-article-typesleader-topicsCopyright & Permissions© 2009 American Speech-Language-Hearing AssociationLoading ...

Introduction Usher syndrome is a common cause of deaf-blindness characterised by progressive visual loss with congenital (types 1 and 2) or adult-onset (type 3) sensorineural hearing loss. Cochlear implantation is one of few effective options to enable patient access to useful sound. Auditory rehabilitation after cochlear implantation may be limited by deterioration of retinal function. Our objective was to evaluate the auditory outcomes of cochlear implantation in patients with Usher syndrome. Method Systematic review of Medline via PubMed, Ovid EMBASE, Web of Science, CENTRAL and clinicaltrials.gov was performed up to 30/03/2020, conducted in accordance with the PRISMA statement. Patient demographics, comorbidity, details of cochlear implantation, auditory and quality of life (QOL) outcomes were extracted and summarised. CRD 42020185102. Results 32 studies reported over 215 cochlear implants in 186 patients with Usher syndrome, comprising subtypes 1 (56 patients), 2 (9 patients), 3 (23 patients), and not specified (98 patients). Where reported, cochlear implantation improved sound detection, speech perception, speech intelligibility, and patient-reported quality of life in the majority of patients with Usher syndrome. Conclusions Outcomes of cochlear implantation were comparable to those of patients without multiple sensory handicap. As clinical practice has evolved to emphasise early, bilateral implantation and access to oral education it is likely that these reported outcomes may underestimate contemporary implant outcomes among young children with Usher syndrome. To avoid multisensory deficits incurred by poor cochlear implant outcomes secondary to late implantation with Usher syndrome-related progressive visual loss, early implantation is crucial in the prelingually deaf Usher group.

Usher's syndrome is a heterogeneous autosomal recessive disorder characterized by dual sensory impairment in the form of profound congenital hearing loss and progressive visual loss due to retinal degeneration. There are only a few reports describing patients with Usher's syndrome presenting with psychotic features, and the exact etiology of its psychiatric manifestation is not clearly known. Herein, the authors report a case of Usher's syndrome with psychotic symptoms. Furthermore, the authors discuss the possible etiologies of psychotic symptoms in such cases and the challenges faced while assessing these symptoms in patients with sensory impairment.

Usher's syndrome is a genetic disorder that causes congenital sensorineural hearing loss, visual impairment due to progressive pigmentary retinopathy, and, often, vestibular dysfunction. The aim of this article is to illustrate a case that clearly demonstrates psychotic symptoms in Usher's syndrome Type III and serves to increase clinical awareness of this disorder and its possible link to psychotic symptoms. There is some evidence in the literature of concurrent psychiatric symptoms, particularly psychotic symptoms, associated with Usher's syndrome, and several theories around this association have been proposed. These theories of associations include a genetic link between the genes responsible for schizophrenia and the genes for Usher's syndrome; a neuropathological explanation as radiologic studies have revealed that patients with Usher's syndrome have CNS abnormalities in multiple brain structures; and a sensory deficit model which proposes that the stressors associated with sensory impairment and the brain's adaptation to changes in sensory inputs place an individual at increased risk for psychopathology.

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.

ResumenEl síndrome de Usher se caracteriza por hipoacusia neurosensorial congénita, retinitis pigmentaria y disfunción vestibular. Es la causa más frecuente de sordoceguera en el mundo. Se divide en tres tipos clínicos y doce subtipos genéticos. Se reporta el caso de una familia afectada por el síndrome de Usher debido a una variante del gen USH1G que codifica para la proteína SANS. Se realizaron los estudios clínicos oculares y auditivos correspondientes para la confirmación clínica del diagnóstico. El estudio molecular consistió en un panel de secuenciación de nueva generación que contenía 14 genes asociados con el síndrome de Usher: MYO7A, USHC1, CDH23, PCDH15, USH1G, CIB2, USH2A, ADGRV1, WHRN, CLRN1, HARS, PDZD7, CEP250, C2orf71. Se trata de una joven de 13 años, de una familia colombiana consanguínea, a quien se le diagnosticó un síndrome de Usher de tipo 1G. Las evaluaciones clínicas confirmaron las alteraciones auditivas, vestibulares y oculares y el análisis molecular identificó la variante homocigota p.Glu171Ter del gen USH1G.Se resalta la importancia del diagnóstico temprano del síndrome de Usher. Aunque la frecuencia de variantes del gen USH1G es baja, no debe subestimarse; por el contrario, se recomienda su búsqueda activa para establecer la etiología exacta en esas familias. Se resalta la importancia de contar con un panel de variantes propias de la población colombiana para lograr diagnósticos más acertados y, en el futuro, buscar terapias génicas.

Usher syndrome is a group of autosomal recessive disorders characterised by progressive visual loss from retinitis pigmentosa and moderate to severe sensorineural hearing loss. Usher syndrome is estimated to account...

Hearing loss (HL) is the most common congenital sensory impairment. Usher syndrome (USH) is the leading genetic etiology of congenital deafness combined with progressive vision loss, and individuals presenting with these symptoms are often assumed to have USH. This can be an erroneous assumption, as there are additional genetic causes of deaf-blindness. Our objective is to describe and accurately diagnose non-USH genetic causes of deaf-blindness. We present three children with hearing and vision loss with clinical and genetic findings suggestive of USH. However, ongoing clinical assessment did not completely support an USH diagnosis, and exome analysis was pursued for all three individuals. Updated genetic testing showed pathogenic variants in ALMS1 in the first individual and TUBB4B in the second and third. Although HL in all three was consistent with USH type 2, vision impairment with retinal changes was noted by age 2 yr, which is unusual for USH. In all three the updated genotype more accurately fit the clinical phenotype. Because USH is the most common form of genetic deaf-blindness, individuals with HL, early vision impairment, and retinal dysfunction are often assumed to have USH. However, additional genes associated with HL and retinal impairment include ALMS1, TUBB4B, CEP78, ABHD12, and PRPS1. Accurate genetic diagnosis is critical to these individuals’ understanding of their genetic conditions, prognosis, vision and hearing loss management, and future access to molecular therapies. If clinically or genetically USH seems uncertain, updated genetic testing for non-USH genes is essential.

Usher syndrome type 1C (USH1C) is a genetic disorder caused by mutations in the USH1C gene, which encodes harmonin, a key component of the mechanoelectrical transduction complex in auditory and vestibular hair cells. USH1C leads to deafness and vestibular dysfunction in humans. An Ush1c knockout (KO) mouse model displaying these characteristic deficits is generated in our laboratory. To examine gene replacement therapy (GT) in this model, a synthetic adeno‐associated viral vector, Anc80L65, driving harmonin expression is administered, to the inner ears of Ush1c KO mice at postnatal day 2 (P2). Remarkably, this single treatment significantly improved auditory brainstem response (ABR) thresholds and balance motor function at 1 month post‐injection, with these effects persisting for up to 10 months. At 12 months post‐treatment, the vestibular function is assessed using the vestibular‐ocular reflexes (VOR) and single vestibular afferent recordings. The GT treatment significantly restored both the canal and otolith VORs and increased vestibular afferent spontaneous firing rates and responses to head rotation and translation. These findings provide the first evidence of long‐lasting restoration of both the auditory and vestibular functions by GT in a novel mouse model of Usher syndrome, highlighting the potential of GT for treating deficits associated with USH1C.

Usher syndrome (USH) is the most common cause of inherited deaf‐blindness. Depending on the type (I, II, or III), hearing impairment and vestibular dysfunction can be variable, but all Usher patients exhibit a progressive loss of vision due to retinitis pigmentosa (RP). Usher syndrome type 1 (USH1) is responsible for 35 – 45% of all Usher cases and is characterized by severe to profound hearing impairment and vestibular dysfunction at birth, as well as, the development of RP in early adolescence. 6–8% of USH1 are caused by mutations in the USH1C gene, which encodes the protein Harmonin. Harmonin has been shown to play an important role in the development and function of auditory hair cells in the cochlea; however, its role in the retina is unknown. Our lab has produced a knock‐in mouse model containing the human USH1C c.216G>A splicing mutation (216A) responsible for USH1 in Acadian patients of south Louisiana. These mice have profound hearing impairment, vestibular dysfunction, loss of visual function and slow retinal degeneration similar to patients. Recently, antisense oligonucleotides (ASOs) targeting the 216A mutation in these mice have been shown to enhance correct Ush1c gene and Harmonin protein expression, and be efficacious in rescuing hearing and vestibular function when administered by intraperitoneal injection (systemic). However, only marginal improvement in visual function was observed; possibly due to an insufficient concentration of the ASO in the eye. The purpose of this study was to evaluate visual function after an intravitreal (local) ASO treatment.Rod and cone photoreceptor function was evaluated by scotopic and photopic electroretinogram (ERG) analysis, respectively, in ASO‐treated 216AA mutant and littermate control mice. An increase in scotopic a‐wave amplitude was observed within 3 months of ASO treatment in 216A mutant mice compared with control littermates, indicating an early improvement in rod function. This improvement was observed when the mice were treated at 1, 3 or 6 months of age, suggesting a large temporal window for successful intervention between adolescence and adulthood. An analysis of photopic ERGs showed no differences in untreated 216AA mutant and control littermates, suggesting cone function is not affected in early stages of disease. These data demonstrate the potential of ASOs for the treatment of retinitis pigmentosa associated with Usher syndrome.Support or Funding InformationThis research was supported by grant #1359140 through the National Science Foundation

À propos d’un cas de syndrome de Usher suivi en psychiatrie : intérêt du diagnostic somatique pour la prise en charge psychiatrique