View source for Usher syndrome

{{Short description|Recessive genetic disorder causing deafblindness}}
{{Infobox medical condition (new)
| name            = Usher syndrome
| synonyms        = Usher–Hallgren syndrome
| image           = Autosomal recessive - en.svg
| caption         = Usher syndrome is inherited in an [[autosomal recessive]] pattern.  The genes implicated in Usher syndrome are described below.
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'''Usher syndrome''', also known as '''Hallgren syndrome''', '''Usher–Hallgren syndrome''', '''retinitis pigmentosa–dysacusis syndrome''' or '''dystrophia retinae dysacusis syndrome''',<ref name="mets_2000">{{cite journal |vauthors=Mets MB, Young NM, Pass A, Lasky JB | year = 2000 | title = Early diagnosis of Usher syndrome in children | journal = Transactions of the American Ophthalmological Society | volume = 98 | pages = 237–45 | pmid = 11190026 | pmc = 1298229}}</ref> is a rare [[genetic disorder]] caused by a mutation in any one of at least 11 [[gene]]s resulting in a combination of [[hearing loss]] and [[visual impairment]]. It is the most common cause of [[deafblindness]] and is at present incurable.

Usher syndrome is classed into three subtypes (I, II, and III) according to the genes responsible and the onset of deafness. All three subtypes are caused by mutations in genes involved in the function of the [[inner ear]] and [[retina]]. These mutations are inherited in an [[autosomal recessive]] pattern.

<!-- Epidemiology and history -->
The occurrence of Usher syndrome varies across the world and across the different syndrome types, with rates as high as 1 in 12,500 in Germany<ref name=":0" /> to as low as 1 in 28,000 in Norway.<ref name=":1" /> Type I is most common in [[Medical genetics of Jews|Ashkenazi Jewish]] and [[Acadian]] populations, and type III is rarely found outside Ashkenazi Jewish and [[Finnish heritage disease|Finnish]]<ref name=":2">{{cite journal|vauthors=Pakarinen L, Tuppurainen K, Laipapala P, Mäntyjärvi M, Puhakka H|year=1996|title=The ophthalmological course of Usher syndrome type III|journal=International Ophthalmology|volume=19|issue=5|pages=307–311|doi=10.1007/BF00130927|pmid=8864816|s2cid=26501078}}</ref> populations. Usher syndrome is named after Scottish ophthalmologist [[Charles Usher]], who examined the pathology and transmission of the syndrome in 1914.

==Types==
===Usher syndrome I===
People with Usher I are born profoundly deaf and begin to lose their [[visual perception|vision]] in the first decade of life. They also exhibit [[balance disorder|balance difficulties]] and learn to walk slowly as children, due to problems in their [[vestibular system]].{{citation needed|date=September 2021}}

Usher syndrome type I can be caused by mutations in any one of several different genes: ''[[CDH23]], [[MYO7A]], [[PCDH15]], [[USH1C]]'' and ''[[USH1G]]''. These genes function in the development and maintenance of [[inner ear]] structures such as hair cells ([[stereocilia]]), which transmit sound and motion signals to the brain. Alterations in these genes can cause an inability to maintain balance (vestibular dysfunction) and hearing loss. The genes also play a role in the development and stability of the retina by influencing the structure and function of both the rod photoreceptor cells and supporting cells called the [[retinal pigmented epithelium]]. Mutations that affect the normal function of these genes can result in [[retinitis pigmentosa]] and resultant vision loss.{{citation needed|date=September 2021}}

Worldwide, the estimated prevalence of Usher syndrome type I is 3 to 6 per 100,000 people in the general population. Type I is more common in people of [[Ashkenazi Jewish]] ancestry (central and eastern European) and in the French-[[Acadian]] populations (Louisiana).<ref name="keatscorey">{{cite journal |last1=Keats |first1=Bronya J.B. |last2=Corey |first2=David P. |title=The Usher syndromes |journal=American Journal of Medical Genetics |date=25 October 2002 |volume=89 |issue=3 |pages=158–166 |doi=10.1002/(SICI)1096-8628(19990924)89:3<158::AID-AJMG6>3.0.CO;2-# |pmid=10704190 |url=https://onlinelibrary.wiley.com/doi/10.1002/(SICI)1096-8628(19990924)89:3%3C158%3A%3AAID-AJMG6%3E3.0.CO%3B2-%23 |access-date=29 June 2022|url-access=subscription }}</ref> Among Acadians, research into haplotype data is consistent with one single mutation being responsible for all cases of Usher syndrome type I.<ref name="keatscorey" />

===Usher syndrome II===
People with Usher II are not born deaf and are generally [[hard-of-hearing]] rather than deaf, and their hearing does not degrade over time;<ref>{{cite journal |last1=Reisser |first1=CFV |last2=Kimberling |first2=WJ |last3=Otterstedde |first3=CR |title=Hearing Loss in Usher Syndrome Type II is Nonprogressive |journal=Annals of Otology, Rhinology & Laryngology |date=2002 |volume=111 |issue=12 |pages=1108–1111 |doi=10.1177/000348940211101208 |pmid=12498372 |s2cid=43346043 |url=https://journals.sagepub.com/doi/abs/10.1177/000348940211101208 |access-date=4 March 2022|url-access=subscription }}</ref> moreover, they do not seem to have noticeable problems with balance.<ref>{{cite journal |last1=Sadeghi |first1=Mehdi |last2=Cohn |first2=Edward S. |last3=Kelly |first3=William J. |last4=Kimberling |first4=William J. |last5=Tranebjoerg |first5=Lisbeth |last6=Möller |first6=Claes |title=Audiological findings in Usher syndrome types IIa and II (non-IIa) |journal=International Journal of Audiology |date=2004 |volume=43 |issue=3 |pages=136–143 |doi=10.1080/14992020400050019 |pmid=15198377 |s2cid=40248505 }}</ref> They also begin to lose their vision later (in the second decade of life) and may preserve some vision even into middle age.{{citation needed|date=September 2021}}

Usher syndrome type II may be caused by mutations in any of three different genes: ''[[USH2A]]'', ''[[GPR98]]'' and ''[[DFNB31]]''. The protein encoded by the'' USH2A ''gene, usherin, is located in the supportive tissue in the inner ear and retina. Usherin is critical for the proper development and maintenance of these structures, which may help explain its role in hearing and vision loss. The location and function of the other two proteins are not yet known.{{citation needed|date=September 2021}}

Usher syndrome type II occurs at least as frequently as type I, but because type II may be underdiagnosed or more difficult to detect, it could be up to three times as common as type I.{{citation needed|date=September 2021}}

===Usher syndrome III===
People with Usher syndrome III are not born deaf but experience a progressive loss of hearing, and roughly half have balance difficulties.{{citation needed|date=September 2021}}

Mutations in only one gene, ''[[CLRN1]]'', have been linked to Usher syndrome type III. ''CLRN1'' encodes clarin-1, a protein important for the development and maintenance of the inner ear and retina. However, the protein's function in these structures, and how its mutation causes hearing and vision loss, is still poorly understood.{{citation needed|date=October 2021}}

The frequency of Usher syndrome type III is significant only in the [[Finns|Finnish population]]<ref name=":2" /> as well as the population of [[Birmingham, UK]],<ref>{{cite journal|vauthors=Hope CI, Bundey S, Proops D, Fielder AR|year=1997 |title=Usher syndrome in the city of Birmingham — prevalence and clinical classification|journal=British Journal of Ophthalmology|volume=81|issue=1|pages=46–53|doi=10.1136/bjo.81.1.46|pmc=1721995|pmid=9135408}}</ref> and individuals of Ashkenazi Jewish heritage. It has been noted rarely in a few other ethnic groups.{{citation needed|date=October 2021}}

==Symptoms and signs==
Usher syndrome is characterized by [[hearing loss]] and a gradual [[visual impairment]]. The hearing loss is caused by a defective [[inner ear]], whereas the vision loss results from [[retinitis pigmentosa]] (RP), a degeneration of the retinal cells. Usually, the [[rod cell]]s of the [[retina]] are affected first, leading to early night blindness ([[nyctalopia]]) and the gradual loss of [[peripheral vision]]. In other cases, early degeneration of the [[cone cell]]s in the [[macula]] occurs, leading to a loss of [[visual acuity|central acuity]]. In some cases, the [[Fovea centralis|fovea]]l vision is spared, leading to "doughnut vision"; central and peripheral vision are intact, but a ring-like [[annulus (mathematics)|annulus]] exists, in which [[visual impairment|vision is impaired]].{{citation needed|date=October 2021}}, around the central region

==Cause==
{| align="right" style="margin-left:1em"
|+Table 1: Genes linked to Usher syndrome<br>
{{Legend inline|#EECCCC|Type I}} {{Legend inline|#D1EEEE|Type II}} {{Legend inline|#EEEED1|Type III}}
|----- bgcolor="#cfcfcf"
!Type&nbsp;
!Freq<ref>{{cite journal |vauthors=Roux AF, Faugere V, Le Guedard S, Pallares-Ruiz N, Vielle A, Chambert S, Marlin S, Hamel C, Gilbert B, Malcolm S, Claustres M | year = 2006 | title = Survey of the frequency of USH1 gene mutations in a cohort of Usher patients shows the importance of cadherin 23 and protocadherin 15 genes and establishes a detection rate of above 90% | journal = J Med Genet | volume = 43 | pages = 763–768 | pmid = 16679490 | doi = 10.1136/jmg.2006.041954 | issue = 9 | pmc = 2564578}}<br />{{cite journal |vauthors=Ouyang XM, Yan D, Du LL, Hejtmancik JF, Jacobson SG, Nance WE, Li AR, Angeli S, Kaiser M, Newton V, Brown SD, Balkany T, Liu XZ | year = 2005 | title = Characterization of Usher syndrome type I gene mutations in an Usher syndrome patient population | journal = Hum Genet |volume = 116 | pages = 292–299 | pmid = 15660226 | doi = 10.1007/s00439-004-1227-2 | issue = 4| s2cid = 22812718 }}</ref>
!Gene locus&nbsp;
!Gene
!Protein&nbsp;
!Function&nbsp;
!Size (AA)&nbsp;
!UniProt
![[OMIM]]
|-
|----- bgcolor="#eecccc"
|valign="middle" align="center"|USH1B
|valign="middle" align="center"|39–55%
|[[Chromosome 11|11]]<nowiki/>q13.5
|valign="middle" align="center"|''[[MYO7A]]''
|valign="middle" align="center"|[[Myosin]] VIIA
|valign="middle" align="center"|[[Motor protein]]
|valign="middle" align="center"|2215
|valign="middle" align="center"|{{uniprot|Q13402}}
|valign="middle" align="center"|{{OMIM|276900||none}}
|-
|----- bgcolor="#eecccc"
|valign="middle" align="center"|USH1C
|valign="middle" align="center"|6–7%
|[[Chromosome 11|11]]<nowiki/>p15.1-p14
|valign="middle" align="center"|''[[USH1C]]''
|valign="middle" align="center"|[[Usher 1C|Harmonin]]
|valign="middle" align="center"|[[PDZ domain|PDZ-domain protein]]
|valign="middle" align="center"|552
|valign="middle" align="center"|{{uniprot|Q9Y6N9}}
|valign="middle" align="center"|{{OMIM|276904||none}}
|-
|----- bgcolor="#eecccc"
|valign="middle" align="center"|USH1D
|valign="middle" align="center"|19–35%
|[[Chromosome 10|10]]<nowiki/>q21-q22
|valign="middle" align="center"|''[[CDH23]]''
|valign="middle" align="center"|[[Cadherin|Cadherin 23]]
|valign="middle" align="center"|[[Cell adhesion]]
|valign="middle" align="center"|3354
|valign="middle" align="center"|{{uniprot|Q9H251}}
|valign="middle" align="center"|{{OMIM|601067||none}}
|-
|----- bgcolor="#eecccc"
|valign="middle" align="center"|USH1E
|valign="middle" align="center"|rare
|[[Chromosome 21|21]]<nowiki/>q21
|valign="middle" align="center"|?
|valign="middle" align="center"|?
|valign="middle" align="center"|?
|valign="middle" align="center"|?
|valign="middle" align="center"|?
|valign="middle" align="center"|{{OMIM|602097||none}}
|-
|----- bgcolor="#eecccc"
|valign="middle" align="center"|USH1F
|valign="middle" align="center"|11–19%
|valign="middle" align="center"|[[Chromosome 10|10]]<nowiki/>q11.2-q21
|valign="middle" align="center"|''[[PCDH15]]''
|valign="middle" align="center"|[[Cadherin|Protocadherin 15]]
|valign="middle" align="center"|[[Cell adhesion]]
|valign="middle" align="center"|1955
|valign="middle" align="center"|{{uniprot|Q96QU1}}
|valign="middle" align="center"|{{OMIM|602083||none}}
|-
|----- bgcolor="#eecccc"
|valign="middle" align="center"|USH1G
|valign="middle" align="center"|7%
|[[Chromosome 17|17]]<nowiki/>q24-q25
|valign="middle" align="center"|''[[USH1G]] ''
|valign="middle" align="center"|SANS
|valign="middle" align="center"|[[Scaffold protein]]
|valign="middle" align="center"|461
|valign="middle" align="center"|{{uniprot|Q495M9}}
|valign="middle" align="center"|{{OMIM|606943||none}}
|-
|----- bgcolor="#d1eeee"
|valign="middle" align="center"|USH2A
|valign="middle" align="center"|80%
|[[Chromosome 1|1]]<nowiki/>q41
|valign="middle" align="center"|''[[USH2A]]''
|valign="middle" align="center"|Usherin
|valign="middle" align="center"|Transmembrane linkage
|valign="middle" align="center"|5202
|valign="middle" align="center"|{{uniprot|O75445}}
|valign="middle" align="center"|{{OMIM|276901||none}}
|-
|----- bgcolor="#d1eeee"
|valign="middle" align="center"|USH2C
|valign="middle" align="center"|15%
|[[Chromosome 5|5]]<nowiki/>q14.3-q21.1
|valign="middle" align="center"|''[[GPR98]]''
|valign="middle" align="center"|VLGR1b
|valign="middle" align="center"|Very large [[GPCR]]
|valign="middle" align="center"|6307
|valign="middle" align="center"|{{uniprot|Q8WXG9}}
|valign="middle" align="center"|{{OMIM|605472||none}}
|-
|----- bgcolor="#d1eeee"
|valign="middle" align="center"|USH2D
|valign="middle" align="center"|5%
|[[Chromosome 9|9]]<nowiki/>q32-q34
|valign="middle" align="center"|''[[DFNB31]]''
|valign="middle" align="center"|Whirlin
|valign="middle" align="center"|[[PDZ domain|PDZ-domain protein]]
|valign="middle" align="center"|907
|valign="middle" align="center"|{{uniprot|Q9P202}}
|valign="middle" align="center"|{{OMIM|611383||none}}
|-
|----- bgcolor="#eeeed1"
|valign="middle" align="center"|USH3A
|valign="middle" align="center"|100%
|[[Chromosome 3|3]]<nowiki/>q21-q25
|valign="middle" align="center"|''[[CLRN1]]''
|valign="middle" align="center"|Clarin-1
|valign="middle" align="center"|Synaptic shaping
|valign="middle" align="center"|232
|valign="middle" align="center"|{{uniprot|P58418}}
|valign="middle" align="center"|{{OMIM|276902||none}}
|}

Usher syndrome is inherited in an [[autosomal recessive]] pattern. Several genes have been associated with Usher syndrome using [[linkage analysis]] of patient families (Table 1) and [[DNA sequencing]] of the identified [[Locus (genetics)|loci]].<ref name="Petit">{{cite journal | last1 = Petit | first1 = C | url = https://pdfs.semanticscholar.org/2027/153c2f19cd88f7f2a753b99c646433de805e.pdf | archive-url = https://web.archive.org/web/20190503103254/https://pdfs.semanticscholar.org/2027/153c2f19cd88f7f2a753b99c646433de805e.pdf | url-status = dead | archive-date = 2019-05-03 | title = Usher syndrome: from genetics to pathogenesis | journal = Annual Review of Genomics and Human Genetics | volume = 2 | pages = 271–97 | year = 2001 | pmid = 11701652 | doi = 10.1146/annurev.genom.2.1.271 | s2cid = 505750 }}</ref><ref name="Reiners">{{cite journal | last1 = Reiners | first1 = J | last2 = Nagel-Wolfrum | first2 = K | last3 = Jürgens | first3 = K | last4 = Märker | first4 = T | last5 = Wolfrum | first5 = U | url = https://www.blogs.uni-mainz.de/fb10-ag-wolfrum/files/2019/01/Reiners_et_al_2006_USH_Rev_ExpEyeRes.pdf | archive-url = https://web.archive.org/web/20190503103839/https://www.blogs.uni-mainz.de/fb10-ag-wolfrum/files/2019/01/Reiners_et_al_2006_USH_Rev_ExpEyeRes.pdf | url-status = dead | archive-date = 2019-05-03 | title = Molecular basis of human Usher syndrome: deciphering the meshes of the Usher protein network provides insights into the pathomechanisms of the Usher disease | journal = Experimental Eye Research | volume = 83 | issue = 1 | pages = 97–119 | year = 2006 | pmid = 16545802 | doi = 10.1016/j.exer.2005.11.010 }}</ref> A mutation in any one of these genes is likely to result in Usher syndrome.{{citation needed|date=October 2021}}

The clinical subtypes Usher I and II are associated with mutations in any one of six (''[[USH1B]]-G'') and three (''[[USH2A]], C-D'') genes, respectively, whereas only one gene, ''[[USH3A]]'', has been linked to Usher III so far. Two other genes, ''USH1A'' and ''[[USH2B]]'', were initially associated with Usher syndrome, but ''USH2B'' has not been verified, and'' USH1A'' was incorrectly determined and does not exist.<ref>{{cite journal | last1 = Gerber | first1 = S | last2 = Bonneau | first2 = D | last3 = Gilbert | first3 = B | last4 = Munnich | first4 = A | last5 = Dufier | first5 = JL | last6 = Rozet | first6 = JM | last7 = Kaplan | first7 = J | title = USH1A: chronicle of a slow death | journal = American Journal of Human Genetics | volume = 78 | issue = 2 | pages = 357–9 | year = 2006 | pmid = 16400615 | pmc = 1380243 | doi = 10.1086/500275 }}</ref> Research in this area is ongoing.{{cn|date=October 2024}}

Using interaction analysis techniques, the identified gene products could be shown to interact with one another in one or more larger [[protein complex]]es. If one of the components is missing, this protein complex cannot fulfill its function in the living cell, and it probably comes to the [[Degeneration (medicine)|degeneration]] the same. The function of this protein complex has been suggested to participate in the [[signal transduction]] or in the [[cell adhesion]] of sensory cells.<ref name="Reiners" />

A study shows that three proteins related to Usher syndrome genes ([[PCDH15]], [[CDH23]], [[GPR98]]) are also involved in [[auditory cortex]] development, in mouse and macaque. Their lack of expression induces a decrease in the number of [[parvalbumin]] [[interneuron]]s. Patients with mutations for these genes could have consequently auditory cortex defects.<ref>{{Cite journal|last1=Libé-Philippot|first1=Baptiste|last2=Michel|first2=Vincent|last3=Monvel|first3=Jacques Boutet de|last4=Gal|first4=Sébastien Le|last5=Dupont|first5=Typhaine|last6=Avan|first6=Paul|last7=Métin|first7=Christine|last8=Michalski|first8=Nicolas|last9=Petit|first9=Christine|date=2017-07-25|title=Auditory cortex interneuron development requires cadherins operating hair-cell mechanoelectrical transduction|journal=Proceedings of the National Academy of Sciences|language=en|volume=114|issue=30|pages=7765–7774|doi=10.1073/pnas.1703408114|issn=0027-8424|pmid=28705869|pmc=5544301|bibcode=2017PNAS..114.7765L |doi-access=free}}</ref>

== Pathophysiology ==
The progressive blindness of Usher syndrome results from [[retinitis pigmentosa]].<ref name="smith_1994" /><ref name="pmid6604514" /> The [[photoreceptor cell]]s usually start to degenerate from the outer periphery to the center of the [[retina]], including the [[macula]]. The degeneration is usually first noticed as night blindness ([[nyctalopia]]); peripheral vision is gradually lost, restricting the visual field ([[tunnel vision]]), which generally progresses to complete blindness. The qualifier ''pigmentosa'' reflects the fact that clumps of pigment may be visible by an [[ophthalmoscope]] in advanced stages of degeneration.<ref name="williams_2007" />

The hearing impairment associated with Usher syndrome is caused by damaged hair cells in the [[cochlea]] of the [[inner ear]] inhibiting electrical impulses from reaching the brain. It is a form of [[dysacusis]].{{cn|date=October 2024}}

==Diagnosis==
Since Usher syndrome is incurable at present, it is helpful to diagnose children well before they develop the characteristic night blindness. Some preliminary studies have suggested as many as 10% of children with congenital severe to profound deafness may have Usher syndrome.<ref name="mets_2000" /> However, a misdiagnosis can have bad consequences.{{citation needed|date=October 2021}}

The simplest approach to diagnosing Usher syndrome is to test for the characteristic [[Chromosome|chromosomal]] mutations. An alternative approach is [[electroretinography]], although this is often disfavored for children since its discomfort can also make the results unreliable.<ref name="mets_2000" /> Parental consanguinity is a significant factor in diagnosis. Usher syndrome I may be indicated if the child is profoundly deaf from birth and especially slow in walking.{{cn|date=October 2024}}

Thirteen other syndromes may exhibit signs similar to Usher syndrome, including [[Alport syndrome]], [[Alström syndrome]], [[Bardet–Biedl syndrome]], [[Cockayne syndrome]], [[spondyloepiphyseal dysplasia congenita]], [[Flynn–Aird syndrome]], [[Friedreich ataxia]], [[Hurler syndrome]] (MPS-1), [[Kearns–Sayre syndrome]] (CPEO), [[Norrie syndrome]], [[osteopetrosis]] (Albers–Schonberg disease), [[Refsum disease]] (phytanic acid storage disease) and [[Zellweger syndrome]] (cerebrohepatorenal syndrome).{{citation needed|date=September 2021}}

===Classification===
Although Usher syndrome has been classified clinically in several ways,<ref>
{{cite journal|author=Hammerschlag V|year=1907|title=Zur Kenntnis der hereditaer-degenerativen Taubstummen und ihre differential diagnostische Bedeutung|journal=Z. Ohrenheilk.|volume=54|pages=18–36}}<br />
{{cite book|title=Retinitis Pigmentosa and Allied Diseases|author=Bell J|publisher=Cambridge University Press|year=1933|edition=2nd|location=London}}<br />
{{cite journal|author=Hallgren B|year=1959|title=Retinitis pigmentosa combined with congenital deafness with vestibulo-cerebellar ataxia and mental abnormality in a proportion of cases: Clinical and geneto-statistical survey|journal=[[Acta Psychiatr Scand Suppl]]|volume=34|issue=138|pages=9–101|doi=10.1111/j.1600-0447.1959.tb08605.x|pmid=14399116|s2cid=221393918}}<br />
{{cite journal|vauthors=Merin S, Auerbach E|year=1976|title=Retinitis pigmentosa|journal=Surv. Ophthalmol.|volume=20|issue=5|pages=303–345|doi=10.1016/S0039-6257(96)90001-6|pmid=817406}}<br />
{{cite book|title=The Heterogeneity of Usher Syndrome|vauthors=Davenport S, Omenn G|publisher=Excerpta Medica Foundation|year=1977|edition=volume 426|location=Amsterdam}}<br />
{{cite journal|vauthors=Gorlin R, Tilsner T, Feinstein S, Duvall AJ|year=1979|title=Usher syndrome type III|journal=Arch. Otolaryngol.|volume=105|issue=6|pages=353–354|doi=10.1001/archotol.1979.00790180051011|pmid=454290}}</ref><ref name="pmid6604514">{{cite journal|vauthors=Fishman GA, Kumar A, Joseph ME, Torok N, Andersonj RJ|year=1983|title=Usher's syndrome: ophthalmic and neuro-otologic findings suggesting genetic heterogeneity|journal=Archives of Ophthalmology|volume=101|issue=9|pages=1367–1374|doi=10.1001/archopht.1983.01040020369005|pmid=6604514}}</ref><ref>{{cite journal|vauthors=Sankila EM, Pakarinen H, Kääriäinen H, Aittomäki K, Karjalainen S, Sistonen P, de la Chapelle A|year=1995|title=Assignment of Usher syndrome type III (USH3) gene to chromosome 3q|journal=Hum. Mol. Genet.|volume=4|issue=1|pages=93–98|doi=10.1093/hmg/4.1.93|pmid=7711740}}</ref> the prevailing approach is to classify it into three clinical sub-types called Usher I, II and III in order of decreasing severity of deafness.<ref name="smith_1994">{{cite journal|vauthors=Smith RJ, Berlin CI, Hejtmancik JF, Keats BJ, Kimberling WJ, Lewis RA, etal|year=1994|title=Clinical diagnosis of the Usher syndromes. Usher Syndrome Consortium|journal=American Journal of Medical Genetics|volume=50|issue=1|pages=32–38|doi=10.1002/ajmg.1320500107|pmid=8160750}}</ref><ref name="williams_2007">{{cite journal|author=Williams DS|year=2007|title=Usher syndrome: Animal models, retinal function of Usher proteins, and prospects for gene therapy|journal=Vision Research|volume=48|issue=3|pages=433–41|doi=10.1016/j.visres.2007.08.015|pmc=2680226|pmid=17936325}}</ref> Although it was previously believed that there was an Usher syndrome type IV, researchers at the [[University of Iowa]] recently{{When|date=October 2018}} confirmed that there is no USH type IV.{{citation needed|date=February 2018}} As described below, these clinical subtypes may be further subdivided by the particular gene mutated; people with Usher I and II may have any one of six and three genes mutated, respectively, whereas only one gene has been associated with Usher III. The function of these genes is still poorly understood.{{citation needed|date=October 2021}}

Usher syndrome is a variable condition; the degree of severity is not tightly linked to whether it is Usher I, II, or III. For example, someone with type III may be unaffected in childhood but go on to develop a profound hearing loss and a very significant loss of sight by early-to-mid adulthood. Similarly, someone with type I, who is therefore profoundly deaf from birth, may keep good central vision until the sixth decade of life or even beyond. People with type II, who have useful hearing with a hearing aid, can experience a wide range of severity of the RP. Some may maintain good reading vision into their 60s, while others cannot see to read while still in their 40s.{{citation needed|date=October 2021}}

Since Usher syndrome is inherited in an [[autosomal recessive]] pattern, both males and females are equally likely to inherit it. [[Consanguinity]] of the parents is a risk factor.{{cn|date=October 2024}}

==Treatment==

Since Usher syndrome results from the loss of a gene, [[gene therapy]] that adds the proper protein back ("gene replacement") may alleviate it, provided the added protein becomes functional. Recent studies of [[knockout mouse|mouse models]] have shown one form of the disease—that associated with a mutation in [[myosin]] VIIa—can be alleviated by replacing the mutant gene using a [[lentivirus]].<ref name="hashimoto_2007" >{{cite journal |vauthors=Hashimoto T, Gibbs D, Lillo C, Azarian SM, Legacki E, Zhang XM, Yang XJ, Williams DS | year = 2007 | title = Lentiviral gene replacement therapy of retinas in a mouse model for Usher syndrome type 1B | journal = Gene Therapy | volume = 14 | pages = 584–594 | pmid = 17268537 | doi = 10.1038/sj.gt.3302897 | issue = 7 | pmc = 9307148 | doi-access = free }}</ref> However, some of the mutated genes associated with Usher syndrome [[Central dogma of molecular biology|encode]] very large proteins—most notably, the ''USH2A'' and ''GPR98'' [[protein]]s, which have roughly 6000 [[amino acid|amino-acid]] residues. Scientists have successfully treated mice with Usher syndrome type 1C, which has a relatively small affected gene.<ref>{{cite news |magazine=[[Scientific American]] |title=Out of the Silence: Gene Therapy Tackles a Common Birth Defect: Deafness |author=Dina Fine Maron |date=December 4, 2018 |url=https://bertarelli.hms.harvard.edu/sites/hwpi.harvard.edu/files/sciamericanarticle_12_2018.pdf?m=1543951180 |pages=72–79}}</ref>

In 2025, in Italy, the first-ever case of sight restoration was reported in a 38-year-old patient affected by Usher syndrome type 1B, one year after receiving gene therapy. [https://www.euronews.com/health/2025/07/30/experimental-treatment-restores-sight-to-man-with-genetic-eye-disorder-in-italy<nowiki>]</nowiki>

== Epidemiology ==
Usher syndrome is responsible for the majority of [[deafblindness]].<ref>{{cite journal|author=Vernon M|year=1969|title=Usher's syndrome — deafness and progressive blindness. Clinical cases, prevention, theory and literature survey|journal=Journal of Chronic Diseases|volume=22|issue=3|pages=133–151|doi=10.1016/0021-9681(69)90055-1|pmid=4897966}}</ref> It occurs in roughly 1 in 23,000 people in the [[United States]],<ref>{{cite journal|vauthors=Boughman J, Vernon M, Shaver K|year=1983|title=Usher syndrome: Definition and estimate of prevalence from two high-risk populations|journal=Journal of Chronic Diseases|volume=36|issue=8|pages=595–603|doi=10.1016/0021-9681(83)90147-9|pmid=6885960}}</ref> 1 in 28,000 in Norway,<ref name=":1">{{cite journal|author=Grøndahl J|year=1987|title=Estimation of prognosis and prevalence of retinitis pigmentosa and Usher syndrome in Norway|journal=Clin. Genet.|volume=31|issue=4|pages=255–264|doi=10.1111/j.1399-0004.1987.tb02804.x|pmid=3594933|s2cid=26853136}}</ref> and 1 in 12,500 in Germany.<ref name=":0">{{cite journal|vauthors=Otterstedde CR, Spandau U, Blankenagel A, Kimberling WJ, Reisser C|year=2001|title=A new clinical classification for Usher's syndrome based on a new subtype of Usher's syndrome type I|journal=Laryngoscope|volume=111|issue=1|pages=84–86|doi=10.1097/00005537-200101000-00014|pmid=11192904|s2cid=41124463}}</ref> People with Usher syndrome represent roughly one-sixth of people with [[retinitis pigmentosa]].<ref name="williams_2007" />

== History ==

Usher syndrome is named after the Scottish ophthalmologist [[Charles Usher]], who examined the [[pathology]] and [[transmission (medicine)|transmission]] of this illness in 1914 based on 69 cases.<ref name="Usher">{{cite journal | author = Usher C | year = 1914 | title = On the inheritance of Retinitis pigmentosa with notes of cases | journal = Roy. Lond. Ophthalmol. Hosp. Rep. | volume = 19 | pages = 130–236}}</ref> However, it was first described in 1858 by [[Albrecht von Graefe (ophthalmologist)|Albrecht von Gräfe]], a pioneer of modern [[ophthalmology]].<ref name="Graefe">{{cite journal | author = von Gräfe A | year = 1858 | title = Exceptionelles Verhalten des Gesichtsfeldes bei Pigmententartung der Netzhaut | journal = Archiv für Ophthalmologie | volume = 4 | pages = 250–253}}</ref> He reported the case of a deaf patient with [[retinitis pigmentosa]], who had two brothers with the same symptoms. Three years later, one of his students, [[Richard Liebreich]], examined the population of Berlin for disease patterns of deafness with retinitis pigmentosa.<ref name="Liebreich">{{cite journal | author = Liebreich R | year = 1861 | title = Abkunft aus Ehen unter Blutsverwandten als Grund von Retinitis pigmentosa | journal = Dtsch. Klin. | volume = 13 | pages = 53}}</ref> Liebreich noted Usher syndrome to be recessive since the cases of blind-deafness combinations occurred particularly in the siblings of blood-related marriages or in families with patients in different generations. His observations supplied the first proofs for the coupled transmission of blindness and deafness since no isolated cases of either could be found in the family trees.{{citation needed|date=October 2021}}

Animal models of this human disease (such as [[knockout mouse|knockout mice]] and [[zebrafish]]) have been developed recently{{When|date=October 2018}} to study the effects of these gene mutations and to test potential cures for Usher syndrome.{{cn|date=October 2024}}

==Society and culture==
===Notable cases===
<!-- Please maintain alphabetical order. -->
* [[Rebecca Alexander]], a [[Psychotherapy|psychotherapist]], [[author]], and recipient of the Helen Keller Achievement Award.{{cn|date=October 2024}}
* [[Cyril Axelrod]], Catholic priest.{{cn|date=October 2024}}
* [[Catherine Fischer]] wrote her autobiography of growing up with Usher syndrome in Louisiana, entitled ''Orchid of the Bayou''.<ref>{{cite book |vauthors=Carroll C, Fischer CH | year = 2001 | title = Orchid of the Bayou: A Deaf Woman Faces Blindness | publisher = Gallaudet University Press | isbn = 978-1-56368-104-2}}</ref>
* [[Katie Kelly (paratriathlete)|Katie Kelly]], a gold medal–winning paralympian.{{cn|date=October 2024}}
* Christian Markovic, and blind-deaf illustrator and designer; Fuzzy Wuzzy Designs.<ref>{{cite web|url=http://www.fuzzywuzzydesign.com/about/|title=Who's Fuzzy|work=Fuzzy Wuzzy Design|access-date=2015-08-07|archive-date=2021-06-29|archive-url=https://web.archive.org/web/20210629022455/https://fuzzywuzzydesign.com/about/|url-status=usurped}}</ref>
* The Israeli [[Nalaga'at]] (do touch) Deaf-blind Acting Ensemble consists of 11 deaf-blind actors, most of whom are diagnosed with Usher syndrome. The theater group has put on several productions and appeared both locally in Israel and abroad in London and Broadway.<ref>{{Cite web |url=http://www.nalagaat.org.il/home.php |title=Nalagaat Center &#124; Home |access-date=2010-11-03 |archive-date=2010-11-24 |archive-url=https://web.archive.org/web/20101124062124/http://www.nalagaat.org.il/home.php |url-status=dead }}</ref>
* Karolina Pakėnaitė,<ref>{{Cite web |title=About Me |url=https://www.deafblindeverestproject.com/about-me |access-date=2025-04-05 |website=DeafBlind Everest Project |language=en-GB}}</ref> a [[PhD student]] at the [[University of Bath]]<ref>{{Cite web |title=CDE PhDs and EngDs |url=https://digital-entertainment.org/alumni-2/#karolina-pakenaite |access-date=2025-04-05 |website=The Centre for Digital Entertainment (CDE) |language=en}}</ref> diagnosed in 2014, and "seeking to be the first deafblind [person] to reach the summit of Mount Everest".<ref>{{Cite web |title=Deafblind PhD student aims for Everest |url=https://www.bath.ac.uk/announcements/deafblind-phd-student-aims-for-everest/ |access-date=2025-04-05 |website=www.bath.ac.uk |language=en}}</ref><ref>{{Cite web |last=Admin@TCA |date=2024-07-17 |title=Meet Karolina – DeafBlind Everest climber |url=https://www.theclimbingacademy.com/tca-life/meet-karolina-deafblind-everest-climber/ |access-date=2025-04-05 |website=The Climbing Academy |language=en-GB}}</ref>
* Christine "Coco" Roschaert, director of the Nepal Deafblind Project, kick-off speaker for Deaf Awareness Week at the [[University of Vermont]], and participant in the [[Gallaudet United Now Movement]].<ref>{{Cite web|url=https://tactiletheworld.wordpress.com/|title=Tactile The World|website=Tactile The World}}</ref>
* Robert Tarango, first deafblind person to star in a movie, in the role of Artie in the Oscar-nominated short film ''[[Feeling Through]]''.{{cn|date=October 2024}}
* John Tracy, the son of actor [[Spencer Tracy]] and namesake of the oralist [[John Tracy Clinic]].{{cn|date=October 2024}}
* [[Teigan Van Roosmalen]], paraolympian.{{cn|date=October 2024}}
* Vendon Wright has written two books describing his life with Usher syndrome, ''I Was Blind but Now I Can See''<ref>{{cite book | author = Wright V | year = 2007 | title = I Was Blind but Now I Can See | publisher = Authorhouse | isbn = 978-1-4208-9101-0}}</ref> and ''Through My Eyes''.<ref>{{cite book | author = Wright V | year = 2007 | title = Through My Eyes | publisher = Pipers' Ash Ltd | isbn = 978-1-904494-86-7}}</ref>
<!-- Please maintain alphabetical order. -->

==References==
{{Reflist}}

==Further reading==
* {{cite book |vauthors=Duncan E, Prickett HT |year=1988 |title=Usher's Syndrome: What It Is, How to Cope, and How to Help |publisher=Charles C. Thomas |isbn=978-0-398-05481-6}}
* {{cite book |vauthors=Stiefel SH, Lewis RA |year=1991 |title=The Madness of Usher's: Coping With Vision and Hearing Loss/Usher Syndrome Type II |publisher=Business of Living Publications |isbn=978-1-879518-06-3}}
* {{cite book |author=Vernon M |year=1986 |title=Answers to your questions about Usher's syndrome (retinitis pigmentosa with hearing loss) |publisher=Foundation Fighting Blindness |id=ASIN B00071QLJ6}}
* {{cite book |author=Vernon M |year=1969 |title=Usher's syndrome: Deafness and progressive blindness: clinical cases, prevention, theory and literature survey |publisher=Pergamon Press |id=ASIN B0007JHOJ4}}

== External links ==
* [https://www.ncbi.nlm.nih.gov/books/NBK1265/ GeneReviews/NCBI/NIH/UW entry on Usher Syndrome Type I]
* [https://www.ncbi.nlm.nih.gov/books/NBK1341/ GeneReviews/NCBI/NIH/UW entry on Usher Syndrome Type II]
* [https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=usher/ NCBI Genetic Testing Registry]
* [https://medlineplus.gov/genetics/condition/usher-syndrome/ General overview from the NIH]
* [https://web.archive.org/web/20060416083222/http://www.nidcd.nih.gov/health/hearing/usher.htm Usher Syndrome] Information from the National Institute on Deafness and Other Communication Disorders (NIDCD).

{{Medical resources
| DiseasesDB      = 13611
| ICD10           = H35.53
| ICD9            =
| ICDO            =
| OMIM            = 276900
| OMIM_mult       = {{OMIM|276901||none}}
| MedlinePlus     =
| eMedicineSubj   =
| eMedicineTopic  =
| MeshID          = D052245
| Orphanet        = 886
| SNOMED CT       = 57838006
}}
{{Hearing and balance}}
{{Cytoskeletal defects}}
{{Authority control}}

[[Category:Autosomal recessive disorders]]
[[Category:Ashkenazi Jews topics]]
[[Category:Cytoskeletal defects]]
[[Category:Diseases named after discoverers]]
[[Category:Diseases of the ear and mastoid process]]
[[Category:Rare syndromes]]
[[Category:Syndromes affecting hearing]]
[[Category:Syndromes affecting the eye]]