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Usher syndrome

Usher syndrome
Classification & external resources
OMIM 276900 276901
DiseasesDB 13611

Usher syndrome (sometimes referred to as "Usher's syndrome") is a relatively rare genetic disorder that is a leading cause of deaf-blindness. Other names for Usher syndrome include Hallgren syndrome, Usher-Hallgren syndrome, rp-dysacusis syndrome and dystrophia retinae dysacusis syndrome.[1] The word syndrome means that multiple symptoms occur together, in this case, deafness and blindness. Usher syndrome is incurable at present, but preliminary experiments with gene therapy in mice are promising.[2]

Usher syndrome has three clinical subtypes, denoted as I, II and III in decreasing order of severity. People with Usher I are born profoundly deaf, and begin to lose their vision in the first decade of life. They also exhibit balance difficulties and learn to walk slowly as children, due to problems in their vestibular system. People with Usher II are also born deaf, but do not seem to have noticeable problems with balance; they also begin to lose their vision later (in the second decade of life) and may preserve some vision even into middle age. People with Usher syndrome III are not born deaf, but experience a gradual loss of their hearing and vision; they may or may not have balance difficulties.

The gradual vision loss of this syndrome is associated with retinitis pigmentosa, which is a degeneration of the retinal cells. The qualifier pigmentosa reflects the fact that clumps of pigment may be visible by an ophthalmoscope in advanced stages of degeneration. Usually, the rod cells of the retina are affected first, leading to early night blindness and the gradual loss of peripheral vision. In other cases, there is early degeneration of the cone cells in the macula, leading to a loss of central acuity. In some cases, the foveal vision is spared, leading to "doughnut vision"; central and peripheral vision are intact, but there is an annulus around the central region in which vision is impaired.

Usher syndrome is an inherited disorder associated with a mutation in any one of roughly 10 genes. The three subtypes correspond to different mutations: Usher syndrome I and II are associated with a mutation in any one of six or three different genes, respectively, whereas only one mutation has been linked with Usher III. Usher syndrome is inherited in an autosomal recessive pattern, meaning that the mutated gene is not found on a sex chromosome (autosomal) and that the syndrome only appears in people in whom both copies of the gene are mutated (recessive). Thus, both males and females are equally likely to inherit Usher syndrome. If both parents have Usher syndrome in the same gene, all their children are overwhelmingly likely to have the same condition; by contrast, the children of a mixed marriage (one parent with Usher syndrome and the other with wild-type genes) are overwhelmingly likely to not have the condition, although they will be all asymptomatic carriers. Since Usher syndrome mutations are recessive, consanguinity of the parents is a risk factor. First recognized in the 19th century, Usher syndrome was the first condition to demonstrate that phenotypes could be inherited in tandem; deafness and blindness are inherited together, but not separately. Animal models of this human disease (such as knockout mice and zebrafish) have been developed recently to study the effects of these gene mutations and to test potential cures for Usher syndrome.


Symptoms and subtypes


Usher syndrome is responsible for the majority of deaf-blindness.[3] It occurs in roughly 1 person in 23,000 in the United States,[4] 1 in 28,000 in Norway[5] and 1 in 12,500 in Germany.[6]

Although Usher syndrome has been classified clinically in several ways,[7] 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.[8] Usher I and II are the more common forms; the fraction of people with Usher III is significant only in a few specific areas, such as Finland[9] and Birmingham.[10] People with Usher I are usually born deaf and often have difficulties in maintaining their balance owing to problems in the vestibular system. Babies with Usher I are usually slow to develop motor skills such as walking. People with Usher II are generally hard-of-hearing rather than deaf, and their hearing does not degrade over time; moreover, they generally have a normal vestibular system. By contrast, people with Usher III experience a progressive loss of hearing and roughly half have vestibular dysfunction. 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 poorly understood as of yet. The hearing impairment associated with Usher syndrome is better understood: damaged hair cells in the cochlea of the inner ear inhibit electrical impulses from reaching the brain.

The progressive blindness of Usher syndrome occurs in all three clinical subtypes and results from retinitis pigmentosa.[8][11]Usually the photoreceptors 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.


Usher syndrome was probably described for the first time in 1858 by Albrecht von Gräfe, a pioneer of modern ophthalmology.[12] 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 pattern of deafness with retinitis pigmentosa.[13] Liebreich noted that the disease was 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 the disease, since no cases of isolated blindness or deafness in the family trees could be found.

The syndrome was named after the British ophthalmologist Charles Usher, who examined the pathology and transmission of this illness in 1914 on the basis of 69 cases.[14]

Associated mutations in genes

Table 1: Genes linked to Usher syndrome
Usher-Type  Gene locus  Gene Protein  Function  OMIM
1B 11q13.5 MYO7A Myosin VIIA Motor protein 276900
1C 11p15.1-p14 USH1C Harmonin PDZ-domain protein 276904
1D 10q21-q22 CDH23 Cadherin 23 Cell adhesion 601067
1E 21q21 ? ? ? 602097
1F 10q11.2-q21 PCDH15 Protocadherin 15 Cell adhesion 602083
1G 17q24-q25 USH1G SANS Scaffold protein 606943
2A 1q41 USH2A Usherin Transmembrane linkage 276901
2C 5q14.3-q21.1 VLGR1 VLGR1b Very large GPCR 605472
2D 9q32-q34 DFNB31 Whirlin PDZ-domain protein 611383
3A 3q21-q25 USH3A Clarin-1 Synaptic shaping 276902

Several genes have been associated with Usher syndrome using linkage analysis of patient families (Table 1) and DNA sequencing of the identified loci.[15][16] A mutation in any one of these genes is likely to result in Usher syndrome. 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.[17] Research in this area is ongoing.

Using interaction analysis techniques it could be shown that the identified gene products interact with one another in one or more larger protein complexes. 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 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.[16]

Usher syndrome I

Worldwide, the estimated prevalence of Usher syndrome type I is 3 to 6 per 100,000 people in the general population.

Usher syndrome type I can be caused by mutations in any one of several different genes: CDH23, MYO7A, PCDH15, Usher 1C, 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 vision loss.

Usher syndrome II

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.

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.

Usher syndrome III

The frequency of Usher syndrome type III is highest in the Finnish population, but it has been noted rarely in a few other ethnic groups.

Mutations in only one gene, the USH3A gene, have been linked to Usher syndrome type III. Also known as the CLRN1 gene, USH3A encodes Clarin-1, a protein that is 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 poorly understood as yet.

Prospects for gene therapy

Since Usher syndrome results from the loss of a gene, gene therapy that adds the proper protein back ("gene replacement") may alleviate it, provided that the added protein becomes functional. Preliminary gene-replacement studies using lentivirus on mouse models have shown promising results.[18] However, some of the mutated genes associated with Usher syndrome code for very large proteins — most notably, the USH2A and GPR98 proteins, which have roughly 6000 amino-acid residues. Gene replacement therapy for such large proteins may be difficult.

Differential 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 that as many as 10% of congenitally deaf children may have Usher syndrome.[1] However, a mis-diagnosis can have bad consequences, e.g., if the parents elect to give the child cochlear implants.

The simplest approach to diagnosing Usher syndrome is to test for the characteristic chromosomal mutations. An alternative approach is electroretinography (ERG), although this is often disfavored for children, since its discomfort can also make the results unreliable.[1] 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.

Thirteen other syndromes may exhibit signs similar to Usher syndrome, including Alport syndrome, Alstrom 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's disease (phytanic acid storage disease), and Zellweger syndrome (cerebro-hepato-renal syndrome).

Individual cases

A 28-year-old woman with Usher syndrome, Rebecca Alexander, was profiled in Marie Claire in November 2007.[19] After graduating from the University of Michigan with excellent marks, Alexander went on Columbia University, where she earned two master's degrees in public health and clinical social work. Today she is a social worker at a school for the deaf, and organizes seminars for the Foundation Fighting Blindness. She's also in private practice as a psychotherapist for eating disorders.

Christine "Coco" Roschaert[20] is a well-known person with Usher syndrome. She has published video blogs at Youtube,[21] , and recently was the kick-off speaker for the Deaf Awareness Week at the University of Vermont.[22] In 2006, she graduated with a degree in Communication Sciences from Gallaudet University; there, she was a hunger striker in the 2006 protest organized by the Gallaudet United Now Movement.[23] Roschaert is now in Nigeria founding the first deafblind program in that country.

A web-community, UsherLife, of people with Usher syndrome was founded on 1 February 2005 by Nick Sturley. Although centered on Great Britain, it offers resources to all people with Usher syndrome. The organization is hosting regular get-togethers in England, such as the Usher Hood Pub in Nottingham[24] and a trip to Brighton pier.[25] Other people with Usher syndrome have posted videos about their lives and condition on YouTube, most notably Ginny Paja-Nyholm.[26] In October 2007, Candice, a mom living in Texas, began blogging about her two daughters, Jasmine and Rebecca; Rebecca has Usher syndrome I.[27]

Catherine Fischer has written a well-received autobiography of growing up with Usher syndrome in Louisiana, entitled Orchid of the Bayou.[28] Similarly, Vendon Wright has written two books describing his life with Usher syndrome, I was blind but now I can see[29] and Through my eyes.[30] Louise Boardman has also written a short book called My son has Usher's Syndrome.[31]

Christian Markovic, an artist living with Usher syndrome, runs a company, Fuzzy Wuzzy Designs.[32]

Spencer Tracy's son John was a well-known person with Usher syndrome who lived a full life.[33] The John Tracy Clinic was founded in 1942 by his mother Louise to offer free help to parents of hearing-impaired infants and preschool children.[1]


  1. ^ a b c d Mets MB, Young NM, Pass A, Lasky JB (2000). "Early diagnosis of Usher syndrome in children". Transactions of the American Ophthalmological Society 98: 237–245. PMID 11190026.
  2. ^ Williams DS (2007). "Usher syndrome: Animal models, retinal function of Usher proteins, and prospects for gene therapy". Vision Research xx: xx–xx. PMID 17936325.
  3. ^ Vernon M (1969). "Usher's syndrome — deafness and progressive blindness. Clinical cases, prevention, theory and literature survey". Journal of Chronic Disorders 22: 133–151. PMID 4897966.
  4. ^ Boughman J, Vernon M, Shaver K (1983). "Usher syndrome: Definition and estimate of prevalence from two high-risk populations". Journal of Chronic Disorders 36: 595–603. PMID 6885960.
  5. ^ Grøndahl J (1987). "Estimation of prognosis and prevalence of retinitis pigmentosa and Usher syndrome in Norway". Clin. Genet. 31: 255–264. PMID 3594933.
  6. ^ Otterstedde CR, Spandau U, Blankenagel A, Kimberling WJ, Reisser C (2001). "A new clinical classication for Usher's syndrome based on a new subtype of Usher's syndrome type I". Laryngoscope 111: 84–86. PMID 11192904.
  7. ^ Hammerschlag V (1907). "Zur Kenntnis der hereditaer-degenerativen Taubstummen und ihre differential diagnostische Bedeutung". Z. Ohrenheilk. 54: 18–36.
    Bell J (1933). Retinitis Pigmentosa and Allied Diseases, 2nd edition, London: Cambridge University Press. 
    Hallgren B (1959). "Retinitis pigmentosa combined with congenital deafness with vestibulo-cerebellar ataxia and mental abnormality in a proportion of cases: Clinical and geneto-statistical survey". Acta Psychiatr. Scand. Suppl. 138: 9–101. PMID 14399116.
    Merin S, Auerbach E (1976). "Retinitis pigmentosa". Surv. Ophthalmol. 20: 303–345. PMID 817406.
    Davenport S, Omenn G (1977). The Heterogeneity of Usher Syndrome, volume 426, Amsterdam: Excerpta Medica Foundation. 
    Gorlin R, Tilsner T, Feinstein S, Duvall AJ (1979). "Usher syndrome type III". Arch. Otolaryngol. 105: 353–354. PMID 454290.
    Fishman G, Kumar A, Joseph ME, Torok N, Anderson RJ (1983). "Usher's syndrome: Ophthalmic and neuro-otologic findings suggesting congenital heterogeneity". Arch. Ophthalmol. 101: 1367–1374. PMID 6604514.
    Sankila EM, Pakarinen H, Kääriäinen H, Aittomäki K, Karjalainen S, Sistonen P, de la Chapelle A (1995). "Assignment of Usher syndrome type III (USH3) gene to chromosome 3q". Hum. Mol. Genetics 4: 93–98. PMID 7711740.
  8. ^ a b Smith RJ, Berlin CI, Hejtmancik JF, Keats BJ, Kimberling WJ, Lewis RA, et al. (1994). "Clinical diagnosis of the Usher syndromes. Usher Syndrome Consortium". American Journal of Medical Genetics 50: 32–38. PMID 8160750.
  9. ^ Pakarinen L, Tuppurainen K, Laipapala P, Mäntyjärvi M, Puhakka H (1996). "The ophthalmological course of Usher syndrome type III". International Ophthalmology 19: 307–311. PMID 8864816.
  10. ^ Hope CI, Bundey S, Proops D, Fielder AR (1997). "Usher syndrome in the city of Birmingham — prevalence and clinical classification". British Journal of Ophthalmology 81: 46–53. PMID 9135408.
  11. ^ Fishman GA, Kumar A, Joseph ME, Torok N, and Andersonj RJ. "Usher's syndrome". Archives of Ophthalmology 109: 1367–1374. PMID 6604514.
  12. ^ von Gräfe A (1858). "Exceptionelles Verhalten des Gesichtsfeldes bei Pigmententartung der Netzhaut". Archiv für Ophthalmologie 4: 250–253.
  13. ^ Liebreich R (1861). "Abkunft aus Ehen unter Blutsverwandten als Grund von Retinitis pigmentosa". Dtsch. Klin. 13: 53.
  14. ^ Usher C (1914). "On the inheritance of Retinitis pigmentosa with notes of cases". Roy. Lond. Ophthalmol. Hosp. Rep. 19: 130–236.
  15. ^ C. Petit: Usher syndrome: from genetics to pathogenesis. Annu.Rev.Genomics Hum.Genet. 2001 (2): 271-297 PMID 11701652
  16. ^ a b J. Reiners et al.: 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;83(1):97-119 PMID 16545802
  17. ^ S. Gerber et al.: USH1A: Chronicle of a Slow Death. Am J Hum Genet. 2006;78(2):357-9. PMID 16400615
  18. ^ Hashimoto T, Gibbs D, Lillo C, Azarian SM, Legacki E, Zhang XM, Yang XJ, Williams DS (2007). "Lentiviral gene replacement therapy of retinas in a mouse model for Usher syndrome type 1B". Gene Therapy 14: 584–594. PMID 17268537.
  19. ^ Alexander R, Grossman AJ (November 2007). "out of sight, out of sound". Marie Claire 14 (11): 191–193.
  20. ^ Coco's blog
  21. ^ Coco's user page at YouTube
  22. ^
  23. ^ First-person account of the 2006 protests at Gallaudet University
  24. ^ First Usher Hood Pub on 21 July 2007 (YouTube)
  25. ^ Trip to Brighton Pier on 9 June 2007 (YouTube)
  26. ^ Ginny's trivia challenge for Usher syndrome
  27. ^ Candice. I'm adopting a Deaf child with Ushers, now what?. Retrieved on 2007-11-07.
  28. ^ Carroll C, Fischer CH (2001). Orchid of the Bayou: A Deaf Woman Faces Blindness. Gallaudet University Press. ISBN 978-1563681042. 
  29. ^ Wright V (2007). I was blind but now I can see. Authorhouse. ISBN 978-1420891010. 
  30. ^ Wright V (2007). Through my eyes. Pipers' Ash Ltd. ISBN 978-1904494867. 
  31. ^ Boardman LS (1985). My son has Usher's Syndrome. Foundation Fighting Blindness. B0007207IG. 
  32. ^ Profile of Christian Markovic of Fuzzy Wuzzy Designs
  33. ^ Associated Press obituary for John Tracy

Additional reading

  • Parker PM (2007). Usher Syndrome - A Bibliography and Dictionary for Physicians, Patients, and Genome Researchers. ICON Group International. ISBN 978-0497113049. 
  • Icon Health Publications (2004). The Official Patient's Sourcebook On Usher Syndrome: Directory For The Internet Age, revised, updated edition, Icon Health Publications. ISBN 978-0597842030. 
  • Stiefel SH, Lewis RA (1991). The Madness of Usher's: Coping With Vision and Hearing Loss/Usher Syndrome Type II. Business of Living Publications. ISBN 978-1879518063. 
  • Duncan E, Prickett HT (1988). Usher's Syndrome: What It Is, How to Cope, and How to Help. Charles C. Thomas. ISBN 978-0398054816. 
  • Vernon M (1986). Answers to your questions about Usher's syndrome (retinitis pigmentosa with hearing loss). Foundation Fighting Blindness. ASIN B00071QLJ6. 
  • Vernon M (1969). Usher's syndrome: Deafness and progressive blindness : clinical cases, prevention, theory and literature survey. Pergamon Press. ASIN B0007JHOJ4. 
This article is licensed under the GNU Free Documentation License. It uses material from the Wikipedia article "Usher_syndrome". A list of authors is available in Wikipedia.
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