Medicine:Usher syndrome

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Short description: Recessive genetic disorder causing deafblindness
Usher syndrome
Other namesUsher–Hallgren syndrome
Usher syndrome is inherited in an autosomal recessive pattern. The genes implicated in Usher syndrome are described below.

Usher syndrome, also known as Hallgren syndrome, Usher–Hallgren syndrome, retinitis pigmentosa–dysacusis syndrome or dystrophia retinae dysacusis syndrome,[1] is a rare genetic disorder caused by a mutation in any one of at least 11 genes 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.

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[2] to as low as 1 in 28,000 in Norway.[3] Type I is most common in Ashkenazi Jewish and Acadian populations, and type III is rarely found outside Ashkenazi Jewish and Finnish[4] 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

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).[5] Among Acadians, research into haplotype data is consistent with one single mutation being responsible for all cases of Usher syndrome type I.[5]

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;[6] moreover, they do not seem to have noticeable problems with balance.[7] They also begin to lose their vision later (in the second decade of life) and may preserve some vision even into middle age.


Usher syndrome III

The frequency of Usher syndrome type III is significant only in the Finnish population[4] as well as the population of Birmingham, UK,[8] and individuals of Ashkenazi Jewish heritage. It has been noted rarely in a few other ethnic groups.

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 cells 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 cells in the macula occurs, 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 a ring-like annulus exists, in which vision is impaired. , around the central region

Cause

Table 1: Genes linked to Usher syndrome
  Type I   Type II   Type III
Type  Freq[9] Gene locus  Gene Protein  Function  Size (AA)  UniProt OMIM
USH1B 39–55% 11q13.5 MYO7A Myosin VIIA Motor protein 2215 Q13402 Online Mendelian Inheritance in Man (OMIM) 276900
USH1C 6–7% 11p15.1-p14 USH1C Harmonin PDZ-domain protein 552 Q9Y6N9 Online Mendelian Inheritance in Man (OMIM) 276904
USH1D 19–35% 10q21-q22 CDH23 Cadherin 23 Cell adhesion 3354 Q9H251 Online Mendelian Inheritance in Man (OMIM) 601067
USH1E rare 21q21 ? ? ? ? ? Online Mendelian Inheritance in Man (OMIM) 602097
USH1F 11–19% 10q11.2-q21 PCDH15 Protocadherin 15 Cell adhesion 1955 Q96QU1 Online Mendelian Inheritance in Man (OMIM) 602083
USH1G 7% 17q24-q25 USH1G SANS Scaffold protein 461 Q495M9 Online Mendelian Inheritance in Man (OMIM) 606943
USH2A 80% 1q41 USH2A Usherin Transmembrane linkage 5202 O75445 Online Mendelian Inheritance in Man (OMIM) 276901
USH2C 15% 5q14.3-q21.1 GPR98 VLGR1b Very large GPCR 6307 Q8WXG9 Online Mendelian Inheritance in Man (OMIM) 605472
USH2D 5% 9q32-q34 DFNB31 Whirlin PDZ-domain protein 907 Q9P202 Online Mendelian Inheritance in Man (OMIM) 611383
USH3A 100% 3q21-q25 CLRN1 Clarin-1 Synaptic shaping 232 P58418 Online Mendelian Inheritance in Man (OMIM) 276902

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 loci.[10][11] 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.[12] Research in this area is ongoing.[citation needed]

Using interaction analysis techniques, the identified gene products could be shown to 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.[11]

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 interneurons. Patients with mutations for these genes could have consequently auditory cortex defects.[13]

Pathophysiology

The progressive blindness of Usher syndrome results from retinitis pigmentosa.[14][15] The photoreceptor cells 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.[16]

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.[citation needed]

Diagnosis

The simplest approach to diagnosing Usher syndrome is to test for the characteristic chromosomal mutations. An alternative approach is electroretinography, 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.[citation needed]


Classification

Although Usher syndrome has been classified clinically in several ways,[17][15][18] 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.[14][16] Although it was previously believed that there was an Usher syndrome type IV, researchers at the University of Iowa recently[when?] confirmed that there is no USH type IV. 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]

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.[citation needed]

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 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.[19] However, some of the mutated genes associated with Usher syndrome encode very large proteins—most notably, the USH2A and GPR98 proteins, which have roughly 6000 amino-acid residues. Scientists have successfully treated mice with Usher syndrome type 1C, which has a relatively small affected gene.[20]

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]

Epidemiology

Usher syndrome is responsible for the majority of deafblindness.[21] It occurs in roughly 1 in 23,000 people in the United States,[22] 1 in 28,000 in Norway,[3] and 1 in 12,500 in Germany.[2] People with Usher syndrome represent roughly one-sixth of people with retinitis pigmentosa.[16]

History

Usher syndrome is named after the Scottish ophthalmologist Charles Usher, who examined the pathology and transmission of this illness in 1914 based on 69 cases.[23] However, it was first described in 1858 by Albrecht von Gräfe, a pioneer of modern ophthalmology.[24] 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.[25] 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. Animal models of this human disease (such as knockout mice and zebrafish) have been developed recently[when?] to study the effects of these gene mutations and to test potential cures for Usher syndrome.[citation needed]

Society and culture

Notable cases

  • Rebecca Alexander, a psychotherapist, author, and recipient of the Helen Keller Achievement Award.[citation needed]
  • Cyril Axelrod, Catholic priest.[citation needed]
  • Catherine Fischer wrote her autobiography of growing up with Usher syndrome in Louisiana, entitled Orchid of the Bayou.[26]
  • Katie Kelly, a gold medal–winning paralympian.[citation needed]
  • Christian Markovic, and blind-deaf illustrator and designer; Fuzzy Wuzzy Designs.[27]
  • 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.[28]
  • Karolina Pakėnaitė,[29] a PhD student at the University of Bath[30] diagnosed in 2014, and "seeking to be the first deafblind [person] to reach the summit of Mount Everest".[31][32]
  • 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.[33]
  • Robert Tarango, first deafblind person to star in a movie, in the role of Artie in the Oscar-nominated short film Feeling Through.[citation needed]
  • John Tracy, the son of actor Spencer Tracy and namesake of the oralist John Tracy Clinic.[citation needed]
  • Teigan Van Roosmalen, paraolympian.[citation needed]
  • Vendon Wright has written two books describing his life with Usher syndrome, I Was Blind but Now I Can See[34] and Through My Eyes.[35]

References

  1. ↑ 1.0 1.1 "Early diagnosis of Usher syndrome in children". Transactions of the American Ophthalmological Society 98: 237–45. 2000. PMID 11190026. 
  2. ↑ 2.0 2.1 "A new clinical classification for Usher's syndrome based on a new subtype of Usher's syndrome type I". Laryngoscope 111 (1): 84–86. 2001. doi:10.1097/00005537-200101000-00014. PMID 11192904. 
  3. ↑ 3.0 3.1 Grøndahl J (1987). "Estimation of prognosis and prevalence of retinitis pigmentosa and Usher syndrome in Norway". Clin. Genet. 31 (4): 255–264. doi:10.1111/j.1399-0004.1987.tb02804.x. PMID 3594933. 
  4. ↑ 4.0 4.1 "The ophthalmological course of Usher syndrome type III". International Ophthalmology 19 (5): 307–311. 1996. doi:10.1007/BF00130927. PMID 8864816. 
  5. ↑ 5.0 5.1 Keats, Bronya J.B.; Corey, David P. (25 October 2002). "The Usher syndromes". American Journal of Medical Genetics 89 (3): 158–166. doi:10.1002/(SICI)1096-8628(19990924)89:3<158::AID-AJMG6>3.0.CO;2-#. PMID 10704190. https://onlinelibrary.wiley.com/doi/10.1002/(SICI)1096-8628(19990924)89:3%3C158%3A%3AAID-AJMG6%3E3.0.CO%3B2-%23. Retrieved 29 June 2022. 
  6. ↑ Reisser, CFV; Kimberling, WJ; Otterstedde, CR (2002). "Hearing Loss in Usher Syndrome Type II is Nonprogressive". Annals of Otology, Rhinology & Laryngology 111 (12): 1108–1111. doi:10.1177/000348940211101208. PMID 12498372. https://journals.sagepub.com/doi/abs/10.1177/000348940211101208. Retrieved 4 March 2022. 
  7. ↑ Sadeghi, Mehdi; Cohn, Edward S.; Kelly, William J.; Kimberling, William J.; Tranebjoerg, Lisbeth; Möller, Claes (2004). "Audiological findings in Usher syndrome types IIa and II (non-IIa)". International Journal of Audiology 43 (3): 136–143. doi:10.1080/14992020400050019. PMID 15198377. 
  8. ↑ "Usher syndrome in the city of Birmingham — prevalence and clinical classification". British Journal of Ophthalmology 81 (1): 46–53. 1997. doi:10.1136/bjo.81.1.46. PMID 9135408. 
  9. ↑ "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%". J Med Genet 43 (9): 763–768. 2006. doi:10.1136/jmg.2006.041954. PMID 16679490. 
    "Characterization of Usher syndrome type I gene mutations in an Usher syndrome patient population". Hum Genet 116 (4): 292–299. 2005. doi:10.1007/s00439-004-1227-2. PMID 15660226. 
  10. ↑ Petit, C (2001). "Usher syndrome: from genetics to pathogenesis". Annual Review of Genomics and Human Genetics 2: 271–97. doi:10.1146/annurev.genom.2.1.271. PMID 11701652. https://pdfs.semanticscholar.org/2027/153c2f19cd88f7f2a753b99c646433de805e.pdf. 
  11. ↑ 11.0 11.1 Reiners, J; Nagel-Wolfrum, K; Jürgens, K; Märker, T; Wolfrum, U (2006). "Molecular basis of human Usher syndrome: deciphering the meshes of the Usher protein network provides insights into the pathomechanisms of the Usher disease". Experimental Eye Research 83 (1): 97–119. doi:10.1016/j.exer.2005.11.010. PMID 16545802. https://www.blogs.uni-mainz.de/fb10-ag-wolfrum/files/2019/01/Reiners_et_al_2006_USH_Rev_ExpEyeRes.pdf. 
  12. ↑ Gerber, S; Bonneau, D; Gilbert, B; Munnich, A; Dufier, JL; Rozet, JM; Kaplan, J (2006). "USH1A: chronicle of a slow death". American Journal of Human Genetics 78 (2): 357–9. doi:10.1086/500275. PMID 16400615. 
  13. ↑ Libé-Philippot, Baptiste; Michel, Vincent; Monvel, Jacques Boutet de; Gal, Sébastien Le; Dupont, Typhaine; Avan, Paul; Métin, Christine; Michalski, Nicolas et al. (2017-07-25). "Auditory cortex interneuron development requires cadherins operating hair-cell mechanoelectrical transduction" (in en). Proceedings of the National Academy of Sciences 114 (30): 7765–7774. doi:10.1073/pnas.1703408114. ISSN 0027-8424. PMID 28705869. Bibcode: 2017PNAS..114.7765L. 
  14. ↑ 14.0 14.1 "Clinical diagnosis of the Usher syndromes. Usher Syndrome Consortium". American Journal of Medical Genetics 50 (1): 32–38. 1994. doi:10.1002/ajmg.1320500107. PMID 8160750. 
  15. ↑ 15.0 15.1 "Usher's syndrome: ophthalmic and neuro-otologic findings suggesting genetic heterogeneity". Archives of Ophthalmology 101 (9): 1367–1374. 1983. doi:10.1001/archopht.1983.01040020369005. PMID 6604514. 
  16. ↑ 16.0 16.1 16.2 Williams DS (2007). "Usher syndrome: Animal models, retinal function of Usher proteins, and prospects for gene therapy". Vision Research 48 (3): 433–41. doi:10.1016/j.visres.2007.08.015. PMID 17936325. 
  17. ↑ 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 ed.). 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 34 (138): 9–101. doi:10.1111/j.1600-0447.1959.tb08605.x. PMID 14399116. 
    "Retinitis pigmentosa". Surv. Ophthalmol. 20 (5): 303–345. 1976. doi:10.1016/S0039-6257(96)90001-6. PMID 817406. 
    The Heterogeneity of Usher Syndrome (volume 426 ed.). Amsterdam: Excerpta Medica Foundation. 1977. 
    "Usher syndrome type III". Arch. Otolaryngol. 105 (6): 353–354. 1979. doi:10.1001/archotol.1979.00790180051011. PMID 454290. 
  18. ↑ "Assignment of Usher syndrome type III (USH3) gene to chromosome 3q". Hum. Mol. Genet. 4 (1): 93–98. 1995. doi:10.1093/hmg/4.1.93. PMID 7711740. 
  19. ↑ "Lentiviral gene replacement therapy of retinas in a mouse model for Usher syndrome type 1B". Gene Therapy 14 (7): 584–594. 2007. doi:10.1038/sj.gt.3302897. PMID 17268537. 
  20. ↑ Dina Fine Maron (December 4, 2018). "Out of the Silence: Gene Therapy Tackles a Common Birth Defect: Deafness". Scientific American: pp. 72–79. https://bertarelli.hms.harvard.edu/sites/hwpi.harvard.edu/files/sciamericanarticle_12_2018.pdf?m=1543951180. 
  21. ↑ Vernon M (1969). "Usher's syndrome — deafness and progressive blindness. Clinical cases, prevention, theory and literature survey". Journal of Chronic Diseases 22 (3): 133–151. doi:10.1016/0021-9681(69)90055-1. PMID 4897966. 
  22. ↑ "Usher syndrome: Definition and estimate of prevalence from two high-risk populations". Journal of Chronic Diseases 36 (8): 595–603. 1983. doi:10.1016/0021-9681(83)90147-9. PMID 6885960. 
  23. ↑ Usher C (1914). "On the inheritance of Retinitis pigmentosa with notes of cases". Roy. Lond. Ophthalmol. Hosp. Rep. 19: 130–236. 
  24. ↑ von Gräfe A (1858). "Exceptionelles Verhalten des Gesichtsfeldes bei Pigmententartung der Netzhaut". Archiv für Ophthalmologie 4: 250–253. 
  25. ↑ Liebreich R (1861). "Abkunft aus Ehen unter Blutsverwandten als Grund von Retinitis pigmentosa". Dtsch. Klin. 13: 53. 
  26. ↑ Orchid of the Bayou: A Deaf Woman Faces Blindness. Gallaudet University Press. 2001. ISBN 978-1-56368-104-2. 
  27. ↑ "Who's Fuzzy". Fuzzy Wuzzy Design. http://www.fuzzywuzzydesign.com/about/. 
  28. ↑ "Nalagaat Center | Home". http://www.nalagaat.org.il/home.php. 
  29. ↑ "About Me" (in en-GB). https://www.deafblindeverestproject.com/about-me. 
  30. ↑ "CDE PhDs and EngDs" (in en). https://digital-entertainment.org/alumni-2/#karolina-pakenaite. 
  31. ↑ "Deafblind PhD student aims for Everest" (in en). https://www.bath.ac.uk/announcements/deafblind-phd-student-aims-for-everest/. 
  32. ↑ Admin@TCA (2024-07-17). "Meet Karolina – DeafBlind Everest climber" (in en-GB). https://www.theclimbingacademy.com/tca-life/meet-karolina-deafblind-everest-climber/. 
  33. ↑ "Tactile The World". https://tactiletheworld.wordpress.com/. 
  34. ↑ Wright V (2007). I Was Blind but Now I Can See. Authorhouse. ISBN 978-1-4208-9101-0. 
  35. ↑ Wright V (2007). Through My Eyes. Pipers' Ash Ltd. ISBN 978-1-904494-86-7. 

Further reading

  • Usher's Syndrome: What It Is, How to Cope, and How to Help. Charles C. Thomas. 1988. ISBN 978-0-398-05481-6. 
  • The Madness of Usher's: Coping With Vision and Hearing Loss/Usher Syndrome Type II. Business of Living Publications. 1991. ISBN 978-1-879518-06-3. 
  • 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. 
Classification
External resources

Template:Hearing and balance Template:Cytoskeletal defects



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