|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, 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 majority 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 to as low as 1 in 28,000 in Norway. Type I is most common in Ashkenazi Jewish and Acadian populations, while type III is rarely found outside Ashkenazi Jewish and Finnish populations. Usher syndrome is named after Scottish ophthalmologist Charles Usher, who examined the pathology and transmission of the syndrome in 1914.
Classification and symptoms
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 an annulus exists around the central region in which vision is impaired.
Although Usher syndrome has been classified clinically in several ways, 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. 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.
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.
Usher syndrome I
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. Babies with Usher I are usually slow to develop motor skills such as walking.
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.
Worldwide, the estimated prevalence of Usher syndrome type I is 3 to 6 per 100,000 people in the general population. Type I has been found to be more common in people of Ashkenazi Jewish ancestry (central and eastern European) and in the French-Acadian populations (Louisiana).
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; moreover, they 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.
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 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 III
People with Usher syndrome III are not born deaf but experience a "progressive" loss of hearing, and roughly half have balance difficulties.
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.
The frequency of Usher syndrome type III is only significant in the Finnish population as well as the population of Birmingham, Alabama, US and individuals of Ashkenazi Jewish heritage. It has been noted rarely in a few other ethnic groups.
|Type||Freq||Gene locus||Gene||Protein||Function||Size (AA)||UniProt||OMIM|
|USH1B||39–55%||11q13.5||MYO7A||Myosin VIIA||Motor protein||2215||276900|
|USH1D||19–35%||10q21-q22||CDH23||Cadherin 23||Cell adhesion||3354||601067|
|USH1F||11–19%||10q11.2-q21||PCDH15||Protocadherin 15||Cell adhesion||1955||602083|
|USH2C||15%||5q14.3-q21.1||GPR98||VLGR1b||Very large GPCR||6307||605472|
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. 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. Research in this area is ongoing.
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 fulfil 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.
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.
The progressive blindness of Usher syndrome results from retinitis pigmentosa. 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.
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 congenitally deaf children may have Usher syndrome. However, a misdiagnosis can have bad consequences.
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. 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, 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).
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. 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. Gene replacement therapy for such large proteins may be difficult.
Usher syndrome is responsible for the majority of deafblindness. It occurs in roughly 1 in 23,000 people in the United States, 1 in 28,000 in Norway, and 1 in 12,500 in Germany. People with Usher syndrome represent roughly one-sixth of people with retinitis pigmentosa.
Usher syndrome is named after the Scottish ophthalmologist Charles Usher, who examined the pathology and transmission of this illness in 1914 on the basis of 69 cases. However, it was first described in 1858 by Albrecht von Gräfe, a pioneer of modern ophthalmology. 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. 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.
The Usher Syndrome Coalition (USC) is an international non-profit organization that provides information and support to individuals living with Usher syndrome, as well as their families.
- A 31-year-old woman with Usher syndrome, Rebecca Alexander, was profiled in Marie Claire in November 2007. After graduating from the University of Michigan with excellent marks, Alexander went on to Columbia University, where she earned two master's degrees in public health and clinical social work. She is an active member of her community, working with various charities in NYC. Alexander's dedication as an active member of her community was most notably recognized when she was selected as a "Community Hero" to run with the Olympic Torch for the 1996 Atlanta Olympic Games in honor of her volunteer work for Project Open Hand, a nonprofit organization delivering meals to people living with HIV/AIDS in the San Francisco Bay area. Alexander received her psychodynamic psychotherapy training through the American Institute of Psychoanalysis. She currently works in private practice specializing in the treatment of mood and anxiety disorders, eating disorders, addictions, disability, and trauma. While currently facilitating group seminars for the Foundation Fighting Blindness during national conferences, Rebecca is also in the process of launching the Usher III Initiative, a nonprofit organization dedicated to science and research that seeks to find a cure for Usher III. Alexander teaches indoor cycling/spin classes with a strong following at select gyms in New York City. She was featured on NBC's Today Show on March 20, 2009, which was nominated for an Emmy award in September 2010. She is the sister of NBC News National Correspondent Peter Alexander. She appeared again on the Today Show in September 2014 with her brother, and discussed her experiences with the disease and her book Not Fade Away: A Memoir of Senses Lost and Found.
- Christine "Coco" Roschaert was born in Ottawa, Ontario on 5 January 1980. She is a well-known person with Usher syndrome. She has published video blogs on YouTube, and was the kick-off speaker for Deaf Awareness Week at the University of Vermont. 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. Roschaert was in Nigeria founding the first deafblind program in that country. Roschaert is now living in Quebec, Canada.
- In 2007, Ginny Paja-Nyholm posted videos about her life with the condition on YouTube.
- In October 2007, Candice, a mom living in Texas, began blogging about her two daughters, Jasmine and Rebecca; Rebecca has Usher syndrome I.
- Catherine Fischer wrote a well-received autobiography of growing up with Usher syndrome in Louisiana, entitled Orchid of the Bayou.
- Vendon Wright has written two books describing his life with Usher syndrome, I was blind but now I can see and Through my eyes.
- Louise Boardman has also written a short book called My son has Usher's Syndrome.
- Christian Markovic is an artist living with Usher syndrome, who runs a company, Fuzzy Wuzzy Designs.
- Spencer Tracy's son John Tracy was a well-known person with Usher syndrome who lived a full life. 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.
- DNA helix co-discoverer and Nobel laureate James D. Watson has homozygous USH1B mutations, according to his published genome. It is not clear why he did not develop the syndrome. This lack of genetic penetrance argues that expression of the phenotype of Usher syndrome may be more complex than originally assumed.
- 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.
- Katie Kelly is a gold medal winning paralympian that was diagnosed in her early 20s. Katie was declared as legally blind in January 2015 and became classified as a vision impaired (PT5) paratriathlete in February 2015. Katie then went on to win National, World and Olympic titles in 2015 and 2016. In 2017, Kelly established the Sports Access Foundation to assist children with a disability with access to sport and recreational facilities.
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- Roux AF, Faugere V, Le Guedard S, Pallares-Ruiz N, Vielle A, Chambert S, Marlin S, Hamel C, Gilbert B, Malcolm S, Claustres M (2006). "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. doi:10.1136/jmg.2006.041954. PMC 2564578. PMID 16679490.
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 (2005). "Characterization of Usher syndrome type I gene mutations in an Usher syndrome patient population". Hum Genet. 116 (4): 292–299. doi:10.1007/s00439-004-1227-2. PMID 15660226.
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- 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.
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- Libé-Philippot, Baptiste; Michel, Vincent; Monvel, Jacques Boutet de; Gal, Sébastien Le; Dupont, Typhaine; Avan, Paul; Métin, Christine; Michalski, Nicolas; Petit, Christine (2017-07-25). "Auditory cortex interneuron development requires cadherins operating hair-cell mechanoelectrical transduction". Proceedings of the National Academy of Sciences. 114 (30): 7765–7774. doi:10.1073/pnas.1703408114. ISSN 0027-8424. PMC 5544301. PMID 28705869.
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- "Tactile The World".
- Coco Roschaert – via YouTube.
- ASL at UVM
- "Xanga 2.0 is Here!".
- An Usher Syndrome Trivia Challenge. 23 April 2007 – via YouTube.
- Candice. "I'm adopting a Deaf child with Ushers, now what?". Retrieved 2007-11-07.
- Carroll C, Fischer CH (2001). Orchid of the Bayou: A Deaf Woman Faces Blindness. Gallaudet University Press. ISBN 978-1-56368-104-2.
- Wright V (2007). I was blind but now I can see. Authorhouse. ISBN 978-1-4208-9101-0.
- Wright V (2007). Through my eyes. Pipers' Ash Ltd. ISBN 978-1-904494-86-7.
- Boardman LS (1985). My son has Usher's Syndrome. Foundation Fighting Blindness. B0007207IG.
- "Who's Fuzzy". Fuzzy Wuzzy Design.
- "Obituary: Spencer Tracy's son dies at 82".
- Green RC, Annas GJ (2008). "The Genetic Privacy of Presidential Candidates". New England Journal of Medicine. 359 (21): 2192–2193. doi:10.1056/NEJMp0808100. PMC 2925179. PMID 19020322.
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- Vernon M (1969). Usher's syndrome: Deafness and progressive blindness : clinical cases, prevention, theory and literature survey. Pergamon Press. ASIN B0007JHOJ4.
- GeneReviews/NCBI/NIH/UW entry on Usher Syndrome Type I
- GeneReviews/NCBI/NIH/UW entry on Usher Syndrome Type II
- NCBI Genetic Testing Registry
- General overview from the NIH
- Usher Syndrome Information from the National Institute on Deafness and Other Communication Disorders (NIDCD).
- Usher Syndrome Coalition