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A leading cause of deafblindness, Usher syndrome (sometimes referred to as “Usher’s syndrome”) is a relatively rare genetic disorder that is associated with a mutation in any one of 10 genes. Other names for Usher syndrome include Hallgren syndrome, Usher-Hallgren syndrome, rp-dysacusis syndrome and dystrophia retinae dysacusis syndrome.[1] Usher syndrome is incurable at present; however, using gene therapy to replace the missing gene, researchers have succeeded in reversing one form of the disease in knockout mice.[2]
This syndrome is characterized by deafness and a gradual vision loss. The hearing loss is associated with a defective inner ear, whereas the vision loss is associated with retinitis pigmentosa (rp), a degeneration of the retinal cells. 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 has three clinical subtypes, denoted as I, II and III in decreasing order of severity.[3] 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.
Usher syndrome is a very variable condition and the degree of severity cannot be totally linked to whether it is Usher 1, 2 or 3. For example, someone with Type 3 may be the least affected 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 1, who is therefore profoundly deaf from birth, may keep good central vision until the sixth decade of life, or even beyond. People with Type, 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 sixties, while others cannot see to read while still in their forties.
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. Since Usher syndrome is inherited in an autosomal recessive pattern, both males and females are equally likely to inherit Usher syndrome. Consanguinity of the parents is a risk factor. Since Usher syndrome mutations are recessive, 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 carriers. 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.
Usher syndrome is named after the British ophthalmologist Charles Usher, who examined the pathology and transmission of this illness in 1914 on the basis of 69 cases.[4] However, it was first described in 1858 by Albrecht von Gräfe, a pioneer of modern ophthalmology.[5] 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.[6] Liebreich noted that Usher syndrome is 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.
Usher syndrome is responsible for the majority of deaf-blindness.[7] The word syndrome means that multiple symptoms occur together, in this case, deafness and blindness. It occurs in roughly 1 person in 23,000 in the United States,[8] 1 in 28,000 in Norway[9] and 1 in 12,500 in Germany.[10] People with Usher syndrome represent roughly one-sixth of people with retinitis pigmentosa.[3]
Usher syndrome is inherited in an autosomal recessive pattern. “Recessive” means that both parents must contribute an appropriate gene for the syndrome to appear, and “autosomal” means that the gene is not carried on one of the sex chromosomes (X or Y), but rather on one of the 22 other pairs. (See the article on human genetics for more details.)
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