Usher syndrome

Usher syndrome (sometimes referred to as "Usher's syndrome") is a relatively rare inherited condition 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. 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.

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. It occurs in roughly 1 person in 23,000 in the United States, 1 in 28,000 in Norway and 1 in 12,500 in Germany.

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. 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 and Birmingham. 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. 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.

History
Usher syndrome was probably described for the first time 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 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.

Associated mutations in genes
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 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 cell.

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

Mutations in the CDH23, MYO7A, PCDH15, Usher 1C (also known as Harmonin), and USH1G (now identified as SANS) genes cause Usher syndrome type I. Usher syndrome type I can be caused by mutations in one of several different genes. 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.

Mutations in the MASS1 (also called VLGR1) and USH2A genes cause Usher syndrome type II. Usher syndrome type II may be caused by mutations in any of three different genes, two of which have been identified to date. These genes are called USH2A and MASS1. Usherin, the protein made by the USH2A gene, is located in 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 precise function of the protein made by the MASS1 gene is 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 the USH3A gene cause Usher syndrome type III. Usher syndrome type III can be caused by mutations in one of at least two genes, only one of which (USH3A) has been identified. The USH3A gene makes a protein that is important for the development and maintenance of the inner ear and retina. The protein's function in these structures, and its role in hearing and vision loss, have not yet been fully explained.

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. 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. 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. 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, dysplasis spondyloepiphysaria 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. 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 is a well-known person with Usher syndrome. She has published video blogs at Youtube,, and recently was the kick-off speaker for the 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 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 and a trip to Brighton pier. Other people with Usher syndrome have posted videos about their lives and condition on YouTube, most notably Ginny Paja-Nyholm. 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 has written a well-received autobiography of growing up with Usher syndrome in Louisiana, entitled Orchid of the Bayou. Similarly, 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, an artist living with Usher syndrome, runs a company, Fuzzy Wuzzy Designs.

Spencer Tracy's son John 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.

Additional reading