Usher syndrome

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.^{[citation needed]}

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.^{[citation needed]}

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.^{[citation needed]}

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.^{[citation needed]}

The frequency of Usher syndrome type III is significant only in the

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.^{[citation needed]}

Cause

Usher syndrome is inherited in an

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.^[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

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.

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 as many as 10% of children with congenital severe to profound deafness may have Usher syndrome.^[1] However, a misdiagnosis can have bad consequences.^{[citation needed]}

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.

Thirteen other syndromes may exhibit signs similar to Usher syndrome, including

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.^{[citation needed]} 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]}

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.^{[citation needed]}

Since Usher syndrome is inherited in an

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]

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

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.

Notable cases

• Rebecca Alexander, a psychotherapist, author, and recipient of the Helen Keller Achievement Award.
• Christine "Coco" Roschaert, director of the Nepal Deafblind Project, kick-off speaker for Deaf Awareness Week at the
  Gallaudet United Now Movement.^[26]
• Catherine Fischer wrote her autobiography of growing up with Usher syndrome in Louisiana, entitled Orchid of the Bayou.^[27]
• Vendon Wright has written two books describing his life with Usher syndrome, I was blind but now I can see^[28] and Through my eyes.^[29]
• Christian Markovic, and blind-deaf illustrator and designer; Fuzzy Wuzzy Designs.^[30]
• John Tracy, the son of actor Spencer Tracy and namesake of the oralist John Tracy Clinic.
• 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.^[32]
• Katie Kelly, a gold medal-winning paralympian.
• Teigan Van Roosmalen, paraolympian.
• Cyril Axelrod, Catholic priest.
• Robert Tarango, first deafblind person to star in a movie, in the role of Artie in the Oscar-nominated short film Feeling Through.

References