NORD gratefully acknowledges Margaret Kenna, MD, MPH, Director of Clinical Research, Dept. of Otolaryngology and Communication Enhancement, Boston Children's Hospital, and the Usher Syndrome Coalition, for assistance in the preparation of this report.
Usher syndrome is a rare genetic disorder primarily characterized by deafness due to an impaired ability of the inner ear and auditory nerves to transmit sensory (sound) input to the brain (sensorineual hearing loss) accompanied by retinitis pigmentosa, a disorder that affects the retina and causes progressive loss of vision. Researchers have identified three clinical types of Usher syndrome. The age at which the symptoms appear and the severity of symptoms that distinguishes the different types of Usher syndrome is determined by the underlying genetic cause. Usher syndrome is inherited as an autosomal recessive genetic trait.
Usher syndrome was first described in 1858 by Albrecht Von Graefe, but was named for Charles Usher, a Scottish eye doctor who identified the disorder’s hereditary nature and recessive inheritance pattern.
Usher syndrome is characterized by deafness due to an impaired ability of the inner ear and auditory nerves to transmit sensory (sound) input to the brain (sensorineural hearing loss) as well as abnormal accumulation of colored (pigmented) material on the nerve-rich membrane (the retina) lining the eyes (retinitis pigmentosa or RP). RP eventually causes retinal degeneration leading to progressive loss of vision and legal blindness. Sensorineural nerve deafness may be profound or mild, and may be progressive. The vision loss caused by RP may begin during childhood or later during life, and often first presents with difficulty seeing at night or in low light (“night blindness”). Studies show that clear central vision may be maintained for many years even while side (peripheral) vision decreases. These narrowed visual fields are also referred to as “tunnel vision.” Issues with balance are seen in individuals with Usher syndrome types 1 and 3.
Usher syndrome type 1 is characterized by profound hearing loss in both ears at birth (congenital deafness) and balance problems. In many cases, affected children do not learn to walk until 18 months of age or later. Vision problems usually begin at approximately the age of ten years to early teens, although some parents report onset in children younger than 10. Usher syndrome type 2 is characterized by moderate to severe hearing loss in both ears at birth. In some cases, hearing loss may worsen over time. Onset of night blindness occurs during the late teens or early twenties. Peripheral vision loss is ongoing, but central vision is usually retained into adulthood. Visual problems associated with Usher syndrome type 2 tend to progress more slowly than those associated with type 1.
Usher syndrome type 3 is characterized by later onset hearing loss, variable balance (vestibular) dysfunction and RP that can present between the second and fourth decade of life. Balance issues occur in approximately 50% of individuals with Usher syndrome type 3.
Usher syndrome is caused by mutations in specific genes. So far, Usher syndrome has been associated with mutations in at least ten genes:
Usher syndrome type 1: MYO7A (USH1B), USH1C, CDH23, PCDH15 (USH1F), SANS (USH1G), and possibly CIB2
Usher syndrome type 2: USH2A, ADGRV1 (previously called VLGR1) WHRN (DFNB31)
Usher syndrome type 3: USH3A (CLRN1), HARS
These genes provide instructions for making proteins involved in normal hearing, vision and balance. Some of these proteins help specialized cells called hair cells to transmit sound from the inner ear to the brain and to sense light and color in the retina of the eye. The function of the some of the proteins produced by genes associated with Usher syndrome is not known.
Some people with Usher syndrome do not have mutations in any of these genes, so there are probably other genes associated with the condition that have not yet been identified.
All types of Usher syndrome are inherited as autosomal recessive traits. Most genetic diseases are determined by the status of two copies of a gene, one received from the father and one from the mother. Recessive genetic disorders occur when an individual inherits two copies of an abnormal gene for the same trait, one from each parent. If an individual inherits one normal gene and one gene for the disease, the person will be a carrier for the disease but usually will not show symptoms. The risk for two carrier parents to both pass on the altered gene and have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females.
Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder.
Usher syndrome affects approximately three to ten in 100,000 people worldwide. Higher than average numbers of people with Usher syndrome have been found among Jewish people in Israel, Berlin, Germany; French Canadians of Louisiana; Argentineans of Spanish descent; and Nigerian Africans. USH3, the rarest form in most populations, comprises about 40% of Usher patients in Finland. Usher syndrome is the most common genetic disorder involving both hearing and vision abnormalities. Usher syndrome types 1 and 2 account for approximately 10 percent of all cases of moderate to profound deafness in children.
Usher syndrome is diagnosed by hearing, balance and vision examinations. A hearing (audiologic) exam measures the frequency and loudness of sounds that a person can hear. An electroretinogram measures the electrical response to the light-sensitive cells in the retina of the eyes. A retinal exam is done to observe the retina and other structures in the back of the eye. Vestibular (balance) function can be assessed by a variety of tests that evaluate different parts of the balance system. Genetic testing is clinically available for most of the genes associated with Usher syndrome.
The treatment of Usher syndrome is directed toward the specific symptoms that are apparent in each individual. Such treatment may require the coordinated efforts of a team of medical professionals, such as pediatricians or internists, specialists who assess and treat hearing and balance impairment (otolaryngologists and audiologists), physicians who specialize in diagnosing and treating eye disorders (ophthalmologists), and/or other health care professionals.
Sensorineural deafness should be assessed and communication options explored as early as possible to provide the child with a solid language base. Hearing aids or cochlear implants will benefit most infants and children with Usher syndrome. American Sign Language may be explored as a communication option. Individuals who sign visually often transfer to tactile sign as vision decreases. Early intervention is important in ensuring that children with Usher syndrome reach their potential. Services that may be beneficial may include special services for children with sensorineural deafness or deaf-blindness and other medical, social, and/or vocational services.
There is currently no known cure for RP, although researchers are working on genetic and other therapies to repair or reverse vision loss associated with RP as well as hearing loss. Some researchers have shown that taking a specific daily dose of vitamin A may slow the progression of retinal degeneration in some people with typical RP and Usher syndrome type 2. Some experts recommend that adult patients with common forms of RP take 15,000 IU daily of vitamin A palmitate under their ophthalmologists’ care, follow a regular balanced diet, and avoid high-dose vitamin E supplementation. Because long-term high-dose vitamin A supplementation (e.g., exceeding 25,000 IU) may cause certain adverse effects, such as liver disease, patients should be regularly monitored by their doctors when taking such supplementation. (The body’s reserves of vitamin A are primarily stored in the liver.) It is essential that any patients with RP considering such supplementation consult with their doctors for necessary evaluation to determine whether it is appropriate or inadvisable in their particular case.
Individuals with RP in association with Usher syndrome may find low-vision aids to be helpful. Other treatment for Usher syndrome is symptomatic and supportive. Agencies that provide services to individuals with hearing and visual loss can be helpful.
Genetic counseling is recommended for affected individuals and their families.
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Lentz J, Keats B. Usher Syndrome Type II. 1999 Dec 10 [Updated 2016 Jul 21]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2018. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1341/ Accessed May 30, 2018.
Usher Syndrome. NIDCD Information Clearinghouse. Last Updated Date:
March 16, 2017. https://www.nidcd.nih.gov/health/usher-syndrome Accessed May 30, 2018.
Usher Syndrome. Genetics Home Reference. Reviewed November 2017. https://ghr.nlm.nih.gov/condition/usher-syndrome. Accessed May 30, 2018.
McKusick VA, ed. Online Mendelian Inheritance in Man (OMIM). Baltimore. MD: The Johns Hopkins University. https://www.omim.org/
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