Natural History and Genetic Studies of Usher Syndrome
Natural History and Genetic Studies of Usher Syndrome
This study will explore clinical and genetic aspects of Usher syndrome, an inherited disease
 causing deafness or impaired hearing, visual problems, and, in some cases, unsteadiness or
 balance problems. Patients with type 1 Usher syndrome usually are deaf from birth and have
 speech and balance problems. Patients with type 2 disease generally are hearing impaired but
 have no balance problems. Patients with type 3 disease have progressive hearing loss and
 balance problems. All patients develop retinitis pigmentosa, an eye disease that causes poor
 night vision and eventually, blindness.

 Patients of any age with Usher syndrome may be eligible for this study. Patients who have had
 eye and hearing evaluations are asked to send their medical records to the research team at
 the National Eye Institute (NEI) for review. They are also asked to have a blood sample drawn
 by a medical professional and sent to NEI for genetic analysis. Finally, they are interviewed
 about their family histories, particularly about other relative with eye disease. Patients
 who have not been evaluated previously have the following tests and procedures at NIH:

 -  Family medical history, especially regarding eye disease. A family tree is drawn.

 -  Blood draw for genetic studies of Usher syndrome.

 -  Eye examination to assess visual acuity and eye pressure, and to examine pupils, lens,
 retina, and eye movements.

 -  Electroretinogram (ERG) to test the function of visual cells. Wearing eye patches, the
 patient sits in a dark room for 30 minutes. Electrodes are taped to the forehead and the
 eye patches are removed. The surface of the eye is numbed with eye drops and contact
 lenses are placed on the eyes. The patient looks inside a hollow, dark globe and sees a
 series of light flashes. Then a light is turned on inside the globe and more flashes
 appear. The contact lenses sense small electrical signals generated by the retina when
 the light flashes.

 -  Fluorescein angiography to evaluate the eye's blood vessels. A yellow dye is injected
 into an arm vein and travels to the blood vessels in the eyes. Pictures of the retina
 are taken using a camera that flashes a blue light into the eye. The pictures show if
 any dye has leaked from the vessels into the retina, indicating possible blood vessel
 abnormality.

 -  Hearing tests to help determine the patient's type of Usher syndrome. Tests to evaluate
 hearing include examination of both ears with an otoscope, evaluation of the middle ear
 and inner ear, and hearing tests using earphones that deliver tones and words the
 subject listens and responds to.

 -  Vestibular testing for balance function. Balance testing involves three procedures:

 Videonystagmography: This test records eye movements with little cameras. First the patient
 follows the movements of some small lights. Next, while wearing goggles, the patient lies on
 an exam table and turns to the right and left. Lastly, a soft stream of air is blown into the
 patient's ears four times, once in each ear with cool air and once in each ear with warm air.

 Rotary chair test: With electrodes placed on the forehead, the patient sits in a rotary chair
 in a dark room. Several red lights appear on the wall of the room and the patient follows the
 lights as they move back and forth. Then the chair turns at several speeds, all slower than a
 merry-go-round.

 Vestibular evoked potential: Electrodes are placed behind the patient's ear and at the base
 of the neck. Seated in a reclining chair and wearing earphones, the patient hears a brief
 series of loud clicking sounds. When the sounds are on, the patient is asked to lift his or
 her head up a few inches from the chair. The electrodes record information from the muscles
 in the neck as the sounds enter the ear.
Background and objectives:

 The Usher syndromes are a group of clinically variable and genetically heterogeneous
 autosomal recessive syndromes. On the basis of clinical findings, at least three types exist.
 Patients with Usher type I are born deaf, have vestibular problems, and are thought to
 perceive night blindness in early childhood. Patients with Usher type II are born with a
 hearing deficit but are able to develop intelligible speech, do not have balance problems;
 night vision problems, and visual field changes are noted later. Patients with Usher type III
 are born with relatively good hearing that deteriorates over a decade or more; they can have
 progressive balance problems and they report night blindness in childhood or teens. Seven
 genes have been mapped so far for Usher type I while five of these genes have been
 identified. For Usher type II, four genes have been mapped and three of these have been
 identified while there is one cloned gene for Usher type III. Quite a lot of information is
 still unknown regarding the genetic nature of this syndrome. The picture of the three
 clinical types of Usher syndrome has also not been well studied up to this point and cross
 sectional studies seems to be the only source of the information available so far, regarding
 the natural history of the disease. The aim of this protocol is to better study the natural
 history of the disease and also make specific genotype-phenotype correlations.

 Study population:

 A total of 200 participants, including patients affected with all three clinical types of
 Usher syndrome and up to 200 unaffected relatives will be enrolled to the protocol.
 Unaffected family members, primarily parents and siblings will be enrolled to provide a blood
 sample when considered helpful for linkage analysis. Family members will be considered
 unaffected if they have had a previous normal examination and they don t have any symptoms of
 decreased night or peripheral vision.

 Methods:

 Participants will undergo ophthalmologic, audiologic and vestibular evaluation in order to be
 clinically characterized. Blood will be obtained by all participating subjects for the
 molecular studies. Patients who cannot come to NIH or a collaborating Institution for
 participation will be asked to provide a blood sample for genotyping and a copy of their
 ophthalmologic, audiology and vestibular records, to classify phenotype. Each off-site
 participant will be consented over the phone by an NEI investigator. All participants will be
 requested to fill out a questionnaire.

 Outcome measures:

 Affected participants will be phenotypically categorized in one of the three clinical types
 based on audiology and vestibular findings
-  INCLUSION CRITERIA:

 Eligible participants must:

 1. have documented neurosensory hearing loss and retinitis pigmentosa and fulfill the
 clinical characteristics for USH1, USH2 and USH3 as defined by the Usher syndrome
 consortium. ; OR

 2. be unaffected family members of a proband with Usher s syndrome, primarily parents and
 siblings. Family members will be considered unaffected by history if they have had
 previous normal ophthalmologic and hearing examinations and if they don't have
 decreased night or peripheral vision.

 EXCLUSION CRITERIA:

 Patients will be ineligible if they:

 1. had an intrauterine infection, perinatal/congenital infections, or intrauterine and
 birth complications. These conditions can result in damage to both the auditory or
 visual system.

 2. have concurrent inherited or acquired conditions that affect the visual and/or
 auditory system and significantly alter the phenotype.

 Both affected and unaffected individuals will be ineligible if they:

 1. Are unwilling or unable to provide a blood sample or unable to undergo the study
 procedures.

 2. Are younger than 2 years old.