Natural History and Genetic Studies of Usher Syndrome

Status:Active, not recruiting
Conditions:Other Indications, Ocular
Therapuetic Areas:Ophthalmology, Other
Age Range:2 - Any
Start Date:March 21, 2005

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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

- 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

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.


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


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.


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

2. Are younger than 2 years old.
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