Natural History and Genetic Studies of Usher Syndrome

Brief Title

Natural History and Genetic Studies of Usher Syndrome

Official Title

Natural History and Genetic Studies of Usher Syndrome

Brief Summary

      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.

Detailed Description

      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

Study Type


Primary Outcome

The primary outcomes of interest are the probands genotype and phenotype.


Retinitis Pigmentosa Syndromic


* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information

Estimated Enrollment


Start Date

March 21, 2005

Completion Date

April 30, 2019

Eligibility 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.


        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.




2 Years - N/A

Accepts Healthy Volunteers



Wadih Zein, M.D., , 

Location Countries

United States

Location Countries

United States

Administrative Informations



Organization ID


Secondary IDs


Responsible Party


Study Sponsor

National Eye Institute (NEI)

Study Sponsor

Wadih Zein, M.D., Principal Investigator, National Eye Institute (NEI)

Verification Date

April 30, 2019