Usher syndrome part IV: Clinical management and research directions

Guest Blogger Danio, one last time:

Part I
Part II
Part III

The current standard of pediatric care mandating that all newborns undergo hearing screenings has been applied successfully throughout much of the industrialized world. Early identification of hearing impairments gives valuable lead-time to parents and health care providers during which they can plan medical and educational interventions to improve the child’s development, acquisition of language skills, and general quality of life.

Up to 12% of children born with hearing loss have Usher syndrome. However, diagnosing Usher syndrome as distinct from various forms of congenital hearing impairment is often impossible until the onset of retinal degeneration years later. The considerable number and size of the genes involved makes genetic screening impractical with the current methods, unless there is a family or community history that can shorten the list of targets by implicating a particular Usher gene or subtype.

The educational and medical interventions undertaken to improve a deaf or hearing-impaired child’s cognitive and social development can vary extensively, based in part on whether the child in question is expected to lose his or her vision later in life. Thus an earlier diagnosis of Usher syndrome is an immediate and critical research goal. The most imminent hope for such a diagnostic advance lies in gene chip screening. With this technology, the patient’s DNA can be screened against a microarray of human genes known to cause deafness (and/or Usher syndrome) when mutated, and variances in the DNA sequence of any screened gene would be detected and analyzed. One such chip is already available for commercial use, and another appears to be approaching clinical availability. The rapid and affordable analysis these microarrays offer will be of tremendous benefit in the early diagnosis and management of Usher syndrome.

In spite of the considerable amount of information about the pathophysiology of Usher syndrome obtained over the past 10 years, there are, as of yet, no clinically applicable treatments targeting the molecular underpinnings of the disease. Following the diagnosis of hearing impairment in a child, the parents may consider hearing aids or, in cases of profound hearing loss, a cochlear implant. The timing of the installation of these devices is critical, as speech development can be significantly impacted if the child does not begin to hear and reproduce spoken sounds in the first few years of life.

Hearing aids, which amplify sound, are appropriate in cases of moderate hearing loss, where hair cell function is only partially impaired, or where more severe hearing loss is restricted to a certain frequency range. In cases of severe to profound sensorineural deafness, as is the case in type 1 Usher syndrome, traditional hearing aids are ineffective. Cochlear implants are surgically placed devices that can substitute to some degree for defective hair cells. An externally worn processor converts the sound signals it receives into electrical impulses and transmits them to the auditory nerve, via electrodes threaded through the cochlea. Here’s a short video of the placement and mechanism of action of this device:

And here is a link that contains several MP3 files simulating how different types of auditory stimuli–speech and music–might sound through a cochlear implant.

The technology of cochlear implants has steadily improved since their introduction, but the device was not initially met with unmitigated approval. Some members of the deaf community have expressed reservations about cochlear implants, as many believe that deafness, and the subsequent requirement for non-verbal forms of communication, are not defects in need of repair. Although this opposition has lessened somewhat in recent years, parents facing these choices can still sometimes receive conflicting advice about cochlear implants. Clearly, the cultural identify of the deaf community is important to consider, but the knowledge that a hearing impaired child will suffer from progressive vision loss later in life could have a considerable impact on the decision to initiate education in a highly visual form of communication rather than undergo the cochlear implantation. Communication options for Usher patients without cochlear implants include tactile signing, in which ASL signs are executed while touching hands, or traditional ASL conducted in close proximity to the deaf-blind individual, within his or her narrow field of vision, with consideration for contrasting background colors so that the signer’s hands are easily visible against his or her clothing.

There is no treatment for the progressive vision loss in Usher patients. The first sign of a vision problem usually occurs when patients report difficulty seeing at night–a symptom that rod photoreceptor loss in the periphery of the eye is already underway. Further degeneration occurs from the periphery inward, resulting in an increasingly restricted visual field. The rate of retinal cell loss is monitored through regular ophthalmological examinations, and although supplementing the diet with DHA, the well known Omega-3 fatty acid, appears to slow the progression of photoreceptor degeneration in a number of retinal diseases, including Usher syndrome, there are no preventative or curative therapies available.

Currently, the most tractable research toward finding a treatment for the retinal disorder focuses on gene replacement therapy. There have been encouraging results using viral vectors to deliver functional copies of the myo7a gene into retinal cells of myo7a mutant mice, and the use of nanoparticles as a delivery system should provide another fruitful avenue of research. The progressive nature of the retinal degeneration in Usher patients lends itself to the application of such treatments. In principle, an effective therapy initiated early enough could begin rescuing photoreceptors from dysfunction and eventual death prior to the onset significant vision loss, further underscoring the importance of developing methods for early diagnosis.

Discovering more about where and how the Usher proteins function in the eye will be important in determining the optimal target for gene replacement therapy, and animal models of the disease will continue to be indispensible both for basic study of the molecular and cellular physiology of Usher syndrome as well as for the testing of new therapies in preparation for clinical trials.


  1. says

    OT, but I saw this on and thought the folks over here would be interested.

    US school district sued over homophobic ‘witch hunt’

    FLORIDA – When a high school senior told her principal that students were taunting her for being a lesbian, he told her homosexuality is wrong, outed her to her parents and ordered her to stay away from children.

    He suspended some of her friends who expressed their outrage by wearing gay pride T-shirts and buttons at Ponce de Leon High School, according to court records. And he asked dozens of students whether they were gay or associated with gay students.

    A small summary and my reaction is posted here.

  2. Nerd of Redhead says

    Danio, Good explanation. Very frustrating though, having a good idea on why something happens, but having no real way to stop it. Looks like a lot of work is needed on all these genetic diseases. There will probably be some overlap in methods to cure or ease the symptoms of these diseases, so progress on one will help the whole field.

  3. Danio says

    Whoops! I muffed the html code for one of my links and inadvertantly chopped a whole segment out of the post. It’s fixed now, if anyone’s still interested–the MP3 files in the now available link (just after the video) are actually really cool to listen to.

  4. says

    Jackal: Ed Brayton was on the case about a month ago. It’s been got.

    I study NZSL down in NZ, and I know that deaf people are often very proud of their community, which is based very strongly on sign language. But there’s no way they’d force a child who was going to go blind to go without an implant. I think the way they work it now is to introduce the implants except in families where the cause of the deafness is known and the child’s parents are both deaf, and if the implant doesn’t take (some children don’t like them) they grow up fully in the Deaf world, and even if it does take a lot of children will still maintain a connection to the Deaf community.

  5. Danio says

    I know that deaf people are often very proud of their community, which is based very strongly on sign language. But there’s no way they’d force a child who was going to go blind to go without an implant.

    No, of course not. I certainly didn’t mean to imply that they would. The purpose of mentioning it at all in this post is that one usually doesn’t know, at the time decisions about implant are being made, that blindness is in store some years down the road. I fully support the wishes of the Deaf community to maintain their cultural identity, as long as parents who are new to the situation receive unbiased facts about their options. It sounds like the system in NZ is a good one, and hopefully we’ll get there in the US someday soon.

  6. hamilton says

    Other symptoms of Usher syndrome include:

    -Uncontrollable R&B singing
    -Above average dancing skills
    -Ability to rid women of their panties

    Just for the sake of completeness, no need to thank me…

  7. Diego says

    There is already a microarray for Usher syndrome, being comercialised by a company in Estonia, Asper Ophthalmics. We’ve been using this and other of their microarrays for quite a while.

  8. Danio says

    Thanks, Diego, that’s great to know. Do you know if this microarray is in use in the US?

  9. says

    This has been a super post. Educational and interesting. Awesome.

    @1 My “prayers” go out to Brokensoldier also, hoping things improve for him.

    Being an atheist, I need another word, but couldn’t think of one. Embarrassing, that.

  10. Helioprogenus says

    Thanks again Danio for truly enlightening us all on something few of us had even heard of.

    The gene therapy angle at treating the vision loss is quite interesting, but we have yet to get beyond our reactive immune system first. I believe there were some papers out as far as gene therapy in patients with certain kinds of leukemia, but they had massive organ failure as a result of the immune system going haywire. It might be quite a while before we get beyond these initial failures. As far as nano-particles go, they’re also likely to set off our immune system. In my humble opinion, it’ll be at least 20 years before we come close to really getting a handle on applying gene therapy to human beings.

  11. Danio says

    Thanks for following the series, Helioprogenus. Your point about the immunity-related dangers of gene therapy is a really good one, but the eye’s immune privilegd status may make this particular tissue a better candidate than most for these sorts of applications. We can only hope!

  12. Helioprogenus says

    “The anatomical structure of the eye may assist in mediating immune deviation. Much of the eye is avascular and there are a number of cellular and physical barriers which enforce the separation from the blood supply. Apart from the physical barriers, the eye produces a number of molecules that may contribute to its ‘immune privilege.’ Such molecules include transforming growth factor (TGF-), melanocyte-stimulating hormone, vasoactive intestinal peptide, calcitonin gene-related peptide (CGRP), Fas ligand, and inhibitors of complement activation and fixation (anterior chamber of the eye). These have been postulated to play a role in inducing different phases of ACAID.”

    Wow, now that’s quite a development. It would be interesting to follow the detailed research on this, and perhaps discover a new biochemical pathway mediated by the intra-ocular environment that can be applied to other areas of the body that may be more susceptible to immune responses (and thus allow for less risky theraputic administration).

  13. Mooser says

    When I was young and in elementary school, my hearing was tested many times. They thought I had some kind of hearing defect, but it turned out I just wasn’t listening.

  14. Harpy says

    I would really appreciate if you would compare the mechanisms of the sensorineural deafness experienced in Stickler’s Syndrome type III and that of Usher’s Syndrome. Are the two mechanistically comparable? Secondly, and less importantly, can you imagine a clinical scenario wherein one could confuse the two syndromes, or do you feel this proposed situation is impossible?

    Thank you.

  15. Danio says

    Hi Harpy,
    From what I understand, Stickler’s Syndrome results from a defect in connective tissue, usually due to mutations in one of several human Collagen genes. It seems similar to Usher syndrome in that it has a lot of clinical variability, but there appear to be a lot more tissues affected in Stickler’s patients, who often have bone-related disorders in addition to hearing and vision problems. The nature of the vision defects in Stickler’s is also unlike that of Usher patients.

    As far as the mechanistic cause of the deafness, a quick pubmed search didn’t turn up much, but I’d guess that if the connective tissue within the organ of Corti that undergirds the hair cells is poorly formed or unstable in some way, hair cell function (and perhaps organization) would probably be impaired.

    I am not a clinician, and I don’t know how Stickler’s patients present at their first diagnosis. Is the hearing loss ever congenital? Hearing loss is detected during the neonatal hearing test in type I and II Usher patients, and this is the only symptom of Usher’s in early life. In cases of type III Usher’s, where the hearing loss is progressive, I would think that it could be clinically distinguishable from Stickler’s on the basis of the other symptoms. The fact that Stickler’s appears to be genetically transmitted in an autosomal dominant manner, meaning that just one mutated copy of the gene will result in the disease phenotype, would also be a helpful clue in reaching the correct diagnosis.