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Usher syndrome part IV: Clinical management and research directions

January 31, 2012

by Jennifer Phillips, Ph.D.

The current standard of pediatric care mandating that all newborns undergo hearing screenings has been applied successfully throughout 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. 

Some percentage of children born with hearing loss have Usher syndrome. Until fairly recently, a diagnosis of Usher syndrome as distinct from various forms of congenital hearing impairment was not made until the onset of retinal degeneration was clinically documented-usually years after birth. The considerable number of genes involved made genetic screening impractical with the methods used up until the last few years, so unless there was a family or community history that could shorten the list of targets by implicating a particular Usher gene or subtype, there just wasn't enough data to proceed. 

Considering that educational and medical intervention designed to impact a deaf or hearing-impaired child's cognitive and social development vary considerably based on whether the child in question is expected to lose his or her vision later in life, an earlier diagnosis of Usher syndrome has been a critical research goal ever since the breadth of the Usher gene list has been known. The most impacting diagnostic advance in the past decade, with respect to earlier identification of Usher children, has been 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. While groundbreaking, there are still some limitations in the availability of this analysis, although hopefully that is a short term problem. A more pervasive problem-ultimately solvable, but on a much more protracted timeline-is the fact that we still can't screen for everything. The genes on the chip usually represent the most common mutations, so if a patient has a rare or unmapped type of USH, it won't be caught by this assay. Searching for new genes, and new variants of known genes to add to the list is an important focus of ongoing research. Developing improved methods of early screening for hereditary vision defects is another. 

In spite of the considerable amount of information about the biological cause and clinical progression of Usher syndrome obtained over the past 10 years, there are, as of yet, no treatments available based on the molecular underpinnings of the disease. Following the diagnosis of hearing impairment in an infant or child, the parents may consider hearing aids or, in cases of profound hearing loss, as is common in most Usher type I patients, 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 year or two of life. Obviously, early diagnosis is critical to the success of this intervention. 

In cases where hair cells are severely affected by disease, traditional hearing aids, which merely amplify sound, are ineffective. Cochlear implants are surgically placed devices that can substitute to some degree for defective hair cells. An implanted processor converts the sound signals it receives into electrical impulses and transmits them directly to the auditory nerve, via wires threaded through the cochlea, basically fulfilling the role of the missing or defective auditory hair cells. Here's a short video of the placement and mechanism of action of this device:

There is currently no treatment for the vision loss suffered in Usher patients. The first sign of a vision problem usually occurs when patients report difficulty seeing at night-a symptom of rod photoreceptor loss in the periphery of the eye. Degeneration of the remaining photoreceptors usually occurs from the periphery inward, resulting in an increasingly restricted visual field. The rate of retinal cell death is monitored through regular ophthalmological examinations, and although some physicians recommend dietary supplements in an effort to slow the progression of photoreceptor degeneration, there are no targeted therapies, either preventative or curative, available. 

Currently, the most tractable possibility of a treatment for the retinal disorder lies in gene replacement therapy. There have been encouraging results using viral vectors to deliver functional copies of genes into retinal cells of mouse models and of humans in research trials (just type "gene therapy" into the Usher Blog's search engine to read about some recent examples). The use of nanoparticles as a delivery system should be another fruitful avenue of research. The slow, 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. 

Ongoing research into where and how the Usher proteins function in auditory and visual cells 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. We will continue to report on the latest developments in this research here on the Usher Blog as results come to light.


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