Hot Off the Lab Bench: Research News on Hearing Loss, Usher Syndrome

This is still not the craftsy blog we've been advertising. Instead we bombard you with science(!!), which from this reporter's perspective is the most exciting thing on earth. I suppose most readers will think otherwise, so I'll try to make it as exciting or, at least, as informative as I can.

I've spent the last two days at conferences at Harvard Medical School in Boston. On Saturday, June 20, the Decibels Foundation, together with Children's Hospital Boston and Harvard Med, sponsored two "Frontiers" conferences for parents and the general public. The morning session was Frontiers in Usher Syndrome and the afternoon was Frontiers in Hearing Loss. These piggy-backed on a 3-day scientific conference, Molecular Biology of Hearing and Deafness. I'll report on the Sunday talks from that one as well.

Probably the best part of going to the meetings was getting to finally meet, in person, some long-time cicircle friends that I've known only via email for over eight years, and to see some local Boston friends again. But the science was pretty exciting too.

This report is organized as follows: Usher Syndrome, Hearing Loss in General, Miscellaneous, in case you feel like skipping around.

Frontiers in Usher Syndrome
Usher Syndrome causes both hearing loss and vision loss due to retinitis pigmentosa. There have been a great many new discoveries about Usher, including some promising treatments for retinitis pigmentosa just within the last few years.

The morning's first speaker was Prof. William Kimberling from the University of Iowa, who introduced Usher Syndrome. Some of the key points he made included:

• There are 3 clinical types of Usher: Type I, Type II, Type III plus a fourth category called "atypical" that doesn't fit either of the first 3. in Type I, there is profound hearing loss from birth and balance problems (children don't walk until after 18 months -- this feature combined with profound hearing loss is something parents should not ignore). The onset of retinitis pigmentosa (RP) in Type I Usher is fairly early. In Type II, hearing loss is moderate to severe and RP doesn't start until later in the teens. In Type III there is a progressive hearing loss, and this type resembles Type II in childhood and Type I in older adults.
• Dr. Kimblerling said that at age 50, at least half of adults with Usher can still read the newspaper. This was good news! Dr. Kimberling showed some simulation slides of what an individual with Usher sees as the disease progresses. Often the earliest symptom is night blindness. In the dark, people with RP see only the bright lights, not shadowy details. Later, vision loss begins to affect daytime vision. It may begin with blocked out patches in the peripheral visual field, and eventually progresses to tunnel vision where a person sees just the center of the visual field. (The picture shown is one from an Australian web site, but is similar to ones shown by Dr. Kimberling.)
  
• Usher occurs much more frequently than was thought previously. It may affect 8% to 10% of all deaf children, and is the next most common genetic cause of deafness after Connexin-26 mutation.
• So far, 12 genes have been discovered that, if abnormal, can cause Usher.
• Early identification of Usher is important because early treatment may delay vision loss. Vitamin A supplements, especially in combination with fish oil or salmon may be helpful but are controversial because Vitamin A is toxic in high doses. Dr. Kimberling cautioned parents not to give supplements to children without a doctor's guidance.
• There are several gene therapy programs now underway for several types of Usher. (More on that with the next talk.)
• Generally speaking, individuals with Usher are not candidates for retinal implants at this time but may be in the future when retinal implants improve (both Dr. Kimberling and the next speaker seemed to agree on this in a question-and-answer session.)
  

The next speaker of the morning was Professor Doctor Uwe Wolfrum from the Johannes Gutenberg University of Mainz, Germany (both he and Dr. Kimberling were in Boston for the scientific conference.) Poor Prof. Wolfrum! His microphone kept moving, so it was hard for the audience to hear his talk and the talk itself was perhaps a bit technical. However, Prof. Wolfrum described some extremely exciting progress on Usher. His laboratory, in collaboration with several research consortia and funded by foundations and families affected by Usher, are starting gene therapy clinical trials! Specifically, they have trials under way or about to begin for retinitis pigmentosa caused by the genes USH1B, USH1C, USH2A, and USH3A. In addition, they are testing a drug called PTC124 to treat USH1C. This drug is a toxic aminoglycoside, but they are hoping that a less toxic version of it can be developed and used. (The drug is injected into the eye, not taken in pill form or intravenously. So far, they are testing it in mice.)

Prof. Wolfrum also answered something the scientist in me was wondering about: how can so many different genes cause Usher? Most of the 12 genes known to cause Usher are not similar to each other and yet they cause a similar disease. Prof. Wolfrum's theory is that the proteins made using the instructions coded for by the Usher genes all work together in big cellular machines (the USH protein "interactome"), both in the sensory cells of the retina as well as in the sensory hair cells in the cochlea. If any part of the machine is broken (i.e. one gene/protein), the whole thing grinds to a halt.

The last part of the morning was a panel discussion. On the panel were the parent of a 4-year-old with Usher I, a 45-year-old with Usher II diagnosed 14 years ago, a parent of a college student recently diagnosed with Usher I and the college student herself. The advice and life experience shared by these individuals was one of the highlights of the morning session. Some of the comments made included:

• Learning about Usher was a relief for the mom of the young child, because not knowing the cause of and the possible reasons behind his balance and coordination problems was frightening.
• Finding out later for the college student (she was diagnosed with retinal disease just weeks before her freshman year at college) was a big blow because she wanted to pursue visual arts, but a blessing as well because if she'd known earlier, she may have been steered away from her passion. She plans to continue with art.
• Finding out about Usher made the family of the college student and the college student herself feel extremely lucky that, despite strong pressure from professionals to sign when she was young, the family had chosen oral communication.
• Finding out about Usher made the family with the young child chose a more auditory path than they had settled on initially and to seek a second implant to allow the child to develop good sound localization ability if and when vision loss progresses.
• The adult, who had hearing loss her whole life, discovered something was wrong with her vision when she noticed herself becoming unusually aware of obstacles she might trip over.
• The 45-year-old said her Usher diagnosis was tough on her parents as well, who began to worry about her a great deal and also about her adult siblings, several of whom had hearing loss as well.
  
• One of the parents emphasized that "knowledge is power" and there is much help to be found. She also reassured parents that her fear that her child would "wake up blind tomorrow" was not likely and that kids with Usher will lead very normal lives.

This was the end of the Usher talks on Saturday. There was a scientific poster presented at the conference by Dr. Margaret Kenna's group at Children's Hospital Boston/Harvard Med. The poster pointed out that it is not easy to detect retinal disease just by routine eye exams -- do not rely on them! Electroretinography (ERG) and dark adapted thresholds (DAT) can be abnormal long before parents notice a child's vision deteriorating. Dr. Kenna, who was also a speaker at the Frontiers conference (see below) and organizer and moderator, also emphasized the importance of early diagnosis of Usher both for helping parents choose communication modality as well as treatments to slow the progress of retinitis pigmentosa.

As a side-note, I observed something I had not seen before at a conference. During the morning session, there was both an ASL interpreter and a CART reporter -- nothing unusual about that. But in addition, there was a second ASL interpreter specifically for one individual. This interpreter sat directly in front of the person she was interpreting for, and had a bright light (a halogen desk lamp) illuminating her face and hands.

Frontiers in Hearing Loss
The whole weekend was not just about Usher. The afternoon session was about hearing loss in general. The first speaker in the afternoon was Prof. Heidi Rehm (pronounced like 'reem') of Harvard Medical School who is the Associate Director of the Harvard Medical School Center for Hereditary Deafness. Dr. Rehm gave a very clear introduction to what genes are and how they are inherited. Some important points made by Dr. Rehm include:

• Today we know that genetic causes are responsible for between 1/2 and 2/3 of all cases of hearing loss. As time goes by and more genes are discovered, the fraction of genetic causes keeps growing. (In other words, an unknown cause becomes known as genetic; an anatomical cause is found to be caused by a gene, etc.)
  
• About 50 genes for nonsyndromic deafness have been identified so far, but there are known to be at least 85 more places in our DNA where there are more deafness genes waiting to be discovered.
• A blood test for genetic screening can be ordered anywhere, like through a pediatrician. It can be nice to have a geneticist or genetic counselor on hand to discuss the results.
• It is not necessary to test the whole family initially, just the affected child. If a deafness mutation is found, it is much less expensive to test other family members for mutations in that one gene alone.
• Connexin-26 is the single most common cause of hearing loss. It probably accounts for 50% of all cases of nonsyndromic recessive (genetic) hearing loss and 15-20% of causes for hearing loss over all.
• A recent study of the progression of connexin-26 hearing loss by Dr. Kenna and Dr. Rehm on 126 patients that they followed for several years found: 38% started out with profound hearing loss (nowhere to progress to), 43% had stable hearing loss levels, and 19% had hearing loss that got progressively worse.
• The connexin-26 protein makes channels between neighboring cells and is thought to control the potassium flow in the cochlea. High levels of potassium that build up when connexin-26 is absent or malfunctioning probably poison and kill hair cells.
• Eating bananas does not help for connexin-26 hearing loss.
  
• Gene tests are unfortunately not available for all deafness genes. The tests are easier and much less expensive for the short genes than long ones. Some of the deafness genes are long.
  
• Today, Monday, June 22, Dr. Rehm's lab is going to be testing the new OtoChip Test for hearing loss and Usher Syndrome that they have developed. It will let them test for mutations in 19 deafness genes all at once. What an exciting day in their lab!
  

The next speaker was Dr. Margaret Kenna, who I've mentioned already. Dr. Kenna is an ENT at Children's Hospital Boston and a researcher at Harvard Med. Dr. Kenna (pronounced 'ken-AY') gave an overview of every kind of congenital hearing loss (congenital means you were born with it; it does not necessarily mean it is genetic, though it could be). Some of the points she made included:

• We have come a long way just in the last 20 years. MRI and CT imaging has improved significantly, vaccines HIB and Prevnar have reduced meningitis dramatically, there are more interventions like cochlear implants and modern hearing aids, and many deafness genes have been discovered BUT, new causes of hearing loss have appeared as well, including interventions like ECMO used for premature infants in the NICU, Lyme disease and HIV, and more noise exposure due to MP3 players (noise-induced hearing losses are difficult to aid effectively since the loss is in the higher frequencies).
• Dr. Kenna showed interesting images of Enlarged Vestibular Aqueducts; she also talked about various infections that can cause hearing loss, among them, cytomegalovirus (CMV) infection, which infects 1% of babies born. Of babies with CMV, 10-15% have symptoms, many with hearing loss at birth. Another 10-15% who were infected with CMV do not have symptoms at birth but will develop hearing loss later.
• Parents should be aware that sometimes insurance does not pay for genetic tests, which is frustrating, but good to know or negotiate in advance.
  

The last speaker of the afternoon Frontiers session was Prof. Albert Edge from Harvard Med/Mass Eye and Ear Infirmary. Prof. Edge's talk was titled "Future Therapies for Inner Ear Degeneration." He talked about both his research and the research of other labs on gene therapy and stem cell therapy for hearing loss. The challenge lies in how to replace hair cells, which do not regenerate on their own if damaged (humans don't grow new cochlear hair cells after birth).

• There are two different genes that people are using stimulate hair cell growth in the cochlea: introducing the gene Atoh1 or shutting off the gene, Rb. Here's a slightly old article about Atoh1 and Dr. Raphael's group who studies it at the University of Michigan.
  
• There are two sources of stem cells: embryonic and adult (from within the individual). Advantages of using adult stem cells is they avoid immune rejection by the body and do not have political or religious conflicts associated with them.
• Stem cell therapies involve injecting stem cells into the inner ear. Dr. Edge's group has shown that stem cells grown in a lab dish can change into both hair cells and neurons and that the neurons can make synapses -- connections with other nerve cells or sensory cells. This is sounding pretty promising!
  
• Dr. Edge and colleagues are using robotics in the laboratory to sift through large numbers of small molecule drugs in order to find those that stimulate hair cell development.
• They are working with engineers from MIT to make a miniature pump (like an insulin pump) to deliver drugs directly to the inner ear in a time-release fashion.

I asked Dr. Edge what he thought the prospects were of repairing a gene responsible for a genetic cause for hearing loss (like connexin-26), and regrowing hair cells as well, and he thought that was a more challenging problem than just regrowing hair cells. Another audience member asked Dr. Edge about preserving cord blood of a sibling -- could that be a good source for stem cells? He answered that one could go ahead and save it, but cautioned that it might never be used because of the uncertainty about how things will go in this field of hair cell regeneration. He was asked (the often-asked question): how soon will gene therapy and stem cell therapy will be available for hearing loss? He answered that they are "several years" away still. I asked him if someone who already has bilateral cochlear implants might be able to use these therapies, and he said that probably not with older implants, but now with the newer, more gentle electrode arrays and insertion methods (and possibly with the shorter arrays), it may be possible.

Miscellaneous
Here are just bits and pieces from the Sunday talks and posters that were up.

• Dr. Richard Smith of the University of Iowa gave a talk in which he stated that if genetic testing is not available to a couple with a deaf child wanting to know the chances of having another deaf child, that the chances are 17%.
• Dr. Smith also said that there is one form of auditory neuropathy in which people do not do well with cochlear implants (DDON Syndrome, caused by a gene or genes on the X chromosome.)
• Dr. Smith also talked about a computer program his group developed called AudioGene. (I thought he said it is available for download but I can't find it anywhere.) It's specific for deafness inherited in a dominant fashion and allows people to input audiograms from themselves or family members. It predicts the gene responsible for their hearing loss.
• There was a poster called "Deaf by Fever!" from a group in Paris describing a form of auditory neuropathy that causes causes profound deafness only when a person has a fever! When their fever goes away, their hearing comes back. Certain mutations in the otoferlin gene (OTOF; a gene known to cause auditory neuropathy) can do this! Is that whacky or what!? (Three siblings were studied. Their hearing loss is in the moderate to mild range normally, and they benefit from hearing aids.)
  
• Scientists are interested in learning more about complex forms of hearing loss, age-related hearing loss and noise-induced hearing loss. It seems there are some individuals whose genetic makeup protects them from noise induced hearing loss more than other people (but don't count on it being you!)

OK, that probably does it for now. Time to start packing for the Northeast Cochlear Implant Convention in Strubridge, Massachusetts!

About the Author: Lydia Gregoret was at one time a chemistry and biochemistry professor who studied protein structure and stability using both computers and laboratory experiments at the University of California, Santa Cruz. She then became a full-time at-home parent for about 8 years. In September of 2009 she embarks on a new career: she begins classes at Northeastern University for an audiology degree (AuD.) Lydia dreams of becoming a cochlear implant audiologist one day.