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Monday, July 25, 2011

Usher syndrome Part I, 2011 edition: An introduction to sensory perception.

by Jennifer Phillips, Ph.D.

Note: this is the first of a four-part installment on the science of Usher syndrome. This series was posted on the Usher Syndrome Coalition Website and the ScienceBlogs network a few years ago, but given the amount of specific Usher science we discuss here on our blog, it may be helpful to readers to have these resources ‘in house’. Part I gives an overview of hearing and vision at the cellular level, parts II and II discuss the known Usher genes and proteins, and their proposed roles in the eye and ear, respectively. Finally, Part IV brings all this cellular and molecular information back to the clinical level, and includes a survey of current and future research directions. Understanding how the human body works, and what goes wrong in any given disease, has value in and of itself. But for those of us hoping and striving for a treatment, a better understanding of the biology of Usher syndrome will be necessary for understanding how potential therapies might work.

Usher syndrome is a genetically recessive condition characterized by hearing impairment--usually from birth--due to defects in the sensory neurons of the inner ear, and vision loss due to retinal degeneration, which begins to occur in childhood or adolescence and progresses through several decades. Additionally, some Usher patients have balance problems associated with the sensory cell defects in the ear. There is a great deal of variation in the clinical presentation of the disease, and three clinical subtypes can be classified by the severity and age of onset of the symptoms. The latest estimates project that Usher syndrome affects about 1 in 6,000 people.

To begin to understand the pathology of this disease, one needs to focus on the affected cell types: Mechanosensory hair cells and photoreceptors. Both are highly specialized types of sensory cells, but they’re performing essentially the same function, namely receiving an environmental stimulus and converting it into an electrical signal that is transmitted to the brain for interpretation. Although the nature of the stimuli—sound and light—are quite different, they are processed in much the same way, and thus it is not surprising to find a number of structural and functional similarities between photoreceptors and hair cells.
Figure 1: comparative anatomy of a photoreceptor cell (A) and a mechanosensory hair cell (B). The Outer Segment (OS) membranes of the photoreceptor are similar in form and function to the stereocilia (SC) of the hair cell. Both cell types contain cilia (labeled CC [connecting cilium] in A; KC [kinocilium] in B) and have specialized synapses (S) through which signals are sent to second-order neurons (‘2nd’, labeled in A; supporting cell projections can be seen at the bottom of the cell in B).
Sensory neurons are constantly stimulated with a complex array of information. Photoreceptors respond to all wavelengths of light within the visible spectrum as well as transmitting information about total light levels and movement. Mechanosensory hair cells can not only respond to physical contact by sound waves, they transmit information detailed enough to determine whether the sound waves in question were generated by a lover’s whisper, breaking glass, or a bow being drawn across the strings of a cello. In order to intercept and convey information at this level of specificity, sensory cells have evolved specialized structures to meet the high demands of both input and output. On the receiving end are intricately organized membranes built to respond to the environmental signals. In photoreceptors, the outer segment contains stacked discs filled with opsin proteins, (remember those?) that trigger a cellular response when activated by light. In the hair cell, the sterocilia (not actually “cilia” at all, but finger- like projections made of the protein actin) move when they encounter sound waves, opening channels through which ions can enter the cell and initiate a response.

On the outbound side of things, these sensory neurons have a mechanism by which they can adequately relay the complexities of the environmental input they receive. In physiology 101, we learn about the classic type of neuronal response, in which the nerve cell needs to reach an action potentials to fire. Basically, these nerves are in a state of rest until they are sufficiently stimulated to elicit a response. Even though these responses to stimuli, such as a command from the brain in the case of motor neurons, or stepping on a sharp rock in the case of pain receptors, are fast, they are usually a simple binary, on/off type of response, and tend to be short lived.

The constant bombardment of information that our sensory cells endure is something along the lines of the chaos of the trading floor of the New York Stock Exchange, 24/7. A conventional neuron relying on action potentials to convey this information would be woefully overmatched in such a situation because it just wouldn’t have time to ‘reload’ under such constant stimulation, nor would it be able to convey the specificity of information in the light or the sound stimulus receiving. Instead, photoreceptors and hair cells keep stockpiles of neurotransmitters tethered to the cell membrane. When the cell is stimulated by the environmental signal, no action potential needs to be achieved. Multiple neurotransmitters are right there, ready to be released, and, unlike a typical neuron, these sensory cells can be active in the long term—for as long as there is a stimulus to report. When these cells release neurotransmitters, they activate neurons waiting nearby to,pass the message through additional channels leading to the sensory processing centers of the brain. The downstream message processing is far too complex to describe here, but the important thing to remember is that the message originates from these specialized sensory cells. They’re responsible for collecting the information in the first place in a way that conveys a great deal of detail and specificity about the environment.

Finally, the presence of a true cilium is yet another commonality between these cells, although its function in each is quite distinct. So, in sum, we have two cell types that use similar cellular equipment to fulfill their roles as reporters of complex environmental information. We know that in cases of Usher syndrome, a genetic disorder, these two cell types are affected. This is strong evidence that the similarity between photoreceptors and hair cells goes deeper than the cellular similarities. In fact, the molecules regulating the specific sensory functions performed by these cells are yet another commonality, and this makes a lot of sense if you’re trying to understand why both hearing AND vision are affected in Usher syndrome. It’s all down to the molecular toolkits these cells use to develop and do their jobs properly.

In Part II, I’ll introduce the proteins affected in Usher syndrome and describe what they tell us about the disease itself.

Monday, July 18, 2011

The Cure?

by Mark Dunning

What if Usher syndrome no longer existed? What if it went the way of Polio and Small Pox? But as with the Polio and Small Pox vaccines, this treatment would not change the fate of those of us who already have Usher syndrome. In short, we’d be the last, a people destined to be a footnote in the history books. How would you feel if no one was ever born with Usher syndrome again?

I don’t know much about preimplantation genetic screening which is not surprising. I don’t know much about a lot of things. Actually, I’m sort of fascinated to even be writing the words preimplantation genetic screening. Five years ago I had never heard of those words and would have never, ever considered writing them in a blog that I co-write with a molecular biologist from Oregon. A lot has changed for me since my daughter was diagnosed with Usher.

One of the things that has changed is that I now sit on the board of directors for a genetics group. I was invited to join because my daughter has Usher syndrome. I’m the consumer representative which means, basically, that I ask dumb questions that everyone else in the room already understands. That’s because 95% of the topics we discuss go over my head like balloons released at a carnival. Every once in a while a string passes close enough that I can reach up and grab it. That happened recently with preimplantation genetic screening and it is where I learned the little I know about the topic.

So here’s the Idiot’s Guide (and I do mean idiot) to preimplantation genetic testing. Using in vitro fertilization an egg (or eggs) is fertilized in a petri dish. The genetic material resulting from this fertilization is then genetically tested for certain known genetic conditions. Based on this testing embryos are chosen that do not have the genetic condition with the intention of ensuring that the coming baby does not have said genetic condition. The chosen embryo(s) is/are then implanted into the mother to continue development.

Preimplantation testing is not done prior to every pregnancy right now nor is there any indication that it will be any time soon. But it is not farfetched to think that someday it might be. When my parents had kids, caesarian sections were almost never done. Now according to Wikipedia (and Wikipedia is always right) almost 20% of births in the US and nearly half the births in China are c-sections. So it is not crazy to think that in vitro fertilization and preimplantation testing might one day become the norm.

So for the sake of this post, let’s imagine a world where preimplantation genetic testing is in fact the norm.

One obvious benefit would be the potential elimination of some terrible disorders, such as Tay-Sachs, a neurological disorder that usually results in children dying before the age of four. The world would undoubtedly be better off without that disease, right? And it would be gone forever. Such testing would allow us to not only identify eggs that had Tay-Sachs but also eggs that were carriers. Since no one would still carry the gene, within a generation Tay-Sachs could be gone.

That would hold true for any genetic condition, including Usher syndrome. And the world would be better off without Usher syndrome, right?

My son spent a recent Saturday playing a soccer game with an exaggerated limp. He claimed to have hurt himself kicking a ball against a wall the day before. I would have held him out of the game but for two reasons. First, the limp changed sides frequently and often disappeared altogether. Second, a hangnail can put him the verge of tears. In short, I love him dearly, but he’s a wimp. That’s OK, so am I.

My daughter on the other hand is tougher than a three dollar steak. She takes knocks on a daily basis that would make a boxer wince and does so without so much as a change of expression. Bella has Usher syndrome. She has spent her life tripping over things and bumping in to things. She falls down a lot. She expects it. She knows how to deal with it. She is an expert at picking herself up. So when she goes down, she pops right back up. Jack, on the other hand, rarely hit the canvass. When he does, he stays down for an extended period more from surprise and inexperience than from any real injury.

So why are my kids so different? Is it genetics? Is Bella genetically designed to be tougher than Jack? Or is it more environmental? Or is it a combination of both? The answer might be simply that Bella has a genetic condition called Usher syndrome that causes her to come in to conflict frequently with her environment and that makes her tougher.

One of the big ethical questions facing preimplantation genetic testing is what genetic traits should a parent be able to eliminate? Diseases like Tay-Sachs are easy decisions. Bringing a child in to the world to suffer and die is not anything anyone would support. But where is the line on suffering? If a gene meant someone was destined to get cancer in their forties, should that be eliminated? How about if the cancer is treatable with a nearly 100% survival rate? According to ABC news, “social research suggests that shorter people…make less money, hold fewer leadership roles and are less sexually active than their taller peers.” That same article states that 10% of the genes that control height have been identified. Someday it will be 100%. When it is, is short stature suffering worth avoiding?

There are treatments for hearing loss. Many in the Deaf community don’t even consider hearing loss to be a handicap. But a large percentage of the causes of hearing loss are genetic. Is hearing loss a trait that should be eliminated?

And what about Usher syndrome? The hearing loss is treatable. There will someday be treatments for the vision loss. So does Usher syndrome bring so much suffering upon families that it should be genetically eliminated?

We recently ran a charity horse show to benefit the Decibels Foundation. My whole family was there. My daughter rode in the show. My father came over to the farm at the crack of dawn to help my sister, my wife, me, and a host of friends set up. My son helped with the raffle and worked the concession stand.

My wife and I started the Decibels Foundation ten years ago because our daughter was born deaf. Decibels does a lot for families with Usher syndrome these days, too, because Usher is turning out to be a much more common cause of hearing loss than first thought.

My parents are the reason I am a carrier of Usher syndrome. My wife is a carrier, too. Because of us, Bella has Usher syndrome. So you could say that our parents are the reason that there was a horse show. Without them, there is no Bella and without Bella, there is no charity horse show, and no benefit to hundreds of other deaf families.

I know a man. He had a son who had Tay-Sachs. His son lived longer than most. He died when he was seven. The boy never left his bed, never said a word. The man started a national Tay-Sachs foundation and has raised millions for research. He has two other children and is the kindest, gentlest, most loving father I have ever met. When I told him I admired his patience and the love he clearly displayed for his children, he said he wasn’t always that way. Tay-Sachs had changed him.

“Character cannot be developed in ease and quiet. Only through experience of trial and suffering can the soul be strengthened, ambition inspired, and success achieved.”- Helen Keller

Here’s a question for you: Has mankind thrived in spite of its challenges or because of them? And what does it mean for society if we eliminate those challenges?

My daughter always stands tall in the face of adversity because she has Usher syndrome. My family is closer and more giving because of Usher syndrome. My friend is a better father because of Tay-Sachs and I dare say I am a better man because of Usher syndrome.

Would we have become who we are without those challenges? And would the human race have achieved what it has without its innumerable challenges?

We watched X-Men: Last Stand the other night. The premise of X-Men is that mutations in the human genome lead to a group of people, mutants, with super powers. In this particular movie, a ‘cure’ is found that can eliminate the mutation, essentially turning the mutants back in to people. This is a source of contention among the mutants. Many are happy just the way they are. Some are worried about what it would mean if everyone else takes the ‘cure’ and they do not. What happens to them?

We sometimes joke with my daughter that she is a mutant like the X-Men. This has always been a source of pride for her, given that they are super heroes and all. During the movie, in one of my frequent bad parenting moments, I casually mentioned to Bella about preimplantation testing. I told her that we might someday have a ‘cure’ like in the movie, a way to ensure that no one would be born with Usher syndrome again. She started to cry. She didn’t want people like her to no longer exist, in part because of the implication that she was something horrible that needed to be eliminated, but also because she didn’t want to be alone. She didn’t want to be the last mutant.

What does it mean to ‘cure’ Usher syndrome? Does it mean viable treatments like cochlear implants? Does it mean identification at birth like PKU where a simple blood test in the first days of life (remember the heel-stick in the maternity ward?) allows a disease that can cause severe mental retardation to be avoided by simple dietary modifications? Or does it mean that the disease, like Polio, is simply eradicated and gone forever? And what would that mean for us, the last families with Usher syndrome?

Preimplantation screening is gaining popularity. A host of genetic disorders, including Usher syndrome, could eventually be eliminated from the human race. At some point in the not too distant future it’s entirely possible that no family will have to suffer the agony of Tay-Sachs or fear for the deaf-blindness of Usher syndrome. And the world would be a better place because of it.