Thursday, February 11, 2010

Breaking News: Stuttering Genes "officially" found


The discovery of stuttering genes are on the front page of the BBC website. But the BBC and all other media are one year slower than myself! I told you about the discovery here reporting from Greg Snyder's letter in January 2009! ;-)

My first prediction of this year has turned out to be true. Dr Dennis Drayna and his group at NIH at Bethesda claim to have found the first genes for stuttering. The scandal of course is that he and his team knew this for  years (!!), but due to the idiotic embargoing from the top science journals, authors are forced to withhold such information until publication thereby depriving the research and wider community from pieces of the jigsaw puzzle. Even though NIH is funded by tax payers' money. That is not good open science for me!

Summary: A variation of a gene causes disruption of the normal metabolism in some brain areas leading to stuttering, and two or more variants of the gene lead to severe health issue.

Conclusion: For all those who have one variant like Greg Snyder just be happy that you only stutter and don't have another variant!

Congratulations to Dennis and his team for hard diligent work! Here is the NIH press release. (Detailed analysis will follow.)

Researchers Discover First Genes for Stuttering
Findings suggest common speech problem, in some cases, may actually be an inherited metabolic disorder

Stuttering may be the result of a glitch in the day-to-day process by which cellular components in key regions of the brain are broken down and recycled, says a study in the Feb. 10 Online First issue of the New England Journal of Medicine. The study, led by researchers at the National Institute on Deafness and Other Communication Disorders (NIDCD), part of the National Institutes of Health, has identified three genes as a source of stuttering in volunteers in Pakistan, the United States, and England. Mutations in two of the genes have already been implicated in other rare metabolic disorders also involved in cell recycling, while mutations in a third, closely related, gene have now been shown to be associated for the first time with a disorder in humans.

“For hundreds of years, the cause of stuttering has remained a mystery for researchers and health care professionals alike, not to mention people who stutter and their families,” said James F. Battey, Jr., M.D., Ph.D., director of the NIDCD. “This is the first study to pinpoint specific gene mutations as the potential cause of stuttering, a disorder that affects 3 million Americans, and by doing so, might lead to a dramatic expansion in our options for treatment.”

Stuttering is a speech disorder in which a person repeats or prolongs sounds, syllables, or words, disrupting the normal flow of speech. It can severely hinder communication and a person’s quality of life. Most children who stutter will outgrow stuttering, although many do not; roughly 1 percent of adults stutter worldwide.  Current therapies for adults who stutter have focused on such strategies as reducing anxiety, regulating breathing and rate of speech, and using electronic devices to help improve fluency.

Stuttering tends to run in families, and researchers have long suspected a genetic component. Previous studies of stuttering in a group of families from Pakistan had been done by Dennis Drayna, Ph.D., a geneticist with the NIDCD, which indicated a place on chromosome 12 that was likely to harbor a gene variant that caused this disorder.

In the latest research, Dr. Drayna and his team refined the location of this place on chromosome 12 and focused their efforts on the new site. They sequenced the genes surrounding a new marker and identified mutations in a gene known as GNPTAB in the affected family members. The GNPTAB gene is carried by all higher animals, and helps encode an enzyme that assists in breaking down and recycling cellular components, a process that takes place inside a cell structure called the lysosome.

They then analyzed the genes of 123 Pakistani individuals who stutter—46 from the original families and 77 who are unrelated—as well as 96 unrelated Pakistanis who don’t stutter, and who served as controls. Individuals from the United States and England also took part in the study, 270 who stutter and 276 who don’t. The researchers found some individuals who stutter possessed the same mutation as that found in the large Pakistani family. They also identified three other mutations in the GNPTAB gene which showed up in several unrelated individuals who stutter but not in the controls.

GNPTAB encodes its enzyme with the help of another gene called GNPTG. In addition, a second enzyme, called NAGPA, acts at the next step in this process. Together, these enzymes make up the signaling mechanism that cells use to steer a variety of enzymes to the lysosome to do their work. Because of the close relationship among the three genes in this process, the GNPTG and NAGPA genes were the next logical place for the researchers to look for possible mutations in people who stutter. Indeed, when they examined these two genes, they found mutations in individuals who stutter, but not in control groups.

The GNPTAB and GNPTG genes have already been tied to two serious metabolic diseases known as mucolipidosis (ML) II and III. MLII and MLIII are part of a group of diseases called lysosomal storage disorders because improperly recycled cell components accumulate in the lysosome. Large deposits of these substances ultimately cause joint, skeletal system, heart, liver, and other health problems as well as developmental problems in the brain. They are also known to cause problems with speech.

“You might ask, why don’t people with the stuttering mutations have more serious complications? Why don’t they have an ML disease?” posed Dr. Drayna, senior author of the paper. “ML disorders are recessive. You need to have two copies of a defective gene in order to get the disease. Nearly all of the unrelated individuals in our study who stuttered had only one copy of the mutation. Also, with stuttering, the protein is still made, but it’s not made exactly right. With ML diseases, the proteins typically aren’t made at all. Still, there are a few complexities remaining to be understood, and we’d like to learn more about them.”

The findings open new research avenues into possible treatments for stuttering. For example, current treatment methods for some lysosomal storage disorders involve injecting manufactured enzyme into a person’s bloodstream to replace the missing enzyme. The researchers wonder if enzyme replacement therapy might be a possible method for treating some types of stuttering in the future.

The researchers estimate that roughly 9 percent of people who stutter possess mutations in one of the three genes. Among the next steps, they are conducting a worldwide epidemiological study to better determine the percentage of people who carry one or more of these mutations. They are also conducting biochemical studies to determine specifically how the mutations affect the enzymes.  A long-term goal is to use these findings to determine how this metabolic defect affects structures within the brain that are essential for fluent speech.

20 comments:

Chata said...

Excellent news. Now it remains only how to implement this as a cure :)

Peter Louw said...

For my own understanding - does this mean that STUTTERING is inherited, or that the POTENTIAL to start stuttering is inherited?

Dave Rowley said...

Peter, my understanding is that it's the potential.


Original article can be read here: http://content.nejm.org/cgi/content/full/NEJMoa0902630

Harry said...

Great news - now what is the next step?

Can medication be created to 'fix'
the gene(s)?

preterosso said...

I don't want to sound skeptical but as I read it's only a small proportion of stutterers (9 per cent)who are carriers of any mutated genes. The history of my family both on my mother's and my father's side is well documented and I still seem to be the only stutterer in the family.

Mark B. said...

Preterosso

Penetrance is the proportion of people who have the particular genetic variant and also show the associated trait. It is very common in genetics to see less than 100% of individuals carrying the genotype to express the phenotype (as geneticists would say it). Also, a genetic mutation may be carried by both your mother and father, and only a fraction of their children would show the trait. Inheritance is much more complicated than direct father-to-son, but the rules are well known and understood.

Ora said...

My understanding is that it's a long road from discovering a gene(s) to discovering a cure.

Discovering a gene is sometimes useful in treating a condition, but there are many conditions which are genetically determined for which no cure is available.

Tom or Mark - Can you say more on this? Is there any reason to think that this discovery might lead to a cure?

Torey said...

I read about this in an AP news piece and from the Stuttering Foundation. I was very dismayed at how this was being portrayed. It's good that new info is found, but people are drawing irresponsible conclusions. It's being touted as "Stuttering is now proven to be genetic!" instead of simply that genes were found that tie to stuttering in a small percentage of cases. There was huge insinuation that "the myth that stuttering is caused by mean parents can now be put away!" To me, it felt like people are using this information to make well meaning teachers or ignorant speech therapists feel better about harm they've done to children, i.e., "eh, it's all genetic."

I'm glad that Tom didn't take that approach.

Mark B. said...

Torey

Stuttering has already been shows to have a genetic component in some people to a high degree of certainty. In breast cancer, one of the first genes found affected an estimated 5% of cases. That, and this "stuttering gene," is what we would expect to find. If there was a single gene that always caused stuttering, we would already know about it. Medical conditions are frequently much more complicated than that.

This discovery does not "prove" anything that can be generalized to all stutterers. It does show that at least in some cases, a particular gene probably sets off the possibility of persistent stuttering. It is reasonable to expect that more such genes will be found, as is true in other such conditions. No one should make more or less of this than the data support.

Mark B. said...

Ora

I am reading the paper. Scientists sometimes have to talk about cures to get the funding that will pay for basic research. They know that cures so not often follow basic research breakthroughs quickly, but if the basic groundwork is not done, the work that will later lead to a cure will not be done either. The fact is, until now, no one has considered lysosyme failure as a cause of stuttering. If there will ever be a cure for people like those in this study, that knowledge may be critical. Now, researchers can start asking direct questions about how lysosyme proteins and stuttering are connected. And the techniques used in this study can be used to find more genes that may have very different effects in different stutterers.

Olivier said...

Thanks Mark for these precisions.

Ora said...

Mark - Thanks for that information.

It's nice to have someone around with a background in genetics. It's fascinating stuff.

preterosso said...

Mark

I understand that there doesn't have to be a single occurrence in my family for me to be the first one with all the "necessary" genetic mistakes which cause stuttering. But if they only found 9 per cent of stutterers with this "stuttering gene", why do the rest of the people stutter? Another gene they haven't discovered yet? Or there are different kinds of stuttering? I, for example have always felt very different from those fellow stutterers I have met (partly during the therapy) in the following respects:
1. I only started stuttering at the age of 14.
2. I knew there was something wrong with me months before my first stuttering experience.
3. I have always felt/knew that suttering itself is only a superficial symptom so much that when I (have to) talk about stuttering it always feels like lying or not talking about what would really be important about it.

Torey said...

Mark - I don't disagree with what you said and appreciate the explanation. My major problem is that, like you said shouldn't be done, people are making much more from this as is really present.

The Stuttering Foundation has such false claims on their website right now, as does this AP article:
http://news.yahoo.com/s/ap/20100211/ap_on_he_me/us_med_stuttering_genes

Mark B. said...

Preterosso

In Pakistan, as in many places, cousin marriages are encouraged. As a result, particular rare genes can get "concentrated" in the family. That is what happened in the families Dr Drayna works with. Similar things happen in the Hutterites in North America - small, closed social groups where everyone is related. Working with these groups makes it easier to find rare genes, so these particular genes are the first ones to be found. If you did the same work in Germany or Canada, you'd have to use much, much larger populations - more money, more time. There may be many more genes that contribute to stuttering at even lower levels, but they will be discovered later.

Your case - onset at 14 - certainly seems to be a rare one. It's certainly also possible that your cause is different from most other stutterers. What makes sense on average doesn't necessarily do the individual any good. I have no stuttering history in my family that I'm aware of for three generations at least, but I'm a classic case.

Anonymous said...

myself, an uncle and cousin all have stuttered since our first words. I tried many years ago to get a speach specialist to look into this and was denied based on being coincidental.

Meanwhile we have Pagaclone in a phase 2B, how is this working for some patients if this is biological?

I do agree it is a long way before proactive steps are taken in terms of biological treatment.

George

Ora said...

Mark -

Is there any significance or interest to the fact that the variant genes are found on chromosome 12? Does this link it with any other genotypes related to different genes on chromosome 12?

What about the fact that we know that the incidence of stuttering is much greater in males than females. Does that suggest that we might expect to find genes implicated in stuttering on chromosome Y (which I believe males have but females don't)?

Thanks for your explanations.

Ora said...

Torey -

I'd be interested to know what you identify as false claims in the AP article that you referenced (http://news.yahoo.com/s/ap/20100211/ap_on_he_me/us_med_stuttering_genes). I looked at it and didn't find anything especially egregious.

Mark B. said...

Ora

Genes can have additive effects - the effect of each sum to the total effect you see in the individual. It is possible that the genes on chromosome 12 were combined in these individuals with genes of lesser effect to produce their stuttering. If one gene produces 70% of the effect, and two produce 15% each, it would be difficult to find the lesser genes without very large sample sizes in the study. Most past genetic studies of stuttering have suggested additive genetic effects with possible environmental effects as well.

On your other question, stuttering is sex-affected, not sex-determined, so the X and Y sex chromosomes are probably not involved.

There are many medical conditions that are very similar to stuttering in that it affects males more often than females.

There could be sex-differentiated triggers like hormones that determine gene expression. The same gene can be expressed at different times during development in different parts of the body for totally different reasons.

Then again, you could think of it this way: all embryos start out female, and some develop as male due to genetic coding. So in a sense, males are females gone bad, and it's not surprising that males have so many more problems than females. ;-)

Torey said...

Ora,
My problem with the article (and the Stuttering Foundation's claims) was that it was drawing irresponsible conclusions. It was going well beyond what the science said.

It says that stuttering tends to run in families but it doesn't say until later that it's ESTIMATED it MIGHT be genetic in half the cases. I've read other estimates that put that number lower.

Several times it makes a reference to parents of SLP's breathing a sigh of relief that they didn't cause their kid's stuttering. I'm an example of a stutterer who started because of over-aggressive speech therapy. I've spoken to numerous others as well. So to make a blanket statement that parents and SLP's don't play a factor in a child starting to stutter is irresponsible. Especially when considering the gene would most likely show a potential to stutter, not a guarantee. Outside factors would still play a part.