Friday, February 19, 2010

More genes found!!!

You must listen to the Stutter Talk interview with Dennis Drayna on his team's discovery of a genetic mechanism for stuttering in 10% of people who stutter. Not once but twice or three times! I did, and here is my summary (and comments in brackets):
  • 8.9% of stutterers have mutations in one of the three related genes, but this number can change. (I agree: there is a large statistical error in drawing a sub sample from the population of stutterers. Not sure about the magnitude, but from 5% to 15% is definitely possible.)
  • Roughly 10% appear to stutter because of mutations in one of three genes.
  • The first gene was first discovered in large Pakistani stuttering families on chromosome 12, and then looked for and found in other stuttering Pakistanis, and US and UK samples of stutterers.
  • The gene is one of two genes responsible for constructing an enzyme used for a specific cellular metabolism.
  • They looked at mutations in the second gene, and found that it also correlates to stuttering.
  • Then they looked at a third gene that is responsible for a second enzyme that is responsible for the second step of the metabolic pathway. And again it correlated to stuttering.
  • Special kinds of cells seem to be especially sensitive to a breakdown of this metabolic pathway, but most others are not.
  • Because mutation carriers do not have any other noticeable symptoms apart from stuttering.
  • We don't know what happens to the remaining 90%.
  • They found more genes correlated to stuttering! (As I said before, if you talk to Dennis, it's like talking to the Dennis one or more years younger! I am convinced he has much more information, and again it will take years until everyone else knows about it. A scandal of the current publishing system in medical sciences!)
  • One could scan for the mutations, but Dennis' team is about science and not a client service provider.
  • A company could well come up with such a service.
  • There is some predictive factor.
  • There has little correlation with severity. Already in the 70s, Prof Kidd found that family history is not related to severity.  (I am not surprised. Severity is very likely due to learned behaviours and physiological reactions to jams in the brain.)
  • Enzyme treatment is feasible, but gene treatment is very delicate. (That's pretty obvious. You just add enzymes to the body, but you would have to add or replace a gene in all cells?)
  • No Pagoclone relationship. (He did not mention that a Chinese team has found a genetic dopamine relationship. What ever happened to research?)
  • Recovery is unclear. (I think his understanding on and thinking about recovery is superficial as I once told him! He also seems to think that it is the same mechanism than in persistent stuttering and the brain compensates. I am not so sure. Has someone ever recover from these mutations?)
  • Brain plasticity is not strong enough for those with the gene mutation. (As I said many times.)
  • A couple of female mutation carriers did not develop stuttering. (Interesting! Did they study them in more details?)
  • Future avenues:
    • Metabolic pathway study: what is the biochemical description?
    • Where are those cells sensitive to the lack of enzyme? They have hints that these cells play a role in emotion. (Maybe the cells keep speech unjammed at strong emotional states?)
    • Make mice with such mutations and try to establish as an experimental model. (I am highly skeptical.)

15 comments:

Dave Rowley said...

Raises more questions than it answers! I suspect that subtyping (Per Alm's work) will become even more important in relation to this.

I agree, the publishing game benefits only publishers, no-one else. But I guess Dennis is under pressure to publish in a high impact journal. We are all in thrall to the publishers!

What did happen to that Chinese research? Should I ask them to ODC so they can be challenged?

Gustaf said...

If I got it right, the recent study only studied a teeny-weeny bit of chromosome 12. Is it the cost of gene sequencing that limited the researchers to study a larger part of the genome? Or is there a good reason to exclude parts of the genome? Why go for chromosome 12 in the first place?

The cost of a full genome is coming down rapidly. At what cost is it reasonable to expect studies (any studies) comparing large groups of full genomes? Is it only a cost issue, or is it a computational issue too, or is it simply not necessary?

Mark B. said...

Gustaf - they looked at chromosome 12 because previous work had located a region on chromosome 12 that was associated with stuttering. In this study, they took the next step and actually sequenced the genes of stutterers and non-stutterers to compare them and find differences.

You always need a segregation study to locate the general region of an affected gene before you do the fine-scale work locating the actual gene.

Mark B. said...

I don't think he said it, but there has been at least one death due to experimental gene therapy. There are many barriers to successful gene therapy. One is that the immune system can attack the carrier of the new DNA - usually a virus. Also, the virus might mutate to become pathogenic. Getting the DNA into the correct cells and keeping it there is also a problem.

I'm interested in the new genes. It will be fascinating if they are not part of the lysosome pathway, like the first three are.

Tom Weidig said...

Gene therapy is absolutely utopia. Enzyme replacement therapy is realistic.

Anonymous said...

enzyme replacement therapy is NOT realistic in the near future. Please....not for stutterers

Tom Weidig said...

Come on! I never said that it is realistic "in the near future." You are twisting my words.

I think it is feasible. There are no technical obstacles that could not be overcome in my view.

Of course, if only administered in adulthood, it's unclear whether it can help.

Mark B. said...

Getting the enzymes into the brain could be a deal-breaker. None of the enzyme-replacement therapies for lysosomal disorders I've read about have gone into the central nervous system.

Anonymous said...

Sorry, I'm not sure how to create a standalone post, so I've had to tack this on here.

There is a a very interesting article on the BBC news website called "Singing 'rewires' damaged brain":

http://news.bbc.co.uk/1/hi/sci/tech/8526699.stm

This says that the part of the brain responsible for singing is different to that for normal speech - something which ties into something I was told at a Per Alm presentation some years ago. But the interesting thing is that stroke patients can be taught to use the 'singing centre' to speak.

As part of the learning process they tap out each syllable using their hands as an "internal pacemaker"... something that again corresponds to what was in one of Per Alm's papers that stuttering could be related to a deficient internal timing mechanism (the internal 'stop and go' signals from the basal ganglia not being distinct enough).

This work on stroke patients sounds like an opportunity to create a new stuttering therapy.

What do you think?

kanstantsin said...

Actually I've heard from at least three different people that "singing can cure the stuttering". Always thought that this is bullsh*t.
Also "tap out each syllable using hands" is the technique I used with some of my speech pathologists, when I was a kid. Looks like it did not help me, I am still stuttering.

Knastantsin said...

Gustaf said

"At what cost is it reasonable to expect studies (any studies) comparing large groups of full genomes? Is it only a cost issue, or is it a computational issue too, or is it simply not necessary?"

It's just a cost issue. It should be cheap enough to do the whole genome sequencing from groups of people in next 2 to 5 years, hopefully. Now it is too expensive, so researchers first try to locate possible candidate gene on a certain chromosome region, and then seqence this small piece of chromosome.

BTW,
the full text of Drayna article is in free access now togehter with comments from journal editor
http://content.nejm.org/cgi/content/full/NEJMoa0902630v1
http://content.nejm.org/cgi/content/full/NEJMe0912594v1

y.vanzaalen said...

Dear all,
Although this research looks promising, the first question that arises is how they diagnosed the person as a person who stutters. Is this done with a Stuttering Severity Instrument, is cluttering considered or not. Or are these people selected on self based diagnosis. Are people included with a low %SS as well as people with a high %SS? And what about the other chromosomes that are known to be involved in stuttering?
I look forward to your responses.

Anonymous said...

good question, in the appendix of the online article, they have the SSI 3 graph table (SSI 3 measures stuttering severity).

Diagnosis: you know a stutterer when you see a stutterer....everyone knows what is stuttering (when they hear), but still no good definition of stuttering vs. not stuttering.

Especially in kids...

Eric said...

I found the note about the link to emotions somewhat interesting.

I'm a pretty mild stutterer as of now, and when I do, I have blocks more than repetitive words...I sort of know when I'm going to stutter and just don't stutter.

Anyway...in my past experiences, it seems that when I am angry, I never have a block and my speech flow is much more fluent and free. I always wondered if there was something in relation to anger and/or neurotransmitters during this emotion that affected the speech areas of the brain.

Has anyone else experienced this with their speech under certain emotions?

ig88sir said...

Eric,
Yes when I am angry I can cut through blocks or the blocks aren't there often.

Whatever helps lower stuttering severity only lasts for a window of time though. The stuttering eventually comes back.