Sunday, December 16, 2012

Genetics Update or Why our community is at least 14'000 years old

Yes, even the Flint Stones might have had to listen to stutterers...

Check out StutterTalk's Peter's as-always excellent interview with Denis Drayna on the "latest Drayna wants to tell us about genetics as of December 2012". Some exciting news: biochemical experiments show that the gene mutation reduces activity of an enzyme by half, the earliest known mutation happened 14'000 years ago, roughly 10% are of the 3-gene subtype, and many more gene signals found.

All-in-all, congratulations to Dennis Drayna's team for their hard and constructive scientific work.

Here are the key nuggets of knowledge and insight that I picked up and commented:

1) They studied the effect of the mutation of the 3 genes of the identified cycle and they see a reduction of the activity of the corresponding enzymes ( a form of protein that accelerates chemical reactions to help the body to produce the stuff it needs to live) by 50%. This fits neatly to a reduced (but not zero) capacity of the brain to function normally in speech. Think of my motorway analogy: we have 2 lanes instead of 4.

2) As we know, more than one gene mutation in the three-gene cycle causes a severe disorder, but only one mutation correlates to stuttering. They also did the biochemical experiment for 2 or 3 mutated genes out of 3, and got a dramatic reduction of 90 respectively 100% of enzyme activity. This neatly explains why 2 and 3 mutation lead to a severe disorder and a single one does not as the body is just about able to handle it biologically.
Nice empirical result, but I expected this, as the body has redundancy built into into gene pool and metabolic cycles, and one gene mutation should most of the time have a relatively mild impact.

3) They found many more signals for genes that correlate with stuttering. The list is getting long. A golden period at NIH for gene hunting. As I said before, deafness for example has at least 100 or so genes. So there is clearly not ONE stuttering gene. Note that they will have huge problem extracting the exact gene or gene combination as the signals that say on which chromosome, but you need much more data to locate the genes or combinations of.

4) They looked at 800 stutterers. 13.5% of the stutterers had a mutation in one of the three genes, which is higher than the first estimate of 9%. He thinks about 10% of stuttering is due to this mutation type. Not sure how reliable this result is, because the sample might be biased. However, this mutation type clearly seems the strongest genetic source of stuttering. They should focus on this subtype of stuttering and try to completely take apart. By analogy, we can then imagine what probably happens in the other subtypes. And that is what they do.

5) Very likely that some people have no genetics. Only 50% have family history. General insults to the brain most likely cause the rest. This makes sense but he should have made the distinction between insult and developmental hiccup. Think of the construction of a house. Two things can go wrong: a badly designed construction plan (genes), and a badly (or temporarily badly) executed construction (for various reasons).

6) They cannot address why some is persistent and some is not. This is a serious open issue. Maybe the 3-gene subtype can shed some light, or do all people who genetically stutter persist into adulthood? Maybe only those with an insult (or developmental hiccup) to the brain go through this recovery phase, but not those with a genetic loading. I need to investigate more. Maybe a reader can comment on this.

7) It is not "your genes determine you", but stuttering is likely to have an innate basis for many. That they bring it to themselves is wrong and destructive, but psychosocial issues modulates severity. Agreed. The longer Drayna is in the field the more he seems to be including psychosocial issues in his disorder picture. The last time I met him at NIH and at a conference, he did not exhibit this more subtle awareness of psychosocial processes.

8) Brain at age 3 very busy and effects happen randomly. Agreed.

9) The 3-gene subtype reduces activity in an enzyme but why does it only affect stuttering? He speaks about animal model and gene switch-on and off. Which nerve cells are specifically affected? Probably just a localised region. They do not see a difference on gross pathology. But one study had a gene knock-out mouse which was totally normal, but had strange motor problem at age one (which is half-life for mice) This seems obvious to me that if gene mutation correlates to stuttering, and leads to reduced activity of a gene that it has to impact regions responsible for a part of speech and motor process. I am not sure whether it is only one region. I don't think so, because for me it is likely a connectivity issue. Brain anatomical studies of stuttering after brain stroke show various spots in a network of regions that can be affected. But maybe the 3-gene subtype only affects one region. Also, the mouse model might not be good enough. We need detailed anatomical studies on deceased 3-gene subtype stutterers. Greg Snyder, how about donating your brain to science? Thanks but please die soon! ;-)

10) It is a speech motor issue. Not completely sure what exactly he means. I need to think about it. But I would not say it is a motor issue per se but rather a performance issue of all motor regions working in harmony.

11) My fav question on Neanderthal stuttering. Can we date the gene mutation he found? Yes, one is approximately 14'000 years old! He says that Neanderthal is 100'000s of years before... No the last ones died 35'000 years. Also, we have 5% of Neanderthal within our gene pool when early homo sapiens came to Europe around 50'000 to 80'000 years ago. Researchers in Leipzig have identified DNA of Neanderthal. Maybe Drayna should search the DNA to see whether they have an identified mutation.

But it is amazing that science can tell us that stutterers existed 14'000 years ago, without any recording of voice! Our community is at least 14'000 years old. The Flint stones' stutterer. 

12) Peter asks about Jerry Maguire's deep brain stimulation studies/treatment. Drayna says that they are invasive studies, and one  needs to think hard if one should do them. He cautions the stuttering community: disappointment over and over again from brilliant new treatments based on anectdodal evidence. Understanding efficacy is a long process.  Wow, for a politically sensitive person this sounds very much like a velvet criticism on Jerry Maguire's approach. I tend to agree with Drayna. We had so many treatment wonders proclaimed and none materialised. Jerry has a history of strongly (and overly from a scientific point of view) advocating pharmaceutical treatments that raised a lot of hopes but which ended with no success in the large random control trials. See Pagaclone. And I constantly get emails from desperate people who believe it will be the wonder drug and that it must work because Jerry told them so. And I got many people who did take medication but stopped after a while. And one person even committed suicide, probably out of desperation. See here.

13) He didn't really answer my questions on how many stuttering projects are funded and whether other groups are working on the genetics of stuttering? He must know more.

14) Are they working with other families who stutter? Yes, he has a Brazilian family, which gives an interesting gene mix. This makes it likely that they are original native people and not of Spanish/Portuguese. Or most likely, a mix between both gene pool. This could indeed give raise to different genes. Let's wait and see. He sounded quite enthusiastic, so maybe they already have results.


Jon said...

I haven't listened to the podcast, but regarding #5: penetrance is a well known (to geneticists) measure of genotype/phenotype ratio. From Wikipedia:

"Penetrance in genetics is the proportion of individuals carrying a particular variant of a gene (allele or genotype) that also express an associated trait (phenotype). In medical genetics, the penetrance of a disease-causing mutation is the proportion of individuals with the mutation who exhibit clinical symptoms. For example, if a mutation in the gene responsible for a particular autosomal dominant disorder has 95% penetrance, then 95% of those with the mutation will develop the disease, while 5% will not."

I'm surprised to see a geneticist suggesting that family history would determine whether the condition was inherited in a particular individual. And in any case, knowledge of family history is quite limited. How can we know whether grandfather stuttered for three years when he was 3-6 years old?

Anonymous said...

Tom :
Hello !
I like your metaphor about house construction.
Thanks for making this interview clear and orderly.

I agree with your comment about "too many hopes" raised by the Maguire approach. Maguire is a fine physician, but some times he can get carried over by his own enthusiasm.

I wish you a happy New Year, with a lot of good news to comment !


Dr M-C Monfrais-Pfauwadel