Saturday, June 19, 2010

Stuttering: a disconnection syndrome

The New England Journal of Medicine in a very generous contribution to free and open science has published the first 100 words of a letter to its Editor by scientists whose research and salary is being probably entirely paid by us, the tax-paying public, Büchel from Hamburg, Watkins from Oxford, and a reply by Drayna from NIH:

To the Editor: In the report by Kang et al. (Feb. 25 issue)1 regarding genetic abnormalities in the lysosomal enzyme–targeting pathway in persistent developmental stuttering, it would have been important to relate the results to recent neuroimaging findings in patients with this disorder. Contrary to the authors' statement that "the underlying causes of stuttering are unknown," studies using diffusion tensor imaging, a technique sensitive to subtle abnormalities in brain white matter, have consistently revealed left-hemisphere white-matter abnormalities in patients with this disorder.2,3,4 Together with studies showing a speech-timing abnormality in such patients, these data strongly suggest a disconnection syndrome.
Looks to me as if Büchel and Watkins are not happy that the genetics paper has left the causes of stuttering unclear. For them, stuttering is clearly a disconnection syndrome. I have never heard that term before, but a similar tone was hit in a recent Chinese brain imaging article. Clearly connectivity issues would lead to a less effective system which leads to occasional speech delay.

But yet again, we are deprived from an open debate. Yet again it is happening behind subscription-closed doors.

8 comments:

ig88sir said...

Does anyone think the lysosomal enzyme abnormality leads to a physical white matter deficit? And if so how would enzyme replacement therapy fix a physical structural abnormality? Would it eventually grow the white matter connections??

ig88sir said...

strengthen the white matter connections rather.. the myelin sheath

Anonymous said...

Have StutterTalk start another petition demanding this paper be made available for public debate.

Silva said...

to the Editor: In the report by Kang et al. (Feb. 25 issue)1 regarding genetic abnormalities in the lysosomal enzyme–targeting pathway in persistent developmental stuttering, it would have been important to relate the results to recent neuroimaging findings in patients with this disorder. Contrary to the authors' statement that "the underlying causes of stuttering are unknown," studies using diffusion tensor imaging, a technique sensitive to subtle abnormalities in brain white matter, have consistently revealed left-hemisphere white-matter abnormalities in patients with this disorder.2,3,4 Together with studies showing a speech-timing abnormality in such patients, these data strongly suggest adisconnection syndrome. The observed mutations in the genes encoding the alpha and beta subunit (GNPTAB) and the gamma subunit (GNPTAG) of GlcNAc-1-phophotransferase and the likely evidence of lysosomal dysfunction in patients with persistent developmental stuttering now provide a possible neurochemical basis for white-matter abnormalities, because lysosomes participate in protein trafficking,5 which is crucial for the biogenesis and maintenance of myelin sheaths.6 Consequently, it is not surprising that a hallmark of mucolipidosis types II and III, disorders caused by mutations in GNPTAB and GNPTAG, is the severe white-matter abnormality documented on magnetic resonance imaging (MRI).


Christian Büchel, M.D.
University Medical Center Hamburg-Eppendorf
Hamburg, Germany
buechel@uke.de


Kate E. Watkins, Ph.D.
University of Oxford
Oxford, United Kingdom

No potential conflict of interest relevant to this letter was reported.

Silva said...

The author replies: We thank Büchel and Watkins for drawing attention to the extensive literature on brain imaging in stuttering. In addition to diffusion tensor imaging, a variety of imaging methods, including positron-emission tomography,1 voxel-based morphometry,2 and functional MRI,3 have consistently shown differences in the brains of patients who stutter, as compared with control subjects. However, because of the significant plasticity of the brain, it is often not possible to know whether these differences are the cause of stuttering or the result of stuttering. Although the mutations that we have identified suggest an effect on lysosomal function, the effect of these mutations on neuronal-cell biology must still be explored. Therefore, morphologic differences in stuttering can be viewed as a phenotype associated with the disorder. Although we agree that knowledge from imaging studies is and will continue to be illustrative, we also believe that knowledge of causative genetic and molecular differences provides a very different and more fundamental level of understanding of this enigmatic disorder.

Dennis Drayna, Ph.D.
National Institutes of Health
Bethesda, MD
drayna@nidcd.nih.gov

Since publication of his article, the author reports no further potential conflict of interest.

Tom Weidig said...

>> Does anyone think the lysosomal enzyme abnormality leads to a physical white matter deficit?

Yes, that's entirely possible. The type of cells that are most affected by the dysfunctional lysosomal cycle might well be prominently present or critically involved in the proper development and functioning of certain fiber connections. Due to the inability of those cells to clean themselves properly, their development and functioning could be stopped or reduced.

However, these mutation are only present in a small share of the stuttering population. So it's very unlikely that the brain imaging's sample contains more than 5-10% of the people with these genes...

>> And if so how would enzyme replacement therapy fix a physical structural abnormality? Would it eventually grow the white matter connections??

I am not sure, but I would not be surprised if the cells are just under-developed. If it's like a plant that is not watered enough and is not flowering well, it will do much better with more water. If the mutation "kills" cells because the cleaning is critical, there is little chance.

ig88sir said...

Does anyone think that a bigger disconnect (i.e.,weaker myelin sheath) has a correlation for stuttering severity? It is a naive simplification but seems to make sense to me. They should do imaging with mild and severe PWS to find out.

Silva said...

- Thanks, Silva.
- You're welcome, Tom.