Correspondence

Genetic Susceptibility to Persistent Stuttering

N Engl J Med 2010; 362:2226-2227June 10, 2010

Article

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.2-4 Together with studies showing a speech-timing abnormality in such patients, these data strongly suggest a disconnection 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.

6 References

1. 1

   Kang C, Riazuddin S, Mundorff J, et al. Mutations in the lysosomal enzyme-targeting pathway and persistent stuttering. N Engl J Med 2010;362:677-685
   Full Text | Web of Science | Medline

2. 2

   Sommer M, Koch MA, Paulus W, Weiller C, Buchel C. Disconnection of speech-relevant brain areas in persistent developmental stuttering. Lancet 2002;360:380-383
   CrossRef | Web of Science | Medline

3. 3

   Watkins KE, Smith SM, Davis S, Howell P. Structural and functional abnormalities of the motor system in developmental stuttering. Brain 2008;131:50-59
   CrossRef | Web of Science | Medline

4. 4

   Chang SE, Erickson KI, Ambrose NG, Hasegawa-Johnson MA, Ludlow CL. Brain anatomy differences in childhood stuttering. Neuroimage 2008;39:1333-1344
   CrossRef | Web of Science | Medline

5. 5

   Saftig P, Klumperman J. Lysosome biogenesis and lysosomal membrane proteins: trafficking meets function. Nat Rev Mol Cell Biol 2009;10:623-635
   CrossRef | Web of Science | Medline

6. 6

   Anitei M, Pfeiffer SE. Myelin biogenesis: sorting out protein trafficking. Curr Biol 2006;16:R418-R421
   CrossRef | Web of Science | Medline

Author/Editor Response

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.

3 References

1. 1

   Fox PT, Ingham RJ, Ingham JC, et al. A PET study of the neural systems of stuttering. Nature 1996;382:158-161
   CrossRef | Web of Science | Medline

2. 2

   Beal DS, Gracco VL, Lafaille SJ, De Nil LF. Voxel-based morphometry of auditory and speech-related cortex in stutterers. Neuroreport 2007;18:1257-1260
   CrossRef | Web of Science | Medline

3. 3

   Lu C, Chen C, Ning N, et al. The neural substrates for atypical planning and execution of word production in stuttering. Exp Neurol 2010;221:146-156
   CrossRef | Web of Science | Medline

Citing Articles (4)

Citing Articles

1. 1

   Shelly Jo Kraft, Ehud Yairi. (2012) Genetic Bases of Stuttering: The State of the Art, 2011. Folia Phoniatrica et Logopaedica 64:1, 33-46
   CrossRef

2. 2

   S.-E. Chang, B. Horwitz, J. Ostuni, R. Reynolds, C. L. Ludlow. (2011) Evidence of Left Inferior Frontal-Premotor Structural and Functional Connectivity Deficits in Adults Who Stutter. Cerebral Cortex 21:11, 2507-2518
   CrossRef

3. 3

   Kate Watkins. 2011. Developmental disorders of speech and language. , 225-238.
   CrossRef

4. 4

   Giuseppe Novelli. (2010) Personalized genomic medicine. Internal and Emergency Medicine 5:S1, 81-90
   CrossRef