Kang C, Riazuddin S, Mundorff J, Krasnewich D, Friedman P, Mullikin JC, Drayna D.

National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, MD, USA.

Abstract

BACKGROUND: Stuttering is a disorder of unknown cause characterized by repetitions, prolongations, and interruptions in the flow of speech. Genetic factors have been implicated in this disorder, and previous studies of stuttering have identified linkage to markers on chromosome 12. METHODS: We analyzed the chromosome 12q23.3 genomic region in consanguineous Pakistani families, some members of which had nonsyndromic stuttering and in unrelated case and control subjects from Pakistan and North America. RESULTS: We identified a missense mutation in the N-acetylglucosamine-1-phosphate transferase gene (GNPTAB), which encodes the alpha and beta catalytic subunits of GlcNAc-phosphotransferase (GNPT [EC 2.7.8.15]), that was associated with stuttering in a large, consanguineous Pakistani family. This mutation occurred in the affected members of approximately 10% of Pakistani families studied, but it occurred only once in 192 chromosomes from unaffected, unrelated Pakistani control subjects and was not observed in 552 chromosomes from unaffected, unrelated North American control subjects. This and three other mutations in GNPTAB occurred in unrelated subjects with stuttering but not in control subjects. We also identified three mutations in the GNPTG gene, which encodes the gamma subunit of GNPT, in affected subjects of Asian and European descent but not in control subjects. Furthermore, we identified three mutations in the NAGPA gene, which encodes the so-called uncovering enzyme, in other affected subjects but not in control subjects. These genes encode enzymes that generate the mannose-6-phosphate signal, which directs a diverse group of hydrolases to the lysosome. Deficits in this system are associated with the mucolipidoses, rare lysosomal storage disorders that are most commonly associated with bone, connective tissue, and neurologic symptoms. CONCLUSIONS: Susceptibility to nonsyndromic stuttering is associated with variations in genes governing lysosomal metabolism. 2010 Massachusetts Medical Society.

Evidence That a Motor Timing Deficit Is a Factor in the Development of Stuttering.

Abstract

PURPOSE: To determine if young children who stutter have a basic motor timing and/or coordination deficit. METHOD: Between-hand coordination and variability of rhythmic motor timing were assessed in 17 children who stutter (aged 4-6 years) and 13 age-matched controls. Children clapped in rhythm with a metronome with a 600 ms inter-beat interval and then attempted to continue to match this target rate for 32 unpaced claps. RESULTS: Children who stutter did not significantly differ from children who are typically developing on mean clapping rate or number of usable trials produced; however, they produced remarkably higher variability levels of inter-clap interval. Of particular interest was the bimodal distribution of the stuttering children on clapping variability. One subgroup of children who stutter clustered within the normal range, but 60% of the children who stutter exhibited timing variability that was greater than the poorest performing non-stuttering child. Children who stutter were not more variable in measures of coordination between the two hands (mean and median phase difference between hands). CONCLUSION: We infer that there is a subgroup of young stuttering children who exhibit a non-speech motor timing deficit and discuss this result as it pertains to recovery or persistence of stuttering.

February 2010

Mutations in the lysosomal enzyme-targeting pathway and persistent stuttering.

Kang C, Riazuddin S, Mundorff J, Krasnewich D, Friedman P, Mullikin JC, Drayna D.

National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, MD, USA.

Abstract

Normal interhemispheric inhibition in persistent developmental stuttering.

Sommer M, Knappmeyer K, Hunter EJ, Gudenberg AW, Neef N, Paulus W

Imaging studies suggest a right hemispheric (pre)motor overactivity in patients with persistent developmental stuttering (PDS). The interhemispheric inhibition (IHI) studied with transcranial magnetic stimulation is an established measure of the interplay between right and left motor areas. We assessed IHI in 15 young male adults with PDS and 15 age-matched fluent-speaking subjects. We additionally studied the ipsilateral silent period (iSP) duration. We found no significant between-group difference for IHI or for iSP duration. We conclude that the interplay between the primary motor cortices is normal in patients with PDS. The abnormal right motor and premotor activity observed in functional imaging studies on PDS are not likely to reflect altered primary motor cortex excitability, but are likely to have a different origin.

Altered effective connectivity and anomalous anatomy in the basal ganglia-thalamocortical circuit of stuttering speakers.

State Key Laboratory of Cognitive Neuroscience and Learning, Beijing Normal University, Beijing, China.

Combining structural equation modeling (SEM) and voxel-based morphometry (VBM), this study investigated the interactions among neural structures in the basal ganglia-thalamocortical circuit (BGTC) in the left hemisphere of stuttering and non-stuttering speakers. Stuttering speakers (n=12) and non-stuttering controls (n=12) were scanned while performing a picture-naming task and a passive-viewing (baseline) task. Results showed significant differences between stuttering and non-stuttering speakers in both effective connectivity and anatomical structures in the BGTC in the left brain. Specifically, compared to non-stuttering speakers, stuttering speakers showed weaker negative connectivity from the left posterior middle temporal gyrus (PMTG) to the putamen, but stronger positive connectivity from the putamen to the thalamus, from the thalamus to the PMTG and anterior supplementary motor area (preSMA), and from the anterior superior temporal gyrus (ASTG) to the preSMA. Accompanying such altered connectivity were anatomical differences: compared to non-stuttering controls, stuttering speakers showed more grey matter (GM) volume concentration in the left putamen, less GM volume concentration in the left medial frontal gyrus and ASTG, and less white matter volume concentration underlying the left posterior superior temporal gyrus inside the BGTC. These results shed significant light on the neural mechanisms (in terms of both functional connectivity and neural anatomy) of stuttering.

The role of large-scale neural interactions for developmental stuttering.

State Key Laboratory of Cognitive Neuroscience and Learning, Beijing Normal University, 19 Xinjiekou Wai Street, Beijing 100875, PR China.

Using the structural equation modeling (SEM) method, the present study examined the role of large-scale neural interactions in developmental stuttering while 10 stuttering and nine non-stuttering subjects performed a covert picture-naming task. Results indicated that the connection patterns were significantly different between stuttering and non-stuttering speakers in both omnibus connection pattern and individual connection path coefficient. Specifically, stuttering speakers showed functional disconnection from the left inferior frontal gyrus to the left motor areas, and altered connectivity in the basal ganglia-thalamus-cortical circuit, and abnormal integration of supramodal information across the cerebellum and several frontal-parietal regions. These results indicate that the large-scale dysfunctional neural interactions may be involved in stuttering speakers' difficulties in planning, execution, and self-monitoring of speech motor sequence during word production.

to fluent controls. We hypothesized that similar differences might be present indicating brain development differences in children at risk of stuttering. Optimized voxel-based morphometry compared gray matter volume (GMV) and diffusion tensor imaging measured fractional anisotropy (FA) in white matter tracts in 3 groups: children with persistent stuttering, children

Brain anatomy differences in childhood stuttering.

Laryngeal and Speech Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA. changsoo@ninds.nih.gov

Stuttering is a developmental speech disorder that occurs in 5% of children with spontaneous remission in approximately 70% of cases. Previous imaging studies in adults with persistent stuttering found left white matter deficiencies and reversed right-left asymmetries compared to fluent controls. We hypothesized that similar differences might be present indicating brain development differences in children at risk of stuttering. Optimized voxel-based morphometry compared gray matter volume (GMV) and diffusion tensor imaging measured fractional anisotropy (FA) in white matter tracts in 3 groups: children with persistent stuttering, children recovered from stuttering, and fluent peers. Both the persistent stuttering and recovered groups had reduced GMV from normal in speech-relevant regions: the left inferior frontal gyrus and bilateral temporal regions. Reduced FA was found in the left white matter tracts underlying the motor regions for face and larynx in the persistent stuttering group. Contrary to previous findings in adults who stutter, no increases were found in the right hemisphere speech regions in stuttering or recovered children and no differences in right-left asymmetries. Instead, a risk for childhood stuttering was associated with deficiencies in left gray matter volume while reduced white matter integrity in the left hemisphere speech system was associated with persistent stuttering. Anatomical increases in right hemisphere structures previously found in adults who stutter may have resulted from a lifetime of stuttering. These findings point to the importance of considering the role of neuroplasticity during development when studying persistent forms of developmental disorders in adults.