Epidemiology of stuttering: 21st century advances.

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 GlcNAcphosphotransferase (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.

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

Mannose-6-phosphate pathway: A review on its role in lysosomal function and dysfunction

Genetic advances in the study of speech and language disorders.

Brain activation abnormalities during speech and non-speech in stuttering speakers.

Stuttering is a speech disorder long recognized to have a genetic component. Recent linkage studies mapped a susceptibility locus for stuttering to chromosome 12 in 46 highly inbred families ascertained in Pakistan. We report here on linkage studies in 100 families of European descent ascertained in the United States, Sweden, and Israel. These families included 252 individuals exhibiting persistent stuttering, 45 individuals classified as recovered from stuttering, and 19 individuals too young to classify. Primary analyses identified moderate evidence for linkage of the broader diagnosis of "ever stuttered" (including both persistent and recovered stuttering) on chromosome 9 (LOD = 2.3 at 60 cM) and of the narrower diagnosis of persistent stuttering on chromosome 15 (LOD = 1.95 at 23 cM). In contrast, sex-specific evidence for linkage on chromosome 7 at 153 cM in the male-only data subset (LOD = 2.99) and on chromosome 21 at 34 cM in the female-only data subset (LOD = 4.5) met genomewide criteria for significance. Secondary analyses revealed a significant increase in the evidence for linkage on chromosome 12, conditional on the evidence for linkage at chromosome 7, with the location of the increased signal congruent with the previously reported signal in families ascertained in Pakistan. In addition, a region on chromosome 2 (193 cM) showed a significant increase in the evidence for linkage conditional on either chromosome 9 (positive) or chromosome 7 (negative); this chromosome 2 region has been implicated elsewhere in studies on autism, with increased evidence for linkage observed when the sample is restricted to those with delayed onset of phrase speech. Our results support the hypothesis that the genetic component to stuttering has significant sex effects.

/pdf/new-complexities-in-the-genetics-of-stuttering-significant-27bq4d960x.pdf

New complexities in the genetics of stuttering: significant sex-specific linkage signals

This study examines the production and reduction patterns of initial /s/ clusters by Hebrew-speaking children with phonological disorders. Data were collected from 30 children with phonological disorders between the ages of 3;5-5;2. The data were elicited by means of a picture-naming task combined with a sentence completion task. Target words consisted of initial clusters, including #sC and #CC clusters. Results revealed that the percentage of correct productions of /s/+approximant clusters were significantly lower than those of the correct productions of other /s/ clusters. The differences between /s/+approximant clusters and the other /s/ clusters also emerged in the reduction patterns, where clusters from the first group were reduced to C1 but clusters from the second group were reduced to C2. There were no differences in the correct productions between the productions of SSP-violating clusters and the SSP-following clusters.

Acquisition of /s/-clusters in Hebrew-speaking children with phonological disorders.

OBJECTIVE The aim of this paper was to describe the error patterns of the dorsal rhotic /ʁ/ in the speech of typically developing Hebrew-speaking children and to examine the prosodic effect (i.e., position in the word and stress pattern) of its production. Method and Participants: The participants included 50 monolingual Hebrew-speaking children aged 2;6-3;3 years. The children performed an articulation task in which they were asked to articulate 18 disyllabic words composed of vowel-adjacent rhotics in initial, medial, and final word positions in both stressed and unstressed syllables. RESULTS The results revealed that dorsal rhotics were produced correctly in 78.7% of the target words. The main error patterns were rhotic deletion and devoicing. There were fewer correct productions in initial word positions than in both medial and final word positions. No stress effect was found. In addition, 76% of the children produced the consonant correctly in over half of their productions. CONCLUSIONS The result demonstrating a higher rate of errors in initial word positions may be due to the relatively late acquisition of the initial onset position in multisyllabic Hebrew words. Alternatively, this finding may result from the greater degree of allophonic variation found in this position. The finding that languages with dorsal rhotics have unique error patterns compared to other rhotics strengthens the evidence that rhotic error patterns are dependent on the rhotics' phonetic characteristics.

Ruth Ezrati

Papers

New complexities in the genetics of stuttering: significant sex-specific linkage signals

Acquisition of /s/-clusters in Hebrew-speaking children with phonological disorders.

Error Patterns of Dorsal Rhotics: Evidence from Hebrew-Speaking Children.