Persistent Stuttering Research Articles

Report of the GNPTAB c.3598G>A, p.Glu1200Lys founder mutation associated with persistent stuttering in South Indian population

Stuttering is a disorder that affects the fluency of speech resulting in interruptions that are highly heritable. The present study aimed to evaluate the occurrence of the founder mutation GNPTAB c.3598G>A, p.Glu1200Lys (rs137853825) which is associated with stuttering. A total of 96 unrelated persistent stutterers from south India were included in this study. Genotyping the exon 19 of the GNPTAB gene by Sanger sequencing identified the pathogenic mutation in 5/96 (5.2 %) participants. A noncoding mutation GNPTAB c.3602+62A>G (rs1952847841) was also detected in 16/96 (16.6 %) cases. Further studies are warranted to identify the pathogenic loci of other genes of the lysosomal pathway, which would provide further insights into the genetic constitution of stuttering.

Risk Factors for the Development of Persistent Stuttering: What Every Pediatrician Should Know.

Early identification and adequate treatment of children who stutter is important, since it has an impact on speech development. Considering the importance of aiding pediatricians to recognize children at risk for developing persistent stuttering, the aim of the present study was to correlate speech fluency characteristics of children, whose parents reported stuttering behaviors, to the risk factors of persistent stuttering. The participants were 419 children aged 2:0 to 11:11 years, who were divided into two groups: children with stuttering complaints (CSC), composed of children whose parents reported the presence of stuttering behaviors; and children with no stuttering complaint (CNSCs), composed of children with no stuttering behaviors. Risk variables were gathered based on a questionnaire answered by parents involving the following variables: sex, presence of family history of stuttering, whether stuttering behaviors were observed for more than 12 months, whether stuttering behaviors began before 5 years of age, increased effort to speak (i.e., syllable and sound repetitions and fixed articulatory positions), negative family attitude towards the child’s speech, and negative attitude towards the child’s own speech. The diagnosis of stuttering was determined by a formal speech assessment by a pathologist (SLP). The risk analysis indicated that increased effort to speak, negative family attitude towards the child’s speech, and complaints of stuttering for more than 12 months were associated with a higher risk of stuttering in children. Therefore, when pediatricians are faced with complaints about the presence of stuttering behaviors and these factors are present, they should immediately refer the patient to an SLP for specific assessment.

Speech and Anxiety Management With Persistent Stuttering: Current Status and Essential Research.

Purpose The purpose of this review article is to provide an overview of the current evidence base for the behavioral management of stuttering and associated social anxiety. Method We overview recent research about stuttering and social anxiety in the context of contemporary cognitive models of social anxiety disorder. That emerging evidence for self-focused attention and safety behavior use with those who stutter is considered in relation to current treatment approaches for stuttering: speech restructuring and social anxiety management. Results The emerging information about social anxiety and stuttering suggests a conflict between the two clinical approaches. For those clients who wish to control their stuttering and where speech restructuring is deemed the most suitable approach, it is possible that speech restructuring may (a) induce or increase self-focused attention, (b) promote the use of safety behaviors, and (c) become a safety behavior itself. This conflict needs to be explored further within clinical and research contexts. Conclusions The issues raised in this review article are complex. It appears that evidence-based speech treatment procedures are in conflict with current best-practice treatment procedures that deal with social anxiety. In this review article, we propose directions for future research to inform the development of improved treatments for those who stutter and recommendations for interim clinical management of stuttering.

Linking Lysosomal Enzyme Targeting Genes and Energy Metabolism with Altered Gray Matter Volume in Children with Persistent Stuttering

Developmental stuttering is a childhood onset neurodevelopmental disorder with an unclear etiology. Subtle changes in brain structure and function are present in both children and adults who stutter. It is a highly heritable disorder, and 12–20% of stuttering cases may carry a mutation in one of four genes involved in intracellular trafficking. To better understand the relationship between genetics and neuroanatomical changes, we used gene expression data from the Allen Institute for Brain Science and voxel-based morphometry to investigate the spatial correspondence between gene expression patterns and differences in gray matter volume between children with persistent stuttering (n = 26, and 87 scans) and their fluent peers (n = 44, and 139 scans). We found that the expression patterns of two stuttering-related genes (GNPTG and NAGPA) from the Allen Institute data exhibited a strong positive spatial correlation with the magnitude of between-group gray matter volume differences. Additional gene set enrichment analyses revealed that genes whose expression was highly correlated with the gray matter volume differences were enriched for glycolysis and oxidative metabolism in mitochondria. Because our current study did not examine the participants’ genomes, these results cannot establish the direct association between genetic mutations and gray matter volume differences in stuttering. However, our results support further study of the involvement of lysosomal enzyme targeting genes, as well as energy metabolism in stuttering. Future studies assessing variations of these genes in the participants’ genomes may lead to increased understanding of the biological mechanisms of the observed spatial relationship between gene expression and gray matter volume.

Association between Rare Variants in AP4E1, a Component of Intracellular Trafficking, and Persistent Stuttering

Stuttering is a common, highly heritable neurodevelopmental disorder characterized by deficits in the volitional control of speech. Whole-exome sequencing identified two heterozygous AP4E1 coding variants, c.1549G>A (p.Val517Ile) and c.2401G>A (p.Glu801Lys), that co-segregate with persistent developmental stuttering in a large Cameroonian family, and we observed the same two variants in unrelated Cameroonians with persistent stuttering. We found 23 other rare variants, including predicted loss-of-function variants, in AP4E1 in unrelated stuttering individuals in Cameroon, Pakistan, and North America. The rate of rare variants in AP4E1 was significantly higher in unrelated Pakistani and Cameroonian stuttering individuals than in population-matched control individuals, and coding variants in this gene are exceptionally rare in the general sub-Saharan West African, South Asian, and North American populations. Clinical examination of the Cameroonian family members failed to identify any symptoms previously reported in rare individuals carrying homozygous loss-of-function mutations in this gene. AP4E1 encodes the ε subunit of the heterotetrameric (ε-β4-μ4-σ4) AP-4 complex, involved in protein sorting at the trans-Golgi network. We found that the μ4 subunit of AP-4 interacts with NAGPA, an enzyme involved in the synthesis of the mannose 6-phosphate signal that targets acid hydrolases to the lysosome and the product of a gene previously associated with stuttering. These findings implicate deficits in intracellular trafficking in persistent stuttering.

The Neurobiological Grounding of Persistent Stuttering: from Structure to Function

Neuroimaging and transcranial magnetic stimulation provide insights into the neuronal mechanisms underlying speech disfluencies in chronic persistent stuttering. In the present paper, the goal is not to provide an exhaustive review of existing literature, but rather to highlight robust findings. We, therefore, conducted a meta-analysis of diffusion tensor imaging studies which have recently implicated disrupted white matter connectivity in stuttering. A reduction of fractional anisotropy in persistent stuttering has been reported at several different loci. Our meta-analysis revealed consistent deficits in the left dorsal stream and in the interhemispheric connections between the sensorimotor cortices. In addition, recent fMRI meta-analyses link stuttering to reduced left fronto-parieto-temporal activation while greater fluency is associated with boosted co-activations of right fronto-parieto-temporal areas. However, the physiological foundation of these irregularities is not accessible with MRI. Complementary, transcranial magnetic stimulation (TMS) reveals local excitatory and inhibitory regulation of cortical dynamics. Applied to a speech motor area, TMS revealed reduced speech-planning-related neuronal dynamics at the level of the primary motor cortex in stuttering. Together, this review provides a focused view of the neurobiology of stuttering to date and may guide the rational design of future research. This future needs to account for the perpetual dynamic interactions between auditory, somatosensory, and speech motor circuits that shape fluent speech.

Analysis of Mannose 6-Phosphate Uncovering Enzyme Mutations Associated with Persistent Stuttering

GlcNAc-1-phosphodiester-N-acetylglucosaminidase ("uncovering enzyme" (UCE); EC 3.1.4.45) is a Golgi enzyme that mediates the second step in the synthesis of the mannose 6-phosphate lysosomal targeting signal on acid hydrolases. Recently, three mutations (two missense and one deletion/frameshift) in the NAGPA gene that encodes UCE have been identified in individuals with persistent stuttering. We now demonstrate that each mutation leads to lower cellular UCE activity. The p.R328C mutation impairs folding in the endoplasmic reticulum, resulting in degradation of a significant portion by the proteasomal system. The p.H84Q mutation also impairs folding and, in addition, decreases the specific activity of the enzyme that folds sufficiently to traffic to the Golgi. The p.F513SfsX113 frameshift mutation adds 113 amino acids to the C terminus of the cytoplasmic tail of the protein, including a VWLL sequence that causes rapid degradation via the proteasomal system. These biochemical findings extend the genetic data implicating mutations in the NAGPA gene in the persistent stuttering phenotype.

Genetic Susceptibility to Persistent Stuttering

Genetic Susceptibility to Persistent Stuttering

Persistent Stuttering: Finding the Key to the Riddle

Defects in lysosomal targeting signals underlie a genetic form of stuttering in a large Pakistani family.

Mutations in the Lysosomal Enzyme–Targeting Pathway and Persistent Stuttering

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. 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. 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. Susceptibility to nonsyndromic stuttering is associated with variations in genes governing lysosomal metabolism.

How the brain repairs stuttering

Stuttering is a neurodevelopmental disorder associated with left inferior frontal structural anomalies. While children often recover, stuttering may also spontaneously disappear much later after years of dysfluency. These rare cases of unassisted recovery in adulthood provide a model of optimal brain repair outside the classical windows of developmental plasticity. Here we explore what distinguishes this type of recovery from less optimal repair modes, i.e. therapy-induced assisted recovery and attempted compensation in subjects who are still affected. We show that persistent stuttering is associated with mobilization of brain regions contralateral to the structural anomalies for compensation attempt. In contrast, the only neural landmark of optimal repair is activation of the left BA 47/12 in the orbitofrontal cortex, adjacent to a region where a white matter anomaly is observed in persistent stutterers, but normalized in recovered subjects. These findings show that late repair of neurodevelopmental stuttering follows the principles of contralateral and perianomalous reorganization.

Genetic Etiology in Cases of Recovered and Persistent Stuttering in an Unselected, Longitudinal Sample of Young Twins

The contribution of genetic factors in the persistence of and early recovery from stuttering was assessed. Data from the Twins Early Development Study were employed. Parental reports regarding stuttering were collected at ages 2, 3, 4, and 7 years, and were used to classify speakers into recovered and persistent groups. Of 12,892 children with at least 2 ratings, 950 children had recovered and 135 persisted in their stutter. Logistic regressions showed that the rating at age 2 was not predictive of later stuttering, whereas ratings at ages 3 and 4 were. Concordance rates were consistently higher for monozygotic than for dizygotic twin pairs (with the exception of girls at age 3). At 3, 4, and 7 years, the liability to stuttering was highly heritable (h2 estimates of between .58 and .66). Heritability for the recovered and persistent groups was also high but did not differ from each other. Stuttering appears to be a disorder that has high heritability and little shared environment effect in early childhood and for recovered and persistent groups of children, by age 7. The clinical implications of the findings are discussed.

A study of familial stuttering

Here we study 13 families with stuttering. Of the 13 families, 9 were persistent stutterers and 4 were recovered stutterers. In the 9 families with persistent stuttering, 24 were male and 10 were females. Of the 4 families with recovered stutterers, 17 were male and 3 were female. Of the 17 males, 12 were persistent stutterers and 5 recovered after adolescence. All females were recovered stutterers. We conclude with a short discussion of recent molecular studies.

Speech Effort Measurement and Stuttering: Investigating the Chorus Reading Effect

The purpose of this study was to investigate chorus reading's (CR's) effect on speech effort during oral reading by adult stuttering speakers and control participants. The effect of a speech effort measurement highlighting strategy was also investigated. Twelve persistent stuttering (PS) adults and 12 normally fluent control participants completed 1-min base rate readings (BR-nonchorus) and CRs within a BR/CR/BR/CR/BR experimental design. Participants self-rated speech effort using a 9-point scale after each reading trial. Stuttering frequency, speech rate, and speech naturalness measures were also obtained. Instructions highlighting speech effort ratings during BR and CR phases were introduced after the first CR. CR improved speech effort ratings for the PS group, but the control group showed a reverse trend. Both groups' effort ratings were not significantly different during CR phases but were significantly poorer than the control group's effort ratings during BR phases. The highlighting strategy did not significantly change effort ratings. The findings show that CR will produce not only stutter-free and natural sounding speech but also reliable reductions in speech effort. However, these reductions do not reach effort levels equivalent to those achieved by normally fluent speakers, thereby conditioning its use as a gold standard of achievable normal fluency by PS speakers.

Predictive factors of persistence and recovery: Pathways of childhood stuttering

This article presents broad preliminary findings from a longitudinal study of stuttering pertaining to differentiation of developmental paths of childhood stuttering, as well as possible early prediction of High Risk, Low Risk, and No Risk for chronic stuttering. More than 100 preschool children who stutter have been closely followed for several years from near the onset of stuttering using a multiple data collection system, with 45 nonstuttering children serving as controls. Thirty-two stuttering and 32 control subjects who have progressed through several stages of the investigation were identified for the present indepth analyses. They represent four subgroups: I. Persistent Stuttering; II. Late Recovery; III. Early Recovery; IV. Control. Comparative data for the groups with special reference to differences in frequency of disfluency, acoustic features, phonologic skills, language development, nonverbal skills, and genetics are presented. The results suggest several promising predictors of recovery and chronicity.

Observation and Experimentation

No AccessJournal of Speech, Language, and Hearing ResearchSpeech1 Apr 1994Observation and ExperimentationA Reply to Gow and Ingham Mark Onslow, Janis van Doorn, Denis Newman, The University of Sydney, AustraliaThe University of Queensland Brisbane, Australia Mark Onslow The University of Sydney, Australia Google Scholar More articles by this author , Janis van Doorn The University of Sydney, Australia Google Scholar More articles by this author , Denis Newman The University of Queensland Brisbane, Australia Google Scholar More articles by this author , The University of Sydney, AustraliaThe University of Queensland Brisbane, Australia https://doi.org/10.1044/jshr.3702.345 SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationTrack Citations ShareFacebookTwitterLinked In References Gow, M. L., & Ingham, R. J. (1992). Modifying electroglottograph-identified intervals of phonation: The effect on stuttering.Journal of Speech and Hearing Research, 35, 495–511. ASHAWireGoogle Scholar Ingham, R. J., Montgomery, G., & Ulliana, L. (1983). The effect of manipulating phonation duration on stuttering.Journal of Speech and Hearing Research, 26, 579–587. ASHAWireGoogle Scholar Onslow, M., van Doom, J., & Newman, D. (1992). Variability of acoustic segment durations after prolonged-speech treatment for stuttering.Journal of Speech and Hearing Research, 35, 529–536. ASHAWireGoogle Scholar Additional Resources FiguresReferencesRelatedDetailsCited byJournal of Speech, Language, and Hearing Research64:1 (59-74)14 Jan 2021Speech and Anxiety Management With Persistent Stuttering: Current Status and Essential ResearchRobyn Lowe, Ross Menzies, Mark Onslow, Ann Packman and Sue O'Brian Volume 37Issue 2April 1994Pages: 345-346 Get Permissions Add to your Mendeley library HistoryReceived: Oct 18, 1993Accepted: Nov 16, 1993 Published in issue: Apr 1, 1994 Metrics Topicsasha-topicsleader-topicsCopyright & PermissionsCopyright © 1994 American Speech-Language-Hearing AssociationPDF downloadLoading ...

Recovery and persistence of stuttering among relatives of stutterers.

Recovery and persistence of stuttering were examined in the first-degree relatives of a large group of adult persistent stutters. The percentage of recovered individuals reported in these families supports the hypothesis that recovered and persistent stuttering are not independent disorders. Sex and type of relative were significant variables in the distributions of recovery and persistence of stuttering. Handedness in male subjects and birth order did not distinguish between recovered and persistent stutterers. Female recovered stutterers had significantly earlier ages of stuttering onset than the other groups (male recovered stutterers and male and female persistent stutterers). Female recovered stutterers also tended to recover earlier than male recovered stutterers, and the durations of stuttering symptoms were similar in both sexes.