Neuroanatomical anomalies associated with rare AP4E1 mutations in people who stutter.
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ABSTRACT:
SUBMITTER: Chow HM
PROVIDER: S-EPMC8633735 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:The onset of developmental stuttering typically occurs between 2 to 4 years of age, coinciding with a period of rapid development in speech, language, motor and cognitive domains. Previous studies have reported generally poorer performance and uneven, or "dissociated" development across speech and language domains in children who stutter (CWS) relative to children who do not stutter (CWNS) (Anderson, Pellowski, & Conture, 2005). The aim of this study was to replicate and expand previous findings by examining whether CWS exhibit dissociated development across speech-language, cognitive, and motor domains that are also reflected in measures of neuroanatomical development. Participants were 66CWS (23 females) and 53CWNS (26 females) ranging from 3 to 10 years. Standardized speech, language, cognitive, and motor skills measures, and fractional anisotropy (FA) values derived from diffusion tensor imaging from speech relevant "dorsal auditory" left perisylvian areas (Hickok & Poeppel, 2007) were analyzed using a correlation-based statistical procedure (Coulter, Anderson, & Conture, 2009) that quantified dissociations across domains. Overall, CWS scored consistently lower on speech, language, cognitive and motor measures, and exhibited dissociated development involving these same measures and white matter neuroanatomical indices relative to CWNS. Boys who stutter exhibited a greater number of dissociations compared to girls who stutter. Results suggest a subgroup of CWS may have incongruent development across multiple domains, and the resolution of this imbalance may be a factor in recovery from stuttering.
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Project description:Deficits in brain white matter have been a main focus of recent neuroimaging studies on stuttering. However, no prior study has examined brain connectivity on the global level of the cerebral cortex in persons who stutter (PWS). In the current study, we analyzed the results from probabilistic tractography between regions comprising the cortical speech network. An anatomical parcellation scheme was used to define 28 speech production-related ROIs in each hemisphere. We used network-based statistic (NBS) and graph theory to analyze the connectivity patterns obtained from tractography. At the network-level, the probabilistic corticocortical connectivity from the PWS group were significantly weaker than that from persons with fluent speech (PFS). NBS analysis revealed significant components in the bilateral speech networks with negative correlations with stuttering severity. To facilitate comparison with previous studies, we also performed tract-based spatial statistics (TBSS) and regional fractional anisotropy (FA) averaging. Results from tractography, TBSS and regional FA averaging jointly highlight the importance of several regions in the left peri-Rolandic sensorimotor and premotor areas, most notably the left ventral premotor cortex (vPMC) and middle primary motor cortex, in the neuroanatomical basis of stuttering.
| S-EPMC3920071 | biostudies-literature
Project description:Speech production difficulties are apparent in people who stutter (PWS). PWS also have difficulties in speech perception compared to controls. It is unclear whether the speech perception difficulties in PWS are independent of, or related to, their speech production difficulties. To investigate this issue, functional MRI data were collected on 13 PWS and 13 controls whilst the participants performed a speech production task and a speech perception task. PWS performed poorer than controls in the perception task and the poorer performance was associated with a functional activity difference in the left anterior insula (part of the speech motor area) compared to controls. PWS also showed a functional activity difference in this and the surrounding area [left inferior frontal cortex (IFC)/anterior insula] in the production task compared to controls. Conjunction analysis showed that the functional activity differences between PWS and controls in the left IFC/anterior insula coincided across the perception and production tasks. Furthermore, Granger Causality Analysis on the resting-state fMRI data of the participants showed that the causal connection from the left IFC/anterior insula to an area in the left primary auditory cortex (Heschl's gyrus) differed significantly between PWS and controls. The strength of this connection correlated significantly with performance in the perception task. These results suggest that speech perception difficulties in PWS are associated with anomalous functional activity in the speech motor area, and the altered functional connectivity from this area to the auditory area plays a role in the speech perception difficulties of PWS.
| S-EPMC4870257 | biostudies-literature
Project description:An increasing body of studies has revealed neuroanatomical impairments in developmental dyslexia. However, whether these structural anomalies are driven by dyslexia (disorder-specific effects), absolute reading performance (performance-dependent effects), and/or further influenced by age (maturation-sensitive effects) remains elusive. To help disentangle these sources, the current study used a novel disorder (dyslexia vs. control) by maturation (younger vs. older) factorial design in 48 Chinese children who were carefully matched. This design not only allows for direct comparison between dyslexics versus controls matched for chronological age and reading ability, but also enables examination of the influence of maturation and its interaction with dyslexia. Voxel-based morphometry (VBM) showed that dyslexic children had reduced regional gray matter volume in the left temporo-parietal cortex (spanning over Heschl's gyrus, planum temporale and supramarginal gyrus), middle frontal gyrus, superior occipital gyrus, and reduced regional white matter in bilateral parieto-occipital regions (left cuneus and right precuneus) compared with both age-matched and reading-level matched controls. Therefore, maturational stage-invariant neurobiological signatures of dyslexia were found in brain regions that have been associated with impairments in the auditory/phonological and attentional systems. On the other hand, maturational stage-dependent effects on dyslexia were observed in three regions (left ventral occipito-temporal cortex, left dorsal pars opercularis and genu of the corpus callosum), all of which were previously reported to be involved in fluent reading and its development. These striking dissociations collectively suggest potential atypical developmental trajectories of dyslexia, where underlying mechanisms are currently unknown but may be driven by interactions between genetic and/or environmental factors. In summary, this is the first study to disambiguate maturational stage on neuroanatomical anomalies of dyslexia in addition to the effects of disorder, reading performance and maturational stage on neuroanatomical anomalies of dyslexia, despite the limitation of a relatively small sample-size. These results will hopefully encourage future research to place greater emphasis on taking a developmental perspective to dyslexia, which may, in turn, further our understanding of the etiological basis of this neurodevelopmental disorder, and ultimately optimize early identification and remediation.
| S-EPMC4790432 | biostudies-literature
Project description:Background and objectivesCongenital anomalies of the kidney and urinary tract (CAKUT) are a frequent cause of renal failure in children, and their detection in utero is now common with fetal screening ultrasonography. The clinical course of CAKUT detected before birth is very heterogeneous and depends on the level of nephron reduction. The most severe forms cause life-threatening renal failure, leading to perinatal death or the need for very early renal replacement therapy.Design, setting, participants, & measurementsThis study reports the screening of two genes (HNF1B and PAX2) involved in monogenic syndromic CAKUT in a cohort of 103 fetuses from 91 families with very severe CAKUT that appeared isolated by fetal ultrasound examination and led to termination of pregnancy.ResultsThis study identified a disease-causing mutation in HNF1B in 12 cases from 11 families and a mutation in PAX2 in 4 unrelated cases. Various renal phenotypes were observed, but no case of bilateral agenesis was associated with HNF1B or PAX2 mutations. Autopsy identified extrarenal abnormalities not detected by ultrasonography in eight cases but confirmed the absence of extrarenal defects in eight other cases. A positive family history of renal disease was not significantly more frequent in cases with an identified mutation. Moreover, in cases with an inherited mutation, there was a great phenotypic variability regarding the severity of the renal disease within a single family.ConclusionsOur results suggest that mutations in genes involved in syndromic CAKUT with Mendelian inheritance are not rare in fetal cases with severe CAKUT appearing isolated at prenatal ultrasound, a finding of clinical importance because of genetic counseling.
| S-EPMC3700697 | biostudies-literature
Project description:A rare mutation in LRP6 has been shown to underlie autosomal dominant coronary artery disease (CAD) and metabolic syndrome in an Iranian kindred. The prevalence and spectrum of LRP6 mutations in the disease population of the United States is not known. Two hundred white Americans with early onset familial CAD and metabolic syndrome and 2,000 healthy Northern European controls were screened for nonconservative mutations in LRP6. Three novel mutations were identified, which cosegregated with the metabolic traits in the kindreds of the affected subjects and none in the controls. All three mutations reside in the second propeller domain, which plays a critical role in ligand binding. Two of the mutations substituted highly conserved arginines in the second YWTD domain and the third substituted a conserved glycosylation site. The functional characterization of one of the variants showed that it impairs Wnt signaling and acts as a loss of function mutation.
| S-EPMC3745535 | biostudies-literature
Project description:Purpose People who stutter (PWS) have more unstable speech motor systems than people who are typically fluent (PWTF). Here, we used real-time magnetic resonance imaging (MRI) of the vocal tract to assess variability and duration of movements of different articulators in PWS and PWTF during fluent speech production. Method The vocal tracts of 28 adults with moderate to severe stuttering and 20 PWTF were scanned using MRI while repeating simple and complex pseudowords. Midsagittal images of the vocal tract from lips to larynx were reconstructed at 33.3 frames per second. For each participant, we measured the variability and duration of movements across multiple repetitions of the pseudowords in three selected articulators: the lips, tongue body, and velum. Results PWS showed significantly greater speech movement variability than PWTF during fluent repetitions of pseudowords. The group difference was most evident for measurements of lip aperture using these stimuli, as reported previously, but here, we report that movements of the tongue body and velum were also affected during the same utterances. Variability was not affected by phonological complexity. Speech movement variability was unrelated to stuttering severity within the PWS group. PWS also showed longer speech movement durations relative to PWTF for fluent repetitions of multisyllabic pseudowords, and this group difference was even more evident as complexity increased. Conclusions Using real-time MRI of the vocal tract, we found that PWS produced more variable movements than PWTF even during fluent productions of simple pseudowords. PWS also took longer to produce multisyllabic words relative to PWTF, particularly when words were more complex. This indicates general, trait-level differences in the control of the articulators between PWS and PWTF. Supplemental Material https://doi.org/10.23641/asha.14782092.
| S-EPMC8323486 | biostudies-literature
Project description:Although over 50 genes are known to cause renal malformation if mutated, the underlying genetic basis, most easily identified in syndromic cases, remains unsolved in most patients. In search of novel causative genes, whole-exome sequencing in a patient with renal, i.e., crossed fused renal ectopia, and extrarenal, i.e., skeletal, eye, and ear, malformations yielded a rare heterozygous variant in the GDF6 gene encoding growth differentiation factor 6, a member of the BMP family of ligands. Previously, GDF6 variants were reported to cause pleiotropic defects including skeletal, e.g., vertebral, carpal, tarsal fusions, and ocular, e.g., microphthalmia and coloboma, phenotypes. To assess the role of GDF6 in the pathogenesis of renal malformation, we performed targeted sequencing in 193 further patients identifying rare GDF6 variants in two cases with kidney hypodysplasia and extrarenal manifestations. During development, gdf6 was expressed in the pronephric tubule of Xenopus laevis, and Gdf6 expression was observed in the ureteric tree of the murine kidney by RNA in situ hybridization. CRISPR/Cas9-derived knockout of Gdf6 attenuated migration of murine IMCD3 cells, an effect rescued by expression of wild-type but not mutant GDF6, indicating affected variant function regarding a fundamental developmental process. Knockdown of gdf6 in Xenopus laevis resulted in impaired pronephros development. Altogether, we identified rare heterozygous GDF6 variants in 1.6% of all renal anomaly patients and 5.4% of renal anomaly patients additionally manifesting skeletal, ocular, or auricular abnormalities, adding renal hypodysplasia and fusion to the phenotype spectrum of GDF6 variant carriers and suggesting an involvement of GDF6 in nephrogenesis.
| S-EPMC7784874 | biostudies-literature
Project description:Background Access to services remains the biggest barrier to helping the most vulnerable in the South African Stuttering Community. This novel stuttering therapy, harnessing an unconscious link between eye and tongue movement, may provide a new therapeutic approach, easily communicated and deliverable online.Objectives This study provides both objective and subjective assessments of the feasibility of this intervention. Assessment tools holistically address all components of stuttering in line with comprehensive treatment approaches: core behaviours, secondary behaviours, anticipation and reactions.Method On receipt of ethical approval, this single-subject case design recruited one adult (21-year-old) male with a developmental stutter (DS). The participant gave informed consent and completed four scheduled assessments: baseline, after 5-week training, 3 months post-intervention and 24 months post-completion. The study used objective assessment tools: Stuttering Severity Instrument-4 (SSI-4); Subjective-assessment tools: SSI-4 clinical use self-report tool (CUSR); Overall Assessment of Speaker's Experience of Stuttering (OASES-A); Premonitory Awareness in Stuttering (PAiS) and Self-Report Stuttering Severity* (SRSS) (*final assessment).Results The participant's scores improved across all assessment measures, which may reflect a holistic improvement. The participant reported that the tool was very useful. There were no negative consequences.Conclusion This case report indicates that this innovative treatment may be feasible. No adverse effects were experienced, and the treatment only benefited the participant. The results justify the design of a pilot randomised feasibility clinical trial.Contribution: The results indicate that this is a needed breakthrough in stuttering therapy as the instructions can be easily translated into any language. It can also be delivered remotely reducing accessibility barriers.
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Project description:BACKGROUND:Heterotaxy syndrome is caused by left-right asymmetry disturbances and is associated with abnormal lateralisation of the abdominal and thoracic organs. The heart is frequently involved and the severity of the abnormality usually determines the outcome. METHODS:We performed a direct sequence analysis of the coding sequence of genes including Zinc Finger Protein of the Cerebellum 3, Left-Right Determination Factor 2, Activin A Receptor Type IIB, and Cryptic in 47 patients with laterality defects and congenital cardiac disease. RESULTS:Of the 47 patients, 31 (66%) had atrioventricular septal defects, 34 (72%) had abnormal systemic venous return, 25 (53%) had transposed or malposed great arteries, and 20 (43%) had pulmonary venous abnormalities. We identified two novel genetic changes in Zinc Finger Protein of the Cerebellum 3, and these variants were not present in 100 ethnically matched control samples. One previously reported missense mutation in Activin A Receptor Type IIB was identified in two unrelated subjects. The genetic changes identified in this study are all located in conserved regions and are predicted to affect protein function in left-right axis formation and cardiovascular development. CONCLUSIONS:Mutations in Zinc Finger Protein of the Cerebellum 3 and Activin A Receptor Type IIB were identified in 4 of the 47 patients with heterotaxy syndrome for a yield of approximately 8.5%. Our results expand the mutation spectrum of monogenic heterotaxy syndrome with associated cardiac anomalies and suggest that there are other causes of heterotaxy yet to be identified.
| S-EPMC3678527 | biostudies-literature