Stuttering associated with a pathogenic variant in the chaperone protein cyclophilin 40.

Stuttering is a common speech disorder that interrupts speech fluency and tends to cluster in families. Typically, stuttering is characterized by speech sounds, words or syllables which may be repeated or prolonged and speech that may be further interrupted by hesitations or 'blocks'. Rare variants in a small number of genes encoding lysosomal pathway proteins have been linked to stuttering. We studied a large four-generation family in which persistent stuttering was inherited in an autosomal dominant manner with disruption of the cortico-basal-ganglia-thalamo-cortical network found on imaging. Exome sequencing of three affected family members revealed the PPID c.808C>T (p.Pro270Ser) variant that segregated with stuttering in the family. We generated a Ppid p.Pro270Ser knock-in mouse model and performed ex vivo imaging to assess for brain changes. Diffusion-weighted MRI in the mouse revealed significant microstructural changes in the left corticospinal tract, as previously implicated in stuttering. Quantitative susceptibility mapping also detected changes in cortico-striatal-thalamo-cortical loop tissue composition, consistent with findings in affected family members. This is the first report to implicate a chaperone protein in the pathogenesis of stuttering. The humanized Ppid murine model recapitulates network findings observed in affected family members.

In-depth characterisation of a cohort of individuals with missense and loss-of-function variants disrupting FOXP2.

BACKGROUND: Heterozygous disruptions of FOXP2 were the first identified molecular cause for severe speech disorder: childhood apraxia of speech (CAS), and yet few cases have been reported, limiting knowledge of the condition. METHODS: Here we phenotyped 28 individuals from 17 families with pathogenic FOXP2-only variants (12 loss-of-function, five missense variants; 14 males; aged 2 to 62 years). Health and development (cognitive, motor, social domains) were examined, including speech and language outcomes with the first cross-linguistic analysis of English and German. RESULTS: Speech disorders were prevalent (23/25, 92%) and CAS was most common (22/25, 88%), with similar speech presentations across English and German. Speech was still impaired in adulthood, and some speech sounds (eg, 'th', 'r', 'ch', 'j') were never acquired. Language impairments (21/25, 84%) ranged from mild to severe. Comorbidities included feeding difficulties in infancy (10/26, 38%), fine (13/26, 50%) and gross (13/26, 50%) motor impairment, anxiety (5/27, 19%), depression (6/27, 22%) and sleep disturbance (10/24, 42%). Physical features were common (22/27, 81%) but with no consistent pattern. Cognition ranged from average to mildly impaired and was incongruent with language ability; for example, seven participants with severe language disorder had average non-verbal cognition. CONCLUSIONS: Although we identify an increased prevalence of conditions like anxiety, depression and sleep disturbance, we confirm that the consequences of FOXP2 dysfunction remain relatively specific to speech disorder, as compared with other recently identified monogenic conditions associated with CAS. Thus, our findings reinforce that FOXP2 provides a valuable entry point for examining the neurobiological bases of speech disorder.

Does vaping affect the taste and smell perception? An exploratory study with New Zealand young adults.

OBJECTIVE: The study aimed to assess potential effects of vaping on individual taste and smell perception in a sample of young adult New Zealanders. DESIGN: This cross-sectional study measured taste and smell perception using intensity and hedonic ratings to two olfactory (i.e., vanillin, methional) and two gustatory stimuli (i.e., sucrose, monosodium glutamate), representing sweet and savoury flavours. Detection sensitivities to sucrose and vanillin were also assessed using a forced choice detection paradigm aligned with the signal detection framework. MANCOVAs were employed to compare sensory perception between groups based on vaping use frequency. Additional regression analyses were conducted to identify potential predictors of intensity and hedonic sensory ratings. SETTING: Participants were recruited from the University of Otago student population and surrounding neighbourhoods of Dunedin, New Zealand in 2023. PARTICIPANTS: The study included 213 university students (98 vapers and 115 non-vapers) RESULTS: We found a significant difference in hedonic ratings for vanillin, indicating a stronger preference among non-vapers. However, no other differences between the two groups were significant. Notably, the use of tobacco and mint flavours were emerged as significant predictors for hedonic responses to the savoury smell and sweet taste stimulus, respectively. No significant differences were observed between groups in the ability to detect weak stimuli. CONCLUSIONS: Our findings suggest that vape use, particularly with specific flavours, may be associated with alterations in hedonic responses to smells. This finding may have potential implications for how vaping affects on food preferences and dietary choices.

Nurses' use of 'wellness' supplements during the COVID-19 pandemic in the United States.

AIM: Quantify disparities and identify correlates and predictors of 'wellness' supplement use among nurses during the first year of the pandemic. DESIGN: Longitudinal secondary analysis of Nurses' Health Studies 2 and 3 and Growing Up Today Study data. METHODS: Sample included 36,518 total participants, 12,044 of which were nurses, who completed surveys during the first year of the COVID-19 pandemic (April 2020 to April 2021). Analyses were conducted in March 2023. Modified Poisson models were used to estimate disparities in 'wellness' supplement use between nurses and non-healthcare workers and, among nurses only, to quantify associations with workplace-related predictors (occupational discrimination, PPE access, workplace setting) and psychosocial predictors (depression/anxiety, county-level COVID-19 mortality). Models included race/ethnicity, gender identity, age and cohort as covariates. RESULTS: Nurses were significantly more likely to use all types of supplements than non-healthcare workers. Lacking personal protective equipment and experiencing occupational discrimination were significantly associated with new immune supplement use. Depression increased the risk of using weight loss, energy and immune supplements. CONCLUSION: Nurses' disproportionate use of 'wellness' supplements during the COVID-19 pandemic may be related to workplace and psychosocial stressors. Given well-documented risks of harm from the use of 'wellness' supplements, the use of these products by nurses is of concern. IMPACT: 'Wellness' supplements promoting weight loss, increased energy, boosted immunity and cleansing of organs are omnipresent in today's health-focused culture, though their use has been associated with harm. This is of added concern among nurses given their risk of COVID-19 infection at work. Our study highlighted the risk factors associated with use of these products (lacking PPE and experiencing occupational discrimination). Findings support prior research suggesting a need for greater public health policy and education around the use of 'wellness' supplements. REPORTING METHOD: STROBE guidelines were followed throughout manuscript. PATIENT OR PUBLIC CONTRIBUTION: No patient or public contribution was involved.

Pediatric healthcare professionals' attitudes and beliefs about weight stigma: A descriptive study.

PURPOSE: Children face weight-based stigma from their healthcare providers at a disconcerting rate, and efforts to mitigate this have been scant. This study aimed to quantify pediatric healthcare professionals' attitudes and beliefs about weight stigma and to determine stigma reduction interventions that are most supported by pediatric healthcare providers. DESIGN AND METHODS: Participants completed two validated instruments which measured implicit and explicit weight bias, respectively. They then completed a researcher-designed questionnaire to assess their attitudes and beliefs about weight stigma, and demographic questions. ANOVA models were used to examine associations between bias measures and participant characteristics, chi-square analyses were used to examine associations between questionnaire responses and participant characteristics, and Spearman's rank was used to determine correlations between weight bias and questionnaire responses. RESULTS: Participants exhibited moderate-to-high levels of implicit and explicit weight bias (mean Implicit Association Test score = 0.59, mean Crandall Anti-Fat Attitudes Score = 38.95). Associations were noted between implicit bias and years in practice (p < 0.05), and implicit bias and occupation (p < 0.05). There was a significant correlation between explicit bias and multiple questionnaire items, suggesting that healthcare providers with greater weight bias are aware of those biases and are ready to take action to address them. CONCLUSION: Though pediatric healthcare exhibit weight-based biases, they are invested in taking steps to mitigate these biases and their impact on patients. PRACTICE IMPLICATIONS: The results of this study can inform the design of future interventions that aim to reduce healthcare-based weight bias, thus improving the quality of pediatric healthcare.

Atypical development of Broca's area in a large family with inherited stuttering.

Developmental stuttering is a condition of speech dysfluency, characterized by pauses, blocks, prolongations and sound or syllable repetitions. It affects around 1% of the population, with potential detrimental effects on mental health and long-term employment. Accumulating evidence points to a genetic aetiology, yet gene-brain associations remain poorly understood due to a lack of MRI studies in affected families. Here we report the first neuroimaging study of developmental stuttering in a family with autosomal dominant inheritance of persistent stuttering. We studied a four-generation family, 16 family members were included in genotyping analysis. T1-weighted and diffusion-weighted MRI scans were conducted on seven family members (six male; aged 9-63 years) with two age and sex matched controls without stuttering (n = 14). Using Freesurfer, we analysed cortical morphology (cortical thickness, surface area and local gyrification index) and basal ganglia volumes. White matter integrity in key speech and language tracts (i.e. frontal aslant tract and arcuate fasciculus) was also analysed using MRtrix and probabilistic tractography. We identified a significant age by group interaction effect for cortical thickness in the left hemisphere pars opercularis (Broca's area). In affected family members this region failed to follow the typical trajectory of age-related thinning observed in controls. Surface area analysis revealed the middle frontal gyrus region was reduced bilaterally in the family (all cortical morphometry significance levels set at a vertex-wise threshold of P < 0.01, corrected for multiple comparisons). Both the left and right globus pallidus were larger in the family than in the control group (left P = 0.017; right P = 0.037), and a larger right globus pallidus was associated with more severe stuttering (rho = 0.86, P = 0.01). No white matter differences were identified. Genotyping identified novel loci on chromosomes 1 and 4 that map with the stuttering phenotype. Our findings denote disruption within the cortico-basal ganglia-thalamo-cortical network. The lack of typical development of these structures reflects the anatomical basis of the abnormal inhibitory control network between Broca's area and the striatum underpinning stuttering in these individuals. This is the first evidence of a neural phenotype in a family with an autosomal dominantly inherited stuttering.

Population-level policy recommendations for the prevention of disordered weight control behaviors: A scoping review.

OBJECTIVE: The aim of this scoping review was to identify recommendations and gaps in knowledge surrounding the prevention of disordered weight control behaviors (DWCBs) through policy. METHOD: A search was conducted in several databases to identify English language articles that described an active policy, recommendation, guideline, or educational curriculum that could be implemented by governments or regulatory bodies to prevent DWCBs or related constructs (e.g., weight stigma, body dissatisfaction). Two researchers independently screened articles with oversight from a third researcher. Data were extracted from the final sample (n = 65) and analyzed qualitatively across all articles and within the domains of education, public policy, public health, industry regulation, and media. RESULTS: Only a single empirical evaluation of an implemented policy to reduce DWCBs was identified. Over one-third of articles proposed recommendations relating to industry regulation and media (n = 24, 36.9%), followed by education (n = 21, 32.3%), public policy (n = 19, 29.2%), and public health (n = 10, 15.4%). Recommendations included school-based changes to curricula, staff training, and anti-bullying policies; legislation to ban weight discrimination; policies informed by strategic science; collaboration with researchers from other fields; de-emphasizing weight in health communications; diversifying body sizes and limiting modified images in media; and restricting the sale of weight-loss supplements. DISCUSSION: The findings of this review highlight gaps in empirically evaluated policies to reduce DWCBs but also promising policy recommendations across several domains. Although some policy recommendations were supported by empirical evidence, others were primarily based on experts' knowledge, highlighting the need for greater research on population-level DWCBs prevention through policy. PUBLIC SIGNIFICANCE: Our scoping review of the evidence on policies for the prevention of disordered weight control behaviors identified several recommendations across the domains of education, public policy, public health, and industry regulation and media. Although few empirical investigations of implemented policies have been conducted, expert recommendations for policies to prevent disordered weight control behaviors among populations are plentiful and warrant future consideration by researchers and policymakers alike.

OBJETIVO: El objetivo de esta revisión sistemática exploratoria fue identificar recomendaciones y lagunas en el conocimiento sobre la prevención de comportamientos disfuncionales de control de peso (DWCB) a través de políticas. MÉTODO: Se realizó una búsqueda en varias bases de datos para identificar artículos en ingel resumenlés que describieran una política activa, recomendación, directriz o currículo educativo que pudieran implementar los gobiernos u organismos reguladores para prevenir DWCB o constructos relacionados (por ejemplo, estigma de peso, insatisfacción corporal). Dos investigadores examinaron de forma independiente los artículos con la supervisión de un tercer investigador. Los datos se extrajeron de la muestra final (n = 65) y se analizaron cualitativamente en todos los artículos y dentro de los dominios de educación, políticas públicas, salud pública, regulación de la industria y medios de comunicación. RESULTADOS: Solo se identificó una evaluación empírica única de una política implementada para reducir los DWCB. Más de un tercio de los artículos propusieron recomendaciones relacionadas con la regulación de la industria y los medios de comunicación (n = 24, 36.9%), seguido de educación (n = 21, 32.3%), políticas públicas (n = 19, 29.2%) y salud pública (n = 10, 15.4%). Las recomendaciones incluyeron cambios en los planes de estudio, capacitación del personal y políticas contra el acoso (bullying); legislación para prohibir la discriminación por peso; políticas basadas en la ciencia estratégica; colaboración con investigadores de otros campos; restar importancia al peso en las comunicaciones sanitarias; diversificar los tamaños corporales y limitar las imágenes modificadas en los medios; y restringir la venta de suplementos para bajar de peso. DISCUSIÓN: Los hallazgos de esta revisión destacan las brechas en las políticas evaluadas empíricamente para reducir los DWCB, pero también las recomendaciones de políticas prometedoras en varios dominios. Aunque algunas recomendaciones de políticas estaban respaldadas por evidencia empírica, otras se basaban principalmente en el conocimiento de expertos, destacando la necesidad de una mayor investigación sobre la prevención de DWCB a nivel poblacional a través de políticas.

Dorsal language stream anomalies in an inherited speech disorder.

Speech disorders are highly prevalent in the preschool years, but frequently resolve. The neurobiological basis of the most persistent and severe form, apraxia of speech, remains elusive. Current neuroanatomical models of speech processing in adults propose two parallel streams. The dorsal stream is involved in sound to motor speech transformations, while the ventral stream supports sound/letter to meaning. Data-driven theories on the role of these streams during atypical speech and language development are lacking. Here we provide comprehensive behavioural and neuroimaging data on a large novel family where one parent and 11 children presented with features of childhood apraxia of speech (the same speech disorder associated with FOXP2 variants). The genetic cause of the disorder in this family remains to be identified. Importantly, in this family the speech disorder is not systematically associated with language or literacy impairment. Brain MRI scanning in seven children revealed large grey matter reductions over the left temporoparietal region, but not in the basal ganglia, relative to typically-developing matched peers. In addition, we detected white matter reductions in the arcuate fasciculus (dorsal language stream) bilaterally, but not in the inferior fronto-occipital fasciculus (ventral language stream) nor in primary motor pathways. Our findings identify disruption of the dorsal language stream as a novel neural phenotype of developmental speech disorders, distinct from that reported in speech disorders associated with FOXP2 variants. Overall, our data confirm the early role of this stream in auditory-to-articulation transformations. 10.1093/brain/awz018_video1 awz018media1 6018582401001.

Speech in children with cerebral palsy.

AIM: To examine the frequency, characteristics, and factors associated with speech delay and disorder in a community sample of children with cerebral palsy (CP). METHOD: Participants were 84 children (37 females, 47 males; aged between 4y 11mo-6y 6mo) with CP identified through a population-based registry. Speech and oromotor function were systematically evaluated to provide a differential diagnosis of articulation, phonological, and motor speech disorders. RESULTS: In total, 82% (69/84) of participants had delayed or disordered speech production, including minimally verbal presentations (n=20). Verbal participants (n=64) presented with dysarthria (78%), articulation delay or disorder (54%), phonological delay or disorder (43%), features of childhood apraxia of speech (CAS) (17%), or mixed presentations across these conditions. Speech intelligibility was poorest in those with dysarthria and features of CAS. Speech delay or disorder in verbal participants was associated with language impairment (p=0.002) and reduced health-related quality of life (p=0.04) (Fisher's exact test). Poorer speech accuracy (i.e. lower percentage consonants correct) correlated with greater impairments in both language (p<0.001) and oromotor function (p<0.001) (Spearman's test). INTERPRETATION: The speech profile of children with CP is characterized by impairment at multiple levels of speech production (phonetic, cognitive-linguistic, neuromuscular execution, and high-level planning/programming), highlighting the importance of a personalized differential diagnosis informing targeted treatment.

Looking to the Future: Speech, Language, and Academic Outcomes in an Adolescent with Childhood Apraxia of Speech.

OBJECTIVE: The clinical course of childhood apraxia of speech (CAS) is poorly understood. Of the few longitudinal studies in the field, only one has examined adolescent outcomes in speech, language, and literacy. This study is the first to report long-term speech, language, and academic outcomes in an adolescent, Liam, with CAS. METHODS: Speech, language, literacy, and academic outcome data were collected, including 3 research-based assessments. Overall, data were available at 17 time points from 3;10 to 15 years. RESULTS: Liam had moderate-to-severe expressive language impairment and poor reading, writing, and spelling up to 10 years. His numeracy was at or above the national average from 8 to 14 years. He made gains in preadolescence, with average expressive language at 11 years and above average reading and writing at 14 years. Nonword reading, reading comprehension, and spelling remained areas of weakness. Receptive language impairment was evident at 13 years, which was an unexpected finding. CONCLUSION: Findings from single cases can be hypothesis generating but require verification in larger cohorts. This case shows that at least some children with CAS may gain ground in adolescence, relative to same age peers, in expressive language and academic areas such as reading and writing.

Risk factors associated with unintentional house fire incidents, injuries and deaths in high-income countries: a systematic review.

OBJECTIVE: To identify the distinguishing risk factors associated with unintentional house fire incidents, injuries and deaths. STUDY DESIGN: Systematic review. METHODS: A range of bibliographical databases and grey literature were searched from their earliest records to January 2016. To ensure the magnitude of risk could be quantified, only those study types which contained a control group, and undertook appropriate statistical analyses were included. A best evidence synthesis was conducted instead of a meta-analysis due to study heterogeneity. RESULTS: Eleven studies investigating a variety of risk factors and outcomes were identified. Studies ranged from medium to low quality with no high quality studies identified. Characteristics commonly associated with increased risk of house fire incidents, injuries and fatalities included: higher numbers of residents, male, children under the age of 5 years, non-working households, smoking, low income, non-privately owned properties, apartments and buildings in poor condition. Several risk factors were only associated with one outcome (eg, living alone was only associated with increased risk of injurious fires), and households with older residents were at increased risk of injurious fires, but significantly less likely to experience a house fire in the first place. CONCLUSIONS: This best evidence synthesis indicates that several resident and property characteristics are associated with risk of experiencing house fire incidents, injuries or death. These findings should be considered by the Fire and Rescue Services and others with a role in fire prevention. Future research should adopt robust, standardised study designs to permit meta-analyses and enable stronger conclusions to be drawn.

All Wales Injury Surveillance System revised: development of a population-based system to evaluate single-level and multilevel interventions.

BACKGROUND: Injury surveillance has been established since the 1990s, but is still largely based upon single-source data from sentinel sites. The growth of electronic health records and developments in privacy protecting linkage technologies provide an opportunity for more sophisticated surveillance systems. OBJECTIVE: To describe the evolution of an injury surveillance system to support the evaluation of interventions, both simple and complex in terms of organisation. METHODS: The paper describes the evolution of the system from one that relied upon data only from emergency departments to one that include multisource data and are now embedded in a total population privacy protecting data linkage system. Injury incidence estimates are compared by source and data linkage used to aid understanding of data quality issues. Examples of applications, challenges and solutions are described. RESULTS: The age profile and estimated incidence of injuries recorded in general practice, emergency departments and hospital admissions differ considerably. Data linkage has enabled the evaluation of complex interventions and measurement of longer-term impact of a wide range of exposures. CONCLUSIONS: Embedding injury surveillance within privacy protecting data linkage environment can transform the utility of a traditional single-source surveillance system to a multisource system. It also facilitates greater involvement in the evaluation of simple and complex healthcare and non-healthcare interventions and contributes to the growing evidence basis underlying the science of injury prevention and control.

New genes for focal epilepsies with speech and language disorders.

The last 2 years have seen exciting advances in the genetics of Landau-Kleffner syndrome and related disorders, encompassed within the epilepsy-aphasia spectrum (EAS). The striking finding of mutations in the N-methyl-D-aspartate (NMDA) receptor subunit gene GRIN2A as the first monogenic cause in up to 20% of patients with EAS suggests that excitatory glutamate receptors play a key role in these disorders. Patients with GRIN2A mutations have a recognizable speech and language phenotype that may assist with diagnosis. Other molecules involved in RNA binding and cell adhesion have been implicated in EAS; copy number variations are also found. The emerging picture highlights the overlap between the genetic determinants of EAS with speech and language disorders, intellectual disability, autism spectrum disorders and more complex developmental phenotypes.

The unintended consequences of school-based health and nutrition policies: a systematic review.

Background: Significant funding and attention are directed toward school-based health and nutrition interventions. Less attention is given to the potential unintended consequences of these policies, especially those that target children and adolescents. This systematic review aimed to elucidate the unintended consequences of school-based health and nutrition policies in the United States. Methods: We conducted a systematic review, adhering to PRISMA guidelines, to analyze quantitative, qualitative, and mixed methods research conducted between January 2013 and September 2023. The search strategy encompassed three databases, identifying 11 articles that met the inclusion criteria. Results: Unintended consequences were organized into four themes: disordered weight control behaviors, parental discomfort or encouragement of disordered weight control behaviors, eating disorder triggers, and financial losses. The analysis of disordered weight control behaviors indicates limited impact on youth, and we noted limited consensus in the assessment of these behaviors. We observed parent concerns about BMI screening and reporting as well as apprehensions about privacy and efficacy. There were fewer articles addressing eating disorder antecedents, although there was evidence that some youths with eating disorders considered school health class a trigger of their disorder. One study was identified that found an increase in food waste following replacement of sugar-sweetened beverages. Implications: Findings underscore the importance of comprehensive evaluation and consideration of unintended consequences in the development and implementation of school-based health policies. Recommendations include further longitudinal research, integrating obesity prevention with eating disorder prevention, and de-implementation when unintended consequences potentially outweigh benefits, such as in BMI screening and surveillance.Systematic Review Registration: Identifier CRD42023467355. https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=467355.

Perisylvian and Hippocampal Anomalies in Individuals With Pathogenic GRIN2A Variants.

Background and Objectives: Pathogenic variants in GRIN2A are associated with a spectrum of epilepsy-aphasia syndromes (EASs). Seizures as well as speech and language disorders occur frequently but vary widely in severity, both between individuals and across the life span. The link between this phenotypic spectrum and brain characteristics is unknown. Specifically, altered brain networks at the root of speech and language deficits remain to be identified. Patients with pathogenic variants in GRIN2A offer an opportunity to interrogate the impact of glutamate receptor dysfunction on brain development. Methods: We characterized brain anomalies in individuals with pathogenic GRIN2A variants and EASs, hypothesizing alterations in perisylvian speech-language regions and the striatum. We compared structural MRI data from 10 individuals (3 children and 7 adults, 3 female) with pathogenic GRIN2A variants with data from age-matched controls (N = 51 and N = 203 in a secondary analysis). We examined cortical thickness and volume in 4 a priori hypothesized speech and language regions (inferior frontal, precentral, supramarginal, and superior temporal) and across the whole brain. Subcortical structures (hippocampus, basal ganglia, thalamus) and the corpus callosum were also compared. Results: Individuals with pathogenic GRIN2A variants showed increased thickness and volume in the posterior part of Broca's area (inferior frontal gyrus, pars opercularis). For thickness, the effects were bilateral but more pronounced in the left (large effect size, η2 = 0.37) than the right (η2 = 0.12) hemisphere. Both volume and thickness were also higher in the bilateral superior temporal region while the supramarginal region showed increased thickness only. Whole-brain analyses confirmed left-sided thickness increases in Broca's area, with additional increases in the occipital and superior frontal cortices bilaterally. Hippocampal volume was reduced in the left hemisphere. There were no age-dependent effects or corpus callosum group differences. Discussion: Anomalies in perisylvian regions, with largest differences in Broca's area, suggest an altered development of classical speech-language networks in GRIN2A-related EAS. Left hippocampal reduction suggests a role for this structure in early speech and language development and is consistent with GRIN2A gene expression in that region. Overall, elucidating the neural correlates of EAS provides insights into the impact of GRIN2A dysfunction, opening avenues for targeted intervention in developmental syndromes with compromised speech-language development.

Small intragenic deletion in FOXP2 associated with childhood apraxia of speech and dysarthria.

Relatively little is known about the neurobiological basis of speech disorders although genetic determinants are increasingly recognized. The first gene for primary speech disorder was FOXP2, identified in a large, informative family with verbal and oral dyspraxia. Subsequently, many de novo and familial cases with a severe speech disorder associated with FOXP2 mutations have been reported. These mutations include sequencing alterations, translocations, uniparental disomy, and genomic copy number variants. We studied eight probands with speech disorder and their families. Family members were phenotyped using a comprehensive assessment of speech, oral motor function, language, literacy skills, and cognition. Coding regions of FOXP2 were screened to identify novel variants. Segregation of the variant was determined in the probands' families. Variants were identified in two probands. One child with severe motor speech disorder had a small de novo intragenic FOXP2 deletion. His phenotype included features of childhood apraxia of speech and dysarthria, oral motor dyspraxia, receptive and expressive language disorder, and literacy difficulties. The other variant was found in a family in two of three family members with stuttering, and also in the mother with oral motor impairment. This variant was considered a benign polymorphism as it was predicted to be non-pathogenic with in silico tools and found in database controls. This is the first report of a small intragenic deletion of FOXP2 that is likely to be the cause of severe motor speech disorder associated with language and literacy problems.

Clinical genetic study of the epilepsy-aphasia spectrum.

PURPOSE: To characterize the frequency and nature of the family history of seizures in probands with epilepsy falling within the epilepsy-aphasia spectrum (EAS) in order to understand the genetic architecture of this group of disorders. METHODS: Patients with epileptic encephalopathy with continuous spike-and-wave during sleep (ECSWS), Landau-Kleffner syndrome (LKS), atypical benign partial epilepsy (ABPE), and intermediate epilepsy-aphasia disorders (IEAD) were recruited. All affected and available unaffected relatives up to three degrees of relatedness underwent phenotyping using a validated seizure questionnaire. Pedigrees were constructed for all families. The proportion of affected relatives according to each degree of relatedness was calculated. The epilepsy phenotypes in close relatives were analyzed. The data were compared to the families of probands with benign childhood epilepsy with centrotemporal spikes (BECTS) using the same methodology. KEY FINDINGS: Thirty-one probands, including five ECSWS, three LKS, one ABPE, and 22 IEAD were recruited. The mean age of seizure onset was 3.9 (range 0.5-7) years. A male predominance was seen (68%, 21/31) . Sixteen (51.6%) of 31 had a positive family history of seizures. Among 1,254 relatives, 30 (2.4%) had a history of seizures: 13 (10.2%) of 128 first-degree relatives, 5 (1.7%) of 291 second-degree relatives, and 12 (1.4%) of 835 third-degree relatives. Thirteen had febrile seizures, including two who had both febrile seizures and epilepsy. Of the 19 relatives with epilepsy, 4 had BECTS, 4 epilepsies with focal seizures of unknown cause, 3 IEAD, and 7 unclassified. One had genetic generalized epilepsy. In the families of the BECTS probands, 9.8% of first-degree, 3% of second-degree, and 1.5% of third-degree relatives had seizures, which was not significantly different from the EAS cohort families. SIGNIFICANCE: The frequencies of seizures in relatives of probands with EAS suggest that the underlying genetic influence of EAS is consistent with complex inheritance and similar to BECTS. The phenotypic pattern observed in the affected relatives comprised predominantly febrile seizures and focal seizures. These findings suggest that a shared genetic predisposition to focal epilepsies underpins the epilepsy-aphasia spectrum.

Modification of the home environment for the reduction of injuries.

BACKGROUND: Injury in the home is common, accounting for approximately a third of all injuries. The majority of injuries to children under five and people aged 75 and older occur at home. Multifactorial injury prevention interventions have been shown to reduce injuries in the home. However, few studies have focused specifically on the impact of physical adaptations to the home environment and the effectiveness of such interventions needs to be ascertained. OBJECTIVES: To determine the effect of modifications to the home environment on the reduction of injuries due to environmental hazards. SEARCH STRATEGY: We searched The Cochrane Library, MEDLINE, EMBASE and other specialised databases. We also scanned conference proceedings and reference lists. We contacted the first author of all included randomised controlled trials. The searches were last updated to the end of December 2009, and were not restricted by language or publication status. SELECTION CRITERIA: Randomised controlled trials. DATA COLLECTION AND ANALYSIS: Two authors screened all abstracts for relevance, outcome and design. Two authors independently assessed methodological quality and extracted data from each eligible study. We performed meta-analysis to combine effect measures, using a random-effects model. We assessed heterogeneity using an I(2) statistic and a Chi(2) test. MAIN RESULTS: We found 28 published studies and one unpublished study. Only two studies were sufficiently similar to allow pooling of data for statistical analyses. Studies were divided into three groups; children, older people and the general population/mixed age group. None of the studies focusing on children or older people demonstrated a reduction in injuries that were a direct result of environmental modification in the home. One study in older people demonstrated a reduction in falls and one a reduction in falls and injurious falls that may have been due to hazard reduction. One meta-analysis was performed which examined the effects on falls of multifactorial interventions consisting of home hazard assessment and modification, medication review, health and bone assessment and exercise (RR 1.09, 95% CI 0.97 to 1.23). AUTHORS' CONCLUSIONS: There is insufficient evidence to determine whether interventions focused on modifying environmental home hazards reduce injuries. Further interventions to reduce hazards in the home should be evaluated by adequately designed randomised controlled trials measuring injury outcomes. Recruitment of large study samples to measure effect must be a major consideration for future trials. Researchers should also consider using factorial designs to allow the evaluation of individual components of multifactorial interventions.

Epilepsy and mental retardation limited to females with PCDH19 mutations can present de novo or in single generation families.

BACKGROUND: Epilepsy and mental retardation limited to females (EFMR) is an intriguing X-linked disorder affecting heterozygous females and sparing hemizygous males. Mutations in the protocadherin 19 (PCDH19) gene have been identified in seven unrelated families with EFMR. METHODS AND RESULTS: Here, we assessed the frequency of PCDH19 mutations in individuals with clinical features which overlap those of EFMR. We analysed 185 females from three cohorts: 42 with Rett syndrome who were negative for MECP2 and CDKL5 mutations, 57 with autism spectrum disorders, and 86 with epilepsy with or without intellectual disability. No mutations were identified in the Rett syndrome and autism spectrum disorders cohorts suggesting that despite sharing similar clinical characteristics with EFMR, PCDH19 mutations are not generally associated with these disorders. Among the 86 females with epilepsy (of whom 51 had seizure onset before 3 years), with or without intellectual disability, we identified two (2.3%) missense changes. One (c.1671C-->G, p.N557K), reported previously without clinical data, was found in two affected sisters, the first EFMR family without a multigenerational family history of affected females. The second, reported here, is a novel de novo missense change identified in a sporadic female. The change, p.S276P, is predicted to result in functional disturbance of PCDH19 as it affects a highly conserved residue adjacent to the adhesion interface of EC3 of PCDH19. CONCLUSIONS: This de novo PCDH19 mutation in a sporadic female highlights that mutational analysis should be considered in isolated instances of girls with infantile onset seizures and developmental delay, in addition to those with the characteristic family history of EFMR.