Human macrophages limit oxidation products in low density lipoprotein

This study tested the hypothesis that human macrophages have the ability to modify oxidation products in LDL and oxidized LDL (oxLDL) via a cellular antioxidant defence system. While many studies have focused on macrophage LDL oxidation in atherosclerosis development, less attention has been given to the cellular antioxidant capacity of these cells. Compared to cell-free controls (6.2 ± 0.7 nmol/mg LDL), macrophages reduced TBARS to 4.42 ± 0.4 nmol/mg LDL after 24 h incubation with LDL (P = 0.022). After 2 h incubation with oxLDL, TBARS were 3.69 ± 0.5 nmol/mg LDL in cell-free media, and 2.48 ± 0.9 nmol/mg LDL in the presence of macrophages (P = 0.034). A reduction of lipid peroxides in LDL (33.7 ± 6.6 nmol/mg LDL) was found in the presence of cells after 24 h compared to cell-free incubation (105.0 ± 14.1 nmol/mg LDL) (P = 0.005). The levels of lipid peroxides in oxLDL were 137.9 ± 59.9 nmol/mg LDL and in cell-free media 242 ± 60.0 nmol/mg LDL (P = 0.012). Similar results were obtained for hydrogen peroxide. Reactive oxygen species were detected in LDL, acetylated LDL, and oxLDL by isoluminol-enhanced chemiluminescence (CL). Interestingly, oxLDL alone gives a high CL signal. Macrophages reduced the CL response in oxLDL by 45% (P = 0.0016). The increased levels of glutathione in oxLDL-treated macrophages were accompanied by enhanced catalase and glutathione peroxidase activities. Our results suggest that macrophages respond to oxidative stress by endogenous antioxidant activity, which is sufficient to decrease reactive oxygen species both in LDL and oxLDL. This may suggest that the antioxidant activity is insufficient during atherosclerosis development. Thus, macrophages may play a dual role in atherogenesis, i.e. both by promoting and limiting LDL-oxidation. © 2005 Hultén et al; licensee BioMed Central Ltd

Self-reported impact of developmental stuttering across the lifespan

Aim To examine the phenomenology of stuttering across the lifespan in the largest prospective cohort to date. Method Participants aged 7 years and older with a history of developmental stuttering were recruited. Self-reported phenotypic data were collected online including stuttering symptomatology, co-occurring phenotypes, genetic predisposition, factors associated with stuttering severity, and impact on anxiety, education, and employment. Results A total of 987 participants (852 adults: 590 males, 262 females, mean age 49 years [SD = 17 years 10 months; range = 18–93 years] and 135 children: 97 males, 38 females, mean age 11 years 4 months [SD = 3 years; range = 7–17 years]) were recruited. Stuttering onset occurred at age 3 to 6 years in 64.0%. Blocking (73.2%) was the most frequent phenotype; 75.9% had sought stuttering therapy and 15.5% identified as having recovered. Half (49.9%) reported a family history. There was a significant negative correlation with age for both stuttering frequency and severity in adults. Most were anxious due to stuttering (90.4%) and perceived stuttering as a barrier to education and employment outcomes (80.7%). Interpretation The frequent persistence of stuttering and the high proportion with a family history suggest that stuttering is a complex trait that does not often resolve, even with therapy. These data provide new insights into the phenotype and prognosis of stuttering, information that is critically needed to encourage the development of more effective speech therapies

Genetic aetiologies for childhood speech disorder: Novel pathways co-expressed during brain development

Childhood apraxia of speech (CAS), the prototypic severe childhood speech disorder, is characterized by motor programming and planning deficits. Genetic factors make substantive contributions to CAS aetiology, with a monogenic pathogenic variant identified in a third of cases, implicating around 20 single genes to date. Here we aimed to identify molecular causation in 70 unrelated probands ascertained with CAS. We performed trio genome sequencing. Our bioinformatic analysis examined single nucleotide, indel, copy number, structural and short tandem repeat variants. We prioritised appropriate variants arising de novo or inherited that were expected to be damaging based on in silico predictions. We identified high confidence variants in 18/70 (26%) probands, almost doubling the current number of candidate genes for CAS. Three of the 18 variants affected SETBP1, SETD1A and DDX3X, thus confirming their roles in CAS, while the remaining 15 occurred in genes not previously associated with this disorder. Fifteen variants arose de novo and three were inherited. We provide further novel insights into the biology of child speech disorder, highlighting the roles of chromatin organization and gene regulation in CAS, and confirm that genes involved in CAS are co-expressed during brain development. Our findings confirm a diagnostic yield comparable to, or even higher, than other neurodevelopmental disorders with substantial de novo variant burden. Data also support the increasingly recognised overlaps between genes conferring risk for a range of neurodevelopmental disorders. Understanding the aetiological basis of CAS is critical to end the diagnostic odyssey and ensure affected individuals are poised for precision medicine trials

Preschool children’s consistency of word production

Consistency of word production contributes to carers’ ability to understand children’s speech. Reports of the proportion of words produced consistently by typically developing preschool children, however, vary widely from 17% to 87%. This paper examines the quantitative (consistency count) and qualitative (e.g. phonemic analysis) characteristics of word consistency in 96 children aged 36–60 months. Children named 15 pictures twice, in separate trials, in the same assessment session. The mean consistency of the production for the whole group was 82%. Older children were more consistent than younger children. Girls were more consistent than boys. Words produced correctly in one trial and in error in another may indicate resolving error patterns. Words produced in error in two different ways provided useful evidence about the nature of inconsistent word production in typically developing children. The clinical and theoretical implications are discussed

Expanding the speech and language phenotype in Koolen-de Vries syndrome: late onset and periodic stuttering a novel feature.

Speech and language impairment is core in Koolen-de Vries syndrome (KdVS), yet only one study has examined this empirically. Here we define speech, language, and functional/adaptive behaviour in KdVS; while deeply characterising the medical/neurodevelopmental phenotype in the largest cohort to date. Speech, language, literacy, and social skills were assessed using standardised measures, alongside an in-depth health and medical questionnaire. 81 individuals with KdVS were recruited (35 female, mean age 9y 10mo), 56 of whom harboured the typical 500-650 kb 17q21.31 deletion. The core medical phenotype was intellectual disability (largely moderate), eye anomalies/vision disturbances, structural brain anomalies, dental problems, sleep disturbance, musculoskeletal abnormalities, and cardiac defects. Most were verbal (62/81, 76.5%), while minimally-verbal communicators used alternative and augmentative communication (AAC) successfully in spite of speech production delays. Speech was characterised by apraxia (39/61, 63.9%) and dysarthria (28/61, 45.9%) in verbal participants. Stuttering was described in 36/47 (76.6%) verbal participants and followed a unique trajectory of late onset and fluctuating presence. Receptive and expressive language abilities were commensurate with one another, but literacy skills remained a relative weakness. Social competence, successful behavioural/emotional control, and coping skills were areas of relative strength, while communication difficulties impacted daily living skills as an area of comparative difficulty. Notably, KdVS individuals make communication gains beyond childhood and should continue to access targeted therapies throughout development, including early AAC implementation, motor speech therapy, language/literacy intervention, as well as strategies implemented to successfully navigate activities of daily living that rely on effective communication

Expanding the speech and language phenotype in Koolen-de Vries syndrome: late onset and periodic stuttering a novel feature

Speech and language impairment is core in Koolen-de Vries syndrome (KdVS), yet only one study has examined this empirically. Here we define speech, language, and functional/adaptive behaviour in KdVS; while deeply characterising the medical/neurodevelopmental phenotype in the largest cohort to date. Speech, language, literacy, and social skills were assessed using standardised measures, alongside an in-depth health and medical questionnaire. 81 individuals with KdVS were recruited (35 female, mean age 9y 10mo), 56 of whom harboured the typical 500-650 kb 17q21.31 deletion. The core medical phenotype was intellectual disability (largely moderate), eye anomalies/vision disturbances, structural brain anomalies, dental problems, sleep disturbance, musculoskeletal abnormalities, and cardiac defects. Most were verbal (62/81, 76.5%), while minimally-verbal communicators used alternative and augmentative communication (AAC) successfully in spite of speech production delays. Speech was characterised by apraxia (39/61, 63.9%) and dysarthria (28/61, 45.9%) in verbal participants. Stuttering was described in 36/47 (76.6%) verbal participants and followed a unique trajectory of late onset and fluctuating presence. Receptive and expressive language abilities were commensurate with one another, but literacy skills remained a relative weakness. Social competence, successful behavioural/emotional control, and coping skills were areas of relative strength, while communication difficulties impacted daily living skills as an area of comparative difficulty. Notably, KdVS individuals make communication gains beyond childhood and should continue to access targeted therapies throughout development, including early AAC implementation, motor speech therapy, language/literacy intervention, as well as strategies implemented to successfully navigate activities of daily living that rely on effective communication

CDK13-related disorder: a deep characterization of speech and language abilities and addition of 33 novel cases

Speech and language impairments are central features of CDK13-related disorder. While pathogenic CDK13 variants have been associated with childhood apraxia of speech (CAS), a systematic characterisation of communication has not been conducted. Here we examined speech, language, non-verbal communication skills, social behaviour and health and development in 41 individuals with CDK13-related disorder from 10 countries (male = 22, median-age 7 years 1 month, range 1-25 years; 33 novel). Most participants used augmentative and alternative communication (AAC) in early childhood (24/41). CAS was common (14/22). Performance varied widely across intellectual ability, social behaviour and expressive language skills, with participants ranging from within average through to the severely impaired range. Receptive language was significantly stronger than expressive language ability. Social motivation was a relative strength. In terms of a broader health phenotype, a quarter had one or more of: renal, urogenital, musculoskeletal, and cardiac malformations, vision impairment, ear infections and/or sleep disturbance. All had gross and fine motor impairments (41/41). Other conditions included mild-moderate intellectual disability (16/22) and autism (7/41). No genotype-phenotype correlations were found. Recognition of CAS, a rare speech disorder, is required to ensure appropriately targeted therapy. The high prevalence of speech and language impairment underscores the importance of tailored speech therapy, particularly early access to AAC supports

Severe childhood speech disorder: gene discovery highlights transcriptional dysregulation

OBJECTIVE:Determining the genetic basis of speech disorders provides insight into the neurobiology of human communication. Despite intensive investigation over the past 2 decades, the etiology of most speech disorders in children remains unexplained. To test the hypothesis that speech disorders have a genetic etiology, we performed genetic analysis of children with severe speech disorder, specifically childhood apraxia of speech (CAS). METHODS:Precise phenotyping together with research genome or exome analysis were performed on children referred with a primary diagnosis of CAS. Gene coexpression and gene set enrichment analyses were conducted on high-confidence gene candidates. RESULTS:Thirty-four probands ascertained for CAS were studied. In 11/34 (32%) probands, we identified highly plausible pathogenic single nucleotide (n = 10; CDK13, EBF3, GNAO1, GNB1, DDX3X, MEIS2, POGZ, SETBP1, UPF2, ZNF142) or copy number (n = 1; 5q14.3q21.1 locus) variants in novel genes or loci for CAS. Testing of parental DNA was available for 9 probands and confirmed that the variants had arisen de novo. Eight genes encode proteins critical for regulation of gene transcription, and analyses of transcriptomic data found CAS-implicated genes were highly coexpressed in the developing human brain. CONCLUSION:We identify the likely genetic etiology in 11 patients with CAS and implicate 9 genes for the first time. We find that CAS is often a sporadic monogenic disorder, and highly genetically heterogeneous. Highly penetrant variants implicate shared pathways in broad transcriptional regulation, highlighting the key role of transcriptional regulation in normal speech development. CAS is a distinctive, socially debilitating clinical disorder, and understanding its molecular basis is the first step towards identifying precision medicine approaches.Michael S. Hildebrand, Victoria E. Jackson, Thomas S. Scerri, Olivia Van Reyk, Matthew Coleman ... Josef Gecz ... et al