Examining pragmatic language development in preschoolers with and without neurodevelopmental disorders: A cross-sectional study.

This cross-sectional study examined the relationship between gender, age, and pragmatic language development in n = 77 Italian preschool children (49-84 months) with and without neurodevelopmental disorders. The sample included 62 children without psychiatric history (n = 34 females, n = 27 males) and n = 15 children with psychiatric history (2 females, n = 13 males). Eight cases (n = 6 males, n = 2 females, 59-75 months) were matched for age and gender. The neurodevelopmental disorder group used the Targeted Observation of Pragmatics in Children's Conversations (TOPICC) tool. Pragmatic language skills were assessed with the Pragmatic Language Abilities (APL), Children's Communication Checklist-Version 2 (CCC-2), and TOPICC scales. Results showed no significant relationship between gender and pragmatic language development subscales, except for a marginally significant relationship with figurative metaphor scores. Age was positively correlated with verbal metaphor, metaphor, implied meaning, and overall pragmatic language skills, but not with figurative metaphor or situations scores. Paired samples t-tests and Wilcoxon tests compared matched groups, revealing significant differences between children with and without neurodevelopmental disorders on the TOPICC, APL, and CCC-2 tools. The findings highlight the importance of early identification and intervention for children with pragmatic language impairment (PLI) and the need for further research with larger samples.

Elesclomol elevates cellular and mitochondrial iron levels by delivering copper to the iron import machinery.

Copper (Cu) and iron (Fe) are redox-active metals that serve as cofactors for many essential cellular enzymes. Disruption in the intracellular homeostasis of these metals results in debilitating and frequently fatal human disorders, such as Menkes disease and Friedreich's ataxia. Recently, we reported that an investigational anticancer drug, elesclomol (ES), can deliver Cu to critical mitochondrial cuproenzymes and has the potential to be repurposed for the treatment of Cu deficiency disorders. Here, we sought to determine the specificity of ES and the ES-Cu complex in delivering Cu to cuproenzymes in different intracellular compartments. Using a combination of yeast genetics, subcellular fractionation, and inductively coupled plasma-mass spectrometry-based metal measurements, we showed that ES and ES-Cu treatment results in an increase in cellular and mitochondrial Fe content, along with the expected increase in Cu. Using yeast mutants of Cu and Fe transporters, we demonstrate that ES-based elevation in cellular Fe levels is independent of the major cellular Cu importer but is dependent on the Fe importer Ftr1 and its partner Fet3, a multicopper oxidase. As Fet3 is metalated in the Golgi lumen, we sought to uncover the mechanism by which Fet3 receives Cu from ES. Using yeast knockouts of genes involved in Cu delivery to Fet3, we determined that ES can bypass Atx1, a metallochaperone involved in Cu delivery to the Golgi membrane Cu pump, Ccc2, but not Ccc2 itself. Taken together, our study provides a mechanism by which ES distributes Cu in cells and impacts cellular and mitochondrial Fe homeostasis.

Capacity of the CCC-2 to Discriminate ASD from Other Neurodevelopmental Disorders.

The Children's Communication Checklist (CCC-2) has demonstrated its usefulness as an instrument to assess discrepancies between the use of structural dimensions of language and the pragmatic and sociointeractive uses of language. The aims of the present paper are: (1) to test the capacity of the Galician adaptation of the CCC-2 to discriminate the linguistic profiles of children with different disorders and (2) to test whether the capacity of the CCC-2 to discriminate the linguistic abilities of children with different disorders is the same at different ages: earlier development and later development. The sample is of 117 children previously diagnosed with different disorders: autism spectrum disorder (ASD), developmental language disorder (DLD), attention deficit with hyperactivity disorder (ADHD), Down syndrome children (DS) and typically developing children (TD). The children were divided into two different age groups: from 4 to 6 and from 7 to 16 years of age. The results indicate that the Galician CCC-2 (1) accurately identified children with and without communicative impairments, (2) distinguished between profiles with a predominance of pragmatic (ASD and ADHD) and structural disorders (DS and DLD) and (3) distinguished between different profiles of pragmatic impairment. The CCC-2 equally identified these profiles at both earlier and later ages. The Galician CCC-2 seems to be a useful instrument for differentiating among different clinical groups and for assessing pragmatic disorders from an early age, which can be valuable for planning early intervention.

Targeting Copper Homeostasis Improves Functioning of vps13Δ Yeast Mutant Cells, a Model of VPS13-Related Diseases.

Ion homeostasis is crucial for organism functioning, and its alterations may cause diseases. For example, copper insufficiency and overload are associated with Menkes and Wilson's diseases, respectively, and iron imbalance is observed in Parkinson's and Alzheimer's diseases. To better understand human diseases, Saccharomyces cerevisiae yeast are used as a model organism. In our studies, we used the vps13Δ yeast strain as a model of rare neurological diseases caused by mutations in VPS13A-D genes. In this work, we show that overexpression of genes encoding copper transporters, CTR1, CTR3, and CCC2, or the addition of copper salt to the medium, improved functioning of the vps13Δ mutant. We show that their mechanism of action, at least partially, depends on increasing iron content in the cells by the copper-dependent iron uptake system. Finally, we present that treatment with copper ionophores, disulfiram, elesclomol, and sodium pyrithione, also resulted in alleviation of the defects observed in vps13Δ cells. Our study points at copper and iron homeostasis as a potential therapeutic target for further investigation in higher eukaryotic models of VPS13-related diseases.

Association between CCC-2 and Structural Language, Pragmatics, Social Cognition, and Executive Functions in Children with Developmental Language Disorder.

(1) Background: Developmental Language Disorder (DLD) is diagnosed when the child experiences problems in language with no known underlying biomedical condition and the information required for its correct evaluation must be obtained from different contexts. The Children's Communication Checklist (CCC-2) covers aspects of a child's communication related to structural language and pragmatic skills, which are linked to social cognition or executive functions. The aim of this article is to examine parents' reports using the Spanish version of the CCC-2 questionnaire and its association with different formal assessments related to communication. (2) Methods: 30 children with DLD (3; 10-9 years old) and 39 age-matched (AM) children with typical development were assessed using formal measures of structural language, pragmatics, social cognition, and executive functions. Parents of children with DLD answered the Spanish version of the CCC-2. (3) Results: The performance of children with DLD was lower in all the formal assessments in comparison to AM children. The CCC-2 was significantly correlated with all the direct child assessments, although only formal measures of structural language predicted both the structural language and pragmatics scales of the CCC-2. (4) Conclusions: The CCC-2 answered by parents was consistent with formal assessments in children with DLD, and structural language seemed to be the best predictor of all the subscales.

Brief Report: Associations Between Autism Characteristics, Written and Spoken Communication Skills, and Social Interaction Skills in Preschool-Age Children on the Autism Spectrum.

We used parent-report data from a prospective longitudinal study to better understand the early strengths in written skills often observed in preschoolers on the spectrum. Consistent with previous research, children demonstrated relative strengths in standardized written communication compared to spoken communication scores on the VABS-II. We found no significant links between children's performance on the written communication subdomain and their autism characteristics or the Social Interaction Deviance Composite score on the CCC-2. Our results emphasize the need for further research into the early strengths in written skills of preschoolers on the spectrum. From a clinical viewpoint, we highlight the need for a comprehensive emergent literacy assessment in this group of children who are at high risk of persistent literacy difficulties.

The Revised Children's Communication Checklist-2 (CCC-R): Factor Structure and Psychometric Evaluation.

The Children's Communication Checklist-2 (CCC-2) is often applied to assess pragmatic language impairment which is highly prevalent in autism spectrum disorder (ASD) and several mental health conditions. We replicated previous findings on the limited applicability of the CCC-2 in clinical samples and the inconsistent findings concerning the factor structure. The aim of the present study was, thus, to develop a concise, simplified, and revised version of the CCC-2 in a large German-speaking sample. Four groups of children and adolescents aged 4 to 17 years were included: ASD (n = 195), intellectual disability (ID, n = 83), diverse mental health conditions (MHC, n = 144) and a typically developing control group (TD, n = 417). We reduced the original number of items from 70 to 39, based on item analysis, exploratory factor analysis and the exclusion of communication-unrelated items. The revised version, CCC-R (α = 0.96), consists of two empirically derived factors: a pragmatic-language (α = 0.96) and a grammatical-semantic-language factor (α = 0.93). All clinical groups (ASD, ID, and MHC) had significantly increased CCC-R total scores, with the highest scores being in the neurodevelopmental disorder groups (ASD and ID). In addition, we found group-specific patterns of elevated pragmatic-language scores in the ASD group and grammatical-semantic scores in the ID group. The CCC-R was comparable to the CCC-2 in distinguishing ASD from the other groups. The CCC-R is proposed as a simplified and easily applied, clinical questionnaire for caregivers, assessing pragmatic language impairments across neurodevelopmental disorders and mental health conditions. LAY SUMMARY: The CCC-2 is a questionnaire designed to identify children who have problems in the social use of language, however, it is limited in its clinical application and exhibits inconsistent factors. We have created a shorter and simpler version of the CCC-2 that we have called the CCC-R which overcomes the previous limitations of the CCC-2. It consists of two subscales: pragmatic language and grammatical-semantic language. The CCC-R can be used as a short and clinically relevant caregiver questionnaire which assesses pragmatic language impairments in children and adolescents. Autism Res 2021, 14: 759-772. © 2021 The Authors. Autism Research published by International Society for Autism Research published by Wiley Periodicals LLC.

Language and Pragmatics Across Neurodevelopmental Disorders: An Investigation Using the Italian Version of CCC-2.

Impairments in structural language and pragmatics are well recognized in different neurodevelopmental disorders, yet in clinical work the discrimination of children with various language difficulties into different diagnostic profile is still a major challenge. Using the CCC-2 questionnaire this study assesses and compares language competences in a sample of Italian children (aged 8-10) with typical development (n = 26) and in children with different neurodevelopmental conditions: high-functioning Autism Spectrum Disorder (n = 19), Language Disorder with associated Developmental Dyslexia (n = 23), Developmental Dyslexia without linguistic impairments (n = 21). The results supported the validity of CCC2 as screening measure that is able to distinguish children with communication impairments from non-impaired peers.

Pragmatic language impairment in children with Noonan syndrome.

Noonan syndrome (NS) is a disorder causing symptoms like short stature, characteristic facial features, congenital heart disease, possible mental retardation, and pragmatic difficulties. This study describes the pragmatic skills in NS and discusses the linguistic profile of 17 informants aged 6-15 years, by comparing the participants' scores on the Children's Communication Checklist, 2nd edition (CCC-2) (Bishop, 2011), with a group of typically developing children of matching age and gender. Language impairments were common in the NS group. The results show that children and adolescents with NS do not have one coherent pragmatic profile. However, 76.5% of the participants displayed communication impairments, and pragmatic skills were significantly lower than in the control group.

Language, learning, and memory in children with and without single-suture craniosynostosis.

OBJECTIVE The language and memory functions of children with and without single-suture craniosynostosis (SSC) were compared at school age (mean 7.45 years, standard deviation [SD] 0.54 years). The children in this cohort were originally recruited in infancy and prior to cranial surgery for those with SSC. METHODS Individual evaluations of 179 school-aged children with SSC and 183 controls were conducted (70% of the original cohort) using standardized measures of language, learning, and memory. Parents participated in an interview about specialized education interventions and school progress. Parents and teachers completed questionnaires about language development. RESULTS Children with SSC (cases) obtained lower scores than controls on all measures. The adjusted differences in language, learning, and memory scores were modest, with SD ranging from 0.0 to -0.4 (p values ranged from 0.001 to 0.99). Censored normal regression was used to account for intervention services received prior to the school-age evaluation; this increased case-control differences (SD range 0.1 to -0.5, p value range 0.001 to 0.50). Mean scores for cases in each SSC diagnostic group were lower than those for controls, with the greatest differences observed among children with unilateral coronal craniosynostosis. CONCLUSIONS Children with SSC continue to show poorer performance than controls on language, learning, and memory tasks at early elementary school age, even when controlling for known confounders, although mean differences are small. Multidisciplinary care, including direct psychological assessment, for children with SSC should extend through school age with a specific focus on language and conceptual learning, as these are areas of potential risk. Future research is needed to investigate language, memory, and learning for this population during the middle to high school years.

Functional characterization of new mutations in Wilson disease gene (ATP7B) using the yeast model.

The Wilson disease gene, a copper transporting ATPase (Atp7b), is responsible for the sequestration of Cu into secretory vesicles, and this function is exhibited by the orthologous Ccc2p in the yeast. In this study, we aimed to characterize clinically relevant new mutations of human ATP7B (p.T788I, p.V1036I and p.R1038G-fsX83) in yeast lacking the CCC2 gene. Expression of human wild type ATP7B gene in ccc2Δ mutant yeast restored the growth deficiency and copper transport activity; however, expression of the mutant forms did not restore the copper transport functions and only partially supported the cell growth. Our data support that p.T788I, p.V1036I and p.R1038G-fsX83 mutations cause functional deficiency in ATP7B functions and suggest that these residues are important for normal ATP7B function.

Stable associations between behavioral problems and language impairments across childhood - the importance of pragmatic language problems.

This study investigated language function associated with behavior problems, focusing on pragmatics. Scores on the Children's Communication Checklist Second Edition (CCC-2) in a group of 40 adolescents (12-15 years) identified with externalizing behavior problems (BP) in childhood was compared to the CCC-2 scores in a typically developing comparison group (n=37). Behavioral, emotional and language problems were assessed by the Strengths and Difficulties Questionnaire (SDQ) and 4 language items, when the children in the BP group were 7-9 years (T1). They were then assessed with the SDQ and the CCC-2 when they were 12-15 years (T2). The BP group obtained poorer scores on 9/10 subscales on the CCC-2, and 70% showed language impairments in the clinical range. Language, emotional and peer problems at T1 were strongly correlated with pragmatic language impairments in adolescence. The findings indicate that assessment of language, especially pragmatics, is vital for follow-up and treatment of behavioral problems in children and adolescents.