Altered Brain Structure in Infants with Turner Syndrome.

Turner syndrome (TS) is a genetic disorder affecting approximately 1:2000 live-born females. It results from partial or complete X monosomy and is associated with a range of clinical issues including a unique cognitive profile and increased risk for certain behavioral problems. Structural neuroimaging studies in adolescents, adults, and older children with TS have revealed altered neuroanatomy but are unable to identify when in development differences arise. In addition, older children and adults have often been exposed to years of growth hormone and/or exogenous estrogen therapy with potential implications for neurodevelopment. The study presented here is the first to test whether brain structure is altered in infants with TS. Twenty-six infants with TS received high-resolution structural MRI scans of the brain at 1 year of age and were compared to 47 typically developing female and 39 typically developing male infants. Results indicate that the typical neuroanatomical profile seen in older individuals with TS, characterized by decreased gray matter volumes in premotor, somatosensory, and parietal-occipital cortex, is already present at 1 year of age, suggesting a stable phenotype with origins in the prenatal or early postnatal period.

Dose-dependent expression of claudin-5 is a modifying factor in schizophrenia.

Schizophrenia is a neurodevelopmental disorder that affects up to 1% of the general population. Various genes show associations with schizophrenia and a very weak nominal association with the tight junction protein, claudin-5, has previously been identified. Claudin-5 is expressed in endothelial cells forming part of the blood-brain barrier (BBB). Furthermore, schizophrenia occurs in 30% of individuals with 22q11 deletion syndrome (22q11DS), a population who are haploinsufficient for the claudin-5 gene. Here, we show that a variant in the claudin-5 gene is weakly associated with schizophrenia in 22q11DS, leading to 75% less claudin-5 being expressed in endothelial cells. We also show that targeted adeno-associated virus-mediated suppression of claudin-5 in the mouse brain results in localized BBB disruption and behavioural changes. Using an inducible 'knockdown' mouse model, we further link claudin-5 suppression with psychosis through a distinct behavioural phenotype showing impairments in learning and memory, anxiety-like behaviour and sensorimotor gating. In addition, these animals develop seizures and die after 3-4 weeks of claudin-5 suppression, reinforcing the crucial role of claudin-5 in normal neurological function. Finally, we show that anti-psychotic medications dose-dependently increase claudin-5 expression in vitro and in vivo while aberrant, discontinuous expression of claudin-5 in the brains of schizophrenic patients post mortem was observed compared to age-matched controls. Together, these data suggest that BBB disruption may be a modifying factor in the development of schizophrenia and that drugs directly targeting the BBB may offer new therapeutic opportunities for treating this disorder.

A tale worth telling: the impact of the diagnosis experience on disclosure of genetic disorders.

BACKGROUND: Research suggests children with genetic disorders exhibit greater coping skills when they are aware of their condition and its heritability. While the experiences parents have at diagnosis may influence their decision to disclose the diagnosis to their children, there is little research into this communication. The aim of the current study was to examine the relationship between the diagnosis experience and the disclosure experience for parents of children with developmental disorders of a known genetic aetiology: parents of children with 22q11.2 deletion syndrome (22q11DS) were compared with a group of parents with children affected with other genetic diagnoses, with a similar age of diagnosis (e.g. fragile X syndrome) and a group where diagnosis generally occurs early (i.e. Down syndrome). METHOD: The sample comprised 559 parents and caregivers of children with genetic developmental disorders, and an online survey was utilised. Items from the questionnaire were combined to create variables for diagnosis experience, parental disclosure experience, child's disclosure experience, and parental coping and self-efficacy. RESULTS: Across all groups parents reported that the diagnosis experience was negative and often accompanied by a lack of support and appropriate information. Sixty-eight per cent of those in the 22q11DS and 58.3% in the Similar Conditions groups had disclosed the diagnosis to their child, whereas only 32.7% of the Down syndrome group had. Eighty-six per cent of the Down syndrome group felt they had sufficient information to talk to their child compared with 44.1% of the Similar Conditions group and 32.6% of the 22q11DS group. Parents reported disclosing the diagnosis to their child because they did not want to create secrets; and that they considered the child's age when disclosing. In the 22q11DS and Similar Conditions groups, a poor diagnosis experience was significantly associated with negative parental disclosure experiences. In the Similar Conditions group, a poor diagnosis experience was also significantly associated with a more negative child disclosure experience. CONCLUSIONS: As expected this study highlights how difficult most parents find the diagnosis experience. Importantly, the data indicate that the personal experiences the parents have can have a long-term impact on how well they cope with telling their child about the diagnosis. It is important for clinicians to consider the long-term ramifications of the diagnosis experience and give the parents opportunities; through, for instance, psychoeducation to prepare for telling their child about the diagnosis. Further research is warranted to explore what type of information would be useful for parents to receive.

Social cognitive training in adolescents with chromosome 22q11.2 deletion syndrome: feasibility and preliminary effects of the intervention.

BACKGROUND: Children with chromosome 22q11.2 deletion syndrome (22q11DS) often have deficits in social cognition and social skills that contribute to poor adaptive functioning. These deficits may be of relevance to the later occurrence of serious psychiatric illnesses such as schizophrenia. Yet, there are no evidence-based interventions to improve social cognitive functioning in children with 22q11DS. METHODS: Using a customised social cognitive curriculum, we conducted a pilot small-group-based social cognitive training (SCT) programme in 13 adolescents with 22q11DS, relative to a control group of nine age- and gender-matched adolescents with 22q11DS. RESULTS: We found the SCT programme to be feasible, with high rates of compliance and satisfaction on the part of the participants and their families. Our preliminary analyses indicated that the intervention group showed significant improvements in an overall social cognitive composite index. CONCLUSIONS: SCT in a small-group format for adolescents with 22q11DS is feasible and results in gains in social cognition. A larger randomised controlled trial would permit assessment of efficacy of this promising novel intervention.

Self-Management and Transition Readiness Assessment: Development, Reliability, and Factor Structure of the STARx Questionnaire.

INTRODUCTION: The Self-Management and Transition to Adulthood with Rx=Treatment (STARx) Questionnaire was developed to collect information on self-management and health care transition (HCT) skills, via self-report, in a broad population of adolescents and young adults (AYAs) with chronic conditions. METHODS: Over several iterations, the STARx questionnaire was created with AYA, family, and health provider input. The development and pilot testing of the STARx Questionnaire took place with the assistance of 1219 AYAs with different chronic health conditions, in multiple institutions and settings over three phases: item development, pilot testing, reliability and factor structuring. RESULTS: The three development phases resulted in a final version of the STARx Questionnaire. The exploratory factor analysis of the third version of the 18-item STARx identified six factors that accounted for about 65% of the variance: Medication management, Provider communication, Engagement during appointments, Disease knowledge, Adult health responsibilities, and Resource utilization. Reliability estimates revealed good internal consistency and temporal stability, with the alpha coefficient for the overall scale being .80. The STARx was developmentally sensitive, with older patients scoring significantly higher on nearly every factor than younger patients. CONCLUSION: The STARx Questionnaire is a reliable, self-report tool with adequate internal consistency, temporal stability, and a strong, multidimensional factor structure. It provides another assessment strategy to measure self-management and transition skills in AYAs with chronic conditions.

Association of the family environment with behavioural and cognitive outcomes in children with chromosome 22q11.2 deletion syndrome.

BACKGROUND: Children with 22q11.2 deletion syndrome (22q11DS) are at risk for social-behavioural and neurocognitive sequelae throughout development. The current study examined the impact of family environmental characteristics on social-behavioural and cognitive outcomes in this paediatric population. METHOD: Guardians of children with 22q11DS were recruited through two medical genetics clinics. Consenting guardians were asked to complete several questionnaires regarding their child's social, emotional and behavioural functioning, as well as family social environment and parenting styles. Children with 22q11DS were asked to undergo a cognitive assessment, including IQ and achievement testing, and measures of attention, executive function and memory. RESULTS: Modest associations were found between aspects of the family social environment and parenting styles with social-behavioural and cognitive/academic outcomes. Regression models indicated that physical punishment, socioeconomic status, parental control and family organisation significantly predicted social-behavioural and cognitive outcomes in children with 22q11DS. CONCLUSION: Characteristics of the family social environment and parenting approaches appear to be associated with functional outcomes of children with 22q11DS. Understanding the impact of environmental variables on developmental outcomes can be useful in determining more effective targets for intervention. This will be important in order to improve the quality of life of individuals affected by 22q11DS.

Social-behavioural functioning in paediatric chronic kidney disease.

Background The social-behavioural functioning of children and adolescents with chronic kidney disease (CKD) is not well studied and not fully understood, with available studies reflecting a mixed set of findings. The primary purpose of this paper is to compare the social-behavioural functioning of children with CKD with typical controls using multiple raters. A secondary analysis also examines the impact of disease severity on social-behavioural functioning. Methods Parental ratings and self-reports on the Behavior Assessment System for Children were obtained from a patient sample of 26 children and adolescents with CKD. This sample was comprised of those with end-stage renal disease (end-stage renal disease; n= 13) and those with chronic renal insufficiency (n= 13). For comparison, a typically developing control group (n= 33) also was ascertained. Results While behaviour ratings by parents and children fell within the average range, parent ratings showed an increased number of internalizing symptoms when compared with the CKD Group. Exploratory analyses revealed parental ratings showing more specific concerns on the Behavior Assessment System for Children individual clinical scales of Anxiety, Depression and Somatization. No differences were observed between the groups on the children's self-ratings, or in terms of numbers of children falling above the 90th percentile for both parent and child ratings. Secondary analyses did not produce any group differences between the chronic renal insufficiency and end-stage renal disease severity groupings. Conclusions These findings failed to show the presence of social-behavioural difficulties in children with CKD, although there may be specific concerns for the presence of internalizing symptoms as per parent ratings. These findings suggest the need for follow-up of the subtle affective symptoms that might be present in children with CKD as recognizing these subthreshold social-behavioural symptoms may be a critical part of their overall clinical care.

The transition from childhood to adulthood with ESRD: educational and social challenges.

OBJECTIVE: The purpose of this review was to examine potential barriers to adulthood transition for children and adolescents with chronic kidney disease (CKD). RESULTS: The literature was reviewed in regards to medical, neuropsychological, psychiatric and psychosocial barriers that may impede successful transition. Adults with CKD since childhood have been found to be at increased risk for neurocognitive impairment, low educational attainment, unemployment, psychiatric disability, and psychosocial adjustment. CONCLUSION: Based on the available literature, intervention strategies are discussed in addition to directions for future research.

Family Experiences with the Diagnosis of Autism Spectrum Disorder: System Barriers and Facilitators of Efficient Diagnosis.

This paper examines family experiences with the efficiency of ASD diagnosis. Children were age 8 or younger with ASD (n = 450). Outcomes were delay from first parent concern to diagnosis, shifting diagnoses, and being told child did not have ASD. Predictors were screening, travel distance, and problems finding providers. Logit models were used to examine associations. Screening was associated with reduced delay in diagnosis; problems finding providers were associated with greater delay. Screening, travel distance, and delay in diagnosis were associated with shifting diagnoses and being told child did not have ASD. Physician and parent training in communication and addressing mental health professional shortages and maldistribution may improve the diagnosis experiences of families of children with ASD.

No evidence for the presence of genetic variants predisposing to psychotic disorders on the non-deleted 22q11.2 allele of VCFS patients.

The velo-cardio-facial syndrome (VCFS) is caused by hemizygous deletions on chromosome 22q11.2. The VCFS phenotype is complex and characterized by frequent occurrence of neuropsychiatric symptoms with up to 25-30% of cases suffering from psychotic disorders compared with only ~1% in the general population (odds ratio≈20-25). This makes the 22q11.2 deletion one of the most prominent risk factors for schizophrenia. However, its penetrance for neuropsychiatric phenotypes is incomplete suggesting that additional risk factors are required for disease development. These additional risk factors could lie anywhere on the genome, but by reducing the normal diploid to a haploid state, the 22q11.2 deletion could result in the unmasking of otherwise recessive alleles or functional variants on the non-deleted 22q11.2 allele. To test this hypothesis, we captured and sequenced the whole 22q11.2 non-deleted region in 88 VCFS patients with (n=40) and without (n=48) psychotic disorders to identify genetic variation that could increase the risk for schizophrenia. Single nucleotide variants (SNVs), small insertions/deletions (indels) and copy number variants were called and their distributions were compared between the two diagnostic groups using variant-, gene- and region-based association tests. None of these tests resulted in statistical evidence for the existence of a genetic variation in the non-deleted allele that would increase schizophrenia risk in VCFS patients. Power analysis showed that our study was able to achieve >80% statistical power to detect association of a risk variant with an odd ratio of ⩾22. However, it is certainly under-powered to detect risk variant of smaller effect sizes. Our study did not provide evidence that genetic variants of very large effect size located on the non-deleted 22q1.2 allele in VCFS patients increase the risk for developing psychotic disorders. Variants with smaller effects may be located in the remaining 22q11.2 allele and elsewhere in the genome. Therefore, whole exome or even genome sequencing for larger sample size would appear to be the next logical steps in the search for the genetic modifiers of the 22q11.2-deletion neuropsychiatric phenotype.

Otitis media, the caregiving environment, and language and cognitive outcomes at 2 years.

OBJECTIVE: To examine the relationship between otitis media with effusion (OME) and associated hearing loss between 6 and 24 months of age and children's language and cognitive development at 2 years of age. STUDY DESIGN: A prospective cohort design in which 86 African-American infants who attended group child-care centers were recruited between 6 and 12 months of age. Between 6 and 24 months, assessments included serial ear examinations using otoscopy and tympanometry, serial hearing tests, two ratings of the childrearing environment at home and in child care, and language and cognitive outcomes at 2 years. RESULTS: Children experienced either unilateral or bilateral OME an average of 63% and reduced hearing sensitivity an average of 44% of the time between 6 and 24 months of age. Although proportion of time with OME or with hearing loss was modestly correlated with measures of language and cognitive skills, these relationships were no longer significant when the ratings of the home and child-care environments were also considered. Children with more OME or hearing loss tended to live in less responsive caregiving environments, and these environments were linked to lower performance in expressive language and vocabulary acquisition at 2 years. CONCLUSIONS: Both OME and hearing loss were more strongly related to the quality of home and child-care environments than to children's language and cognitive development. Study results might be explained either by suggesting that children in less responsive caregiving environments experience conditions that make them more likely to experience OME and/or by suggesting that it may be more difficult for caregivers to be responsive and stimulating with children with more OME.

Determinants of academic achievement in children with psychiatric disorders.

Academic achievement within a child psychiatric sample was examined as a function of six variables: IQ, socioeconomic status, age, sex, neuropsychological status, and the severity of behavioral disturbance. As expected, the results revealed a different pattern of predictors than what is generally the case of normal school-aged children. The results underscored the importance of neuropsychological factors, more than IQ and demographic variables, in understanding the academic deficits often seen in children with significant mental and emotional disturbance.

Double-blind, placebo-controlled study of amantadine hydrochloride in the treatment of children with autistic disorder.

OBJECTIVE: To test the hypothesis that amantadine hydrochloride is a safe and effective treatment for behavioral disturbances--for example, hyperactivity and irritability--in children with autism. METHOD: Thirty-nine subjects (intent to treat; 5-19 years old; IQ > 35) had autism diagnosed according to DSM-IV and ICD-10 criteria using the Autism Diagnostic Interview-Revised and the Autism Diagnostic Observation Schedule-Generic. The Aberrant Behavior Checklist-Community Version (ABC-CV) and Clinical Global Impressions (CGI) scale were used as outcome variables. After a 1-week, single-blind placebo run-in, patients received a single daily dose of amantadine (2.5 mg/kg per day) or placebo for the next week, and then bid dosing (5.0 mg/kg per day) for the subsequent 3 weeks. RESULTS: When assessed on the basis of parent-rated ABC-CV ratings of irritability and hyperactivity, the mean placebo response rate was 37% versus amantadine at 47% (not significant). However, in the amantadine-treated group there were statistically significant improvements in absolute changes in clinician-rated ABC-CVs for hyperactivity (amantadine -6.4 versus placebo -2.1; p = .046) and inappropriate speech (-1.9 versus 0.4; p = .008). CGI scale ratings were higher in the amantadine group: 53% improved versus 25% (p = .076). Amantadine was well tolerated. CONCLUSIONS: Parents did not report statistically significant behavioral change with amantadine. However, clinician-rated improvements in behavioral ratings following treatment with amantadine suggest that further studies with this or other drugs acting on the glutamatergic system are warranted. The design of these and similar drug trials in children with autistic disorder must take into account the possibility of a large placebo response.

Proton MR spectroscopy in children with bipolar affective disorder: preliminary observations.

BACKGROUND AND PURPOSE: Bipolar affective disorder (BPAD) can have its onset during childhood, but the diagnosis may be difficult to establish on the basis of clinical findings alone. Our purpose was to determine whether proton MR spectroscopy can be used to identify abnormalities in the brain of children with BPAD. METHODS: Ten children, ages 6 to 12 years, underwent clinical testing to establish the diagnosis of BPAD. After a drug washout period, all patients underwent MR spectroscopy in which a TE of 135 was used along with a single-voxel placement in both frontal and temporal lobes during a single session. Peaks from N-acetylaspartate (NAA), choline (Cho), glutamate/ glutamine (Glu/Gln), and lipids were normalized with respect to the creatine (Cr) peak to obtain ratios of values of peak areas. These data were compared with those obtained in 10 non-age-matched control subjects. To corroborate our data, five children with BPAD also underwent 2D MR spectroscopic studies of the frontal lobes with parameters similar to those used in the single-volume studies. RESULTS: All children with BPAD had elevated levels of Glu/Gln in both frontal lobes and basal ganglia relative to the control group. Children with BPAD had elevated lipid levels in the frontal lobes but not in the temporal lobes. Levels of NAA and Cho were similar for all locations in both groups. Two-dimensional MR spectroscopic studies in five children with BPAD confirmed the presence of elevated lipids in the frontal lobes. CONCLUSION: Our preliminary observations suggest that MR spectroscopy may show abnormalities in children with BPAD not found in unaffected control subjects. It remains to be established whether these abnormalities are a signature of the disease and can be used as a screening test.

Definitional issues and neurobiological foundations of selected severe neurodevelopmental disorders.

This article reviews current definitional issues, selected neuropsychological findings, and presumed neurobiological underpinnings of two of the more commonly identified severe neurodevelopmental disorders: mental retardation and autistic disorder. Although these disorders represent two of the more common severe neurodevelopmental disorders encountered by child neuropsychologists practicing in clinical and research settings, they have not received the amount of attention from the field of neuropsychology as other kinds of neurodevelopmental disorders. Although there are few definitional controversies surrounding these disorders, findings accrued to date reveal solid evidence for neurological processes underlying each of these disorders. In addition, each of these diagnoses likely represents a heterogeneous group of disorders, suggesting that a syndrome analysis approach would prove beneficial for increasing our understanding of each disorder. Conclusions are drawn for the clinician and researcher, particularly with respect to using a neuropsychological perspective and assessment strategies with children with more severe disorders.

Behavioral manifestations of neuropsychological impairment in children with psychiatric disorders.

The behavioral manifestations of neuropsychological impairment were examined in a sample of hospitalized boys with psychiatric disorders. The presence of neuropsychological deficits was found to be associated with more extensive behavior problems regardless of factors such as IQ, socioeconomic status, and whether there was a documented history of brain injury. However, the relationship applied specifically to younger as opposed to older subjects, and mainly involved internalizing rather than externalizing behavior problems. The results are taken to suggest that the behavioral manifestations of neuropsychological impairment may change with development.

Cross-validation of a psychometric system for screening neuropsychological abnormality in older children.

The Discriminant Equation (DE) represents a recently developed system for screening neuropsychological abnormality in older children. The DE was subjected to cross-validation on a sample of 82 child and adolescent psychiatric patients referred for a comprehensive neuropsychological assessment. An overall hit rate of 79.3% correct classification was found which supported the validity of the DE in predicting neuropsychological impairment. The findings are discussed in relation to population characteristics and the nature of the criterion to be predicted as they may affect the application of neuropsychological screening procedures.

Prediction of group membership in developmental dyslexia, attention deficit hyperactivity disorder, and normal controls using brain morphometric analysis of magnetic resonance imaging.

This study explored the utility of using selected brain morphometric indices for predicting group membership for children with developmental dyslexia (n = 10), attention deficit hyperactivity disorder: combined type (n = 10), and a control group (n = 10). Subjects ranged in age from 6.1 to 16 years (M = 10.5 years, SD = 2.8). None of the subjects were diagnosed with mental retardation, nor did any of the subjects have a history of seizure disorder, head trauma, or other neurodevelopmental disorders. WISC-R Full Scale IQ ranged from 87 to 149 (M = 114.4, SD = 13.3) with no significant differences noted between the clinical groups. Six brain regions, as defined by MRI scans, were selected a priori for inclusion in a discriminant function analysis. Reliability of the morphometric measures ranged from 0.94 to 0.97. One significant discriminant function was generated which accounted for about 61.4% of the variance between groups. The predictive discriminant analysis using the six morphometric MRI measurements classified subjects with an overall 60% accuracy with the best accuracy found for the developmental dyslexia and control groups. A predictive discriminant analysis incorporating these six morphometric measures as well as chronological age and FSIQ increased the overall classification accuracy to 87% with the misclassfied subjects assigned to one of the clinical groups. The findings support the presumed neurological basis for many neurodevelopmental disorders. They also underline the importance of including brain morphometric measures in predictive models.

Frontal lobe functioning in conduct disordered juveniles: preliminary findings.

This investigation assessed the hypothesis that conduct disordered juveniles may suffer from a maturational lag in the development of behaviors believed associated with the frontal cortex. Twenty conduct disorder (CD) juveniles and 20 normal comparison subjects were compared on nine Lurian tasks that measure behavior attributed to frontal lobe functioning. A three-way ANOVA, with gender, race, and group as factors of interest, revealed significant differences on the verbal conflict task, verbal retroactive inhibition task, and on a measure of receptive vocabulary. Using receptive vocabulary as a covariate, an ANCOVA showed no significant differences between the groups on any of the tasks. These findings appear to support the potential impact that language dysfunction can have in the development of disinhibitory behavior. Other interpretations of the findings are presented.

Proton MR spectroscopy in psychiatric and neurodevelopmental childhood disorders: early experience.

Variations in brain morphology are increasingly being found in patients with psychiatric disorders. There is early evidence that some metabolic abnormalities may also be present in these patients. In many patients with psychiatric disorders, the diagnosis is not straight forward and may be confounded by co-morbid processes. Establishing the correct diagnosis is important as it leads to institution of appropriate therapies. Descriptions of the authors early experience using proton MR spectroscopy in the evaluation of children with bipolar affective disorder, attention deficit hyperactivity disorder, neurodevelopmental abnormalities in patients with neurofibromatosis type 1, and the effects of certain types of treatment used for these disorders are discussed.