ASD, ADHD, mental health conditions and psychopharmacology in neurogenetic syndromes: parent survey.

BACKGROUND: There are a number of neurogenetic syndromes with well described behavioural phenotypes including fragile X syndrome, Prader-Willi syndrome, Williams syndrome and velo-cardio-facial syndrome (VCFS). Autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD) and psychiatric conditions are often associated with the syndromes. METHOD: Parents (n = 381) of school-aged children with one of the four syndromes in the UK and Ireland were asked whether their child had been professionally diagnosed with ASD, ADHD or a mental health condition. Parents were also asked whether their child had been prescribed medication for behavioural or psychiatric reasons. RESULTS: The highest level of reported diagnoses of ASD and ADHD was in fragile X syndrome. In all syndrome groups, lower rates of diagnosis were reported in comparison to previously published research. Prescribing of medication for behavioural/psychiatric reasons was highest in fragile X syndrome although the highest usage of melatonin was in Williams syndrome. CONCLUSION: Reasons for a lower recognition of ASD, ADHD and mental health conditions in clinical practice compared with research studies may include 'diagnostic overshadowing' due to presence of intellectual disability and a genetic syndrome. However, there may also be a lack of belief in the utility of such diagnoses in neurogenetic syndromes among relevant professionals and/or lack of access to professionals with sufficient expertise in the recognition of such diagnoses in those with neurogenetic syndromes. The low rates of prescribing of medication for behavioural/psychiatric reasons may reflect the low level of clinical diagnoses or lack of belief in the utility of psychopharmacology in this population.

Predicting reading comprehension academic achievement in late adolescents with velo-cardio-facial (22q11.2 deletion) syndrome (VCFS): a longitudinal study.

BACKGROUND: The primary objective of the current study was to examine the childhood predictors of adolescent reading comprehension in velo-cardio-facial syndrome (VCFS). Although much research has focused on mathematics skills among individuals with VCFS, no studies have examined predictors of reading comprehension. METHODS: 69 late adolescents with VCFS, 23 siblings of youth with VCFS and 30 community controls participated in a longitudinal research project and had repeat neuropsychological test batteries and psychiatric evaluations every 3 years. The Wechsler Individual Achievement Test-2nd edition (WIAT-II) Reading Comprehension subtest served as our primary outcome variable. RESULTS: Consistent with previous research, children and adolescents with VCFS had mean reading comprehension scores on the WIAT-II, that were approximately two standard deviations below the mean and word reading scores approximately one standard deviation below the mean. A more novel finding is that relative to both control groups, individuals with VCFS demonstrated a longitudinal decline in reading comprehension abilities yet a slight increase in word reading abilities. In the combined control sample, WISC-III FSIQ, WIAT-II Word Reading, WISC-III Vocabulary and CVLT-C List A Trial 1 accounted for 75% of the variance in Time 3 WIAT-II Reading Comprehension scores. In the VCFS sample, WISC-III FSIQ, BASC-Teacher Aggression, CVLT-C Intrusions, Tower of London, Visual Span Backwards, WCST Non-perseverative Errors, WIAT-II Word Reading and WISC-III Freedom from Distractibility index accounted for 85% of the variance in Time 3 WIAT-II Reading Comprehension scores. A principal component analysis with promax rotation computed on the statistically significant Time 1 predictor variables in the VCFS sample resulted in three factors: Word reading decoding/Interference control, Self-Control/Self-Monitoring and Working Memory. CONCLUSIONS: Childhood predictors of late adolescent reading comprehension in VCFS differ in some meaningful ways from predictors in the non-VCFS population. These results offer some guidance for how best to consider intervention efforts to improve reading comprehension in the VCFS population.

Abnormalities in brain white matter in adolescents with 22q11.2 deletion syndrome and psychotic symptoms.

BACKGROUND: 22q11.2 Deletion Syndrome (22q11DS) is considered to be a promising cohort to explore biomarkers of schizophrenia risk based on a 30 % probability of developing schizophrenia in adulthood. In this study, we investigated abnormalities in the microstructure of white matter in adolescents with 22q11DS and their specificity to prodromal symptoms of schizophrenia. METHODS: Diffusion Magnetic Resonance Imaging (dMRI) data were acquired from 50 subjects with 22q11DS (9 with and 41 without prodromal psychotic symptoms), and 47 matched healthy controls (mean age 18 +/-2 years). DMRI measures, including fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD) were calculated and compared between groups using the Tract Based Spatial Statistics (TBSS) method. Additionally, correlations between dMRI measures and scores on positive symptoms were performed. RESULTS: Reductions in MD, AD and RD (but not FA) were found in the corpus callosum (CC), left and right superior longitudinal fasciculus (SLF), and left and right corona radiata in the entire 22q11DS group. In addition, the 22q11DS subgroup with prodromal symptoms showed reductions in AD and MD, but no changes in RD when compared to the non-prodromal subgroup, in CC, right SLF, right corona radiata and right internal capsule. Finally, AD values in these tracts correlated with the scores on the psychosis subscale. CONCLUSION: Microstructural abnormalities in brain white matter are present in adolescent subjects with prodromal psychotic symptoms.

An fMRI study of facial emotion processing in children and adolescents with 22q11.2 deletion syndrome.

BACKGROUND: 22q11.2 deletion syndrome (22q11DS, velo-cardio-facial syndrome [VCFS]) is a genetic disorder associated with interstitial deletions of chromosome 22q11.2. In addition to high rates of neuropsychiatric disorders, children with 22q11DS have impairments of face processing, as well as IQ-independent deficits in visuoperceptual function and social and abstract reasoning. These face-processing deficits may contribute to the social impairments of 22q11DS. However, their neurobiological basis is poorly understood. METHODS: We used event-related functional magnetic resonance imaging (fMRI) to examine neural responses when children with 22q11DS (aged 9-17 years) and healthy controls (aged 8-17 years) incidentally processed neutral expressions and mild (50%) and intense (100%) expressions of fear and disgust. We included 28 right-handed children and adolescents: 14 with 22q11DS and 14 healthy (including nine siblings) controls. RESULTS: Within groups, contrasts showed that individuals significantly activated 'face responsive' areas when viewing neutral faces, including fusiform-extrastriate cortices. Further, within both groups, there was a significant positive linear trend in activation of fusiform-extrastriate cortices and cerebellum to increasing intensities of fear. There were, however, also between-group differences. Children with 22q11DS generally showed reduced activity as compared to controls in brain regions involved in social cognition and emotion processing across emotion types and intensities, including fusiform-extrastriate cortices, anterior cingulate cortex (Brodmann area (BA) 24/32), and superomedial prefrontal cortices (BA 6). Also, an exploratory correlation analysis showed that within 22q11DS children reduced activation was associated with behavioural impairment-social difficulties (measured using the Total Difficulties Score from the Strengths and Difficulties Questionnaire [SDQ]) were significantly negatively correlated with brain activity during fear and disgust processing (respectively) in the left precentral gyrus (BA 4) and in the left fusiform gyrus (FG, BA 19), right lingual gyrus (BA 18), and bilateral cerebellum. CONCLUSIONS: Regions involved in face processing, including fusiform-extrastriate cortices, anterior cingulate gyri, and superomedial prefrontal cortices (BA 6), are activated by facial expressions of fearful, disgusted, and neutral expressions in children with 22q11DS but generally to a lesser degree than in controls. Hypoactivation in these regions may partly explain the social impairments of children with 22q11DS.

How might stress contribute to increased risk for schizophrenia in children with chromosome 22q11.2 deletion syndrome?

The most common human microdeletion occurs at chromosome 22q11.2. The associated syndrome (22q11.2DS) has a complex and variable phenotype with a high risk of schizophrenia. While the role of stress in the etiopathology of schizophrenia has been under investigation for over 30 years (Walker et al. 2008), the stress-diathesis model has yet to be investigated in children with 22q11.2DS. Children with 22q11.2DS face serious medical, behavioral, and socioemotional challenges from infancy into adulthood. Chronic stress elevates glucocorticoids, decreases immunocompetence, negatively impacts brain development and function, and is associated with psychiatric illness in adulthood. Drawing knowledge from the extant and well-developed anxiety and stress literature will provide invaluable insight into the complex etiopathology of schizophrenia in people with 22q11.2DS while suggesting possible early interventions. Childhood anxiety is treatable and stress coping skills can be developed thereby improving quality of life in the short-term and potentially mitigating the risk of developing psychosis.