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Kate Baker of the Veterinary Cytology Schoolhouse and Pocket Pathologist in Tennessee, USA presents some challenging and interesting feline cytology cases.

BackgroundDDX3X variants are a common cause of intellectual disability (ID) in females. Previous studies have reported high rates of autism spectrum disorder and emotional-behavioural difficulties within this group. However, no study has compared social and emotional characteristics in individuals with DDX3X variants to individuals with other monogenic causes of ID.MethodsTwenty-three females with pathogenic or likely pathogenic DDX3X variants were recruited via UK regional genetics centres, genetic research cohorts, and family support groups. Twenty-three females with ID and variants in other genes were recruited via the same routes. Phenotypic data were collected through semi-structured interviews and standardised questionnaires.ResultsIn line with previous research, we found a wide range of adaptive, social and emotional function within the DDX3X group. Autism characteristics assessed via the Social Responsiveness Scale (SRS) did not differ between DDX3X and comparison groups, while levels of anxiety and self-injurious behaviour (SIB) scores assessed via the Developmental Behaviour Checklist (DBC) were significantly higher in the DDX3X group. Autistic characteristics, anxiety and SIB scores were positively correlated within the DDX3X group. Individuals with DDX3X missense variants had poorer adaptive abilities than those with protein truncating variants as previously reported, but DDX3X variant type did not significantly predict emotional and behavioural characteristics.ConclusionsWe provide quantitative evidence that overall incidence of autistic characteristics is not higher amongst girls and women with DDX3X variants than expected for ID. However, the DDX3X group demonstrates more SIBs and anxiety symptoms than expected, with close relationships between SIBs and anxiety, and between anxiety and autistic characteristics. Future work is warranted to explore the multilevel mechanisms contributing to social and emotional development in individuals with DDX3X variants, and consider whether these mechanisms are specific to this genetic diagnosis or shared with a subset of people with ID due to other causes.

Given the move toward competency-based veterinary education and the subsequent reevaluation of veterinary curricula, there is a need for specialties to provide guidance to veterinary college administrators and educators on the core knowledge and skills pertaining to their specialty to ensure their inclusion in revised or redesigned curricula. The American Society for Veterinary Clinical Pathology (ASVCP) Education Committee sought to create a list of competencies specific to clinical pathology expected of graduating veterinarians. The stimulus for this project was the American Veterinary Medical Association Council on Education Standards of Accreditation for Colleges of Veterinary Medicine, further driven by the 2018 publication of the Association of American Veterinary Medical Colleges Competency-Based Veterinary Education Working Group framework. The recommendations made in this document are the culmination of the 2016 ASVCP Education Forum for Discussion, multiple remote subcommittee communications, and feedback obtained from ASVCP membership. The final framework includes 8 clinical pathology–focused domains of competence with 20 clinical pathology competencies and 61 clinical pathology illustrative sub-competencies. The clinical pathology–focused domains of competence are: the pre-analytical phase of testing, laboratory medicine and instrumentation, principles of test selection and interpretation, hematology and hemostasis, chemistry, endocrinology, urinalysis, and cytology. These are not intended to replace the nine established AAVMC domains of competence with supportive competencies and illustrative sub-competencies but to guide institutions for how clinical pathology aligns within the competency-based veterinary education (CBVE) framework for the practice-ready veterinary graduate. This clinical pathology competency framework may prove useful and empowering during discussions of curriculum revisions and redesigns.

PurposeSynaptotagmin-1 (SYT1) is a critical mediator of neurotransmitter release in the central nervous system. Previously reported missense SYT1 variants in the C2B domain are associated with severe intellectual disability, movement disorders, behavioural disturbance and EEG abnormalities. Here, we expand the genotypes and phenotypes and identify discriminating features of this disorder.MethodsWe describe 22 individuals with 15 de novo missense SYT1 variants. Evidence for pathogenicity is discussed, including ACMG criteria, known structure-function relationships, and molecular dynamics simulations. Quantitative behavioural data for 14 cases are compared to other monogenic neurodevelopmental disorders.ResultsFour variants lie in the C2A domain with the remainder in the C2B. We classify 6 variants as pathogenic, 4 as likely pathogenic, and 5 as variants of uncertain significance. Prevalent clinical phenotypes include delayed developmental milestones, ophthalmic problems, abnormal EEG, movement disorders and sleep disturbance. Discriminating behavioural characteristics were severity of motor and communication impairment, presence of motor stereotypies and mood instability.ConclusionSYT1 variants associated with neurodevelopmental disorder extend beyond previously reported regions, and the phenotypic spectrum encompasses a broader range of severity than initially reported. This work guides diagnosis and molecular understanding of this rare neurodevelopmental disorder, and highlights a key role for SYT1 function in emotional regulation, motor control and emergent cognitive function.

Summary Rotten food, maggots, bodily waste—all elicit disgust in humans. Disgust promotes survival by encouraging avoidance of disease vectors 1 but is also implicated in prejudice toward minority groups; avoidance of environmentally beneficial foods, such as insect protein; and maladaptive avoidance behavior in neuropsychiatric conditions. 2 , 3 , 4 , 5 Unlike fear, pathological disgust is not improved substantially by exposure therapy clinically, 6 nor in experimental work does behavioral avoidance of disgusting images habituate following prolonged exposure. 7 , 8 Under normal physiological conditions, perception of disgusting stimuli disrupts myoelectrical rhythms in the stomach, 9 , 10 , 11 , 12 , 13 inducing gastric dysrhythmias that correlate with neural signatures of disgust. 11 However, the causal role of gastric rhythm in disgust avoidance is unknown. We manipulated gastric rhythm using domperidone, a peripheral dopamine D2/D3 antagonist and common anti-emetic, at a dose (10 mg) that acts to convert gastric dysrhythmias to normal rhythms. 9 In a preregistered, randomized, double-blind, placebo-controlled crossover design in 25 healthy volunteers (aged 18–25), we measured the effects of domperidone on core disgust avoidance, using eye tracking to measure implicit (oculomotor) avoidance of disgusting images (feces) before and after an “exposure” intervention (monetary reinforcement for looking at disgusting images). 7 , 8 We find that domperidone significantly reduces oculomotor disgust avoidance following incentivized exposure. This suggests that domperidone may weaken the “immunity” of disgust to habituation, putatively by reducing gastric dysrhythmias during incentivized engagement with disgusting stimuli. This indicates a causal role for disgust-related visceral changes in disgust avoidance, supporting the hypothesis that physiological homeostasis contributes to emotional experience.

Dynamic connectivity in functional brain networks is a fundamental aspect of cognitive development, but we have little understanding of the mechanisms driving variability in these networks. Genes are likely to influence the emergence of fast network connectivity via their regulation of neuronal processes, but novel methods to capture these rapid dynamics have rarely been used in genetic populations. The current study redressed this by investigating brain network dynamics in a neurodevelopmental disorder of known genetic origin, by comparing individuals with a ZDHHC9‐associated intellectual disability to individuals with no known impairment. We characterised transient network dynamics using a Hidden Markov Model (HMM) on magnetoencephalography (MEG) data, at rest and during auditory oddball stimulation. The HMM is a data‐driven method that captures rapid patterns of coordinated brain activity recurring over time. Resting‐state network dynamics distinguished the groups, with ZDHHC9 participants showing longer state activation and, crucially, ZDHHC9 gene expression levels predicted the group differences in dynamic connectivity across networks. In contrast, network dynamics during auditory oddball stimulation did not show this association. We demonstrate a link between regional gene expression and brain network dynamics, and present the new application of a powerful method for understanding the neural mechanisms linking genetic variation to cognitive difficulties.

BackgroundA major challenge when investigating intellectual disability (ID) is the selection of assessment tools that are sensitive to cognitive diversity within the ID population. This study introduces a new touchscreen-based method, FarmApp, which aims to measure competence in relatively low-level cognitive processes (selective attention, short-term visuospatial memory, longer-term recognition memory) which contribute to complex aspects of learning and behaviour.MethodsHere we describe the FarmApp design, testing and analysis procedures. We report the feasibility and validity of the method, and demonstrate its utility for measuring change over time, and for comparing groups defined by aetiology.ResultsWe found that FarmApp can be completed by a higher proportion of young people with ID than traditional psychometric tests. FarmApp performance correlates with standardised neuropsychological tests of attention and working memory, and with questionnaire measures of ADHD-relevant behavioural difficulties. Individual performance slopes over a two-week period correlate with general ability and behavioural difficulties, indicating that FarmApp is sensitive to meaningful dynamic variation in cognitive performance. Finally, we compared the FarmApp performance of two groups of young people with ID, defined by the physiological function of ID-associated genetic variants (functional network groups: chromatin-related and synaptic-related), and found that groups differ on attention parameters but not on memory ones.ConclusionFarmApp is a feasible, valid and useful alternative to traditional neuropsychological tests. It can increase access to cognitive assessment for individuals with ID. It adds the opportunity to monitor variation in performance over time and determine capacity to acquire task competence in addition to baseline ability. Our comparison between functional network groups supports the proposal that cognitive processes contributing to ID are differentially influenced by specific genetic aetiologies. In summary, we introduce a new tool for cognitive assessment in ID, with the potential for multiple future applications in clinical practice and research.

Funder: Baily Thomas Charitable Fund; doi: http://dx.doi.org/10.13039/501100001262, Background: The relationships between specific genetic aetiology and phenotype in neurodevelopmental disorders are complex and hotly contested. Genes associated with intellectual disability (ID) can be grouped into networks according to gene function. This study explored whether individuals with ID show differences in autism spectrum characteristics (ASC), depending on the functional network membership of their rare, pathogenic de novo genetic variants. Methods: Children and young people with ID of known genetic origin were allocated to two broad functional network groups: synaptic physiology (n = 29) or chromatin regulation (n = 23). We applied principle components analysis to the Social Responsiveness Scale to map the structure of ASC in this population and identified three components—Inflexibility, Social Understanding and Social Motivation. We then used Akaike information criterion to test the best fitting models for predicting ASC components, including demographic factors (age, gender), non-ASC behavioural factors (global adaptive function, anxiety, hyperactivity, inattention), and gene functional networks. Results: We found that, when other factors are accounted for, the chromatin regulation group showed higher levels of Inflexibility. We also observed contrasting predictors of ASC within each network group. Within the chromatin regulation group, Social Understanding was associated with inattention, and Social Motivation was predicted by hyperactivity. Within the synaptic group, Social Understanding was associated with hyperactivity, and Social Motivation was linked to anxiety. Limitations: Functional network definitions were manually curated based on multiple sources of evidence, but a data-driven approach to classification may be more robust. Sample sizes for rare genetic diagnoses remain small, mitigated by our network-based approach to group comparisons. This is a cross-sectional study across a wide age range, and longitudinal data within focused age groups will be informative of developmental trajectories across network groups. Conclusion: We report that gene functional networks can predict Inflexibility, but not other ASC dimensions. Contrasting behavioural associations within each group suggest network-specific developmental pathways from genomic variation to autism. Simple classification of neurodevelopmental disorder genes as high risk or low risk for autism is unlikely to be valid or useful.

Children and adolescents with developmental problems are at increased risk of experiencing mental health problems. The Strengths and Difficulties Questionnaire (SDQ) is widely used as a screener for detecting mental health difficulties in these populations, but its use thus far has been restricted to groups of children with diagnosed disorders (e.g., ADHD). Transdiagnostic approaches, which focus on symptoms and soften or remove the boundaries between traditional categorical disorders, are increasingly adopted in research and practice. The aim of this study was to assess the potential of the SDQ to detect concurrent mental health problems in a transdiagnostic sample of children. The sample were referred by health and educational professionals for difficulties related to learning (N = 389). Some had one diagnosis, others had multiple, but many had no diagnoses. Parent-rated SDQ scores were significantly positively correlated with parent ratings of mental health difficulties on the Revised Child Anxiety and Depression Scale (RCADS). Ratings on the SDQ Emotion subscale significantly predicted the likelihood of having concurrent clinical anxiety and depression scores. Ratings on the Hyperactivity subscale predicted concurrent anxiety levels. These findings suggest the SDQ could be a valuable screening tool for identifying existing mental health difficulties in children recognized as struggling, as it can be in typically developing children and those with specific diagnoses.

BackgroundGenes associated with Intellectual disability (ID) can be grouped into networks according to gene function. This study asked whether individuals with ID show differences in autism spectrum characteristics (ASC), depending on the functional network membership of their rare, pathogenic de novo genetic variants.MethodsChildren and young people with ID of known genetic origin were allocated to two broad functional network groups: synaptic physiology (n=29) or chromatin regulation (n=23). We applied principle components analysis to the Social Responsiveness Scale to map the structure of ASC in this population, and identified three components – Inflexibility, Social Understanding and Social Motivation. We then used Akaike Information Criterion (AIC) to test the best fitting models for predicting ASC components, including demographic factors (age, gender), non-ASC behavioural factors (global adaptive function, anxiety, hyperactivity, inattention) and gene functional networks.ResultsWe found that, when other factors are accounted for, the chromatin regulation group showed higher levels of Inflexibility. We also observed contrasting predictors of ASC within each network group. Within the chromatin regulation group, Social Understanding was associated with inattention, and Social Motivation was predicted by hyperactivity. Within the synaptic group, Social Understanding was associated with hyperactivity, and Social Motivation was linked to anxiety.ConclusionWe report that gene functional networks can predict Inflexibility, but not other ASC dimensions. Contrasting behavioural associations within each group suggests network-specific developmental pathways from genomic variation to autism. Simple classification of neurodevelopmental disorder genes as high risk or low risk for autism is unlikely to be valid or useful.

BackgroundIntellectual disability has a complex effect on the well-being of affected individuals and their families. Previous research has identified multiple risk and protective factors for parental mental health, including socioeconomic circumstances and child behaviour.AimsThis study explored whether genetic cause of childhood intellectual disability contributes to parental well-being.MethodChildren from across the UK with intellectual disability due to diverse genetic causes were recruited to the IMAGINE-ID study. Primary carers completed the Development and Well-being Assessment, including a measure of parental distress (Everyday Feeling Questionnaire). Genetic diagnoses were broadly categorised into aneuploidy, chromosomal rearrangements, copy number variants (CNVs) and single nucleotide variants.ResultsCompared with the UK general population, IMAGINE-ID parents (n = 888) reported significantly elevated emotional distress (Cohen's d = 0.546). Within-sample variation was related to recent life events and the perceived impact of children's difficulties. Impact was predicted by child age, physical disability, autistic characteristics and other behavioural difficulties. Genetic diagnosis also predicted impact, indirectly influencing parental well-being. Specifically, CNVs were associated with higher impact, not explained by CNV inheritance, neighbourhood deprivation or family structure.ConclusionsThe mental health of parents caring for a child with intellectual disability is influenced by child and family factors, converging on parental appraisal of impact. We found that genetic aetiologies, broadly categorised, also influence impact and thereby family risks. Recognition of these risk factors could improve access to support for parents, reduce their long-term mental health needs and improve well-being of individuals with intellectual disability.

Aims Key governing guidelines recognise that the holistic and complex needs of neuro-oncology patients are best served by a cohesive multidisciplinary team (MDT). Achieving a joint Clinical Nurse Specialist (CNS) and Allied Healthcare Professional (AHP) clinic (including Speech and Language Therapy, Physiotherapy, Dietetics and Occupational Therapy) for neuro-oncology patients has been a longstanding vision at Velindre Cancer Centre (VCC) in Cardiff. A successful funding application to Welsh Government in July 2020 allowed the establishment of a virtual “one stop shop” clinic with CNS and AHPs available along the care trajectory to improve patient and carer quality of life. The project reports on whether this innovative clinic model successfully achieved the desired coordinated, anticipatory and holistic care. Method The project utilised service improvement methodology principles with aims inherent within quarterly timeframes. This included robust data collection on patient attendances and interventions, improving patient education and self-management and wide patient, care and staff engagement by means of questionnaires and semi-structured interviews. The mixed methods approach yielded rich quantitative and qualitative data. Results The data demonstrates an increasing demand for the joint neuro-oncology clinic indicating that additional resources may be required. From triangulation of patient, carer and wider team engagement the key benefits were perceived to be having accessibility to the team in a convenient way, the provision of support and timely information and the overall perception of enhanced holistic care. Conclusion The data demonstrates the huge successes of the joint neuro-oncology clinic so far, including improvements to patient and carer quality of life, wider VCC benefits and cost saves. The persuasive case was presented to Welsh Government, and ongoing endorsement has been achieved for the next financial year.

Background De novo loss of function mutations in STXBP1 are a relatively common cause of epilepsy and intellectual disability (ID). However, little is known about the types and severities of behavioural features associated with this genetic diagnosis. Methods To address this, we collected systematic phenotyping data encompassing neurological, developmental, and behavioural characteristics. Participants were 14 individuals with STXBP1-associated neurodevelopmental disorder, ascertained from clinical genetics and neurology services UK-wide. Data was collected via standardised questionnaires administered to parents at home, supplemented by researcher observations. To isolate discriminating phenotypes, the STXBP1 group was compared to 33 individuals with pathogenic mutations in other ID-associated genes (ID group). To account for the potential impact of global cognitive impairment, a secondary comparison was made to an ability-matched subset of the ID group (low-ability ID group). Results The STXBP1 group demonstrated impairments across all assessed domains. In comparison to the ID group, the STXBP1 group had more severe global adaptive impairments, fine motor difficulties, and hyperactivity. In comparison to the low-ability ID group, severity of receptive language and social impairments discriminated the STXBP1 group. A striking feature of the STXBP1 group, with reference to both comparison groups, was preservation of social motivation. Conclusions De novo mutations in STXBP1 are associated with complex and variable neurodevelopmental impairments. Consistent features, which discriminate this disorder from other monogenic causes of ID, are severe language impairment and difficulties managing social interactions, despite strong social motivation. Future work could explore the physiological mechanisms linking motor, speech, and social development in this disorder. Understanding the developmental emergence of behavioural characteristics can help to focus clinical assessment and management after genetic diagnosis, with the long-term aim of improving outcomes for patients and families. Electronic supplementary material The online version of this article (10.1186/s11689-019-9278-9) contains supplementary material, which is available to authorized users.

Patients termed to have radioiodine-refractory differentiated thyroid cancer (RR-DTC) cannot accumulate sufficient radioiodine for a therapeutic response due to sodium iodide symporter (NIS) dysregulation via diminished expression and/or altered plasma membrane localisation. Previous studies identified novel therapeutics to increase NIS expression, but these are associated with poor tolerance and resistance. Meanwhile, regulation of NIS plasma membrane localisation remains poorly defined and, despite protein-protein interactions being well-described to modulate trafficking events, the NIS interactome is limited. Here, two novel functional NIS interactors – ADP-ribosylation factor 4 (ARF4) and valosin-containing protein (VCP) – were identified by mass spectrometry, which positively and negatively modulated radioiodine uptake respectively. In papillary thyroid cancer (PTC), ARF4 is downregulated, and VCP overexpressed, which may provide a putative explanation for repressed NIS function. Subsequent investigations identified co-localisation between ARF4 and NIS at the Golgi as well as co-incident trafficking at the plasma membrane, which led to the hypothesis that ARF4 promotes NIS trafficking to the plasma membrane. In contrast, VCP decreased NIS protein expression, which was suggestive of a role for VCP in NIS processing and degradation. Pharmacological inhibitors Eeyarestatin-1 and NMS-873 overcame VCP inhibition of NIS function, which may highlight a novel therapeutic strategy for RR-DTC.

Functional connectivity is the statistical association of neuronal activity time courses across distinct brain regions, supporting specific cognitive processes. This coordination of activity is likely to be highly important for complex aspects of cognition, such as the communication of fluctuating task goals from higher‐order control regions to lower‐order, functionally specific regions. Some of these functional connections are identifiable even when relevant cognitive tasks are not being performed (i.e. at rest). We used magnetoencephalographic recordings projected into source space to demonstrate that resting state networks in childhood have electrophysiological underpinnings that are evident in the spontaneous fluctuations of oscillatory brain activity. Using the temporal structure of these oscillatory patterns we were able to identify a number of functional resting state networks analogous to those reported in the adult literature. In a second analysis we fused this dynamic temporal information with the spatial information from a functional magnetic resonance imaging analysis of functional connectivity, to demonstrate that inter‐subject variability in these electrophysiological measures of functional connectivity is correlated with individual differences in cognitive ability: the strength of connectivity between a fronto‐parietal network and lower‐level processing areas in inferior temporal cortex was associated with spatial working memory capacity, as measured outside the scanner with educationally relevant standardized assessments. This study represents the first exploration of the electrophysiological mechanisms underpinning resting state functional connectivity in source space in childhood, and the extent to which the strength of particular connections is associated with cognitive ability.

Baker, Gordon et al. present the first international case series describing the neurodevelopmental disorder associated with Synaptotagmin 1 (SYT1) de novo missense mutations. Key features include movement abnormalities, severe intellectual disability, and hallmark EEG alterations. Expression of patients’ SYT1 mutations in mouse neurons disturbs presynaptic vesicle dynamics in a mutation-specific manner., Synaptotagmin 1 (SYT1) is a critical mediator of fast, synchronous, calcium-dependent neurotransmitter release and also modulates synaptic vesicle endocytosis. This paper describes 11 patients with de novo heterozygous missense mutations in SYT1. All mutations alter highly conserved residues, and cluster in two regions of the SYT1 C2B domain at positions Met303 (M303K), Asp304 (D304G), Asp366 (D366E), Ile368 (I368T) and Asn371 (N371K). Phenotypic features include infantile hypotonia, congenital ophthalmic abnormalities, childhood-onset hyperkinetic movement disorders, motor stereotypies, and developmental delay varying in severity from moderate to profound. Behavioural characteristics include sleep disturbance and episodic agitation. Absence of epileptic seizures and normal orbitofrontal head circumference are important negative features. Structural MRI is unremarkable but EEG disturbance is universal, characterized by intermittent low frequency high amplitude oscillations. The functional impact of these five de novo SYT1 mutations has been assessed by expressing rat SYT1 protein containing the equivalent human variants in wild-type mouse primary hippocampal cultures. All mutant forms of SYT1 were expressed at levels approximately equal to endogenous wild-type protein, and correctly localized to nerve terminals at rest, except for SYT1M303K, which was expressed at a lower level and failed to localize at nerve terminals. Following stimulation, SYT1I368T and SYT1N371K relocalized to nerve terminals at least as efficiently as wild-type SYT1. However, SYT1D304G and SYT1D366E failed to relocalize to nerve terminals following stimulation, indicative of impairments in endocytic retrieval and trafficking of SYT1. In addition, the presence of SYT1 variants at nerve terminals induced a slowing of exocytic rate following sustained action potential stimulation. The extent of disturbance to synaptic vesicle kinetics is mirrored by the severity of the affected individuals’ phenotypes, suggesting that the efficiency of SYT1-mediated neurotransmitter release is critical to cognitive development. In summary, de novo dominant SYT1 missense mutations are associated with a recognizable neurodevelopmental syndrome, and further cases can now be diagnosed based on clinical features, electrophysiological signature and mutation characteristics. Variation in phenotype severity may reflect mutation-specific impact on the diverse physiological functions of SYT1.

Studies of genomic copy number variants (CNVs) have identified genes associated with autism spectrum disorder (ASD) and intellectual disability (ID) such as NRXN1, SHANK2, SHANK3 and PTCHD1. Deletions have been reported in PTCHD1 however there has been little information available regarding the clinical presentation of these individuals. Herein we present 23 individuals with PTCHD1 deletions or truncating mutations with detailed phenotypic descriptions. The results suggest that individuals with disruption of the PTCHD1 coding region may have subtle dysmorphic features including a long face, prominent forehead, puffy eyelids and a thin upper lip. They do not have a consistent pattern of associated congenital anomalies or growth abnormalities. They have mild to moderate global developmental delay, variable degrees of ID, and many have prominent behavioral issues. Over 40% of subjects have ASD or ASD-like behaviors. The only consistent neurological findings in our cohort are orofacial hypotonia and mild motor incoordination. Our findings suggest that hemizygous PTCHD1 loss of function causes an X-linked neurodevelopmental disorder with a strong propensity to autistic behaviors. Detailed neuropsychological studies are required to better define the cognitive and behavioral phenotype.

This study explores sun protection attitudes, preferences, and behaviors among young adult males participating in an open-field activity with extreme ultraviolet radiation exposure. Male drum corps members (n = 137) responded to survey questions regarding their behavior and willingness to engage in sun protection and barriers to sunscreen usage. A subset of members (n = 31) participated in cognitive interviews exploring various sunscreen products and intervention techniques. Participants were knowledgeable about health risks and protection benefits regarding sun exposure. Generally, males had positive attitudes and normative beliefs about using sunscreen. A barrier to sunscreen re-application was lack of adequate time to reapply sunscreen during the open field activity. Males preferred a towelette application method, but were unfamiliar with its efficacy and proper use. Thus, they were more likely to use the more familiar sunscreen spray. To increase sun protection behaviors and lower skin cancer risk for males participating in open-field activities, breaks must be allotted every 2 h and have sufficient time to allow sunscreen application. Future development and research into delivery systems that rapidly and evenly apply sunscreen may help lower exposure in this population.

1AbstractKnowledge of genetic cause in neurodevelopmental disorders can highlight molecular and cellular processes critical for typical development. Furthermore, the relative homogeneity of neurodevelopmental disorders of known genetic origin allows the researcher to establish the subsequent neurobiological processes that mediate cognitive and behavioural outcomes. The current study investigated white matter structural connectivity in a group of individuals with intellectual disability due to mutations in ZDHHC9. In addition to shared cause of cognitive impairment, these individuals have a shared cognitive profile, involving oro-motor control difficulties and expressive language impairment. Analysis of structural network properties using graph theory measures showed global reductions in mean clustering coefficient and efficiency in the ZDHHC9 group, with maximal differences in frontal and parietal areas. Regional variation in clustering coefficient and local efficiency across cortical regions in cases and controls were significantly associated with known pattern of expression of ZDHHC9 in the normal adult human brain. The results demonstrate that a mutation in a single gene impacts upon white matter organisation across the whole-brain, but also shows regionally specific effects, according to variation in gene expression. Furthermore, these regionally specific patterns may link to specific developmental mechanisms, and correspond to specific cognitive deficits.

Skin cancer is a major public health concern, and tanning remains a modifiable risk factor. Multidimensional influences, including psychosocial, individual, environmental, and policy-related factors, create the milieu for individuals to engage in tanning. Parents and physicians can modify the behavior of teens and young adults using strategies based on harm reduction. Environmental and policy-related factors similar to those used to limit smoking by restricting access of minors to cigarettes in the United States in the 20th century need to be created. Federal regulations can restrict direct advertising and the excise tax can be increased to a prohibitive amount. Social networking may assist with affect regulation.

This review discusses diagnostic genetic assessment for adults with idiopathic intellectual disability, considering the potential yields and limitations of currently available investigations.Genome-wide microarray analysis is now a routine diagnostic test. Estimated yields for clinically significant copy number variants in adults with idiopathic intellectual disability are at least 10%. The medical and neuropsychiatric phenotypes of recurrent genomic disorders are being established. Many single gene causes of intellectual disability have been identified, most notably for X-linked intellectual disability. Ascribing causality, determination of recurrence risk, and prognostication for rare or unique variants remain challenging.Clinical evaluation and investigations (both nongenetic and genetic) can yield an aetiological diagnosis for a growing proportion of individuals with intellectual disability. Not all adults with intellectual disability will ever have received such an assessment. Genetic diagnosis can provide an explanation for lifelong disabling cognitive disorder, guide prognosis, and highlight medical comorbidities. A key outcome is clarification of recurrence risk and facilitation of reproductive choices. However, there are limited data on the desirability and acceptability of genetic diagnosis amongst adult patients with intellectual disability and their families, and concern that ethical principles and practices may be changing without scrutiny. The decision to embark on diagnostic review requires careful consideration for each individual.

PURPOSE OF REVIEW: The aim is to discuss the clinical features of psychiatric illness in 22q11.2 deletion syndrome (22q11DS), and to review current evidence that a core neuropsychiatric phenotype could underlie the full spectrum of different presentations. RECENT FINDINGS: Individuals carrying the 22q11.2 microdeletion are at risk for diverse psychiatric diagnoses across the lifespan, including schizophrenia in a significant minority, and anxiety or mood disorder in the majority. Symptoms and cognitive disruptions can be grouped into domains: attention-executive deficits, social-cognitive deficits, anxiety-affective dysregulation, and psychotic phenomena. These domains do not respect the boundaries of traditional diagnostic categories, and can be consistently recognized in children, adolescents and adults. There is early evidence that some symptom-domain disruptions may predict adult psychiatric morbidity. SUMMARY: If a core neuropsychiatric phenotype does exist in 22q11DS, its detection is likely to require dimensional assessment of subtle aspects of cognitive and emotional processing, not encompassed by current diagnostic systems. A core phenotype would account for disruptions across multiple symptom domains, directly reflecting genetic and neurobiological mechanisms. Relative severity of a core phenotype would predict risk for multiple psychiatric disorders, and could, therefore, be an important target for therapeutic and preventive interventions. A core phenotype meeting these criteria has not yet been defined for 22q11DS.

22q11 deletion syndrome (22q11DS) is a common genetic condition associated with learning disability and high risk for psychiatric illness, in particular schizophrenia. Previous neuroimaging studies in children and adults with 22q11DS have uncovered a number of abnormalities, but have not differentiated between features relating to cognitive impairment and features relating to risk for schizophrenia. This structural MRI study compares adolescents with 22q11DS (n=14) to adolescents with idiopathic learning disability (n=13) and to typically-developing controls (n=14). Voxel-based morphometry and region-of-interest volumetric analyses were employed to test specific hypotheses based on prior studies of 22q11DS. Features that differentiated 22q11DS participants from both matched-IQ and higher-IQ controls were total white matter volume reduction, occipito-parietal and anterior temporal grey matter reduction, frontal and insula grey matter enlargement, and corpus callosum enlargement. On the other hand, hippocampal volume and cerebellar hemisphere reductions differed between 22q11DS and higher-IQ controls only. The neuroanatomical substrates for cognitive impairment and psychiatric illness in 22q11DS are at least partially separable. Correlations between regional volumetric abnormalities and age suggest that exaggerated processes of normal adolescent brain maturation contribute to psychosis-risk in 22q11DS, consistent with previous findings in childhood-onset schizophrenia.

Background22q11 deletion syndrome is associated with high rates of psychiatric morbidity, especially schizophrenia. If common neurodevelopmental trajectories characterise 22q11 deletion syndrome and idiopathic schizophrenia, then similar ‘premorbid’ features would be predicted.AimsTo define psychopathology in adolescents and young adults with 22q11 deletion syndrome.MethodIndividuals with 22q11 deletion syndrome (n=25) and age- and IQ-matched comparison participants (n=25), along withtheir parents/carers, completed standardised semi-structured assessments.ResultsPsychiatric disorders were more prevalent among those with the syndrome and included attention deficit, depression and anxiety; nearly half reported transient psychotic experiences. Inappropriate emotionality and disrupted social behaviour were also common. Poor functional adjustment was associated with schizotypal symptoms and was more marked in older individuals. Conclusions 22q11 deletion syndrome is associated with significant psychopathology prior to adulthood. Double the proportion expected to develop schizophrenia reported psychotic phenomena. These findings imply a continuum of developmental disruption in 22q11 deletion syndrome, associated with declining mental health in early adulthood.

Background Rare pathogenic variants in membrane-associated guanylate kinase (MAGUK) genes cause intellectual disability (ID) and have recently been associated with neuropsychiatric risk in the non-ID population. However, it is not known whether risk for psychiatric symptoms amongst individuals with ID due to MAGUK gene mutations is higher than expected for the degree of general intellectual impairment, nor whether specific cognitive differences are associated with disruption to this gene functional network. Methods This study addresses these two questions via behavioural questionnaires and cognitive testing, applying quantitative methods previously validated in populations with ID. We compared males with X-linked ID caused by mutations in three MAGUK genes (PAK3, DLG3, OPHN1; n = 9) to males with ID caused by mutations in other X chromosome genes (n = 17). Non-parametric and parametric analyses were applied as appropriate to data. Results Groups did not differ in age, global cognitive impairment, adaptive function or epilepsy prevalence. However, individuals with MAGUK gene mutations demonstrated significantly higher psychopathology risks, comprising elevated total problem behaviours, prominent hyperactivity and elevated scores on an autism screening checklist. Despite these overt difficulties, individuals in the MAGUK group performed more accurately than expected for age and intelligence quotient (IQ) on computerised tests of visual attention, convergent with mouse models of MAGUK loss-of-function. Conclusions Our findings support a role for MAGUK genes in influencing cognitive parameters relevant to psychiatric risk. In addition to establishing clear patterns of impairment for this group, our findings highlight the importance of careful phenotyping after genetic diagnosis, showing that gene functional network disruptions can be associated with specific psychopathological risks and cognitive differences within the context of ID. Electronic supplementary material The online version of this article (doi:10.1186/s11689-015-9105-x) contains supplementary material, which is available to authorized users.

Objective Systematic investigation of individuals with intellectual disability after genetic diagnosis can illuminate specific phenotypes and mechanisms relevant to common neurodevelopmental disorders. We report the neurological, cognitive and neuroanatomical characteristics of nine males from three families with loss-of-function mutations in ZDHHC9 (OMIM #300799). Methods All known cases of X-linked intellectual disability (XLID) due to ZDHHC9 mutation in the United Kingdom were invited to participate in a study of neurocognitive and neuroimaging phenotypes. Results Seven out of nine males with ZDHHC9 mutations had been diagnosed with epilepsy, exceeding epilepsy risk in XLID comparison subjects (P = 0.01). Seizure histories and EEG features amongst ZDHHC9 mutation cases shared characteristics with rolandic epilepsy (RE). Specific cognitive deficits differentiated males with ZDHHC9 mutations from XLID comparison subjects and converged with reported linguistic and nonlinguistic deficits in idiopathic RE: impaired oromotor control, reduced verbal fluency, and impaired inhibitory control on visual attention tasks. Consistent neuroanatomical abnormalities included thalamic and striatal volume reductions and hypoplasia of the corpus callosum. Interpretation Mutations in ZDHHC9 are associated with susceptibility to focal seizures and specific cognitive impairments intersecting with the RE spectrum. Neurocognitive deficits are accompanied by consistent abnormalities of subcortical structures and inter-hemispheric connectivity. The biochemical, cellular and network-level mechanisms responsible for the ZDHHC9-associated neurocognitive phenotype may be relevant to cognitive outcomes in RE.

Background: Through the increased availability and sophistication of genetic testing, it is now possible to identify causal diagnoses in a growing proportion of children with neurodevelopmental disorders. In addition to developmental delay and intellectual disability, many genetic disorders are associated with high risks of psychopathology, which curtail the wellbeing of affected individuals and their families. Beyond the identification of significant clinical needs, understanding the diverse pathways from rare genetic mutations to cognitive dysfunction and emotional–behavioural disturbance has theoretical and practical utility. Methods: We overview (based on a strategic search of the literature) the state-of-the-art on causal mechanisms leading to one of the most common childhood behavioural diagnoses – attention deficit hyperactivity disorder (ADHD) – in the context of specific genetic disorders. We focus on new insights emerging from the mapping of causal pathways from identified genetic differences to neuronal biology, brain abnormalities, cognitive processing differences and ultimately behavioural symptoms of ADHD. Findings: First, ADHD research in the context of rare genotypes highlights the complexity of multilevel mechanisms contributing to psychopathology risk. Second, comparisons between genetic disorders associated with similar psychopathology risks can elucidate convergent or distinct mechanisms at each level of analysis, which may inform therapeutic interventions and prognosis. Third, genetic disorders provide an unparalleled opportunity to observe dynamic developmental interactions between neurocognitive risk and behavioural symptoms. Fourth, variation in expression of psychopathology risk within each genetic disorder points to putative moderating and protective factors within the genome and the environment. Conclusion: A common imperative emerging within psychopathology research is the need to investigate mechanistically how developmental trajectories converge or diverge between and within genotype-defined groups. Crucially, as genetic predispositions modify interaction dynamics from the outset, longitudinal research is required to understand the multi-level developmental processes that mediate symptom evolution. Keywords: Rare genotypes, causal pathways, developmental mechanisms, ADHD risk.

More than one hundred congenital anomaly syndromes have now been attributed to structural or functional disruption of the primary immotile cilium (ciliopathies). Whilst most are rare, collectively the ciliopathies may affect as many as 1 in 700 of the general population. The majority of ciliopathies are multi-system disorders. Neuroanatomical, neurological, cognitive, psychiatric and behavioural features (central nervous system phenotypes) are frequently but not universally observed. This chapter aims to systematically collate clinical information related to central nervous system (CNS) phenotypes across the ciliopathy spectrum. There are notable similarities in the types of structural brain abnormalities and functional deficits observed across the spectrum, albeit with variations in frequency of abnormalities between syndromes (in part reflected in diagnostic criteria). Considerable variation exists within syndromes in the extent and severity of CNS abnormalities. Underlying genetic and developmental mechanisms are emerging, and it is anticipated that integration of clinical observation with interdisciplinary basic science will reap benefits in the following years, both for understanding of these complex disorders and for improved patient outcomes.

Objective To evaluate the Structured Interview for Tanning Abuse and Dependence (SITAD). Design Longitudinal survey. Setting College campus. Participants A total of 296 adults. Main Outcome Measures The SITAD modified items from the Structured Clinical Interview for DSM-IV Axis I Disorders that focus on opiate abuse and dependence. Indoor tanning (IT) behavioral patterns and opiate-like reactions to tanning were measured, and IT behavior was measured 6 months later. Results Of 296 participants, 32 (10.8%) met the SITAD criteria for tanning abuse (maladaptive pattern of tanning as manifested by failure to fulfill role obligations, physically hazardous tanning, legal problems, or persistent social or interpersonal problems) and 16 (5.4%) for tanning dependence as defined by 3 or more of the following: loss of control, cut down, time, social problems, physical or psychological problems, tolerance, and withdrawal. The IT frequency in dependent tanners was more than 10 times the rate in participants who do not meet the SITAD criteria for tanning abuse or dependence. Tanning-dependent participants were more likely to report being regular tanners (75%; odds ratio, 7.0). Dependent tanners scored higher on the opiate-like reactions to tanning scale than did abuse tanners, who scored higher than those with no diagnosis. Conclusions The SITAD demonstrated some evidence of validity, with tanning-dependent participants reporting regular IT, higher IT frequency, and higher scores on an opiate-like reactions to tanning scale. A valid tanning dependence screening tool is essential for researchers and physicians as a tanning-dependent diagnosis may facilitate a better understanding of tanning motivations and aid in the development of efficacious intervention programs.

Genes expressed during development regulate the emergent structure and function of the growing brain. Genetic mechanisms interact with environmental influences to predispose individuals to structural and functional brain disorders. The embryological sequence of nervous system development is relatively well understood. Longitudinal neuroimaging studies have highlighted that prolonged postnatal brain change is associated with acquisition of higher level cognitive skills such as language, memory and executive function. However, understanding of developmental neurobiology has not yet been extensively integrated with systems neuroscience, to identify key molecular and cellular mechanisms relevant to human cognition. Furthermore, little is known about genetic variants that constrain embryological and later brain development to influence neurological and cognitive outcomes in developmental disabilities and psychiatric disorders. Following the completion of the Human Genome Project, new technologies have enabled an extraordinary expansion in knowledge of genetic sequence variation, gene expression and epigenetics. Establishing convergence between developmental biology, systems neuroscience and genomics to understand the neurobiological bases for neurodevelopmental disorders remains an exciting challenge for the next decades. Key Concepts: Brain development involves differentiation of highly specialised cell types, in predictable temporal sequences, and their organisation into precise spatial systems. Genetic variation interacts with environmental influences to predispose individuals to structural and functional brain disorders, by influencing developmental mechanisms. Major events in early nervous system development include induction of the neural plate, neurogenesis, differentiation of neuronal and glial cell types, and migration of cells into their correct position. Postnatal brain development, including maturation of white matter tracts and synaptic pruning in response to stimulation and behaviour, is also important, but the neurobiology is much less well understood. Both early and later developmental processes may be disrupted by genetic mutations or influenced by sequence variation, but links from gene to brain to cognitive functions are complex and require investigation by convergent methods. New methods of investigating genomic organisation and the structure and function of the living human brain are increasingly being integrated to elucidate molecular and cellular mechanisms of relevance to neurodevelopmental disorders. Keywords: development; brain; neurodevelopmental; neurobiology; disorders

Cilia are ubiquitous cell surface organelles with diverse roles from embryogenesis to adult life. The neurodevelopmental functions of the cilium are currently under investigation in animal systems, but relevance to human brain development remains uncertain. We present the first systematic investigation of structural neuroanatomy in a ciliopathy-Bardet-Biedl syndrome (BBS). Qualitative and quantitative aspects of brain structure were evaluated via magnetic resonance imaging in 10 patients with BBS (ages 14-28 years). In comparison to age and gender-matched healthy controls, BBS patients had significantly reduced total gray matter (GM) volume but no total white matter (WM) or cerebrospinal fluid volume changes. Voxel-based morphometric analysis indicated regional GM volume loss bilaterally in the anterior temporal lobes and in the medial orbitofrontal cortex, and WM volume loss in the right inferior longitudinal fasciculus. Region-of-interest measurements revealed reduced volume of the hippocampus. Two patients were found to have ventriculomegaly. Global GM reduction and regional volume reductions in the temporal lobe may underlie the learning disabilities and behavioral problems experienced by some patients with BBS. These findings are consistent with previous observations in mouse models of BBS, and further implicate the cilium in neurodevelopmental processes relevant to human cognitive function.

Background Microdeletions at 22q11.2 greatly increase the risk of schizophrenia in early adulthood (relative risk ≈ 25–30). We hypothesized that before the onset of schizophrenia, individuals with 22q11DS would manifest specific cognitive and neurophysiological anomalies (endophenotypes) in common with individuals at high risk for schizophrenia in the general population. We further predicted that the catechol-O-methyltransferase Val 108/158 Met polymorphism, located within the deleted chromosomal segment, would modify the severity of endophenotypic features. Methods 22q11DS adolescents and young adults (aged 13–21) were compared with age- and IQ-matched control subjects on measures that are associated with risk of idiopathic schizophrenia. Results 22q11DS subjects displayed poorer verbal working memory and expressive language performance than control subjects. Auditory mismatch negativity (MMN) event-related potentials were reduced at frontal electrodes but were intact at temporal sites. Presence of the COMT 108/158 Met allele on the single intact chromosome 22 was associated with more marked MMN amplitude reduction and poorer neuropsychological performance. Neither COMT Val 108/158 Met allele influenced psychiatric symptoms. Conclusions 22q11DS is associated with neurodevelopmental characteristics that are similar to idiopathic schizophrenia. The COMT Val 108/158 Met polymorphism modifies the severity of endophenotypes for schizophrenia, indicating that impaired catecholamine regulation contributes to neuropsychiatric risk in 22q11DS.

Introduction Cognitive neuropsychiatry was recently defined (Halligan and David 2001) as a ‘systematic and theoretically driven approach to explain clinical psychopathologies in terms of deficits to normal cognitive mechanisms’. The aim of cognitive neuropsychiatry is to identify the neural substrates of cognitive mechanisms that, when impaired, may underlie the phenomenology of psychiatric disorder. Consequently, it is a quintessentially multidisciplinary endeavour, founded in both basic neuroscience and clinical psychiatry. The progress being made in identifying circumscribed brain circuits that are involved in specific cognitive tasks, with the aid of functional neuro-imaging techniques, is remarkable, yet relatively little discussion has been addressed to the issue of the genetic mechanisms that direct the development of these neurocognitive systems. There is increasing convergence between the identification of specific neural substrates and subjective experience, such as the recognition of certain emotions. The addition of genetics and developmental science to the research agenda will increase the power of the discipline to dissect aetiologies and pathological mechanisms. Approaches to gene-finding in psychiatric research Most psychiatric genetic research has focused on the hunt for genes that predispose to complex and heterogeneous clinical conditions, such as schizophrenia or manic depression (McGuffin et al. 2001). Additionally, human behavioural genetics has to date focused largely on the identification of genes that contribute to individual phenotypic variance in a trait (see Chapter 1 by Plomin).

The occurrence of human cerebellar serotonin 5-HT2A receptors (5-HT2AR) is equivocal and their status in schizophrenia unknown. Using a range of techniques, we investigated cerebellar 5-HT2AR expression in 16 healthy subjects and 16 subjects with schizophrenia. Immunocytochemistry with a monoclonal antibody showed labelling of Purkinje cell bodies and dendrites, as well as putative astrocytes. Western blots showed a major band at ∼45 kDa. Receptor autoradiography and homogenate binding with [3H]ketanserin revealed cerebellar 5-HT2AR binding sites present at levels approximately a third of that in prefrontal cortex. 5-HT2AR mRNA was detected by reverse transcriptase-polymerase chain reaction, with higher relative levels in men than women. Several aspects of 5-HT2AR expression were altered in schizophrenia. 5-HT2AR immunoreactivity in Purkinje cells was partially redistributed from soma to dendrites and was increased in white matter. 5-HT2AR mRNA was decreased in the male patients. 5-HT2AR measured by dot blots and [3H]ketanserin binding (Bmax and Kd) were not significantly altered in schizophrenia. These data show that 5-HT2AR gene products (mRNA, protein, binding sites) are expressed in the human cerebellum at nonnegligible levels; this bears upon 5-HT2AR imaging studies which use the cerebellum as a reference region. 5-HT2AR expression is altered in schizophrenia; the shift of 5-HT2AR from soma to dendrites is noteworthy since atypical antipsychotics have the opposite effect. Finally, the results emphasise that expression of a receptor gene is a mutifaceted process. Measurement of multiple parameters is necessary to give a clear picture of the normal situation and to show the profile of alterations in a disease. Synapse 42:104–114, 2001. © 2001 Wiley-Liss, Inc.

Aim Breathlessness is one the most common problems experienced in cancer; evidence suggests that up to 79% will encounter this distressing symptom, which can undermine functional ability and compromise independence. Evidence suggests that while there are breathlessness management programmes, few exist specifically for cancer and none provided care and advice cross the eight domains which are physical, psychological, practical, nutritional, social, spiritual, financial and information. Method A survey of breathlessness programmes for people with cancer across South East Wales revealed inadequate provision, with current services unable to meet the demand. Additionally, they did not cover the eight domains of care necessary for the provision of holistic care. An evidence based non-pharmacological breathlessness management programme was developed as well as a workforce education programme to ensure the right level of skills and competence of those delivering the pathway. Results Fourty people were referred and 22 were seen. The most common presenting tumour sites were breast (N=12), lung (N=9), pancreas (N=3) and ovary (N=3). Of the patients who entered the pathway, 19 (83%) self-managed successfully and 3 (17%) required referral for specialist care such as nutrition, occupational therapy and physiotherapy. Conclusions and discussion While dyspnoea is not routinely assessed and is an expected burden for many people with cancer, simple self-management techniques used as this pathway can empower such people to cope a little better with the distress and life limiting effects of their dyspnoea. As this is a patient led intervention, they determine what level of advice and information they want and thus they are able to control this as well as the level of professional intervention accessed. Finally, though the pathway was developed primarily for people with cancer, it has been shown that it can be effortlessly transferred to other conditions where breathing may be compromised.

Objective To assess speech abilities in adolescents born preterm and investigate whether there is an association between specific speech deficits and brain abnormalities. Study design Fifty adolescents born prematurely (

Childhood speech and language deficits are highly prevalent and are a common feature of neurodevelopmental disorders. However, it is difficult to investigate the underlying causal pathways because many diagnostic groups have a heterogeneous aetiology. Studying disorders with a shared genetic cause and shared cognitive deficits can provide crucial insight into the cellular mechanisms and neural systems that give rise to those impairments. The current study investigated structural brain differences of individuals with mutations in ZDHHC9, which is associated with a specific neurodevelopmental phenotype including prominent speech and language impairments and intellectual disability. We used multiple structural neuroimaging methods to characterise neuroanatomy in this group, and observed bilateral reductions in cortical thickness in areas surrounding the temporo-parietal junction, parietal lobule, and inferior frontal lobe, and decreased microstructural integrity of cortical, subcortical-cortical, and interhemispheric white matter projections. These findings are compared to reports for other genetic groups and genetically heterogeneous disorders with a similar presentation. Overlap in the neuroanatomical phenotype suggests a common pathway that particularly affects the development of temporo-parietal and inferior frontal areas, and their connections.

The commonest autosomal deletion, 22q11.2 deletion syndrome (22q11DS) is a multisystem disorder varying greatly in severity and age of identification between affected individuals. Holistic care is best served by a multidisciplinary team, with an anticipatory approach. Priorities tend to change with age, from feeding difficulties, infections and surgery of congenital abnormalities particularly of the heart and velopharynx in infancy and early childhood to longer-term communication, learning, behavioural and mental health difficulties best served by evaluation at intervals to consider and initiate management. Regular monitoring of growth, endocrine status, haematological and immune function to enable early intervention helps in maintaining health. Conclusion: Guidelines to best practice management of 22q11DS based on a literature review and consensus have been developed by a national group of professionals with consideration of the limitations of available medical and educational resources.