Analysis of Copy Number Variants identifies new candidate genes for Autism Spectrum Disorder and Intellectual Disability

Autism spectrum disorder (ASD) and Intellectual Disability (ID) are complex neuropsychiatric disorders characterized by extensive clinical and genetic heterogeneity and with overlapping risk factors. The aim of my project was to further investigate the role of Copy Numbers Variants (CNVs), identified through genome-wide studies performed by the Autism Geome Project (AGP) and the CHERISH consortium in large cohorts of ASD and ID cases, respectively. Specifically, I focused on four rare genic CNVs, selected on the basis of their impact on interesting ASD/ID candidate genes: a) a compound heterozygous deletion involving CTNNA3, predicted to cause the lack of functional protein; b) a 15q13.3 duplication containing CHRNA7; c) a 2q31.1 microdeletion encompassing KLHL23, SSB and METTL5; d) Lastly, I investigated the putative imprinting regulation of the CADPS2 gene, disrupted by a maternal deletion in two siblings with ASD and ID. This study provides further evidence for the role of CTNNA3, CHRNA7, KLHL23 and CADPS2 as ASD and/or ID susceptibility genes, and highlights that rare genetic variation contributes to disease risk in different ways: some rare mutations, such as those impacting CTNNA3, act in a recessive mode of inheritance, while other CNVs, such as those occurring in the 15q13.3 region, are implicated in multiple developmental and/or neurological disorders possibly interacting with other susceptibility variants elsewhere in the genome. On the other hand, the discovery of a tissue-specific monoallelic expression for the CADPS2 gene, implicates the involvement of epigenetic regulatory mechanisms as risk factors conferring susceptibility to ASD/ID.

Corpus callosum index and long-term disability in multiple sclerosis patients

Prediction of long-term disability in patients with multiple sclerosis (MS) is essential. Magnetic resonance imaging (MRI) measurement of brain volume may be of predictive value but sophisticated MRI techniques are often inaccessible in clinical practice. The corpus callosum index (CCI) is a normalized measurement that reflects changes of brain volume. We investigated medical records and 533 MRI scans at diagnosis and during clinical follow-up of 169 MS patients (mean age 42 +/- 11 years, 86% relapsing-remitting MS, time since first relapse 11 +/- 9 years). CCI at diagnosis was 0.345 +/- 0.04 and correlated with duration of disease (p = 0.002; r = -0.234) and expanded disability status scale (EDSS) score at diagnosis (r = -0.428; p < 0.001). Linear regression analyses identified age, duration of disease, relapse rate and EDSS at diagnosis as independent predictors for disability after mean of 7.1 years (Nagelkerkes' R:0.56). Annual CCI decrease was 0.01 +/- 0.02 (annual tissue loss: 1.3%). In secondary progressive MS patients, CCI decrease was double compared to that in relapsing-remitting MS patients (p = 0.04). There was a trend of greater CCI decrease in untreated patients compared to those who received disease modifying drugs (p = 0.2). CCI is an easy to use MRI marker for estimating brain atrophy in patients with MS. Brain atrophy as measured with CCI was associated with disability progression but it was not an independent predictor of long-term disability.

Association of bone attrition with knee pain, stiffness and disability: a cross-sectional study

Bone pathologies as detected on MRI are associated with the presence of pain in knee osteoarthritis (OA). The authors examined whether bone attrition assessed on x-rays was associated with pain, stiffness and disability.

Does land-based exercise reduce pain and disability associated with hip osteoarthritis? A meta-analysis of randomized controlled trials

Objective To determine if clinical guidelines recommending therapeutic exercise for people with hip osteoarthritis (OA) are supported by rigorous scientific evidence. Methods A meta-analysis of randomized controlled trials (RCTs) recruiting people with hip OA and comparing some form of land-based exercise program (as opposed to exercises conducted in the water) with a non-exercise group in terms of hip pain and/or self-reported physical function. Results Thirty-two RCTs were identified, but only five met the inclusion criteria. Only one of the five included RCTs restricted recruitment to people with hip OA, the other four RCTs also recruiting participants with knee OA. The five included studies provided data on 204 and 187 hip OA participants for pain and physical function, respectively. Combining the results of the five included RCTs using a fixed-effects model demonstrated a small treatment effect for pain (standardized mean difference (SMD) −0.38; 95% confidence interval (CI) −0.67 to −0.09). No significant benefit in terms of improved self-reported physical function was detected (SMD −0.02; 95% CI −0.31 to 0.28). Conclusion Currently there is only silver level evidence (one small RCT) supporting the benefit of land-based therapeutic exercise for people with symptomatic hip OA in terms of reduced pain and improved physical function. The limited number and small sample size of the included RCTs restricts the confidence that can be attributed to these results.

Child and adolescent psychiatric genetics

The current status of child and adolescent psychiatric genetics appears promising in light of the initiation of genome-wide association studies (GWAS) for diverse polygenic disorders and the molecular elucidation of monogenic Rett syndrome, for which recent functional studies provide hope for pharmacological treatment strategies. Within the last 50 years, tremendous progress has been made in linking genetic variation to behavioral phenotypes and psychiatric disorders. We summarize the major findings of the Human Genome Project and dwell on largely unsuccessful candidate gene and linkage studies. GWAS for the first time offer the possibility to detect single nucleotide polymorphisms and copy number variants without a priori hypotheses as to their molecular etiology. At the same time it is becoming increasingly clear that very large sample sizes are required in order to enable genome wide significant findings, thus necessitating further large-scaled ascertainment schemes for the successful elucidation of the molecular genetics of childhood and adolescent psychiatric disorders. We conclude by reflecting on different scenarios for future research into the molecular basis of early onset psychiatric disorders. This review represents the introductory article of this special issue of the European Child and Adolescent Psychiatry.

Disability in people clinically at high risk of psychosis

Decline in social functioning occurs in individuals who later develop psychosis.

Attacks on German public figures, 1968-2004: warning behaviors, potentially lethal and non-lethal acts, psychiatric status, and motivations

Fourteen non-terrorist attackers of public figures in Germany between 1968 and 2004 were intensively studied, with a particular focus on warning behaviors, attack behaviors, and the relationship between psychiatric diagnosis, symptoms, and motivations for the assault. A large proportion of the attackers were severely mentally ill, and most likely to be in the potentially lethal rather than the non-lethal group. A new typology of seven warning behaviors was applied to the data, and all were present, most frequently fixation and pathway warning behavior, and least frequently a direct threat. Psychiatric diagnosis could be closely linked to motivation when analyzed at the level of symptom and content of thought, often delusional. Most of the attacks were directed at political figures, and the majority occurred after 1995.

Reduced endurance of the cervical flexor muscles in patients with concurrent temporomandibular disorders and neck disability

Subjects with temporomandibular disorders (TMDs) have been found to have clinical signs and symptoms of cervical dysfunction. Although many studies have investigated the relationship between the cervical spine and TMD, no study has evaluated the endurance capacity of the cervical muscles in patients with TMD. Thus the objective of this study was to determine whether patients with TMD had a reduced endurance of the cervical flexor muscles at any level of muscular contraction when compared with healthy subjects. One hundred and forty-nine participants provided data for this study (49 subjects were healthy, 54 had myogenous TMD, and 46 had mixed TMD). There was a significant difference in holding time at 25% MVC between subjects with mixed TMD when compared to subjects with myogenous TMD and healthy subjects. This implies that subjects with mixed TMD had less endurance capacity at a lower level of contraction (25% MVC) than healthy subjects and subjects with myogenous TMD. No significant associations between neck disability, jaw disability, clinical variables and neck flexor endurance test were found.

Problems in functioning from the patient perspective using the International Classification of Functioning, Disability and Health (ICF) as a reference

We conducted a qualitative, multicenter study using a focus group design to explore the lived experiences of persons with any kind of primary sleep disorder with regard to functioning and contextual factors using six open-ended questions related to the International Classification of Functioning, Disability and Health (ICF) components. We classified the results using the ICF as a frame of reference. We identified the meaningful concepts within the transcribed data and then linked them to ICF categories according to established linking rules. The six focus groups with 27 participants yielded a total of 6986 relevant concepts, which were linked to a total of 168 different second-level ICF categories. From the patient perspective, the ICF components: (1) Body Functions; (2) Activities & Participation; and (3) Environmental Factors were equally represented; while (4) Body Structures appeared poignantly less frequently. Out of the total number of concepts, 1843 concepts (26%) were assigned to the ICF component Personal Factors, which is not yet classified but could indicate important aspects of resource management and strategy development of those who have a sleep disorder. Therefore, treatment of patients with sleep disorders must not be limited to anatomical and (patho-)physiological changes, but should also consider a more comprehensive view that includes patient's demands, strategies and resources in daily life and the contextual circumstances surrounding the individual.

Identification of problems in functioning of people with sleep disorders in a clinical setting using the International Classification of Functioning Disability and Health (ICF) Checklist

We conducted an explorative, cross-sectional, multi-centre study in order to identify the most common problems of people with any kind of (primary) sleep disorder in a clinical setting using the International Classification of Functioning, Disability and Health (ICF) as a frame of reference. Data were collected from patients using a structured face-to-face interview of 45-60 min duration. A case record form for health professionals containing the extended ICF Checklist, sociodemographic variables and disease-specific variables was used. The study centres collected data of 99 individuals with sleep disorders. The identified categories include 48 (32%) for body functions, 13 (9%) body structures, 55 (37%) activities and participation and 32 (22%) for environmental factors. 'Sleep functions' (100%) and 'energy and drive functions', respectively, (85%) were the most severely impaired second-level categories of body functions followed by 'attention functions' (78%) and 'temperament and personality functions' (77%). With regard to the component activities and participation, patients felt most restricted in the categories of 'watching' (e.g. TV) (82%), 'recreation and leisure' (75%) and 'carrying out daily routine' (74%). Within the component environmental factors the categories 'support of immediate family', 'health services, systems and policies' and 'products or substances for personal consumption [medication]' were the most important facilitators; 'time-related changes', 'light' and 'climate' were the most important barriers. The study identified a large variety of functional problems reflecting the complexity of sleep disorders. The ICF has the potential to provide a comprehensive framework for the description of functional health in individuals with sleep disorders in a clinical setting.

Factor Structure of the Neck Disability Index

BACKGROUND CONTEXT: The Neck Disability Index frequently is used to measure outcomes of the neck. The statistical rigor of the Neck Disability Index has been assessed with conflicting outcomes. To date, Confirmatory Factor Analysis of the Neck Disability Index has not been reported for a suitably large population study. Because the Neck Disability Index is not a condition-specific measure of neck function, initial Confirmatory Factor Analysis should consider problematic neck patients as a homogenous group. PURPOSE: We sought to analyze the factor structure of the Neck Disability Index through Confirmatory Factor Analysis in a symptomatic, homogeneous, neck population, with respect to pooled populations and gender subgroups. STUDY DESIGN: This was a secondary analysis of pooled data. PATIENT SAMPLE: A total of 1,278 symptomatic neck patients (67.5% female, median age 41 years), 803 nonspecific and 475 with whiplash-associated disorder. OUTCOME MEASURES: The Neck Disability Index was used to measure outcomes. METHODS: We analyzed pooled baseline data from six independent studies of patients with neck problems who completed Neck Disability Index questionnaires at baseline. The Confirmatory Factor Analysis was considered in three scenarios: the full sample and separate sexes. Models were compared empirically for best fit. RESULTS: Two-factor models have good psychometric properties across both the pooled and sex subgroups. However, according to these analyses, the one-factor solution is preferable from both a statistical perspective and parsimony. The two-factor model was close to significant for the male subgroup (p<.07) where questions separated into constructs of mental function (pain, reading headaches and concentration) and physical function (personal care, lifting, work, driving, sleep, and recreation). CONCLUSIONS: The Neck Disability Index demonstrated a one-factor structure when analyzed by Confirmatory Factor Analysis in a pooled, homogenous sample of neck problem patients. However, a two-factor model did approach significance for male subjects where questions separated into constructs of mental and physical function. Further investigations in different conditions, subgroup and sex-specific populations are warranted.

Does the Presence of a Learning Disability Elicit a Stigmatization?

Aims: To determine whether or not a Learning Disability(LD) label leads to stigmatization. Study Design: This research used a 2(sex of participant) x 2(LD label)x 2 (Sex of stimulus person) factorial design. Place and Duration of Study: Bucknell University, between October 2010 and April 2011. Methodology: Sample: We included 200 participants (137 women and 63 men, ranging in age from 18 – 75 years, M = 26.41. Participants rated the stimulus individual on 27 personality traits, 8 Life success measures, and the Big-5 personality dimensions. Also, participants completed a Social Desirability measure. Results: A MANOVA revealed a main effect for the Learning Disability description, F(6, 185) = 6.41 p< .0001, eta2 = .17,for the Big-5 personality dimensions, Emotional Stability, F(1, 185) = 13.39, p < .001, eta2 = .066, and Openness to Experiences F(1,185) = 7.12, p< .008, eta2 = .036.Stimulus individuals described as having a learning disability were perceived as being less emotionally stable and more open to experiences than those described as not having a learning disability. Another MANOVA revealed a main effect for having a disability or not, F(8, 183) = 4.29, p< .0001, eta2 = .158, for the Life Success items, Attractiveness, F(1, 198) = 16.63, p< .0001, eta2 = .080, and Future Success,F(1, 198) = 4.57, p< .034, eta2 = .023. Stimulus individuals described as having a learning disability were perceived as being less attractive and with less potential for success than those described as not having a learning disability. Conclusion: The results of this research provide evidence that a bias exists toward those who have learning disabilities. The mere presence of an LD label had the ability to cause a differential perception of those with LDs and those without LDs.

Identifying the Negative Stigma Associated with Having a Learning Disability

Those with learning disabilities (LDs) can be characterized as a minority group, and like most groups of minorities they face a distinct stigma by the larger population. While there iscurrently a lack of research in understanding LD stigma, it has become increasingly important given the push for inclusive classrooms settings. In this study it was hypothesized that regardlessof a participants’ gender, when participants were given a hypothetical description of a person that included information indicating that the individual has a LD, the participants would rate that individual less favorably. Results were consistent with the hypothesis. Participants perceived the hypothetical LD individual as being less attractive, less successful, less emotionally stable,and more open to new experiences when compared to those participants who were given the non-LD description. These results show a level of negative bias in our population towards those with LDs. It is hoped that this research will help address the goal of inclusion and equality for those with LDs and aid in finding ways to identify, address, and attenuate these stigmatizations within all aspects of our society.