A family study of symbolic learning and synaptic plasticity in autism spectrum disorder.

The current study presents a male with autism spectrum disorder (ASD) and a 3q29 deletion, and three healthy first-degree relatives. Our magnetic resonance imaging (MRI) dataset included a healthy control subset. We describe a comprehensive multimodal approach, including equivalence class formation, neurocognitive testing, MRI, and electroencephalography (EEG)-based cortical plasticity, which can provide new insights into socio-communicative and learning impairments and neural underpinnings in ASD. On neurocognitive testing, the proband showed reduced processing speed, attending behavior, and executive function. He required more training trials in equivalence class training compared with family members and exhibited impaired priming of words compared with priming with images. The proband had smaller intracranial volume and surface area and a larger visual evoked potential (VEP) C1 amplitude than family members and intact long-term potentiation (LTP)-like visual cortex plasticity. Together, these results suggest that 3q29 deletion-related ASD is associated with impaired problem-solving strategies in complex socio-communicative and learning tasks, smaller intracranial and surface area, altered VEP amplitude, and normal LTP-like visual cortex plasticity. Further studies are needed to clarify whether this multimodal approach can be used to identify ASD subgroups with distinct neurobiological alterations and to uncover mechanisms underlying socio-communicative and learning impairments. Lay Summary: We studied learning, brain activity, and brain structure in a person with autism and a genetic aberration, and his close relatives. Compared with relatives, the person with autism required more training for learning, and visual learning was better than verbal learning. This person had some changes in the activity of the visual cortex, and the size and the surface area of the brain were reduced. Knowledge about learning and brain mechanisms is valuable for the development of training programs for individuals with autism.

Behavioral and neuropsychological profile of a male patient with mosaic PCDH19 mutation.

Mutations in the protocadherin 19 gene (PCDH19) are associated with a female-restricted form of epilepsy. As the disorder has an X-reversed inheritance pattern, men are usually healthy carriers. PCDH19 epilepsy among men due to mosaicism is rare but probably underdiagnosed. We describe the longitudinal development of the behavioral and neuropsychological profile of a male with a mosaic PCDH19 mutation based on assessments carried out at 9, 11, 15, and 19 years of age. He was diagnosed with mild intellectual disability and autism spectrum disorder and had marked deficits in so-called hot executive functions related to emotion, as opposed to purely cognitive aspects of executive functions, the so-called cold executive functions. Although his epilepsy improved and cognition remained stable, executive dysfunction and behavioral problems became the prominent clinical features with age.

Attitudes among parents of persons with autism spectrum disorder towards information about genetic risk and future health.

Clinical relevance of genetic testing is increasing in autism spectrum disorder (ASD). Information about genetic risk may contribute to improved diagnostics, treatment and family planning, but may also be perceived as a burden. Knowledge about the families' preferences with regard to genetic risk information is important for both health care professionals and policy makers. We investigated attitudes towards sharing information about genetic risk of ASD and knowledge about future health among parent members of the Norwegian Autism Association (N = 1455) using a questionnaire, and the relationships with parent and child characteristics, such as age, gender and ASD severity. Most preferred autonomy in deciding whom to inform about genetic risk of ASD (74.4%) and a minority supported extensive intra-familial disclosure of the genetic risk (41.1%). The majority agreed that it is an obligation to know as much as possible relevant for future health (58.0%) and only 51.7% agreed to a principle of a 'right not to know'. In regression models, the attitudes were associated with opinions about benefits and harms of genetic testing (e.g., treatment, family planning, understanding of ASD pathology, insurance discrimination and family conflict). In sum, the findings show that most parents want to know as much as possible relevant for their children's future health and keep their autonomy and intra-familial confidentiality about genetic risk information. Nearly half of the parents were not concerned with a "right not to know". These attitudes can inform development of guidelines and bioethics in the age of genomic precision medicine.

Higher vitamin B12 levels in neurodevelopmental disorders than in healthy controls and schizophrenia: A comparison among participants between 2 and 53 years.

Recent studies suggest that both high and low levels of vitamin B12 (vitB12) may have negative health impacts. We measured VitB12 in patients with the Neurodevelopmental disorders (ND) (n = 222), comprised of Autism Spectrum Disorders, specific Developmental disorders, and Intellectual Disability (aged 2-53 years), schizophrenia (n = 401), and healthy controls (HC) (n = 483). Age-and gender-adjusted vitB12 z-scores were calculated by comparisons with a reference population (n = 76 148). We found higher vitB12 in ND (median 420 pmol/L, mean z-score: 0.30) than in HC (316 pmol/L, z-score: 0.06, P < .01) and schizophrenia (306 pmol/L, z-score: -0.02, P < .001), which was significant after adjusting for age, gender, vitB12 supplement, folate, hemoglobin, leukocytes, liver, and kidney function (P < .02). In ND, 20% (n = 44) had vitB12 above 650 pmol/L, and 1% (n = 3) had below 150 pmol/L (common reference limits). In 6.3% (n = 14) of ND, vitB12 was above 2SD of mean in the age-and gender-adjusted reference population, which was more frequent than in HC (n = 8, 1.6%), OR: 4.0, P = .001. Low vitB12 was equally frequent as in HC, and vitB12 z-scores were equal across the age groups. To conclude, vitB12 was higher in ND than in HC and schizophrenia, suggesting a specific feature of ND, which warrants further studies to investigate the underlying mechanisms.

Autism spectrum disorder polygenic scores are associated with every day executive function in children admitted for clinical assessment.

Autism spectrum disorder (ASD) and other neurodevelopmental disorders (NDs) are behaviorally defined disorders with overlapping clinical features that are often associated with higher-order cognitive dysfunction, particularly executive dysfunction. Our aim was to determine if the polygenic score (PGS) for ASD is associated with parent-reported executive dysfunction in everyday life using the Behavior Rating Inventory of Executive Function (BRIEF). Furthermore, we investigated if PGS for general intelligence (INT) and attention deficit/hyperactivity disorder (ADHD) also correlate with BRIEF. We included 176 children, adolescents and young adults aged 5-22 years with full-scale intelligence quotient (IQ) above 70. All were admitted for clinical assessment of ASD symptoms and 68% obtained an ASD diagnosis. We found a significant difference between low and high ASD PGS groups in the BRIEF behavior regulation index (BRI) (P = 0.015, Cohen's d = 0.69). A linear regression model accounting for age, sex, full-scale IQ, Social Responsiveness Scale (SRS) total score, ASD, ADHD and INT PGS groups as well as genetic principal components, significantly predicted the BRI score; F(11,130) = 8.142, P < 0.001, R2 = 0.41 (unadjusted). Only SRS total (P < 0.001), ASD PGS 0.1 group (P = 0.018), and sex (P = 0.022) made a significant contribution to the model. This suggests that the common ASD risk gene variants have a stronger association to behavioral regulation aspects of executive dysfunction than ADHD risk or INT variants in a clinical sample with ASD symptoms. Autism Res 2020, 13: 207-220. © 2019 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: People with autism spectrum disorder (ASD) often have difficulties with higher-order cognitive processes that regulate thoughts and actions during goal-directed behavior, also known as executive function (EF). We studied the association between genetics related to ASD and EF and found a relation between high polygenic score (PGS) for ASD and difficulties with behavior regulation aspects of EF in children and adolescents under assessment for ASD. Furthermore, high PGS for general intelligence was related to social problems.

Neuropsychiatric phenotype in relation to gene variants in the hemizygous allele in 3q29 deletion carriers: A case series.

BACKGROUND: Genetic risk variants in the hemizygous allele may influence neuropsychiatric manifestations and clinical course in 3q29 deletion carriers. METHODS: In-depth phenotypic assessment in two deletion carriers included medical records, medical, genetic, psychiatric and neuropsychological evaluations, brain MRI scan and EEG. Blood samples were analyzed for copy number variations, and deep sequencing of the affected 3q29 region was performed in patients and seven first-degree relatives. Risk variants were identified through bioinformatic analysis. RESULTS: One deletion carrier was diagnosed with learning difficulties and childhood autism, the other with mild intellectual disability and schizophrenia. EEG abnormalities in childhood normalized in adulthood in both. Cognitive abilities improved during adolescence in one deletion carrier. Both had microcytic, hypochromic erythrocytes and suffered from chronic pain and fatigue. Molecular and bioinformatic analyses identified risk variants in the hemizygous allele that were not present in the homozygous state in relatives in genes involved in cilia function and insulin action in the autistic individual and in synaptic function and neurosteroid transport in the subject with schizophrenia. CONCLUSION: 3q29 deletion carriers may undergo developmental phenotypic transition and need regular medical follow-up. Identified risk variants in the remaining hemizygous allele should be explored further in autism and schizophrenia research.

A Role for the Transcription Factor Nk2 Homeobox 1 in Schizophrenia: Convergent Evidence from Animal and Human Studies.

Schizophrenia is a highly heritable disorder with diverse mental and somatic symptoms. The molecular mechanisms leading from genes to disease pathology in schizophrenia remain largely unknown. Genome-wide association studies (GWASs) have shown that common single-nucleotide polymorphisms associated with specific diseases are enriched in the recognition sequences of transcription factors that regulate physiological processes relevant to the disease. We have used a "bottom-up" approach and tracked a developmental trajectory from embryology to physiological processes and behavior and recognized that the transcription factor NK2 homeobox 1 (NKX2-1) possesses properties of particular interest for schizophrenia. NKX2-1 is selectively expressed from prenatal development to adulthood in the brain, thyroid gland, parathyroid gland, lungs, skin, and enteric ganglia, and has key functions at the interface of the brain, the endocrine-, and the immune system. In the developing brain, NKX2-1-expressing progenitor cells differentiate into distinct subclasses of forebrain GABAergic and cholinergic neurons, astrocytes, and oligodendrocytes. The transcription factor is highly expressed in mature limbic circuits related to context-dependent goal-directed patterns of behavior, social interaction and reproduction, fear responses, responses to light, and other homeostatic processes. It is essential for development and mature function of the thyroid gland and the respiratory system, and is involved in calcium metabolism and immune responses. NKX2-1 interacts with a number of genes identified as susceptibility genes for schizophrenia. We suggest that NKX2-1 may lie at the core of several dose dependent pathways that are dysregulated in schizophrenia. We correlate the symptoms seen in schizophrenia with the temporal and spatial activities of NKX2-1 in order to highlight promising future research areas.

Health and disease in adults with Down syndrome.

BACKGROUND: The increasing life expectancy of persons with Down syndrome calls for a knowledge of conditions that frequently occur in adults with the syndrome and of which health personnel should be particularly aware. METHOD: The article is based on a literature search in PubMed and the authors' clinical experience with the patient group. RESULTS: Altered immune system function, muscular hypotonia, dysmorphic otolaryngologic features and premature ageing contribute to health problems. The group is susceptible to infections, particularly of the respiratory and the gastrointestinal tract. Congenital heart defects may give rise to symptoms, also in adults. Many also develop mitral valve disease, including those without congenital heart defects. Hypothyroidism develops in up to half, and coeliac disease in one of five. Obstructive sleep apnoea syndrome occurs in approximately half. Sensorineural hearing loss and cataract may occur before the age of 30. Atlantoaxial instability occurs, and radiological examination of the neck must take place before intervention under general anaesthesia. Behavioural changes with loss of skills, withdrawal, psychomotoric retardation and mutism occur frequently from the age of 30 and may be symptoms of mental illness or the onset of Alzheimer's dementia. INTERPRETATION: Adults with Down syndrome need to undergo regular medical examinations, and we recommend an annual check-up with the primary doctor. Screening for hearing loss and cataract is also recommended every three and five years, respectively. In the event of concomitant symptoms, particularly related to neurological and psychiatric conditions, the patient can be referred to the habilitation service.

Mutilation anxiety differs among females with fibromyalgia and functional dyspepsia and population controls.

BACKGROUND: Studies using self-report rating scales suggest a considerable overlap regarding symptom complaints in patients with fibromyalgia (FM) and functional dyspepsia (FD), while clinical assessments point to important psychological differences. PURPOSE: To test the hypothesis that measurement of psychological state by means of content analysis of speech will demonstrate differentiation between the two patient groups and between patients with these disorders and age-matched population-based random sample controls. METHOD: The Giessener Symptom Complaints Checklist assessed somatic complaints. The computerised Gottschalk-Gleser content analysis method assessed psychological state in 42 females with FM, 17 females with FD and 48 population-based, randomly selected control subjects. RESULTS: FM patients score higher on mutilation anxiety than FD and control subjects. FD patients had the highest score for death anxiety. Mutilation anxiety and low hope score identified FM patients (sensitivity 68%, specificity 81%, overall classification 75%), but only 19% of the variation in total somatic complaints could be predicted from these or other psychological state scores. In FD patients, however, death anxiety explained 59% of the variance in gastrointestinal complaints. INTERPRETATION: Psychological state was differentiated among the three groups. Mutilation anxiety may be a psychological marker of an underlying neurobiological vulnerability for FM or may represent a secondary long-term consequence of chronic illness. In FD, death anxiety is directly related to symptom complaints, suggesting a stronger etiological association between emotions and somatic complaints in this disorder.

Altered dopamine D2 receptor function in fibromyalgia patients: a neuroendocrine study with buspirone in women with fibromyalgia compared to female population based controls.

BACKGROUND: To what extent fibromyalgia belongs to affective spectrum disorders or anxiety spectrum disorders remains disputed. Buspirone induces a hypothermic response, which most likely is due to 5-HT(1A) autoreceptor stimulation, and growth hormone (GH) release, which probably is related to postsynaptic 5-HT(1A) receptor stimulation. The prolactin response to buspirone has been suggested to be mediated through dopamine (DA) antagonistic effects. OBJECTIVES: Based on the assumption that fibromyalgia is more strongly related to stress and anxiety than affective spectrum disorders, we hypothesized that compared to population controls, fibromyalgia patients should demonstrate an increased prolactin response (DA sensitivity) to buspirone challenge test, but no difference in hypothermic response or GH release (5HT sensitivity). METHOD: A 60-mg dose of buspirone was given orally to 22 premenopausal women with fibromyalgia and 14 age and sex matched healthy control subjects. Core body temperature, growth hormone and prolactin levels were analyzed at baseline and after 60, 90, and 150 min. RESULTS: Fibromyalgia patients showed an augmented prolactin response to buspirone compared to controls. Temperature and growth hormone responses did not differ from controls. CONCLUSIONS: Dopaminergic rather than serotonergic neurotransmission is altered in fibromyalgia, suggesting increased sensitivity or density of dopamine D(2) receptors in fibromyalgia patients. Stress and anxiety is an important modulator of dopaminergic neurotransmission. Our results suggest that fibromyalgia is related to anxiety and associated with disturbance in the stress response systems.

[Functional somatic diseases--a review]. / Funksjonelle somatiske lidelser--en oversikt.

Functional somatic illness is a clinical concept used to define medically unexplained somatic symptoms considered to express psychological distress. Functional somatic illness may express underlying psychiatric disorders (e.g. fibromyalgia due to non-fearful panic disorder, irritable bowel syndrome due to bipolar disorder). Sustained physiological activation caused by stressful life events combined with catastrophic thinking may be another cause. Functional somatic illness may also be caused by classic conditioning of physiological responses that may have been triggered by biological or emotional stimuli. Operant conditioning may also be a cause. The therapeutic alliance relies on acceptance of the reality of the subjective complaints, without a priori acceptance of the patient's attribution of the cause of the symptoms. We recommend initial exploration of the patient's own ideas about aetiology, including appropriate medical tests. The physician should then change the agenda to a biopsychosocial perspective and identify current stressors and psychosocial variables that reinforce symptoms. Only a few randomised trials have been performed. They suggest that psychological treatment should be systematic and structured, with a focus on information, alternative ways of perception, and problem solving. Active forms of physiotherapy and psychopharmacological drugs may be of some benefit in selected patients.

[Whiplash injuries--a psychosomatic perspective]. / Nakkeskader med whiplashmekanisme--et psykosomatisk perspektiv.

BACKGROUND: Psychosocial impairment after whiplash injury could be extensive; presumably about 15% of whiplash patients suffer from long lasting disabling health problems and about 5% do not return to work. MATERIAL AND METHODS: A PubMed search of all available literature on whiplash and whiplash-associated disorders was performed. RESULTS: Psychosocial impairment following whiplash injury is influenced by vulnerability factors, the biomechanical trauma and factors affecting symptom formation. Vulnerability factors indicating a poorer prognosis include low mental abilities, previous mental illness, old age and female sex, pre-existing cervical degenerative changes, narrow spinal canal and high neurobiological reactivity to sustained activation. The actual physical trauma consists of a nonphysiologic kinematic response in the cervical column, which may induce stress in neural structures, facet joints and musculature. Activation of reflex connections may lead to disturbances in the posture control and autonomic system. Trauma-related prognostic factors include head position at impact and degree of acute psychological stress reactions. Manual work, expectation of disability and an ongoing compensation claim case seem to be important moderator variables affecting symptom formation. INTERPRETATION: An integrated psychosomatic model is needed to explain psychosocial impairment after whiplash injury as presented.

Factors explaining variance in perceived pain in women with fibromyalgia.

BACKGROUND: We hypothesized that a substantial proportion of the subjectively experienced variance in pain in fibromyalgia patients would be explained by psychological factors alone, but that a combined model, including neuroendocrine and autonomic factors, would give the most parsimonious explanation of variance in pain. METHODS: Psychometric assessment included McGill Pain Questionnaire, General Health Questionnaire, Hospital Anxiety and Depression Rating Scale, Eysenck personality Inventory, Neuroticism and Lie subscales, Toronto Alexithymia Scale, and Multidimensional Health Locus of Control Scale and was performed in 42 female patients with fibromyalgia and 48 female age matched random sample population controls. A subgroup of the original sample (22 fibromyalgia patients and 13 controls) underwent a pharmacological challenge test with buspirone to assess autonomic and adrenocortical reactivity to serotonergic challenge. RESULTS: Although fibromyalgia patients scored high on neuroticism, anxiety, depression and general distress, only a minor part of variance in pain was explained by psychological factors alone. High pain score was associated with high neuroticism, low baseline cortisol level and small drop in systolic blood pressure after buspirone challenge test. This model explained 41.5% of total pain in fibromyalgia patients. In population controls, psychological factors alone were significant predictors for variance in pain. CONCLUSION: Fibromyalgia patients may have reduced reactivity in the central sympathetic system or perturbations in the sympathetic-parasympathetic balance. This study shows that a biopsychosocial model, including psychological factors as well as factors related to perturbations of the autonomic nervous system and hypothalamic-pituitary-adrenal axis, is needed to explain perceived pain in fibromyalgia patients.