[Show abstract][Hide abstract] ABSTRACT: Elevated whole-blood serotonin and decreased plasma melatonin (a circadian synchronizer hormone that derives from serotonin) have been reported independently in patients with autism spectrum disorders (ASDs). Here, we explored, in parallel, serotonin, melatonin and the intermediate N-acetylserotonin (NAS) in a large cohort of patients with ASD and their relatives. We then investigated the clinical correlates of these biochemical parameters. Whole-blood serotonin, platelet NAS and plasma melatonin were assessed in 278 patients with ASD, their 506 first-degree relatives (129 unaffected siblings, 199 mothers and 178 fathers) and 416 sex-and age-matched controls. We confirmed the previously reported hyperserotonemia in ASD (40% (35–46%) of patients), as well as the deficit in melatonin (51% (45–57%)), taking as a threshold the 95th or 5th percentile of the control group, respectively. In addition, this study reveals an increase of NAS (47% (41–54%) of patients) in platelets, pointing to a disruption of the serotonin-NAS–melatonin pathway in ASD. Biochemical impairments were also observed in the first-degree relatives of patients. A score combining impairments of serotonin, NAS and melatonin distinguished between patients and controls with a sensitivity of 80% and a specificity of 85%. In patients the melatonin deficit was only significantly associated with insomnia. Impairments of melatonin synthesis in ASD may be linked with decreased 14-3-3 proteins. Although ASDs are highly heterogeneous, disruption of the serotonin-NAS–melatonin pathway is a very frequent trait in patients and may represent a useful biomarker for a large subgroup of individuals with ASD. Translational Psychiatry (2014) 4, e●●; doi:10.1038/tp.2014.120; published online xx xxx 2014 INTRODUCTION Autism spectrum disorders (ASDs) are complex, heterogeneous and multifactorial disorders characterized by impaired social communication and repetitive/stereotyped behaviors. The diag-nosis of ASD currently relies entirely on patient clinical evaluation.
[Show abstract][Hide abstract] ABSTRACT: SHANK genes code for scaffold proteins located at the post-synaptic density of glutamatergic synapses. In neurons, SHANK2 and SHANK3 have a positive effect on the induction and maturation of dendritic spines, whereas SHANK1 induces the enlargement of spine heads. Mutations in SHANK genes have been associated with autism spectrum disorders (ASD), but their prevalence and clinical relevance remain to be determined. Here, we performed a new screen and a meta-analysis of SHANK copy-number and coding-sequence variants in ASD. Copy-number variants were analyzed in 5,657 patients and 19,163 controls, coding-sequence variants were ascertained in 760 to 2,147 patients and 492 to 1,090 controls (depending on the gene), and, individuals carrying de novo or truncating SHANK mutations underwent an extensive clinical investigation. Copy-number variants and truncating mutations in SHANK genes were present in ∼1% of patients with ASD: mutations in SHANK1 were rare (0.04%) and present in males with normal IQ and autism; mutations in SHANK2 were present in 0.17% of patients with ASD and mild intellectual disability; mutations in SHANK3 were present in 0.69% of patients with ASD and up to 2.12% of the cases with moderate to profound intellectual disability. In summary, mutations of the SHANK genes were detected in the whole spectrum of autism with a gradient of severity in cognitive impairment. Given the rare frequency of SHANK1 and SHANK2 deleterious mutations, the clinical relevance of these genes remains to be ascertained. In contrast, the frequency and the penetrance of SHANK3 mutations in individuals with ASD and intellectual disability-more than 1 in 50-warrant its consideration for mutation screening in clinical practice.
[Show abstract][Hide abstract] ABSTRACT: Perceiving others in pain generally leads to empathic concern, consisting of both emotional and cognitive processes. Empathy deficits have been considered as an element contributing to social difficulties in individuals with autism spectrum disorders (ASD). Here, we used functional magnetic resonance imaging and short video clips of facial expressions of people experiencing pain to examine the neural substrates underlying the spontaneous empathic response to pain in autism. Thirty-eight adolescents and adults of normal intelligence diagnosed with ASD and 35 matched controls participated in the study. In contrast to general assumptions, we found no significant differences in brain activation between ASD individuals and controls during the perception of pain experienced by others. Both groups showed similar levels of activation in areas associated with pain sharing, evidencing the presence of emotional empathy and emotional contagion in participants with autism as well as in controls. Differences between groups could be observed at a more liberal statistical threshold, and revealed increased activations in areas involved in cognitive reappraisal in ASD participants compared with controls. Scores of emotional empathy were positively correlated with brain activation in areas involved in embodiment of pain in ASD group only. Our findings show that simulation mechanisms involved in emotional empathy are preserved in high-functioning individuals with autism, and suggest that increased reappraisal may have a role in their apparent lack of caring behavior.
[Show abstract][Hide abstract] ABSTRACT: Despite the widely-held understanding that the biological changes that lead to autism usually occur during prenatal life, there has been relatively little research into the functional development of the brain during early infancy in individuals later diagnosed with autism spectrum disorder (ASD).
This review explores the studies over the last three years which have investigated differences in various brain regions in individuals with ASD or who later go on to receive a diagnosis of ASD.
We used PRISMA guidelines and selected published articles reporting any neurological abnormalities in very early childhood in individuals with or later diagnosed with ASD.
Various brain regions are discussed including; the amygdala; cerebellum; frontal cortex and lateralised abnormalities of the temporal cortex during language processing. This review discusses studies investigating head circumference, electrophysiological markers and inter-hemispheric synchronisation. All the recent findings from the beginning of 2009 across these different aspects of defining neurological abnormalities are discussed in light of earlier findings.
The studies across these different areas reveal the existence of atypicalities in the first year of life, well before ASD is reliably diagnosed. Cross-disciplinary approaches are essential to elucidate the pathophysiological sequence of events that lead to ASD.
[Show abstract][Hide abstract] ABSTRACT: This study investigated the utility of adult and infant vocalisation in the prediction of child psychopathology. Families were sampled from the Avon Longitudinal Study of Parents and Children (ALSPAC) birth cohort. Vocalisation patterns were obtained from 180 videos (60 cases and 120 randomly selected sex-matched controls) of parent-infant interactions when infants were one year old. Cases were infants who had been subsequently diagnosed aged seven years, with at least one psychiatric diagnostic categorisation using the Development and Wellbeing Assessment. Psychopathologies included in the case group were disruptive behaviour disorders, oppositional-conduct disorders, Attention Deficit Hyperactivity Disorder, pervasive development disorder, and emotional disorders. Associations between infant and parent vocalisations and later psychiatric diagnoses were investigated. Low frequencies of maternal vocalisation predicted later development of infant psychopathology. A reduction of five vocalisations per minute predicted a 44% (95%CI: 11-94%; p-value=0.006) increase in the odds of an infant being a case. No association was observed between infant vocalisations and overall case status. In sum, altered vocalisation frequency in mother-infant interactions at one year is a potential risk marker for later diagnosis of a range of child psychopathologies.
Research in developmental disabilities 01/2013; 34(3):985-993. · 4.41 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To establish which social interactive behaviours predict later psychiatric diagnosis, we examined 180 videos of a parent-infant interaction when children were aged one year, from within the Avon Longitudinal Study of Parents and Children (ALSPAC) cohort. Sixty of the videos involved infants who were later diagnosed with a psychiatric disorder at seven years, and 120 were a randomly selected sex-matched control group. Interactive behaviours for both the caregiver and the one year old infant were coded from the videos according to eight holistic categories of interpersonal engagement: Well-being, Contingent Responsiveness, Cooperativeness, Involvement, Activity, Playfulness, Fussiness, and Speech. Lower levels of adult activity and speech in interaction at one year significantly predicted overall diagnosis of child psychiatric disorder.
Research in developmental disabilities 10/2012; 34(1):562-572. · 4.41 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The striking excess of affected males in autism spectrum disorders (ASD) suggests that genes located on chromosome X contribute to the etiology of these disorders. To identify new X-linked genes associated with ASD, we analyzed the entire chromosome X exome by next-generation sequencing in 12 unrelated families with two affected males. Thirty-six possibly deleterious variants in 33 candidate genes were found, including PHF8 and HUWE1, previously implicated in intellectual disability (ID). A nonsense mutation in TMLHE, which encodes the ɛ-N-trimethyllysine hydroxylase catalyzing the first step of carnitine biosynthesis, was identified in two brothers with autism and ID. By screening the TMLHE coding sequence in 501 male patients with ASD, we identified two additional missense substitutions not found in controls and not reported in databases. Functional analyses confirmed that the mutations were associated with a loss-of-function and led to an increase in trimethyllysine, the precursor of carnitine biosynthesis, in the plasma of patients. This study supports the hypothesis that rare variants on the X chromosome are involved in the etiology of ASD and contribute to the sex-ratio disequilibrium.
[Show abstract][Hide abstract] ABSTRACT: One of the challenges of developmental psychopathology is to determine whether identifiable pathways to developmental disorders exist in the first months or years of life. Early identification of such disorders poses a similar challenge for clinical services. Using data from a large contemporary birth cohort, we examined whether psychopathology at age seven can be predicted from clinician observation at one year. Two groups of clinical raters observed videos of caregiver-infant interaction. Neither group of raters could reliably identify any precursors of later development of psychopathology in the one-year-old infants in this setting.
Research in developmental disabilities 07/2012; 33(6):2292-300. · 4.41 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Disruptive behaviour disorders (DBDs), including attention-deficit/hyperactivity disorder (ADHD), oppositional defiant disorder (ODD) and conduct disorder (CD) are chronic disorders with significant overlap in aetiology and presentation. An integrative examination of environmental risk factors is lacking. Six literature searches of web-based bibliographic databases were completed to identify literature on DBDs in general and five disorders in particular: CD, ODD, ADHD, deficits of attention, motor control and perception, and reactive attachment disorder. Searches were filtered to focus on studies including diagnostic assessment, focussing on environmental risk and protective factors in the first 4 years of life. The database searches generated 9806 papers of which 47 were reviewed after filters had been applied. The evidence suggests links between a number of early life risk factors and DBDs, including prenatal cigarette smoking and alcohol use, prenatal viral illness, maternal stress and anxiety, low birthweight, peri-partum and early neonatal complications, parental stress and parenting styles in infancy, early deprivation, adoption and separation. Despite the understanding that there is sharing of risk factors between the DBDs, there has been a disproportionate focus on the role of certain risk factors at the expense of others and the field is weakened by difficulties in controlling for all potential confounding variables.
Child Care Health and Development 02/2012; 38(5):611-28. · 1.70 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: A subgroup of persons with anorexia nervosa (AN) have been proposed to have sociocommunicative problems corresponding to autism spectrum disorders [ASDs, i.e. DSM-IV pervasive developmental disorders (PDDs): autistic disorder, Asperger's disorder, PDD not otherwise specified (NOS)]. Here, clinical problems, personality traits, cognitive test results and outcome are compared across 16 subjects (32%) with teenage-onset AN who meet or have met ASD criteria (AN+ASD), 34 ASD-negative AN subjects and matched controls from a longitudinal Swedish study including four waves of independent assessments from the teens to the early thirties.
The fourth wave included the Structured Clinical Interview for DSM-IV (SCID)-I and the SCID-II (cluster C, i.e. 'anxious' PDs) interviews, the Asperger Syndrome Diagnostic Interview, self-assessments by the Autism Spectrum Quotient and the Temperament and Character Inventory, neurocognitive tests by subscales from the Wechsler scales, continuous performance tests, Tower of London, and Happé's cartoons.
The ASD assessments had substantial inter-rater reliability over time (Cohen's κ between 0.70 and 0.80 with previous assessments), even if only six subjects had been assigned a diagnosis of an ASD in all four waves of the study, including retrospective assessments of pre-AN neurodevelopmental problems. The AN+ASD group had the highest prevalence of personality disorders and the lowest Morgan-Russell scores. The non-ASD AN group also differed significantly from controls on personality traits related to poor interpersonal functioning and on neurocognitive tests.
A subgroup of subjects with AN meet criteria for ASDs. They may represent the extreme of neurocognitive and personality problems to be found more generally in AN.
Psychological Medicine 12/2011; 42(9):1957-67. · 5.43 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Autistic-like traits (ALTs), that is restrictions in intuitive social interaction, communication and flexibility of interests and behaviors, were studied in two population-based Swedish twin studies, one in children and one in adults: (1) to examine whether the variability in ALTs is a meaningful risk factor for concomitant attention deficit hyperactivity disorder (ADHD), anxiety, conduct problems, depression and substance abuse, and (2) to assess whether common genetic and environmental susceptibilities can help to explain co-existence of ALTs and traits associated with such concomitant problems.
Two nationwide twin cohorts from Sweden (consisting of 11 222 children and 18 349 adults) were assessed by DSM-based symptom algorithms for autism. The twins were divided into six groups based on their degree of ALTs and the risk for concomitant mental health problems was calculated for each group. Genetic and environmental susceptibilities common to ALTs and the other problem types were examined using bivariate twin modeling.
In both cohorts, even the lowest degree of ALTs increased the risk for all other types of mental health problems, and these risk estimates increased monotonically with the number of ALTs. For all conditions, common genetic and environmental factors could be discerned. Overall, the phenotypic correlation between ALTs and the traits examined were less pronounced in adulthood than in childhood and less affected by genetic compared with environmental factors.
Even low-grade ALTs are relevant to clinical psychiatry as they increase the risk for several heterotypical mental health problems. The association is influenced partly by common genetic and environmental susceptibilities. Attention to co-existing ALTs is warranted in research on a wide range of mental disorders.
Psychological Medicine 03/2011; 41(11):2423-33. · 5.43 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Melatonin is a powerful antioxidant and a synchronizer of many physiological processes. Alteration of the melatonin pathway has been reported in circadian disorders, diabetes and autism spectrum disorders (ASD). However, very little is known about the genetic variability of melatonin receptors in humans. Here, we sequenced the melatonin receptor MTNR1A and MTNR1B, genes coding for MT1 and MT2 receptors, respectively, in a large panel of 941 individuals including 295 patients with ASD, 362 controls and 284 individuals from different ethnic backgrounds. We also sequenced GPR50, coding for the orphan melatonin-related receptor GPR50 in patients and controls. We identified six non-synonymous mutations for MTNR1A and ten for MTNR1B. The majority of these variations altered receptor function. Particularly interesting mutants are MT1-I49N, which is devoid of any melatonin binding and cell surface expression, and MT1-G166E and MT1-I212T, which showed severely impaired cell surface expression. Of note, several mutants possessed pathway-selective signaling properties, some preferentially inhibiting the adenylyl cyclase pathway, others preferentially activating the MAPK pathway. The prevalence of these deleterious mutations in cases and controls indicates that they do not represent major risk factor for ASD (MTNR1A case 3.6% vs controls 4.4%; MTNR1B case 4.7% vs 3% controls). Concerning GPR50, we detected a significant association between ASD and two variations, Delta502-505 and T532A, in affected males, but it did not hold up after Bonferonni correction for multiple testing. Our results represent the first functional ascertainment of melatonin receptors in humans and constitute a basis for future structure-function studies and for interpreting genetic data on the melatonin pathway in patients.
PLoS ONE 07/2010; 5(7):e11495. · 3.53 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To compare telephone interview screening for child psychiatric/neuropsychiatric disorders using the inventory of Autism-Tics, Attention deficit/hyperactivity disorder (AD/HD) and other Comorbidities (A-TAC) with results from the Child Behavior Checklist (CBCL).
The A-TAC is a parent telephone interview focusing on autism spectrum disorders (ASDs) and co-existing problems, developed for lay interviewers.
A-TAC telephone interviews and CBCL questionnaires were obtained from parents of 106 Swedish twin pairs aged 9 and 12 years.
Correlations between A-TAC modules and CBCL scales aimed at measuring similar concepts were generally significant albeit modest, with correlation coefficients ranging from 0.30 through 0.55.
The A-TAC has convergent validity with the CBCL in several problem areas, but the A-TAC also provides more detailed and specific assessments of ASD symptoms and related neuropsychiatric problems.
Nordic journal of psychiatry 03/2010; 64(3):218-24. · 0.99 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Reliable, valid, and easy-to-administer instruments to identify possible caseness and to provide proxies for clinical diagnoses are needed in epidemiological research on child and adolescent mental health.The aim of this study is to provide further validity data for a parent telephone interview focused on Autism--Tics, Attention-deficit/hyperactivity disorder (AD/HD), and other Comorbidities (A-TAC), for which reliability and preliminary validation data have been previously reported.
Parents of 91 children clinically diagnosed at a specialized Child Neuropsychiatric Clinic, 366 control children and 319 children for whom clinical diagnoses had been previously assigned were interviewed by the A-TAC over the phone. Interviewers were blind to clinical information. Different scores from the A-TAC were compared to the diagnostic outcome.
Areas under ROC curves for interview scores as predictors of clinical diagnoses were around 0.95 for most disorders, including autism spectrum disorders (ASDs), attention deficit/hyperactivity disorder (AD/HD), tic disorders, developmental coordination disorders (DCD) and learning disorders, indicating excellent screening properties. Screening cut-off scores with sensitivities above 0.90 (0.95 for ASD and AD/HD) were established for most conditions, as well as cut-off scores to identify proxies to clinical diagnoses with specificities above 0.90 (0.95 for ASD and AD/HD).
The previously reported validity of the A-TAC was supported by this larger replication study using broader scales from the A-TAC-items and a larger number of diagnostic categories. Short versions of algorithms worked as well as larger. Different cut-off levels for screening versus identifying proxies for clinical diagnoses are warranted. Data on the validity for mood problems and oppositional defiant/conduct problems are still lacking. Although the A-TAC is principally intended for epidemiological research and general investigations, the instrument may be useful as a tool to collect information in clinical practice as well.
[Show abstract][Hide abstract] ABSTRACT: Autism is a highly heritable disorder but the specific genes involved remain largely unknown. The higher prevalence of autism in men than in women, in conjunction with a number of other observations, has led to the suggestion that prenatal brain exposure to androgens may be of importance for the development of this condition. Prompted by this hypothesis, we investigated the potential influence of variation in the androgen receptor (AR) gene on the susceptibility for autism. To this end, 267 subjects with autism spectrum disorder and 617 controls were genotyped for three polymorphisms in exon 1 of the AR gene: the CAG repeat, the GGN repeat and the rs6152 SNP. In addition, parents and affected siblings were genotyped for 118 and 32 of the cases, respectively. Case–control comparisons revealed higher prevalence of short CAG alleles as well as of the A allele of the rs6152 SNP in female cases than in controls, but revealed no significant differences with respect to the GGN repeat. Analysis of the 118 families using transmission disequilibrium test, on the other hand, suggested an association with the GGN polymorphism, the rare 20-repeat allele being undertransmitted to male cases and the 23-repeat allele being overtransmitted to female cases. Sequencing of the AR gene in 46 patients revealed no mutations or rare variants. The results lend some support for an influence of the studied polymorphisms on the susceptibility for autism, but argue against the possibility that mutations in the AR gene are common in subjects with this condition.
[Show abstract][Hide abstract] ABSTRACT: To explore attachment narratives in children diagnosed with reactive attachment disorder (RAD).
We compared attachment narratives, as measured by the Manchester Child Attachment Story Task, in a group of 33 children with a diagnosis of RAD and 37 comparison children.
The relative risk (RR) for children with RAD having an insecure attachment pattern was 2.4 (1.4-4.2) but 30% were rated as securely attached. Within the RAD group, children with a clear history of maltreatment were more likely to be Insecure-Disorganised than children without a clear history of maltreatment.
Reactive attachment disorder is not the same as attachment insecurity, and questions remain about how attachment research informs clinical research on attachment disorders.
Journal of Child Psychology and Psychiatry 05/2009; 50(8):931-42. · 5.42 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Life-course persistent conduct disorder is a major public health problem with implications for individual health and for society at large. Recent evidence has shown that treatment can be cost-effective, and early symptom detection is improving. We weigh the evidence for and against the introduction of population screening for conduct disorder in early childhood using Wilson and Jungner's criteria.
Archives of Disease in Childhood 05/2009; 94(10):812-6. · 2.91 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: This study aimed to investigate electrophysiological correlates of initial attention orienting to temporally novel sound in children with autism (CWA).
Twenty-one CWA (4-8 years) and 21 age-matched typically developing children (TDC) were presented with pairs of clicks separated by a 0.5s intra-pair interval, with longer (7-9s) intervals between pairs. Children watched a silent movie during click presentation. We assessed EEG perturbations and event-related potentials (ERP) in response to sounds of different temporal novelty - first (S1) and second (S2) clicks in the pair.
In TDC, the early attention-modulated midtemporal N1c wave evoked by S1 and corresponding EEG phase locking and power increase were right-lateralized and were bilaterally higher than those evoked by S2. CWA demonstrated abnormal S1 responses, characterized by reduced N1c amplitude and EEG phase locking in the right midtemporal region, reversed leftward lateralization of the phase locking, and diminished later frontal N2 wave. Their brain responses to S2 were essentially normal.
The impaired right hemispheric processing of temporary and contextually novel information and suboptimal lateralization of normally right-lateralized attention networks may be important features of autistic disorder.
Results of this study contribute to the understanding of autism neurobiology.
Clinical neurophysiology: official journal of the International Federation of Clinical Neurophysiology 04/2009; 120(3):520-9. · 3.12 Impact Factor