Visual scanning during emotion recognition in long-term recovered anorexia nervosa: An eye-tracking study.

OBJECTIVE: To examine Facial Emotion Recognition (FER) and visual scanning behavior (eye-tracking) during FER in women long-term recovered from teenage-onset anorexia nervosa (recAN) with and without autism spectrum disorder (±ASD) and age-matched comparison women (COMP), using a sensitive design with facial emotion expressions at varying intensities in order to approximate real social contexts. METHOD: Fifty-seven 38-47-year-old women (26 recAN of whom six with ASD, 31 COMP) participated in the study. They completed a non-verbal FER task, consisting of matching basic emotions at different levels of expression intensity with full emotional expressions. Accuracy, response time and visual scanning behavior were measured. RESULTS: There were no differences between recAN-ASD and COMP in FER accuracy and visual scanning behavior during FER, including eye viewing and hyperscanning. In an exploratory analysis, recAN+ASD were more accurate than recAN-ASD in identifying expressions at low intensity, but not at medium or high expression intensity. Accuracy was not associated with the extent of attention to the eye region. DISCUSSION: Our data indicate that women long-term recovered from adolescent-onset AN do not have deficits in basic FER ability and visual scanning behavior during FER. However, the presence of comorbid ASD might affect face processing in recovered AN. Future studies investigating basic FER in acute and recovered AN and other conditions need to ensure that the stimuli used are sensitive enough to detect potential deficits.

Meta-analysis of SHANK Mutations in Autism Spectrum Disorders: a gradient of severity in cognitive impairments.

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.

Mutations in the gene encoding the synaptic scaffolding protein SHANK3 are associated with autism spectrum disorders.

SHANK3 (also known as ProSAP2) regulates the structural organization of dendritic spines and is a binding partner of neuroligins; genes encoding neuroligins are mutated in autism and Asperger syndrome. Here, we report that a mutation of a single copy of SHANK3 on chromosome 22q13 can result in language and/or social communication disorders. These mutations concern only a small number of individuals, but they shed light on one gene dosage-sensitive synaptic pathway that is involved in autism spectrum disorders.

Genetic and functional analyses of SHANK2 mutations suggest a multiple hit model of autism spectrum disorders.

Autism spectrum disorders (ASD) are a heterogeneous group of neurodevelopmental disorders with a complex inheritance pattern. While many rare variants in synaptic proteins have been identified in patients with ASD, little is known about their effects at the synapse and their interactions with other genetic variations. Here, following the discovery of two de novo SHANK2 deletions by the Autism Genome Project, we identified a novel 421 kb de novo SHANK2 deletion in a patient with autism. We then sequenced SHANK2 in 455 patients with ASD and 431 controls and integrated these results with those reported by Berkel et al. 2010 (n = 396 patients and n = 659 controls). We observed a significant enrichment of variants affecting conserved amino acids in 29 of 851 (3.4%) patients and in 16 of 1,090 (1.5%) controls (P = 0.004, OR = 2.37, 95% CI = 1.23-4.70). In neuronal cell cultures, the variants identified in patients were associated with a reduced synaptic density at dendrites compared to the variants only detected in controls (P = 0.0013). Interestingly, the three patients with de novo SHANK2 deletions also carried inherited CNVs at 15q11-q13 previously associated with neuropsychiatric disorders. In two cases, the nicotinic receptor CHRNA7 was duplicated and in one case the synaptic translation repressor CYFIP1 was deleted. These results strengthen the role of synaptic gene dysfunction in ASD but also highlight the presence of putative modifier genes, which is in keeping with the "multiple hit model" for ASD. A better knowledge of these genetic interactions will be necessary to understand the complex inheritance pattern of ASD.

Extreme ("pathological") demand avoidance in autism: a general population study in the Faroe Islands.

Research into Pathological Demand Avoidance (PDA), which has been suggested to be a subgroup within the Autism Spectrum Disorder (ASD), is almost nonexistent in spite of the frequent reference to the condition in clinical practice. The total population of 15 to 24-year-olds in the Faroe Islands was screened for ASD, and 67 individuals were identified who met diagnostic criteria for ASD (corresponding to a general population prevalence of ASD of almost 1 %). Of these 67, 50 had parents who were interviewed using the Diagnostic Interview for Social and Communication Disorders (DISCO-11) which contains 15 "PDA-specific" items. Nine individuals met criteria for "possible clinical diagnosis of PDA", meaning that almost one in five of all with ASD also had indications of having had PDA in childhood, and that 0.18 % of the total population had had the combination of ASD and PDA. However, at the time of assessment, only one of the 9 individuals with possible PDA still met "full criteria". PDA possibly constitutes a considerable minority of all cases with ASD diagnosed in childhood, but criteria for the condition are unlikely to be still met in later adolescence and early adult life.

Heterozygous FA2H mutations in autism spectrum disorders.

BACKGROUND: Widespread abnormalities in white matter development are frequently reported in cases of autism spectrum disorders (ASD) and could be involved in the disconnectivity suggested in these disorders. Homozygous mutations in the gene coding for fatty-acid 2-hydroxylase (FA2H), an enzyme involved in myelin synthesis, are associated with complex leukodystrophies, but little is known about the functional impact of heterozygous FA2H mutations. We hypothesized that rare deleterious heterozygous mutations of FA2H might constitute risk factors for ASD. METHODS: We searched deleterious mutations affecting FA2H, by genotyping 1256 independent patients with ASD genotyped using Genome Wide SNP arrays, and also by sequencing in independent set of 186 subjects with ASD and 353 controls. We then explored the impact of the identified mutations by measuring FA2H enzymatic activity and expression, in transfected COS7 cells. RESULTS: One heterozygous deletion within 16q22.3-q23.1 including FA2H was observed in two siblings who share symptoms of autism and severe cognitive impairment, axial T2-FLAIR weighted MRI posterior periventricular white matter lesions. Also, two rare non-synonymous mutations (R113W and R113Q) were reported. Although predictive models suggested that R113W should be a deleterious, we did not find that FA2H activity was affected by expression of the R113W mutation in cultured COS cells. CONCLUSIONS: While our results do not support a major role for FA2H coding variants in ASD, a screening of other genes related to myelin synthesis would allow us to better understand the role of non-neuronal elements in ASD susceptibility.

Autism in the Faroe Islands: diagnostic stability from childhood to early adult life.

Childhood autism or autism spectrum disorder (ASD) has been regarded as one of the most stable diagnostic categories applied to young children with psychiatric/developmental disorders. The stability over time of a diagnosis of ASD is theoretically interesting and important for various diagnostic and clinical reasons. We studied the diagnostic stability of ASD from childhood to early adulthood in the Faroe Islands: a total school age population sample (8-17-year-olds) was screened and diagnostically assessed for AD in 2002 and 2009. This paper compares both independent clinical diagnosis and Diagnostic Interview for Social and Communication Disorders (DISCO) algorithm diagnosis at two time points, separated by seven years. The stability of clinical ASD diagnosis was perfect for AD, good for "atypical autism"/PDD-NOS, and less than perfect for Asperger syndrome (AS). Stability of the DISCO algorithm subcategory diagnoses was more variable but still good for AD. Both systems showed excellent stability over the seven-year period for "any ASD" diagnosis, although a number of clear cases had been missed at the original screening in 2002. The findings support the notion that subcategories of ASD should be collapsed into one overarching diagnostic entity with subgrouping achieved on other "non-autism" variables, such as IQ and language levels and overall adaptive functioning.

Mutations of the X-linked genes encoding neuroligins NLGN3 and NLGN4 are associated with autism.

Many studies have supported a genetic etiology for autism. Here we report mutations in two X-linked genes encoding neuroligins NLGN3 and NLGN4 in siblings with autism-spectrum disorders. These mutations affect cell-adhesion molecules localized at the synapse and suggest that a defect of synaptogenesis may predispose to autism.

Somatic problems and self-injurious behaviour 18 years after teenage-onset anorexia nervosa.

The aim of this study was to study long-term outcome of physical health and self-injurious behaviour (SIB) in anorexia nervosa (AN). Fifty-one adolescent-onset AN cases, originally recruited after community screening, and 51 matched controls (COMP) were interviewed regarding somatic problems and SIB and physically examined 18 years after AN onset, at mean age 32 years. Six individuals had an eating disorder (ED). No one had died. The AN group weighed less than the COMP group. The frequency of somatic problems did not differ between groups. Dental enamel lesions and shorter than expected stature occurred only in the AN group. Dysdiadochokinesis was overrepresented in the AN group and age of AN onset was lower among those with the neurological deficit. Severe SIB occurred only in the AN group, predominantly during adolescence. To conclude, somatic problems were common in both groups. Most individuals in the AN group had recovered from their ED, but weight revealed a persistent restricted eating behaviour.

Genetic variations of the melatonin pathway in patients with attention-deficit and hyperactivity disorders.

Melatonin is a powerful antioxidant and a synchronizer of many physiological processes. Alteration in melatonin signaling has been reported in a broad range of diseases, but little is known about the genetic variability of this pathway in humans. Here, we sequenced all the genes of the melatonin pathway -AA-NAT, ASMT, MTNR1A, MTNR1B and GPR50 - in 321 individuals from Sweden including 101 patients with attention-deficit/hyperactivity disorder (ADHD) and 220 controls from the general population. We could find several damaging mutations in patients with ADHD, but no significant enrichment compared with the general population. Among these variations, we found a splice site mutation in ASMT (IVS5+2T>C) and one stop mutation in MTNR1A (Y170X) - detected exclusively in patients with ADHD - for which biochemical analyses indicated that they abolish the activity of ASMT and MTNR1A. These genetic and functional results represent the first comprehensive ascertainment of melatonin signaling deficiency in ADHD.

An investigation of ribosomal protein L10 gene in autism spectrum disorders.

BACKGROUND: Autism spectrum disorders (ASD) are severe neurodevelopmental disorders with the male:female ratio of 4:1, implying the contribution of X chromosome genetic factors to the susceptibility of ASD. The ribosomal protein L10 (RPL10) gene, located on chromosome Xq28, codes for a key protein in assembling large ribosomal subunit and protein synthesis. Two non-synonymous mutations of RPL10, L206M and H213Q, were identified in four boys with ASD. Moreover, functional studies of mutant RPL10 in yeast exhibited aberrant ribosomal profiles. These results provided a novel aspect of disease mechanisms for autism--aberrant processes of ribosome biosynthesis and translation. To confirm these initial findings, we re-sequenced RPL10 exons and quantified mRNA transcript level of RPL10 in our samples. METHODS: 141 individuals with ASD were recruited in this study. All RPL10 exons and flanking junctions were sequenced. Furthermore, mRNA transcript level of RPL10 was quantified in B lymphoblastoid cell lines (BLCL) of 48 patients and 27 controls using the method of SYBR Green quantitative PCR. Two sets of primer pairs were used to quantify the mRNA expression level of RPL10: RPL10-A and RPL10-B. RESULTS: No non-synonymous mutations were detected in our cohort. Male controls showed similar transcript level of RPL10 compared with female controls (RPL10-A, U = 81, P = 0.7; RPL10-B, U = 61.5, P = 0.2). We did not observe any significant difference in RPL10 transcript levels between cases and controls (RPL10-A, U = 531, P = 0.2; RPL10-B, U = 607.5, P = 0.7). CONCLUSION: Our results suggest that RPL10 has no major effect on the susceptibility to ASD.

Adolescent-onset anorexia nervosa: 18-year outcome.

BACKGROUND: The long-term outcome of anorexia nervosa is insufficiently researched. AIMS: To study prospectively the long-term outcome and prognostic factors in a representative sample of people with teenage-onset anorexia nervosa. METHOD: Fifty-one people with anorexia nervosa, recruited by community screening and with a mean age at onset of 14 years were compared with 51 matched comparison individuals at a mean age of 32 years (18 years after disorder onset). All participants had been examined at ages 16 years, 21 years and 24 years. They were interviewed for Axis I psychiatric disorders and overall outcome (Morgan-Russell assessment schedule and the Global Assessment of Functioning). RESULTS: There were no deaths. Twelve per cent (n=6) had a persisting eating disorder, including three with anorexia nervosa. Thirty-nine per cent of the anorexia nervosa group met the criteria for at least one psychiatric disorder. The general outcome was poor in 12%. One in four did not have paid employment owing to psychiatric problems. Poor outcome was predicted by premorbid obsessive-compulsive personality disorder, age at onset of anorexia nervosa and autistic traits. CONCLUSIONS: The 18-year outcome of teenage-onset anorexia nervosa is favourable in respect of mortality and persisting eating disorder.

Reproduction and offspring status 18 years after teenage-onset anorexia nervosa--a controlled community-based study.

OBJECTIVE: To study reproduction in a representative group of anorexia nervosa (AN) cases. METHOD: Fifty-one adolescent-onset AN cases (48 women; three men), originally recruited after community screening, and 51 matched comparison cases (COMP) were interviewed 18 years after AN onset at a mean age of 32 years, regarding pregnancies and early development of the children. RESULTS: The results of the 48 AN and 48 COMP group women are reported in the present study. Six women still had an eating disorder (ED), none of whom had become a mother. Twenty-seven women in the AN group and 31 women in the COMP group had children. Three women had an ED during pregnancy. Mean age at birth of the first child was lower in the AN group. Five AN women reported postpartum depression. Children in the AN group had significantly lower birth weight than the children in the COMP group. No other complications during pregnancy and the neonatal period differed across groups. Feeding difficulties were not overrepresented among the children of the AN group. DISCUSSION: Adults who had recovered from teenage-onset AN did not differ in most aspects from matched controls with respect to pregnancies and development of their offspring.

Asperger syndrome and autism: a comparative longitudinal follow-up study more than 5 years after original diagnosis.

Prospective follow-up study of 70 males with Asperger syndrome (AS), and 70 males with autism more than 5 years after original diagnosis. Instruments used at follow-up included overall clinical assessment, the Diagnostic Interview for Social and Communication Disorders, Wechsler Intelligence Scales, Vineland Adaptive Behavior Scales, and Global Assessment of Functioning Scale. Specific outcome criteria were used. Outcome in AS was good in 27% of cases. However, 26% had a very restricted life, with no occupation/activity and no friends. Outcome in the autism group was significantly worse. Males with AS had worse outcomes than expected given normal to high IQ. However, outcome was considerably better than for the comparison group of individuals with autism.

Analysis of X chromosome inactivation in autism spectrum disorders.

Autism spectrum disorders (ASD) are complex genetic disorders more frequently observed in males. Skewed X chromosome inactivation (XCI) is observed in heterozygous females carrying gene mutations involved in several X-linked syndromes. In this study, we aimed to estimate the role of X-linked genes in ASD susceptibility by ascertaining the XCI pattern in a sample of 543 informative mothers of children with ASD and in a sample of 163 affected girls. The XCI pattern was also determined in two control groups (144 adult females and 40 young females) with a similar age distribution to the mothers sample and affected girls sample, respectively. We observed no significant excess of skewed XCI in families with ASD. Interestingly, two mothers and one girl carrying known mutations in X-linked genes (NLGN3, ATRX, MECP2) showed highly skewed XCI, suggesting that ascertainment of XCI could reveal families with X-linked mutations. Linkage analysis was carried out in the subgroup of multiplex families with skewed XCI (> or = 80:20) and a modest increased allele sharing was obtained in the Xq27-Xq28 region, with a peak Z-score of 1.75 close to rs719489. In summary, our results suggest that there is no major X-linked gene subject to XCI and expressed in blood cells conferring susceptibility to ASD. However, the possibility that rare mutations in X-linked genes could contribute to ASD cannot be excluded. We propose that the XCI profile could be a useful criteria to prioritize families for mutation screening of X-linked candidate genes.

Autism in the Faroe Islands: an epidemiological study.

The Faroe Islands are considered to be a genetic isolate. This population study of the prevalence of autism sought to identify a representative cohort for future genetic studies. In 2002 all schools were screened for autism spectrum disorders. The target population were all children born in 1985 through 1994 and living in the Faroe Islands on December 31, 2002. Children who screened positive for autism characteristics were examined using the Diagnostic Interview for Social and Communication Disorders (DISCO). Of the children aged 8 through 17 years, 0.56% had childhood autism, Asperger syndrome or atypical autism. The male:female ratio was just under 6:1. The prevalence of autism in the Faroe Islands was very similar to that reported from many western countries.

Brief report: Decreased bone mineral density as a long-term complication of teenage-onset anorexia nervosa.

OBJECTIVE: To follow up bone mineral density (BMD) 4 years after decreased BMD was diagnosed in adult individuals with teenage-onset anorexia nervosa (AN). METHOD: In a previous study BMD was assessed in 39 individuals (36 women, 3 men) 11 years after AN onset. Decreased BMD occurred in a minority. In the present study, a 4-year follow-up of individuals with decreased BMD, 11 AN women were reassessed by using dual energy X-ray absorptiometry (DXA). Two women still had an eating disorder (ED). RESULTS: Eight out of eleven women met criteria for decreased BMD/osteoporosis. There was an increase in BMD of total body and lumbar spine (LS). There was a relationship between lumbar BMD and BMI. CONCLUSION: At follow-up of decreased BMD in adult women with teenage-onset of AN, there is a possibility of improvement of BMD.

Asperger syndrome in males over two decades: Quality of life in relation to diagnostic stability and psychiatric comorbidity.

This study examined objective quality of life (work, academic success, living situation, relationships, support system) and subjective quality of life (Sense of Coherence and Short-Form Health Survey-36) in an adult sample of males ( n = 50, mean age: 30 years) with Asperger syndrome diagnosed in childhood and followed prospectively over two decades. The association between long-term diagnostic stability of an autism spectrum disorder and/or comorbid psychiatric disorders with quality of life was also examined. The results showed great variability as regards quality of life. The subsample that no longer fulfilled an autism spectrum disorder had full-time jobs or studies (10/11), independent living (100%), and reported having two or more friends (100%). In the stable autism spectrum disorder group, 41% had full-time job or studies, 51% lived independently, and 33% reported two or more friends, and a significant minority had specialized employments, lived with support from the government, or had no friends. Academic success was positively correlated with IQ. A majority of the total group scored average Sense of Coherence scores, and the mean for Short-Form Health Survey-36 was above average regarding psychical health and below average regarding mental health. Stability of autism spectrum disorder diagnosis was associated with objective but not subjective quality of life, while psychiatric comorbidity was associated with subjective but not objective quality of life.

Boys with Asperger Syndrome Grow Up: Psychiatric and Neurodevelopmental Disorders 20 Years After Initial Diagnosis.

We examined comorbid psychiatric and neurodevelopmental disorders in fifty adult males (mean age 30 years) with Asperger syndrome (AS) diagnosed in childhood and followed up prospectively for almost two decades (13-26 years). Only three of the 50 men had never met criteria for an additional psychiatric/neurodevelopmental diagnosis and more than half had ongoing comorbidity (most commonly either ADHD or depression or both). Any psychiatric comorbidity increased the risk of poorer outcome. The minority of the AS group who no longer met criteria for a full diagnosis of an autism spectrum disorder were usually free of current psychiatric comorbidity. The high rate of psychiatric/neurodevelopmental comorbidities underscores the need for a full psychiatric/neurodevelopmental assessment at follow-up of males with AS.

Asperger syndrome in childhood - personality dimensions in adult life: temperament, character and outcome trajectories.

BACKGROUND: Temperament and character have been shown to be important factors in understanding psychiatric and neurodevelopmental disorder. Adults with autism spectrum disorder (ASD) have repeatedly been shown to have a distinct temperament and character, but this has not been evaluated in relation to psychiatric comorbidity and ASD diagnostic stability. AIMS: To examine temperament and character in males that were diagnosed with ASD in childhood and followed prospectively over almost two decades. METHOD: Temperament and character were assessed in 40 adult males with a childhood diagnosis of ASD. Results were analysed by the stability of ASD diagnosis over time and current psychiatric comorbidity. RESULTS: Three distinct temperament and character profiles emerged from the data. Those no longer meeting criteria for ASD had high reward dependence while those with a stable ASD diagnosis and psychiatric comorbidity showed elevated harm avoidance and low self-directedness and cooperativeness. Finally, those with a stable ASD and no comorbidity showed low novelty seeking and somewhat elevated harm avoidance. CONCLUSIONS: Temperament and character are important factors correlated with long-term diagnostic stability and psychiatric comorbidity in males diagnosed with ASD in childhood. DECLARATION OF INTEREST: None. COPYRIGHT AND USAGE: © The Royal College of Psychiatrists 2016. This is an open access article distributed under the terms of the Creative Commons Non-Commercial, No Derivatives (CC BY-NC-ND) licence.