CNTN6 mutations are risk factors for abnormal auditory sensory perception in autism spectrum disorders.

Contactin genes CNTN5 and CNTN6 code for neuronal cell adhesion molecules that promote neurite outgrowth in sensory-motor neuronal pathways. Mutations of CNTN5 and CNTN6 have previously been reported in individuals with autism spectrum disorders (ASDs), but very little is known on their prevalence and clinical impact. In this study, we identified CNTN5 and CNTN6 deleterious variants in individuals with ASD. Among the carriers, a girl with ASD and attention-deficit/hyperactivity disorder was carrying five copies of CNTN5. For CNTN6, both deletions (6/1534 ASD vs 1/8936 controls; P=0.00006) and private coding sequence variants (18/501 ASD vs 535/33480 controls; P=0.0005) were enriched in individuals with ASD. Among the rare CNTN6 variants, two deletions were transmitted by fathers diagnosed with ASD, one stop mutation CNTN6W923X was transmitted by a mother to her two sons with ASD and one variant CNTN6P770L was found de novo in a boy with ASD. Clinical investigations of the patients carrying CNTN5 or CNTN6 variants showed that they were hypersensitive to sounds (a condition called hyperacusis) and displayed changes in wave latency within the auditory pathway. These results reinforce the hypothesis of abnormal neuronal connectivity in the pathophysiology of ASD and shed new light on the genes that increase risk for abnormal sensory perception in ASD.

Genetic and functional analyses demonstrate a role for abnormal glycinergic signaling in autism.

Autism spectrum disorder (ASD) is a common neurodevelopmental condition characterized by marked genetic heterogeneity. Recent studies of rare structural and sequence variants have identified hundreds of loci involved in ASD, but our knowledge of the overall genetic architecture and the underlying pathophysiological mechanisms remains incomplete. Glycine receptors (GlyRs) are ligand-gated chloride channels that mediate inhibitory neurotransmission in the adult nervous system but exert an excitatory action in immature neurons. GlyRs containing the α2 subunit are highly expressed in the embryonic brain, where they promote cortical interneuron migration and the generation of excitatory projection neurons. We previously identified a rare microdeletion of the X-linked gene GLRA2, encoding the GlyR α2 subunit, in a boy with autism. The microdeletion removes the terminal exons of the gene (GLRA2(Δex8-9)). Here, we sequenced 400 males with ASD and identified one de novo missense mutation, p.R153Q, absent from controls. In vitro functional analysis demonstrated that the GLRA2(Δex8)(-)(9) protein failed to localize to the cell membrane, while the R153Q mutation impaired surface expression and markedly reduced sensitivity to glycine. Very recently, an additional de novo missense mutation (p.N136S) was reported in a boy with ASD, and we show that this mutation also reduced cell-surface expression and glycine sensitivity. Targeted glra2 knockdown in zebrafish induced severe axon-branching defects, rescued by injection of wild type but not GLRA2(Δex8-9) or R153Q transcripts, providing further evidence for their loss-of-function effect. Glra2 knockout mice exhibited deficits in object recognition memory and impaired long-term potentiation in the prefrontal cortex. Taken together, these results implicate GLRA2 in non-syndromic ASD, unveil a novel role for GLRA2 in synaptic plasticity and learning and memory, and link altered glycinergic signaling to social and cognitive impairments.

The sociocommunicative deficit subgroup in anorexia nervosa: autism spectrum disorders and neurocognition in a community-based, longitudinal study.

BACKGROUND: 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. METHOD: 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. RESULTS: 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. CONCLUSIONS: 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.

Autistic-like traits and their association with mental health problems in two nationwide twin cohorts of children and adults.

BACKGROUND: 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. METHOD: 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. RESULTS: 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. CONCLUSIONS: 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.

Abnormal melatonin synthesis in autism spectrum disorders.

Melatonin is produced in the dark by the pineal gland and is a key regulator of circadian and seasonal rhythms. A low melatonin level has been reported in individuals with autism spectrum disorders (ASD), but the underlying cause of this deficit was unknown. The ASMT gene, encoding the last enzyme of melatonin synthesis, is located on the pseudo-autosomal region 1 of the sex chromosomes, deleted in several individuals with ASD. In this study, we sequenced all ASMT exons and promoters in individuals with ASD (n=250) and compared the allelic frequencies with controls (n=255). Non-conservative variations of ASMT were identified, including a splicing mutation present in two families with ASD, but not in controls. Two polymorphisms located in the promoter (rs4446909 and rs5989681) were more frequent in ASD compared to controls (P=0.0006) and were associated with a dramatic decrease in ASMT transcripts in blood cell lines (P=2 x 10(-10)). Biochemical analyses performed on blood platelets and/or cultured cells revealed a highly significant decrease in ASMT activity (P=2 x 10(-12)) and melatonin level (P=3 x 10(-11)) in individuals with ASD. These results indicate that a low melatonin level, caused by a primary deficit in ASMT activity, is a risk factor for ASD. They also support ASMT as a susceptibility gene for ASD and highlight the crucial role of melatonin in human cognition and behavior.

Constitutional downregulation of SEMA5A expression in autism.

There is strong evidence for the importance of genetic factors in idiopathic autism. The results from independent twin and family studies suggest that the disorder is caused by the action of several genes, possibly acting epistatically. We have used cDNA microarray technology for the identification of constitutional changes in the gene expression profile associated with idiopathic autism. Samples were obtained and analyzed from 6 affected subjects belonging to multiplex autism families and from 6 healthy controls. We assessed the expression levels for approximately 7,700 genes by cDNA microarrays using mRNA derived from Epstein-Barr virus-transformed B lymphocytes. The microarray data were analyzed in order to identify up- or downregulation of specific genes. A common pattern with nine downregulated genes was identified among samples derived from individuals with autism when compared to controls. Four of these nine genes encode proteins involved in biological processes associated with brain function or the immune system, and are consequently considered as candidates for genes associated with autism. Quantitative real-time PCR confirms the downregulation of the gene encoding SEMA5A, a protein involved in axonal guidance. Epstein-Barr virus should be considered as a possible source for altered expression, but our consistent results make us suggest SEMA5A as a candidate gene in the etiology of idiopathic autism.

Bipolar disorder, schizophrenia, and other psychotic disorders in adults with childhood onset AD/HD and/or autism spectrum disorders.

Individuals with attention-deficit/hyperactivity disorder (AD/HD) and autism spectrum disorders (ASD) often display symptoms from other diagnostic categories. Exclusion criteria in the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) and the International Statistical Classification of Diseases and Related Health Problems (ICD-10) impede the use of categorical diagnoses to describe the particular problem constellation in a patient. In this study, we describe the prevalence and patterns of comorbid bipolar and psychotic disorders in 241 consecutively referred adult patients with AD/HD and/or ASD. Thirty per cent of patients with AD/HD had comorbid ASD and 38% of patients with ASD had comorbid AD/HD. Of the subjects with ASD, 7% had bipolar disorder with psychotic features, and 7.8% had schizophrenia or another psychotic disorder. The corresponding figures for the patients with AD/HD were 5.0% and 5.0%, respectively. Current diagnostic criteria have to be revised to acknowledge the comorbidity of bipolar and/or psychotic disorders in AD/HD and ASD.

Etiology and pathophysiology of autistic behavior: clues from two cases with an unusual variant of neuroaxonal dystrophy.

Two unrelated individuals with autistic behavior had numerous swollen axon terminals (spheroids) located in specific brain regions relevant to their behavioral symptoms. Spheroids are characteristic of neuroaxonal dystrophy, but the clinical profile and anatomic distribution of the lesions in these two patients differed from those of previously described patients with neuroaxonal dystrophy. Spheroids were numerous in the sensory nuclei of the spinal cord and medulla, specific nuclei and the reticular formation of the brainstem tegmentum, hypothalamus, anterior and dorsomedial thalamus, hippocampus, and cingulate and orbitofrontal cortices. Spheroids were sparse in the primary and association cortices and basal ganglia and absent in the hemispheric white matter. Cerebellar atrophy was present in both cases but associated with spheroids in only one case. These cases represent a new variant of neuroaxonal dystrophy in which behavioral symptoms characteristic of autism dominated the clinical picture. Neuroaxonal dystrophy should be included in the list of diseases that may be found in persons with autism.

The Asperger Syndrome (and high-functioning autism) Diagnostic Interview (ASDI): a preliminary study of a new structured clinical interview.

The development of the Asperger Syndrome (and high-functioning autism) Diagnostic Interview (ASDI) is described. Preliminary data from a clinical study suggest that inter-rater reliability and test-retest stability may be excellent, with kappas exceeding 0.90 in both instances. The validity appears to be relatively good. No attempt was made in the present study to validate the instrument as regards the distinction between Asperger syndrome and high-functioning autism.

Ten-year follow-up of adolescent-onset anorexia nervosa: psychiatric disorders and overall functioning scales.

The aim of this study was to assess prospectively the long-term outcome in a representative sample of teenage-onset anorexia nervosa (AN) in respect of psychiatric disorders and overall outcome. Fifty-one AN cases, recruited by community screening, with a mean age of onset of 14 years, was contrasted with 51 matched comparison cases at a mean age of 24 years (10 years after AN onset). All 102 cases had been examined at ages 16 and 21 years. At 24 years all probands were interviewed regarding psychiatric disorders (SCID-I) and overall outcome (Morgan-Russell assessment schedule, the GAF). There were no deaths at 10-year follow-up. One in four in the AN group had a persisting eating disorder (ED), including three who still had anorexia nervosa. Lifetime diagnoses of affective disorders and obsessive-compulsive disorder were over-represented in the AN group. Outcome according to Morgan-Russell was poor in 27%, intermediate in 29%, and good in 43%. According to the GAF, half the AN group had a poor psychosocial functioning. These were subjects with either a persisting ED or lifelong problems with social interaction or obsessive-compulsive behaviour. Ten-year outcome of teenage-onset AN is favourable in the majority of cases; most individuals have recovered from their ED and have no other axis I disorder. However, half the AN group reported poor psychosocial outcome, in most cases explained by a persisting ED or chronic obsessive-compulsive behaviour/social interaction problems.

Regional cerebral blood flow in weight-restored anorexia nervosa: a preliminary study.

Twenty-one individuals (19 females, two males) with teenage-onset anorexia nervosa (AN), 19 of whom were weight restored, were assessed using single-photon emission computed tomography (SPECT) 7 years after onset of AN, at a mean age of 22 years. For comparison we recruited a younger group without neuropsychiatric disorder (mean age 9:8 years; five females, four males) who underwent SPECT at follow-up after an operation for coarctation of the aorta or because of lymphatic leukaemia. Ethical considerations precluded the study of regional cerebral blood flow (rCBF) in participants with completely normal development. The group with AN showed marked hypoperfusion of temporal, parietal, occipital, and orbitofrontal lobes compared to the contrast group. rCBF was not correlated to body mass index in any of the groups. Results suggest that, even long after re-feeding has occurred, AN may be associated with moderate to severe cerebral blood flow hypoperfusion in the temporoparietal (or temporoparietooccipital) region and in the orbitofrontal region. A limitation of the study is that the young contrast group in this study could be expected to have a higher global rCBF than the group with AN. However, this should not significantly affect the relative values used in this study.

Depressive disorders in teenage-onset anorexia nervosa: a controlled longitudinal, partly community-based study.

The study objective was to examine the prevalence and course of depressive disorders (DDs) in teenage-onset anorexia nervosa (AN) over a period of 10 years. Fifty-one adolescents with AN and a sex- and age-matched control group (n = 51) were assessed at ages 16, 21, and 24 years. Probands and controls were examined in depth using semistructured and structured interviews. Their parents were interviewed on the occasion of the first examination. DDs were assessed using DSM-III-R criteria. Subjects with AN had a greatly increased rate of DDs (85%) of all kinds and at all ages as compared with control subjects. The risk of DD during the follow-up period from 21 up to and including 24 years could be predicted by diagnostic group status and the presence of DD during the period from 16 to 21 years, while the risk of DD during the follow-up period from 16 up to and including 21 years was solely predicted by the presence of AN at age 16 years. Long-term resolution of the eating disorder (ED) was associated with the absence of mood disorder or vice versa. Bipolar disorder (BP) occurred at roughly the expected rate (11%) among subjects (probands and controls) with major depression (MDD). In conclusion, depression is a very common comorbid problem in AN: more than four of five individuals with teenage-onset AN had at least one episode of DSM-III-R depression (MD or dysthymia [DT]) within 10 years after onset of the ED. AN appears to trigger the first episode of depression, but once it is manifest, depression predicts further depressive episodes.

Ten-year follow-up of adolescent-onset anorexia nervosa: physical health and neurodevelopment.

To study the development of physical health and some neuromotor functions in anorexia nervosa (AN) 51 individuals (48 females, three males) with a mean AN onset of 14 years, recruited after community screening, were followed prospectively together with 51 age-, sex-, and school-matched individuals without AN (controls). About 10 years after AN onset, all individuals were examined in respect of physical health and neurodevelopment. There were no deaths. Weight and height had normalised, except in three participants with persistent AN. Significantly more participants with AN had a physical complaint/disorder, including hirsutism. This might be a long-term complication in weight restored AN. Dysdiadochokinesis occurred almost exclusively among individuals with former AN in accordance with our previous studies.

Ten-year follow-up of adolescent-onset anorexia nervosa: personality disorders.

OBJECTIVE: To study the development of personality disorders, especially those involving obsessions, compulsions, and social interaction problems, in a representative group of anorexia nervosa (AN) cases. METHOD: The prevalence of personality disorders, obsessive-compulsive disorder, and autism spectrum disorders at mean age 24 years (10 years after reported onset) was examined in 51 adolescent-onset AN cases recruited after community screening and 51 comparison cases matched for age, sex, and school. All 102 cases had originally been examined at age 16 years and followed up at 21 years. At 24 years, structured and validated psychiatric diagnostic interviews were performed by a psychiatrist who was blind to original diagnosis. The majority of AN cases (94%) were weight-restored. RESULTS: Personality disorders, particularly cluster C, and autism spectrum disorders were overrepresented in the AN group. Obsessive-compulsive personality disorder and/or autism spectrum disorder was diagnosed in a subgroup of AN cases in all 3 studies. This subgroup had a very poor psychosocial outcome. CONCLUSIONS: Persistent problems with obsessions, compulsions, and social interaction characterized a substantial minority of weight-restored AN cases at 10-year follow-up. These problems appear to be constitutional rather than a result of AN, and they may warrant a different treatment approach.

Genome-wide scan for autism susceptibility genes. Paris Autism Research International Sibpair Study.

Family and twin studies have suggested a genetic component in autism. We performed a genome-wide screen with 264 microsatellites markers in 51 multiplex families, using non-parametric linkage methods. Families were recruited by a collaborative group including clinicians from Sweden, France, Norway, the USA, Italy, Austria and Belgium. Using two-point and multipoint affected sib-pair analyses, 11 regions gave nominal P -values of 0.05 or lower. Four of these regions overlapped with regions on chromosomes 2q, 7q, 16p and 19p identified by the first genome-wide scan of autism performed by the International Molecular Genetic Study of Autism Consortium. Another of our potential susceptibility regions overlapped with the 15q11-q13 region identified in previous candidate gene studies. Our study revealed six additional regions on chromosomes 4q, 5p, 6q, 10q, 18q and Xp. We found that the most significant multipoint linkage was close to marker D6S283 (maximum lod score = 2.23, P = 0.0013).

Familial factors in anorexia nervosa: a community-based study.

A group of 51 cases with teenage anorexia nervosa (AN; including a total population of cases from one birth cohort) were compared with a sex-, age-, and school-matched group of 51 cases on familial factors. The subjects were examined at age 16 and 21 years. In the first study, mothers of both groups were interviewed regarding physical and psychiatric disorders among first-degree relatives. In the followup study, the subjects were interviewed according to the same structured interview schedule. The data from these interviews were deidentified, and case notes were prepared by a clinician blind to group status. The randomly assorted case notes were then submitted to an experienced psychiatrist who also was blind to group status. There were more relatives with a history and symptoms suggestive of pervasive developmental disorders (PDD) and major depression in the AN group. There was also significantly more death in first-degree relatives of anorexia nervosa cases. In respect to many axis I DSM-IV diagnoses, including eating disorders and substance abuse, there were no significant differences across groups. Instead we found PDD symptoms, major depression, and death in first-degree relatives to be important in the AN group.

[Two sides of patients with eating disorders. One wants to get better, the other resists]. / Två sidor finns inom patienten med ätstörning: den ena vill bli frisk, den andra kämpar emot.

Anorexia and bulimia nervosa patients often require long-term treatment. The efficacy of different treatment approaches is insufficiently known, and for many years well-defined treatment goals were lacking. However, treatment studies are being published, or are under way. In this paper, the authors attempt to summarize the current state-of-knowledge in the field of eating disorder treatment.

Alexithymia in anorexia nervosa: a controlled study using the 20-item Toronto Alexithymia Scale.

The 20-item Toronto Alexithymia Scale (TAS) was completed at the age of 22 years by individuals who had previously suffered from anorexia nervosa (AN), and also by members of a comparison group. The AN and comparison groups had been recruited from community samples. Overall, the TAS scores did not clearly discriminate between the two groups. However, the AN group was significantly more often represented among subjects with the highest TAS scores. A subgroup with empathy disorder tended to have particularly high scores. It is concluded that alexithymia, as defined using the TAS-20, is found only in a subgroup of individuals with AN, and possibly more often in those who are also clinically diagnosed as suffering from empathy disorder. The TAS-20 is not suitable for screening of AN in the general population.