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.

Anorexia nervosa in 51 Swedish adolescents: premorbid problems and comorbidity.

Fifty-one teenage cases with anorexia nervosa (AN) were compared with 51 age-, sex-, and school-matched cases with respect to premorbid developmental, physical, and psychiatric problems and comorbidity at the time of examination. Almost half of the AN group consisted of the total population of AN cases in one birth cohort. There were more premorbid personality problems in the AN group. Obsessive compulsive problems were very common in this group, as was undue concern about physical appearance. Depressive symptoms during the course of the eating disorder were almost universal in the AN group, but it did not appear that such symptoms had preceded the eating disorder. It seems that there may be a number of subgroups with AN and that the majority of these can be better understood in the light of factors intrinsic to the patients themselves rather than in the context of deviant family interaction.

The family background in anorexia nervosa: a population-based study.

A group of 51 cases with anorexia nervosa (including a total population of cases from one birth cohort) was compared with a sex-, age- and school-matched group of 51 cases on various measures of family demography and interactions. There was no support for the notion of a "typical anorexia nervosa family." However, there were more major problems in the anorexia group and there was also a higher prevalence of dead first-degree relatives and depression in the mothers.

Anorexia nervosa outcome: six-year controlled longitudinal study of 51 cases including a population cohort.

OBJECTIVE: Controlled study of intermediate term outcome of representative cases with adolescent-onset anorexia nervosa. METHOD: A group of 51 cases with anorexia nervosa with a mean age of reported onset of 14.3 years (including a total population of cases from one birth cohort) were compared with a sex-, age-, and school-matched group of 51 comparison subjects on various measures of outcome at a mean age of 21.0 years (6.7 years after reported onset and 4.9 years after the original diagnostic study). There was no attrition. This paper reports on results obtained using the Morgan-Russell scales. RESULTS: Forty-seven percent of the anorexia nervosa cases reported that they were recovered. In the unrecovered group all aspects of outcome were worse in the anorexia nervosa than in the comparison group. Differences between the two groups were particularly pronounced with regard to aspects of social relationships. CONCLUSIONS: Outcome was fairly similar to that reported in recent clinic-based samples. Poor outcome was associated with the presence of empathy deficits (problems understanding about other people's perspectives and difficulties interacting reciprocally). There is a need to find ways of subgrouping anorexia nervosa cases at onset. The subgroup with empathy deficits warrants more intensive study in future research and clinical practice.

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.

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.

Do some cases of anorexia nervosa reflect underlying autistic-like conditions?

In a sample of 51 teenagers with anorexia nervosa (AN)-which included 24 cases constituting the total population of AN cases born in 1970-several had shown social, communicative and behaviour patterns suggestive of autistic-like conditions as children, long before the onset of AN. One of the three boys in the AN group had Asperger syndrome. Three of the 48 girls had histories suggesting high functioning autism and continued to show many features typical of autism. Two further girls had Tourette syndrome and obsessive-compulsive traits in combination with social interaction problems. Eighteen other girls met criteria for obsessive-compulsive personality disorder (OCPD) and most of these also had had moderate-severe childhood social interaction problems. In a sex- and age-matched comparison group from the same schools, two girls had OCPD, but none had autistic-like conditions or Tourette syndrome. The results are discussed in the context of a recently suggested link between Asperger syndrome, Tourette syndrome and obsessive-compulsive problems, and it is suggested that AN in a subgroup of cases might represent a disorder belonging in the same class as autism and autistic-like conditions.

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.

[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.

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.

Chromosomes in anorexia nervosa. A study of 47 cases including a population-based group: a research note.

Forty-seven cases with anorexia nervosa (including a total population group) and 47 sex-, age-, and school-matched comparison cases were subjected to chromosome analyses in a blind fashion. No major abnormalities were found in any of the cases. Sex chromatin was analysed in buccal smears from the girls. No differences between the anorexia nervosa and the comparison cases were found. It seems that chromosomal/sex chromatin analyses in anorexia nervosa are not warranted.

Anorexia nervosa in a Swedish urban region. A population-based study.

The total population of 15-year-olds in Göteborg, Sweden, were screened in 1985 for anorexia nervosa using brief questionnaires, growth charts and individual school nurse reports. An accumulated frequency of anorexia of 0.84% for girls up to and including 15 years of age was obtained, with 85% of the cases fulfilling DSM-III-R criteria. Boys were affected just over one-tenth as often as girls. The frequency of anorexia nervosa appeared to be much higher in private than in comprehensive schools. The peak age of onset seemed to be 14 years.

Anorexia nervosa: who sees the patients and who do the patients see?

Two samples of patients with DSM-III-R anorexia nervosa, one identified by screening of a total population cohort and the other a mixed screening and referral group, were contrasted with a comparison group of sex-, age- and school-matched individuals. The rates and types of services consulted and treatment given were analyzed. The groups with anorexia nervosa tended to differ somewhat in these respects, although the numbers were too small for meaningful statistical calculations to be made. Only half of the total population sample had ever received any treatment for the eating disorder, even many years after anorexia nervosa onset in the teenage period. The implications of these findings are discussed both in terms of clinical needs and as they relate to previous research in anorexia nervosa, which has almost exclusively referred to non-population-based groups of patient.

Anorexia nervosa 6 years after onset: Part II. Comorbid psychiatric problems.

A sample of anorexia nervosa (AN) cases recruited after community screening were contrasted with an age-, sex-, and school-matched comparison (COMP) group with regard to comorbidity at age 21 years, approximately 6 years after the reported onset of the eating disorder. Both groups had originally been examined at age 16 years. Most of the AN cases no longer met criteria for AN, but many continued to meet criteria for bulimia nervosa (BN) or eating disorder NOS. In addition, there was a high rate of obsessive-compulsive disorders (OCDs). Affective disorders had been common throughout the follow-up period, but tended to follow the course of the eating disorder rather than to precede or postdate it. Underlying personality disorders tended to predict poor outcome.