Disruptive CHD8 mutations define a subtype of autism early in development.

Autism spectrum disorder (ASD) is a heterogeneous disease in which efforts to define subtypes behaviorally have met with limited success. Hypothesizing that genetically based subtype identification may prove more productive, we resequenced the ASD-associated gene CHD8 in 3,730 children with developmental delay or ASD. We identified a total of 15 independent mutations; no truncating events were identified in 8,792 controls, including 2,289 unaffected siblings. In addition to a high likelihood of an ASD diagnosis among patients bearing CHD8 mutations, characteristics enriched in this group included macrocephaly, distinct faces, and gastrointestinal complaints. chd8 disruption in zebrafish recapitulates features of the human phenotype, including increased head size as a result of expansion of the forebrain/midbrain and impairment of gastrointestinal motility due to a reduction in postmitotic enteric neurons. Our findings indicate that CHD8 disruptions define a distinct ASD subtype and reveal unexpected comorbidities between brain development and enteric innervation.

Subgrouping the autism "spectrum": reflections on DSM-5.

DSM-5 has moved autism from the level of subgroups ("apples and oranges") to the prototypical level ("fruit"). But making progress in research, and ultimately improving clinical practice, will require identifying subgroups within the autism spectrum.

Neurodevelopmental Disorders (ASD and ADHD): DSM-5, ICD-10, and ICD-11.

Neurodevelopmental disorders, specifically autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD) have undergone considerable diagnostic evolution in the past decade. In the United States, the current system in place is the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), whereas worldwide, the International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10) serves as a general medical system. This review will examine the differences in neurodevelopmental disorders between these two systems. First, we will review the important revisions made from the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR) to the DSM-5, with respect to ASD and ADHD. Next, we will cover the similarities and differences between ASD and ADHD classification in the DSM-5 and the ICD-10, and how these differences may have an effect on neurodevelopmental disorder diagnostics and classification. By examining the changes made for the DSM-5 in 2013, and critiquing the current ICD-10 system, we can help to anticipate and advise on the upcoming ICD-11, due to come online in 2017. Overall, this review serves to highlight the importance of progress towards complementary diagnostic classification systems, keeping in mind the difference in tradition and purpose of the DSM and the ICD, and that these systems are dynamic and changing as more is learned about neurodevelopmental disorders and their underlying etiology. Finally this review will discuss alternative diagnostic approaches, such as the Research Domain Criteria (RDoC) initiative, which links symptom domains to underlying biological and neurological mechanisms. The incorporation of new diagnostic directions could have a great effect on treatment development and insurance coverage for neurodevelopmental disorders worldwide.

Determination of psychosis-related clinical profiles in children with autism spectrum disorders using latent class analysis.

In children with autism spectrum disorders (ASD), high rates of idiosyncratic fears and anxiety reactions and thought disorder are thought to increase the risk of psychosis. The critical next step is to identify whether combinations of these symptoms can be used to categorise individual patients into ASD subclasses, and to test their relevance to psychosis. All patients with ASD (n = 84) admitted to a specialist national inpatient unit from 2003 to 2012 were rated for the presence or absence of impairment in affective regulation and anxiety (peculiar phobias, panic episodes, explosive reactions to anxiety), social deficits (social disinterest, avoidance or withdrawal and abnormal attachment) and thought disorder (disorganised or illogical thinking, bizarre fantasies, overvalued or delusional ideas). Latent class analysis of individual symptoms was conducted to identify ASD classes. External validation of these classes was performed using as a criterion the presence of hallucinations. Latent class analysis identified two distinct classes. Bizarre fears and anxiety reactions and thought disorder symptoms differentiated ASD patients into those with psychotic features (ASD-P: 51 %) and those without (ASD-NonP: 49 %). Hallucinations were present in 26 % of the ASD-P class but only 2.4 % of the ASD-NonP. Both the ASD-P and the ASD-NonP class benefited from inpatient treatment although inpatient stay was prolonged in the ASD-P class. This study provides the first empirically derived classification of ASD in relation to psychosis based on three underlying symptom dimensions, anxiety, social deficits and thought disorder. These results can be further developed by testing the reproducibility and prognostic value of the identified classes.

[Autism Spectrum Disorder and DSM-5: Spectrum or Cluster?]. / Autistische Störungen nach DSM-5: Spektrum oder Cluster?

Within the new DSM-5, the currently differentiated subgroups of "Autistic Disorder" (299.0), "Asperger's Disorder" (299.80) and "Pervasive Developmental Disorder" (299.80) are replaced by the more general "Autism Spectrum Disorder". With regard to a patient-oriented and expedient advising therapy planning, however, the issue of an empirically reproducible and clinically feasible differentiation into subgroups must still be raised. Based on two Autism-rating-scales (ASDS and FSK), an exploratory two-step cluster analysis was conducted with N=103 children (age: 5-18) seen in our social-pediatric health care centre to examine potentially autistic symptoms. In the two-cluster solution of both rating scales, mainly the problems in social communication grouped the children into a cluster "with communication problems" (51 % and 41 %), and a cluster "without communication problems". Within the three-cluster solution of the ASDS, sensory hypersensitivity, cleaving to routines and social-communicative problems generated an "autistic" subgroup (22%). The children of the second cluster ("communication problems", 35%) were only described by social-communicative problems, and the third group did not show any problems (38%). In the three-cluster solution of the FSK, the "autistic cluster" of the two-cluster solution differentiated in a subgroup with mainly social-communicative problems (cluster 1) and a second subgroup described by restrictive, repetitive behavior. The different cluster solutions will be discussed with a view to the new DSM-5 diagnostic criteria, for following studies a further specification of some of the ASDS and FSK items could be helpful.

Autism in context 1: Classification, counting and causes.

This review paper describes our current perspective of autism spectrum disorders (ASD), taking into account past, current and future classification systems and the evolving definitions of ASD. International prevalence rates from 1965 to 2012 are presented and key issues, including whether there is an epidemic of autism and what this means in terms of thinking about possible causes of autism, are discussed. Also discussed is the need for high quality national data collection in Australia and the evidence, and lack of evidence, for the many theoretical causes of ASD. The lack of robust classification of autism along with limited high quality evidence base about its prevalence and possible causes leaves ample space for future discoveries.

Terminological debate over language impairment in children: forward movement and sticking points.

BACKGROUND: There is no agreed terminology for describing childhood language problems. In this special issue Reilly et al. and Bishop review the history of the most widely used label, 'specific language impairment' (SLI), and discuss the pros and cons of various terms. Commentators from a range of backgrounds, in terms of both discipline and geographical background, were then invited to respond to each lead article. AIMS: To summarize the main points made by the commentators and identify (1) points of consensus and disagreement, (2) issues for debate including the drivers for change and diagnostic criteria, and (3) the way forward. CONCLUSIONS & IMPLICATIONS: There was some common ground, namely that the current situation is not tenable because it impedes clinical and research progress and impacts on access to services. There were also wide-ranging disagreements about which term should be adopted. However, before debating the broad diagnostic label it is essential to consider the diagnostic criteria and the systems used to classify childhood language problems. This is critical in order to facilitate communication between and among clinicians and researchers, across sectors (in particular health and education), with the media and policy-makers and with families and individuals who have language problems. We suggest four criteria be taken into account when establishing diagnostic criteria, including: (1) the features of language, (2) the impact on functioning and participation, (3) the presence/absence of other impairments, and (4) the language trajectory or pathway and age of onset. In future, these criteria may expand to include the genetic and neural markers for language problems. Finally, there was overarching agreement about the need for an international and multidisciplinary forum to move this debate forward. The purpose would be to develop consensus regarding the diagnostic criteria and diagnostic label for children with language problems. This process should include canvassing the views of families and people with language problems as well as the views of policy-makers.

An etiologic classification of autism spectrum disorders.

BACKGROUND: Autism spectrum disorders (ASD) represent a common phenotype related to multiple etiologies, such as genetic, brain injury (e.g., prematurity), environmental (e.g., viral, toxic), multiple or unknown causes. OBJECTIVES: To devise a clinical classification of children diagnosed with ASD according to etiologic workup. METHODS: Children diagnosed with ASD (n = 436) from two databases were divided into groups of symptomatic cryptogenic or idiopathic, and variables within each database and diagnostic category were compared. RESULTS: By analyzing the two separate databases, 5.4% of the children were classified as symptomatic, 27% as cryptogenic and 67.75% as idiopathic. Among other findings, the entire symptomatic group demonstrated language delays, but almost none showed evidence for regression. Our results indicate similarities between the idiopathic and cryptogenic subgroups in most of the examined variables, and mutual differences from the symptomatic subgroup. The similarities between the first two subgroups support prior evidence that most perinatal factors and minor physical anomalies do not contribute to the development of core symptoms of autism. CONCLUSIONS: Differences in gender and clinical and diagnostic features were found when etiology was used to create subtypes of ASD. This classification could have heuristic importance in the search for an autism gene(s).

[DMS-5 - attention-deficit/hyperactivity disorder]. / DSM-5 - Aufmerksamkeitsdefizit-/Hyperaktivitätsstörungen.

Modifications to the DSM-5 criteria for the diagnosis of attention-deficit/hyperactivity disorders are described and discussed. The main modifications concern the onset of the disorder, the reduction on the number of criteria fulfilled for a diagnosis in patients aged 17 years or older, and the elimination of autism spectrum disorders as an exclusion criterion for this diagnosis. These changes are mainly welcomed. However, the demanded increase in the age for the latest onset of the disorder may prove to be problematic.

[Autism Spectrum Disorder in DSM-5 - concept, validity, and reliability, impact on clinical care and future research]. / Autismus-Spektrum Störung nach DSM-5. Konzeptualisierung validität und reliabilität, bedeutung für klinik, Versorgung und forschung.

Autism Spectrum Disorder (ASD) in DSM-5 comprises the former DSM-IV-TR diagnoses of Autistic Disorder, Asperger's Disorder and PDD-nos. The criteria for ASD in DSM-5 were considerably revised from those of ICD-10 and DSM-IV-TR. The present article compares the diagnostic criteria, presents studies on the validity and reliability of ASD, and discusses open questions. It ends with a clinical and research perspective.

[Autism spectrum syndrome replaces Asperger syndrome and autism]. / Autismspektrumsyndrom ersätter Aspergers syndrom och autism.

Autism spectrum disorder describes a behaviourally defined impairment in social interaction and communication, along with the presence of restricted interests and repetitive behaviours. Although the etiology is mostly unknown, it is evident that biological factors affect the brain and result in the autistic clinical presentation. Assessment for diagnosing autism spectrum disorder should be comprehensive in order to cover all sorts of problems related to the disorder. Knowledge and experience from working with neurological and psychiatric disorders are a prerequisite for quality in the examination. Up to now, there is no cure for autism spectrum disorder, but support and adaptations in education are nevertheless important for obtaining sufficient life quality for the patients and the family.

[ESSENCE gathers the diagnoses into a whole]. / ESSENCE samlar diagnoserna till en helhet.

Co-existence of attention-deficit/hyperactivity disorder, oppositional defiant disorder, tic disorders, developmental coordination disorder, language disorder, learning problems, and autism spectrum disorder and sharing of symptoms across disorders, contribute to the typical clinical presentation in child psychiatry as well as in developmental medicine. The acronym ESSENCE refers to Early Symptomatic Syndromes Eliciting Neurodevelopmental Clinical Examinations. Affected children are brought for clinical assessment because of impairing symptoms that raise concern before the age of about 5 years in general development, communication and language, social inter-relatedness, motor coordination, attention, activity, behaviour, mood, and/or sleep. Such children are usually in need of a range of expert assessments, but a holistic approach is rarely taken from the start. Major problems in at least one ESSENCE domain before 5 years of age predict poor mental health later in life. Expert ESSENCE centres for assessment, habilitation and treatment of these children are needed.

[Diagnosis and therapy are still challenging, despite the rapid growth of knowledge]. / Diagnostik och terapi utmanar än, trots snabb tillväxt av kunskap.

Psychiatric diagnoses are not reflections of the aetiology of the disorder, but rather lists of symptoms with considerable overlaps, which hamper research and may cause confusion. The diagnoses of autism spectrum disorder, attention deficit hyperactivity disorder and tic disorder are often comorbid along with a number of other symptomatic syndromes. Individual immune responsivity is possibly involved in pathophysiological mechanisms. Multiple environmental factors may contribute to the clinical phenotypes. Recent research supports to some extent the involvement of dietary and nutritional factors in ADHD. In spite of impressive progress in the molecular biological understanding of the pathophysiology of these disorders, treatment options are still limited and more research is warranted.

[Autism spectrum disorders - epidemiology, symptoms, comorbidity and diagnosis]. / Zaburzenia ze spektrum autyzmu - epidemiologia, objawy, wspólzachorowalnosc i rozpoznawanie.

In the new classification of American Psychiatric Association - DSM-5 - a category of autistic spectrum disorders (ASD) was introduced, which replaced autistic disorder, Asperger syndrome, childhood disintegrative disorder and pervasive developmental disorder not otherwise specified. ASD are defined by two basic psychopathological dimensions: communication disturbances and stereotyped behaviors, and the diagnosis is complemented with the assessment of language development and intellectual level. In successive epidemiological studies conducted in 21 century the prevalence of ASD has been rising, and currently is estimated at 1% in general population. The lifetime psychiatric comorbidity is observed in majority of patients. The most common coexisting diagnoses comprise disorders ofanxiety-affective spectrum, and in about 1/3 of patients attention deficit/ hyperactivity disorders could be diagnosed. Prodromal symptoms of ASD may emerge before 12 months of life, however reliability of diagnosis at such an early age is poor. Several screening instruments, based on the parental and/or healthcare professional assessments may be helpful in ASD detection. However, structured interviews and observation schedules remain the gold standard of diagnosis.

[DSM-5: neurodevelopmental disorders]. / Het hoofdstuk 'neurodevelopmental disorders' in de DSM-5.

BACKGROUND: The 5th edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM) was published in May, 2013. AIM: To review the changes in the diagnostic criteria for autism spectrum disorder (ASD) and ADHD in DSM-5, compared to DSM-IV. METHOD: The diagnostic criteria for ASD and ADHD in DSM-IV and DSM-5 are compared. The new diagnostic criteria are summarised and relevant literature is discussed. RESULTS: The new category ASD includes the majority of the pervasive developmental disorders; however, in DSM-5, patients without stereotypical patterns of behaviour or interests will, from now on, be classified as having Social Communication Disorder. The threshold for meeting the diagnostic criteria for adhd has been lowered slightly. However, this is supported by clinical and epidemiological data and is unlikely to result in over-diagnosis. CONCLUSION: Research into subtypes of asd may stagnate as a result of the changes introduced in DSM-5. For clinicians, the diagnostic criteria for ASD and ADHD may be more clear-cut and possibly more user-friendly than the diagnostic criteria for these disorders as given in dsm-iv.

Measurement equivalence of the autism symptom phenotype in children and youth.

BACKGROUND: The Autism Diagnostic Interview-Revised (ADI-R) is a gold standard assessment of Autism Spectrum Disorder (ASD) symptoms and behaviours. A key underlying assumption of studies using the ADI-R is that it measures the same phenotypic constructs across different populations (i.e., males/females, younger/older, verbal/nonverbal). The objectives of this study were to evaluate alternative measurement models for the autism symptom phenotype based on the ADI-R algorithm items and to examine the measurement equivalence of the most parsimonious and best fitting model across subgroups of interest. METHODS: Data came from the Autism Genome Project consortium and consisted of 3,628 children aged 4-18 years (84.2% boys and 75% verbal). Twenty-eight algorithm items applicable to both verbal and nonverbal participants were used in the analysis. Measurement equivalence of the autism phenotype was examined using categorical confirmatory factor analysis. RESULTS: A second-order model resembling the proposed DSM-5 two-factor structure of the phenotype showed good overall fit, but not for all the subgroups. The autism symptom phenotype was best indexed by the first-order, six-factor measurement model proposed by Liu et al. (2011). This model was well fitting and measurement equivalent across subgroups of participants (age, verbal ability and sex). CONCLUSIONS: The autism symptom phenotype is adequately characterized by a six-factor measurement model; this model appears to be measurement equivalent across subgroups of children and youth with ASD that differ in age, sex and verbal ability. The two-factor model provides equally good fit for the sample as a whole, but comparison of these two dimensions between subgroups that might differ in terms of age, sex or verbal ability is challenged by lack of measurement equivalence.

Diagnosing autism spectrum disorder: who will get a DSM-5 diagnosis?

BACKGROUND: Introduction of proposed criteria for DSM-5 Autism Spectrum Disorder (ASD) has raised concerns that some individuals currently meeting diagnostic criteria for Pervasive Developmental Disorder (PDD; DSM-IV-TR/ICD-10) will not qualify for a diagnosis under the proposed changes. To date, reports of sensitivity and specificity of the new criteria have been inconsistent across studies. No study has yet considered how changes at the 'sub domain' level might affect overall sensitivity and specificity, and few have included individuals of different ages and ability levels. METHODS: A set of DSM-5 ASD algorithms were developed using items from the Diagnostic Interview for Social and Communication Disorders (DISCO). The number of items required for each DSM-5 subdomain was defined either according to criteria specified by DSM-5 (Initial Algorithm), a statistical approach (Youden J Algorithm), or to minimise the number of false positives while maximising sensitivity (Modified Algorithm). The algorithms were designed, tested and compared in two independent samples (Sample 1, N = 82; Sample 2, N = 115), while sensitivity was assessed across age and ability levels in an additional dataset of individuals with an ICD-10 PDD diagnosis (Sample 3, N = 190). RESULTS: Sensitivity was highest in the Initial Algorithm, which had the poorest specificity. Although Youden J had excellent specificity, sensitivity was significantly lower than in the Modified Algorithm, which had both good sensitivity and specificity. Relaxing the domain A rules improved sensitivity of the Youden J Algorithm, but it remained less sensitive than the Modified Algorithm. Moreover, this was the only algorithm with variable sensitivity across age. All versions of the algorithm performed well across ability level. CONCLUSIONS: This study demonstrates that good levels of both sensitivity and specificity can be achieved for a diagnostic algorithm adhering to the DSM-5 criteria that is suitable across age and ability level.

High-functioning autism spectrum disorder as a basic disorder in adult psychiatry and psychotherapy: psychopathological presentation, clinical relevance and therapeutic concepts.

Autism spectrum disorder (ASD) is characterized by deficits in social cognition and competence, communication, highly circumscribed interests and a strong desire for routines. Besides, there are specific abnormalities in perception and language. Typical symptoms are already present in early childhood. Traditionally autism has been regarded as a severe form of neurodevelopmental disorder which goes along with overtly abnormal language, learning difficulties and low IQ in the majority of cases. However, over the last decades, it has become clear that there are also many patients with high-functioning variants of ASD. These are patients with normal language at a superficial level of description and normal and sometimes above average intelligence. In high-functioning variants of the disease, they may run unrecognized until late in adult life. High-functioning ASD is associated with a very high prevalence of comorbid classical psychiatric disorders such as depression, anxiety, ADHD, tics, psychotic symptoms or emotionally unstable syndromes. In many such cases, there is a causal relationship between ASD and the comorbid psychiatric conditions in that the specific ASD symptoms result in chronic conflicts, misunderstandings and failure in private and vocational relationships. These problems in turn often lead to depression, anxiety and sometimes psychosis-like stress reactions. In this constellation, ASD has to be regarded as a basic disorder with causal relevance for secondary psychiatric syndromes. In this paper, we summarize the classical presentation of high-functioning ASD in adult psychiatry and psychotherapy and suggest a nosological model to classify different ASD conditions instead. To conclude, we outline first treatment concepts in out- and in-patient settings.

Proposed changes to the American Psychiatric Association diagnostic criteria for autism spectrum disorder: implications for young children and their families.

The American Psychiatric Association has revised the diagnostic criteria for their DSM-5 manual. Important changes have been made to the diagnosis of the current (DSM-IV) category of Pervasive Developmental Disorders. This category includes Autistic Disorder (autism), Asperger's Disorder, and Pervasive Developmental Disorder Not Otherwise Specified (PDD-NOS). The DSM-5 deletes Asperger's Disorder and PDD-NOS as diagnostic entities. This change may have unintended consequences, including the possibility that the new diagnostic framework will adversely affect access to developmental interventions under Individuals with Disabilities Education Act (IDEA) programs, Early Intervention (for birth to 2 years olds) and preschool special education (for 3 and 4 years olds). Changing the current diagnosis of PDD-NOS to a "Social Communication Disorder" focused on language pragmatics in the DSM-5 may restrict eligibility for IDEA programs and limit the scope of services for affected children. Young children who meet current criteria for PDD-NOS require more intensive and multi-disciplinary services than would be available with a communication domain diagnosis and possible service authorization limited to speech-language therapy. Intensive behavioral interventions, inclusive group setting placements, and family support services are typically more available for children with an autism spectrum disorder than with diagnoses reflecting speech-language delay. The diagnostic distinction reflective of the higher language and social functioning between Asperger's Disorder and autism is also undermined by eliminating the former as a categorical diagnosis and subsuming it under autism. This change may adversely affect treatment planning and misinform parents about prognosis for children who meet current criteria for Asperger's Disorder.

Developmental language disorders: challenges and implications of cross-group comparisons.

Historically, specific language impairment (SLI) and language deficits associated with autism spectrum disorders (ASD) have been viewed as distinct developmental language disorders. However, over the last decade or so, a considerable amount of research has explored general similarities or specific areas of overlap between children with SLI and ASD based on language and cognitive profiles, neuroimaging findings, and genetic research. The clinical classification schemes that are used to identify the children necessarily influence the extent to which SLI and ASD are viewed as overlapping or distinct conditions. Yet, the criteria used to diagnose these two populations vary across countries and even across investigators within a given country. This necessarily impacts the findings from comparative investigations of these groups. With these challenges in mind, clinical implications of evidence for similarities and distinctions between children with SLI and ASD will be discussed with respect to differential diagnosis and treatment.