You are on page 1of 11

Eur J Pediatr (2008) 167:1091–1101 DOI 10.



What’s new in autism?
Jean G. Steyaert & Wouter De La Marche

Received: 10 March 2008 / Accepted: 14 May 2008 / Published online: 3 July 2008 # Springer-Verlag 2008

Abstract This review on autism spectrum disorder (ASD) focusses on recent insights in the clinical picture, such as continuity of the phenotype and the concept of broader phenotype, on epidemiology and on clinical issues relevant to physicians, including new methods for early screening and diagnosis, psychiatric and somatic co-morbidity, and the expansion of so-called complementary and alternative treatments. ASD is a disorder with mainly genetic causes and recent insights show that a variety of genetic mechanisms may be involved, i.e. single gene disorders, copy number variations and polygenic mechanisms. Technological advances in genetics have lead to a number of promising findings, which, together with other lines of fundamental research, suggest that ASD may be a disorder of connectivity in the brain, at least in a subgroup of patients. It is possible that part of the genetic load in autism actually reflects gene– environment interaction, but there is no evidence for purely environmental causes in a substantial number of cases. Clinical research suggests that ASD may be a multi-system disorder in at least a subgroup of subjects, affecting the gastro-intestinal (GI) tract, the immune system and perhaps other systems. Behavioural treatments remain the cornerstone of management, and are mainly aimed at stimulation of the domains of impaired development and reducing secondary behaviours. These treatments are constantly being
J. G. Steyaert (*) : W. De La Marche Department of Child and Adolescent Psychiatry, Katholieke Universiteit Leuven (UZ Leuven), Herestraat 49, 3000 Leuven, Belgium e-mail: J. G. Steyaert Department of Clinical Genetics, University Hospital of Maastricht, Maastricht, The Netherlands

refined, but the main progress in this area may be the increase of research on effectiveness. Keywords Autism . Review . Autism spectrum disorders . Pervasive developmental disorders Abbreviations ADHD Attention deficit and hyperactivity disorder ASD Autism spectrum disorder BAP Broader autism phenotype CAM Complementary and alternative medical treatments CDD Childhood disintegrative disorder DSM-IV Diagnostic and statistical manual of mental disorders, 4th edition GERD Gastro-oesophageal reflux disorder LKS Landau-Kleffner syndrome MEG Magnetoencephalography MNS Mirror neuron system PECS Picture exchange communication system PDD Pervasive developmental disorder PDD-NOS Pervasive developmental disorder not otherwise specified NLD Non-verbal learning disability SLI Specific language impairment TEACCH Treatment and Education of Autistic and related Communication-handicapped Children TSC Tuberous sclerosis complex

Introduction Since the first descriptions of early infantile autism [74] and Asperger’s syndrome [7], scientific findings have taken

41. There is still some ambiguity with this term [121]. the concept of BAP is confusing at the phenotypical level: do these relatives have a PDDNOS. not that of the so-called broader autism phenotype (BAP). a very mild ASD or just a normal variance? Researchers on the phenotype and genetics of ASD have pushed forward the concept of “narrow. For the sake of comprehensiveness. the ASD phenotype is a part of a broader genetic condition [53].g. i. Brain imaging. The same is true for children with so-called nonverbal learning disorder (NLD) [92.g. Smith-Lemni-Opitz syndrome (OMIM #270400) and 22q11-deletion (OMIM #192430) [4. but not fulfilling all of the diagnostic criteria of autism. This refers to relatives of subjects with ASD who have some characteristics of ASD but do not fulfil the criteria for it and have little or no impairment [40. in prevalence studies. PDD-NOS satisfies a diagnostic need for children with severe and pervasive impairment in the development of at least one of the symptom domains of autism. Both the prevalence of ASD and scientific findings on the subject seem to have exploded in the past two decades.e. One problem of the term PDD-NOS is that it may also apply to a number of subjects with quite different neuro-developmental disorders. Rett syndrome (OMIM #312750). geneticists will be interested in relatives with mild phenotypes. requiring more analogous therapeutic approaches. the authors summarise and discuss recent findings on different domains of research in autism. neuroscience and genetics have generated huge amounts of data. The classification systems DSM-IV [2] and ICD-10 [132] describe the autism phenotype in three domains: impairments in social interactions. 104]. fragile-X syndrome (OMIM #300624). e. BAP may be present in almost one in three first-degree relatives of subjects with an ASD [41]. as some authors limit the term ASD strictly to subjects with mild to severe deficits in the three core domains of autism. Rett syndrome. with probably more related aetiologies. while hypotheses on the pathogenesis. spanning the range from definitely impaired subjects to subjects with characteristics of ASD in the range of the normal population [128].1092 Eur J Pediatr (2008) 167:1091–1101 autism and autism spectrum disorders (ASD) from a rare and intriguing psychiatric condition to a rather common neuro-developmental disorder. . The diagnostic overlap between PDD-NOS and other neuro-developmental disorders also requires that clinicians seeing children with ASD/PDD have sufficient knowledge of other neurodevelopmental disorders in order to guarantee adequate differential diagnosis. In this review. Meanwhile. PDDs include Asperger’s syndrome. Many aspects of the condition remain unclear. We choose the former delineation. Besides autistic disorder. led to the development of the term “pervasive developmental disorders” (PDDs) [124]. 109]. while the public expects clinicians in childcare to be well acquainted with it. The large number of research articles on autism (4.467 PubMed hits for the last 5 years) does not allow a fully unbiassed review of the literature. OMIM #191100). nowadays. in particular. It is now the preferred term in many European countries. ASD or PDD has been used by the authors of a research article in order to be sure to which clinical group the findings apply. but where the criteria for specific PDDs are not met. a number of older articles were added.g. and absorbed by stereotypical movements and interests. thus. consequently equating the term ASD with the term PDD. with limited. Other authors include the other PDDs. Kanner [74] was the first to describe the child psychiatric disorder that is. while communication therapists will rather carry out research on children with severe phenotypes. This has led to diagnostic ambiguity and the term “autistic spectrum disorders” (ASDs) was introduced in the early 1990s. clinicians must deal with high expectations from parents and patients. children with severe specific language impairment (SLI) may have pervasive communication deficits and fulfil the criteria for PDDNOS. 108. childhood disintegrative disorder and PDD not otherwise specified (PDD-NOS). No quantitative statements are made. Another important aspect of the phenotype is the delineation of syndromic versus isolated ASD: in syndromic ASD. as this defines a more homogeneous group of disorders. The recognition of conditions with social-communicative impairment related to autism. connecting different research levels. In this manuscript. with a particular focus on clinical issues. Finally. e. The clinical picture In 1943. except that the signs and symptoms should be impairing. are still embryonic. unless there is a specific purpose for mentioning PDD. tuberous sclerosis complex (TSC. e. still accepted as the typical phenotype of autistic disorder. The question of delineation may be strongly influenced by the research field of the authors. even opting for the more restrictive definition of ASD does not solve all problems. In conclusion. impairments in communication. and restricted and repetitive patterns of behaviour and interests. there is no entire consensus about the terminology and one should check which definition of autism.” “broader” and “mild” phenotypes. and aetiological links are even more questionable. we will further use the more narrow definition of ASD. While there is evidence that these symptoms are genetically related to the symptoms in the proband. Emerging theories on the pathogenesis of autism are discussed briefly. including autistic disorder. bizarre or absent communication. mostly aloof children. Asperger’s syndrome and less specific clinical pictures. where the phenotypical links with ASD are imprecise.

see [133]). and these are very limited in ASD [119]. A large Canadian study reported a mild but significant increase in prevalence in consecutive birth cohorts [52]. Most studies report a male to female ratio of around 4:1 [8. There might be some diagnostic bias however. even found a prevalence of 1% for all PDDs in an urban area [12]. Association studies with candidate genes have led to some positive results [53. Several studies demonstrated that different domains of ASD are inherited independently [56. it may point to environmental effects. the fragileX gene [61]. ranging from 3. 53.000. the contactin-associated protein-like 2 gene [1] and genes involved in the regulated secretion pathway. Two carefully conducted studies in the US [8] and the UK [30] do not report significantly increased rates between different birth cohorts. very recently. molecular biology has already thrown some light on pathways involved in autism [102]. The BAP is distinct from normal variation [33]. and it is possible that different genes [53] and biological pathways contribute to different parts of the ASD phenotype. which plays a role in the secretion of neurotrophic factors [26. represents approximately 6–15% of all persons with autism. These and other findings suggest a complex heritability of autism. in twin studies. it is probably higher. The increase in prevalence of ASD is mainly administrative and linked to the broadening of diagnostic criteria and the improvement of diagnostic capacity [100. as the same cut-off scores are used for both males and females. research on other possible causes has begun to emerge. An important question is whether there is an “autism epidemic” [130]. late 1970s. even in single gene disorders associated with ASD. Nonetheless. The average recurrence risk in siblings is around 2–8% in families with one affected sibling [95]. Though differences in diagnostic procedures may partly underlie this finding. while there are mild gender differences for numerous aspects of typical development. 50. A limitation of candidate gene association studies is that they require pre-existing hypotheses about the involved neurobiological systems. A multi-site surveillance conducted by the US Centers for Disease Control and Prevention found marked regional differences in the prevalence of ASD [8]. 116]. Together with unique chromosomal anomalies. both in persons with normal intelligence and with mental retardation. More than 20 linkage studies have led to a host of candidate chromosome regions [60]. the focus was directed on the genetic causes [50] and. The genetics of ASDs Family and twin studies with narrow as well as broad definitions of the phenotype have generated overwhelming evidence that ASDs have a high heritability [9. The concordance rate for autism is 70% in monozygotic twins and rises to 90% if broader criteria are taken into account [83].6 per 1. Many of the candidate genes found so far play a role in synapse formation and plasticity.e. Besides genetic heterogeneity. the neurexin [77] and neuroligin genes [68]. 103]: (first-degree) relatives who have a significantly higher score in a least one symptom domain of ASD but who are not markedly impaired. The alarming increase in prevalence reported by the media is largely unsubstantiated. 52].000 to 10. A broader interpretation of the diagnostic criteria and the emergence of the concept of PDDs have led to an increase of the prevalence rates to around 34 per 10. i. 28]. In these genetically relatively simple models. approximately 1 in 2 in TSC and 1 in 4 in fragile-X syndrome. as demonstrated by the fact that. only a fraction of the subjects with the genetic condition has ASD. Asperger and several researchers in the 1960s and 1970s suggested underlying biological anomalies. suggesting a role for the serotonin system. the glutamate system and others [102]. The high heritability of ASD (see next section) does not rule out neither environmental effects nor gene–environment interaction. The biology of ASDs Kanner. 83]. this group. 107].000 children (for an overview. 49. A small secular increase in prevalence could also reflect such effects.000 for all PDDs [30]. cannot be differentiated from pure genetic effects. Since the .Eur J Pediatr (2008) 167:1091–1101 1093 125]. which. 26– 29]. 60]. Baird et al.e.000 children for autism [133] and 60 per 10. there is also important phenotypical heterogeneity. In families with more than one affected child. possibly higher in persons with normal intelligence. There is evidence for a BAP [41. It should be noted that the high heritability of ASD may partly reflect gene–environment interaction effects. it is difficult to compare different birth cohorts [97]. As the application of diagnostic criteria has changed. with demonstrable genetic aetiology. i. Other research methods include studying subjects with ASD associated with a single gene disorder or with a unique chromosomal defect affecting only one gene [1. with limited concordance between the studies. the administrative prevalence of ASD is still below the prevalence measured in epidemiological studies [116].3 per 1. These findings support the hypothesis that errors in neuronal connectivity may be causal in at least a sub- Epidemiology Early studies on the prevalence of autism reported prevalence rates in the range of 4–5 per 10. and the fraction is likely to be higher when micro-array comparative genome hybridisation is used [114].

in a majority of cases with autistic developmental regression before the age of 3 years. West or Lennox-Gastaut syndrome [18].000 [51]. Imitation has a key role in social cognition [55]. Courchesne and Pierce [37] found that early brain overgrowth is most pronounced in the frontal lobes. the gyrus fusiformis. Recently. a neural system in primates activated both when the subject performs an action and when it observes the same action performed by another individual. most of these CNVs are in different loci and. 72]. the specific diagnostic category of childhood disintegrative disorder (CDD) is used [2]. The endophenotype approach proposes that. disentangling them is important in the genetic counselling of families with an affected member. e.1094 Eur J Pediatr (2008) 167:1091–1101 population of subjects with ASD [57]. the cerebellum and the frontal lobes [13]. There are some early results of this approach. EEG patterns characteristic of LKS are found more frequently than in language regression with other characteristics of autistic regression. Epileptic abnormalities without clinical symptoms of epilepsy are frequent in ASD. abnormalities found in the adult brain may as well reflect a true anomaly in a given structure as the end-stage of compensatory development. Some brain imaging studies support this proposal [39]. and not the preceding developmental trajectory. though the “rare” variants group with major gene effects may be more frequent than expected. It is tempting to link dysfunctions in the MNS to early development in ASD. but does not apply to all children with ASD. Earlier structural and functional magnetic resonance imaging (fMRI) studies suggested anomalies in specific brain structures. The association between developmental regression. i. they are generally not characteristic for LKS. In the case of regression to autism after the age of 4 years. microduplications) have been found to be associated with ASD in a significant number of subjects and are repeated in different study populations. Even during the day-time. in particular during sleep [11]. A limitation of MRI and fMRI is that subjects are often adolescents or adults and that the findings only reflect the present state of the brain structure or functioning in the subject.e.2 [81. no epilepsy or other neurological disorders can be found [106]. 120] as a means to unravel the neurobiology of ASD and facilitate the search for candidate genes. In infants. the correlation between clinical paroxysmal phenomena and epileptic EEG abnormalities is limited in children with ASD [76]. In a small number of cases. Autism.e. It is generally assumed that the former group represents rare variants and the latter group more common variants. and even when EEG abnormalities occur in the latter group. The deregulation of cell growth. The discovery of the mirror neuron system (MNS) [43]. As the genetic and biological heterogeneity of ASD becomes more obvious. the subjects can be subgrouped on the basis of neurocognitive or biological characteristics that lay between the phenotype and the genotype. 82]. like magnetoencephalography (MEG) and EEG/ERP may be more promising. i. Though still equivocal. 128] and 15q11–13[53]. However. techniques that are applicable in very young children. has brought insight in the neural basis of imitation and perhaps of empathy. Early brain overgrowth occurs in children with ASD of all levels of cognitive functioning. a significantly higher frequency of de novo copy number variations (CNVs) was found children with ASD [114]. The prevalence of CDD is estimated at less than 1 in 10. A few chromosomal anomalies (microdeletions. apoptosis and/or white matter development in the first year(s) of life have been suggested as an underlying mechanism. epilepsy and developmental regression Epilepsy occurs in 8 to 42% of subjects with ASD [24] and often begins at a later age than epilepsy without ASD. suggest an increased incidence of germ line mutations in the parents of children who develop ASD than that they are loci that might play a role in a larger group of subjects with ASD [134]. the head circumference highly correlates with the total brain volume. 101]. These various findings suggest that both major gene effects and polygenic mechanisms—additive effect of several genes with minor impact—can lead to ASD. Anatomy and brain imaging The best replicated anatomic finding in ASD is the acceleration of head circumference growth in infancy [38. Autistic regression before the age of 3 years occurs in approximately 1 in 3 children with ASD [108]. Language regression with epileptic phenomena may be associated with Landau-Kleffner syndrome (LKS) or with autistic regression. These different mechanisms predict highly different heritability risks and. 16p11. though there is neither direct evidence of MNS damage in ASD nor of the causal direction of the association between MNS dysfunction and ASD. autistic regression is associated with an epileptic syndrome. rather. much attention has been paid to socalled endophenotypes [58. there are more argu- . There is evidence that these are two distinct conditions rather than one spectrum [94]: in isolated language regression. In order to understand early brain development in autism. the amygdala. followed by an earlier deceleration in head circumference growth [36]. i. Many findings have not been replicated [45. Taken together.e. According to the theory of interactive specialisation of the brain [70.g. epilepsy and ASD is even more complex [108]. in psychiatric conditions with genetic heterogeneity. association of large head circumference and an allele of the HOXA1-gene [32]. consequently.

published an article that associated measles or combined MMR vaccination. including lower validity in children under 2 years of age [31] or when they are used by untrained clinicians. The validity of autism screening instruments in children between one and two years of age. motor development and adaptive behaviour. Diagnosis and aetiological investigations Diagnosis of ASD Amongst clinicians. while it is unclear whether this is a consequence of autistic symptoms or a primary GI problem. 23.aap. in the absence of neurological signs. there is no diagnostic laboratory test. Levy et al. Nonetheless. but the findings are inconsistent and there is certainly not enough evidence [47] to start treatments targetting the immune system. they have some limitations. [85] confirmed the increased incidence of GI symptoms but found no association with dietary intake. In conclusion. Buie [22] found GERD in 24% of children with ASD and GI complaints. such as fears and acting-out behaviour. MMR vaccination. 87] and the Autism Diagnostic Interview—Revised (ADI-R) [88] have been well validated and their combination is now considered as the “gold standard” for ASD diagnosis [16]. Early treatment might restore that developmental trajectory towards more functional behaviour. Jyonouchi et al. A second rationale is that part of the impairment in ASD stems from secondary behaviour problems. Valicenti-McDermott et al. it has become increasingly clearer that ASD has varying trajectories in early development and that symptoms may overlap with normal developmental variance and with mental retardation [111. there is no argument for EEG or brain imaging in the group with autistic regression before the age of 3 years. the question is still regularly raised by parents and should be answered appropriately. see Lord and Corsello [86]). e. 122]. found a significantly high lifetime prevalence (70%) of GI symptoms in children with ASD compared to children with normal development or with other developmental disorders [123]. more attention has been paid to the equivocal association between ASD and GI symptoms. 52]. there is a wide consensus that treatment of ASD should start as early as possible. language. leading to overestimation of the abilities of the child. 135]. Though several co-authors retracted the article and large-scale epidemiological studies have never supported this association [44. gastro-intestinal (GI) symptoms and ASD [126]. 14]. [73] found deregulation in the production of cytokines against some food components. though hard evidence is rather limited [65]. Firstly. followed by referral to specialised teams in cases of positive screening [34]. The diagnosis is clinical and is based on the diagnostic criteria developed in the DSM-IV [2] and ICD-10 [132] and is supported by standardised diagnostic instruments. . Early psycho-education of the environment and behavioural treatment of specific problems may prevent secondary signs and symptoms and improve adaptive autism. that early treatment may curb some autistic characteristics that may have their own developmental momentum started but not amplified by genetic predisposition. while EEG is recommended in regression after that age. The Autism Diagnostic Observation Schedule (ADOS) [89. The reported GI symptoms are various: loose stools. The Developmental.cfm). atypical tummy aches and complaints suggesting gastro-oesophageal reflux disease (GERD). and should at least include the testing of cognitive abilities. They included food selectivity as a GI symptom. as the adaptive behaviour of children with ASD is often significantly lower than their cognitive abilities [78]. such as interviews and questionnaires (for an overview. Autism questionnaires require less clinical training than interviews and their diagnostic validity is lower. immunology and gastro-intestinal problems In 1998. Several studies have described autoimmune abnormalities and immune dysfunction (for a review. To date. at the same time. While early diagnosis is quite straightforward in severe autism. like the Modified Checklist for Autism in Toddlers (MCHAT) [10. as suggested by some researchers [59].Eur J Pediatr (2008) 167:1091–1101 1095 ments that CDD may be associated with epileptic phenomena [11. The current policy in infants and toddlers is a two-stage approach. see [6]). Recently. The latter is of particular importance. A comprehensive assessment of the strengths and weaknesses of the child is necessary in addition to the categorial diagnosis of ASD. The American Association of Pediatrics [71] provides guidelines and screening instruments for paediatricians (http://www. Wakefield et al. Dimensional and Diagnostic interview (3di) [118] is a new structured interview for the diagnosis of ASDs which offers the possibility to extend the interview to co-morbid disorders.g. chronic constipation. The rationale is twofold. has improved. if a lack of special interest in human faces in early infancy impairs the development of early social skills and. stimulates the development of stereotypical interest for objects than early intervention focussed at stimulating the interest in human faces might improve later social skills. suggesting a role of nonallergic food hypersensitivity. with wide screening by clinicians with no particular expertise in autism.

Individual or group training programmes have not shown much effectiveness. fasting glycaemia and lipidaemia. different approaches have been studied for their effective- . social and functional communication abilities are considered to be a priority in early treatment [105]. It is now increasingly accepted to make these comorbid diagnoses. 21. Tourette’s syndrome (approximately 10%) and other conditions are often present [15. There is now a growing interest for developmental-pragmatic approaches in which the focus is not necessarily spoken language [105]. Recent research [17. as children may be at higher risk for behavioural activation and disinhibition. In the past decade. 42. EEG is warranted when neurological signs or paroxysmal phenomena are present and in the case of regression after the age of 3 years. Medication trials have been performed with various medications and aimed at different target symptoms. attention deficit and hyperactivity disorder (ADHD). Other antipsychotic drugs are used for similar behaviour. Risperidone has been demonstrated to be beneficial for irritability. it has not been proven that psychopharmacotherapy may lead to significant improvement of the core symptoms of ASD [48]. Nevertheless. like teaching the child to express what he or she wants and feels by diverse means. or to change dysfunctional symptoms. as pupils with ASD often do not generalise the acquired skills to other contexts. but a significant effect on social-communicative features has not been demonstrated [93]. 35. ness and long-term outcome. Structured interviews like the 3di [118] or the DISC-IV [115] are additional tools to assess co-morbid psychiatric disorders. long registration is recommended. it is difficult to set up effectiveness studies for psychopharmacological treatment [5]. the full criteria for ADHD (approximately 25%). height. the need for training social communication skills remains present. if possible. but clear differences between the programmes have not yet emerged [105]. 113] Pharmacotherapy To date. 66. blood pressure and body mass index (BMI). 25] has been developed as an effective method to teach communication to children with autism. and more success is expected from fostering social communicative competence on-site across the different situations of an individual’s day [91]. A broader knowledge of child psychiatric conditions is necessary for a good appreciation of co-morbidity. 75] and may lead to considerable additional behavioural impairment [63]. If performed. repetitive behaviours and aggression. The Picture Exchange Communication System (PECS) [20. while evidence of therapeutic effects in Treatment issues Behavioural treatments Nowadays. but research-based evidence of their effectiveness is lacking.e. Paediatric assessment A comprehensive paediatric history and clinical examination are essential in children with ASD. these should be used with great care in children with ASD. Due to the heterogeneity of clinical presentation and most impairing symptoms in ASD. and the best consequence of the secretin hype was that it demonstrated that the research community has an ability to respond faster than in the past to such claims [110]. Their use in children has been much debated. high-resolution karyotype and DNA testing for fragile-X syndrome. 99]. Metabolic and other targetted tests or brain imaging can be performed on clinical indication. Most trials are open-label studies and case reports. and checking for possible effects of hyperprolactinaemia [35]. Earlier behavioural programmes focussed on the acquisition of speech in children with autism. 98]. as these will guide additional laboratory tests. The most important factor of success is an individualised approach [96. and there is only a limited number of randomised control trials (RCTs) [69. 110]. including sleep deprivation EEG [76]. i. Considering the possible long-term endocrine and metabolic side effects of classic and secondgeneration antipsychotics [3. In children with ASD and normal acquisition of spoken language. Selective serotonin reuptake inhibitors (SSRIs) are regularly used in patients with ASD. but functional communication. Miracle therapies like secretin treatment have soon proved to be unfounded [84]. and. 54. 80] on diagnostic yield and practice guidelines like those of the American Academy of Pediatrics [71] propose a rather conservative approach to additional laboratory tests: audiology evaluation in preschoolers. and the risk may be even greater in children with ASD [127]. strictly structured behavioural interventions are being supplemented with naturalistic behavioural interventions [67.1096 Eur J Pediatr (2008) 167:1091–1101 Comorbid psychiatric disorders The DSM-IV considers autism as a pre-emptive diagnosis and rules out the concurrent diagnosis of many co-morbid conditions. both for depressive disorder and for compulsive behaviour. To target skills other than communication. Preliminary recommendations propose to monitor every three months during the first year of life and then annually the weight. while it may reduce secondary or co-morbid symptoms to some extent. There is some debate on whether genetic testing should be performed in all children with ASD or only in children with mental retardation or dysmorphic signs.

examination by a clinical geneticist is recommended. approaches stimulating communication skills at an age as early as possible seem very promising besides older approaches based on adaptation of the environment. apart from the general insight that it behaves as a complex disorder. with heterogeneous aetiologies and effects on brain and cognition. a host of novel therapies have been developed.g. Though the clinical increase is still below the scientific prevalence level.g. So far. such as Treatment and Education of Autistic and related Communicationhandicapped Children (TEACCH). Other medical treatments Mostly based on hypotheses on the pathogenesis and incidental observations. and there are no particular contraindications. many of these treatments are not as harmless as parents like to think. One promising hypothesis that links a number of genetic and neurobiological findings is that of anomalies in brain connectivity. have rather demonstrated the lack of effect. infant siblings of children with ASD. side effects of antifungal agents or steroids. psycho-stimulants are being used for comorbid ADHD in ASD [48]. which deserve appropriate treatment. antifungal agents to reduce intestinal candida overgrowth and chelating agents. physicians cannot just discard the somatic questions that parents may have about their child with ASD. a 25-fold increase compared with 30 years ago. treatments targetting the immune system. Amongst the proposed treatments are elimination diets. so-called complementary and alternative medicine (CAM) have gained a large market share in the treatment of autism and often receive more attention in the media than scientifically proven treatments [117]. Though the genetic complexity makes it unlikely that a simple test with good screening properties will ever be found. If many genes are involved. The increase is mainly due to improving knowledge about the clinical picture. amongst which gastro-oesophageal reflux disorder (GERD) is perhaps the most relevant. the immune system and the gastro-intestinal (GI) tract. A real secular increase is at most low. or complications of strict elimination diets in growing children. and these should primarily be guided by history and clinical examination. Anomalies without much clinical relevance have been found in the immune system. Only the hearing test in young children and high-resolution karyotype and DNA for fragile-X are recommended in all children. However. it is possible that other systems of the organism are affected by the same genes. which will be very helpful in accepting or discarding some of the hypotheses about environmental factors and proposed “alternative” therapies and elimination diets. by the American Academy of Pediatrics. current findings suggest that. On hypothetical grounds. and when they have been performed. On the other hand. e. the number of effect studies of behavioural treatments is limited and . As there is no definite aetiological theory. there is only evidence of small environmental effects in the pathogenesis of ASD. Effective guidelines have been developed. the broadening of diagnostic criteria and the increase of diagnostic capacity. e. but in the coming years. stating that ASD is a disorder solely affecting brain development. growing insight in both the small-scale epidemiology and in the neurobiology of ASD may lead to the discovery of gene–environment interactions. micro-array technology will allow the prediction of the risk level in specific populations. It has been suggested that the required dosage of methylphenidate in ASD+ADHD is lower than in ADHD. At this stage. it has been proposed that SSRIs may modify key neurodevelopmental processes in very young children with ASD [19]. Nevertheless.g. e. Financial limitations may push parents to opt for CAMs only. dietary supplements and vitamins.g. almost three quarters of children with ASDs receive CAMs [62] in combination with more traditional treatments. and an array of GI complaints have been described.g. there are no comprehensive guidelines for aetiological investigations. Early detection is a particular challenge for genetic and neurobiological research in autism. Amongst treatments at the behaviour level. Conclusions The prevalence of autism spectrum disorder (ASD) seems to explode. a higher prevalence of food hypersensitivity [90]. but there is no research to support this. In the USA. A comprehensive and critical review can be found in Levy and Hyman’s paper [84]. e. many children with ASD have unusual somatic characteristics and complaints. Nonpsychiatric physicians are confronted with diagnostic and management questions for this group. e. To focus additional genetic testing. there is no comprehensive theory on the neurobiology of ASD. as famously demonstrated in the secretin case: the incidental observation that the core symptoms of autism improved significantly in three children after secretin perfusion [64] was not substantiated in 12 out of 13 placebo-controlled trials [46]. Considering the potential side effects of some of the above-mentioned treatments. Rigorous effect studies have not been performed for most of these therapies. it exceeds existing diagnostic and therapeutic capacity in many countries. with current estimates being around 1/160 people. in particular in children who are limited in communicating physical discomfort. in the coming years. More and more often. steroids. Consequently.Eur J Pediatr (2008) 167:1091–1101 1097 this group is limited [79].

1098 Eur J Pediatr (2008) 167:1091–1101 autism at 18 months of age: a 6-year follow-up study. Van de Ven WJM. Biol Psychiatry 61:545–550 4. pp 37–92 8. Strunge L. 4th edn. Fombonne E (2005) Pervasive developmental disorders in preschool children: confirmation of high prevalence. Meldrum D. DC 3. Kates WR (2007) Autistic spectrum disorders in velo-cardio facial syndrome (22q11. 19. Arnold LE. Arnold LE. Hornsey H. Carey JC (2006) Etiologic yield of autistic spectrum disorders: a prospective study. Baron-Cohen S. association. Devriendt K (2007) Identification and characterization of the TRIP8 and REEP3 genes on chromosome 10q21. Behav Modif 25:725–744 Buie T (2007) Gastrointestinal disorders and autism. Shprintzen RJ. Psychol Med 29:1151–1159 Battaglia A (2007) On the selection of patients with developmental delay/mental retardation and autism spectrum disorders for genetic studies. United States. 16. Am J Med Genet C Semin Med Genet 142:3–7 Besag FM (2004) Behavioral aspects of pediatric epilepsy syndromes. even if it is not evidence based. 11. Ledbetter DH. J Child Neurol 20:27–31 Carr D. Gottesman I. Van de Water J (2004) Is autism an autoimmune disease? Autoimmun Rev 3:557–562 7. AbdulSabur N. Anderson GM. Steyaert J. Crepel A. Frost L (2001) The Picture Exchange Communication System. McDougle CJ. Simonoff E. Acknowledgements This research was supported by the Clinical Research Fund of the University Hospital Leuven and by the Flanders Fund for Scientific Research (grant ZKB5798). Gillberg C (1992) Can autism be detected at 18 months? The needle. Cambridge University Press. Semin Speech Lang 19:373–388 Bondy A. Simonoff E. 15. 12. Eur Child Adolesc Psychiatry 16:61–66 Canitano R. electroencephalographic abnormalities. Posey DJ. J Autism Dev Disord 37:724–737 Castermans D. McGough JJ. 13. their side effects. Creemers JW. Washington. and the CHAT. Stallone K. Nelson SF. Duvall JA. Izaguirre J. the purely symptomatic effect of psychotropic drugs. 2002. McCracken JT. 21. Tierney E.and long-term risperidone treatment on prolactin levels in children with autism. Fremont WP. Klin A. Parthoens E. Washington. Schrander-Stumpel CT. Charman T. Volders K. 27. Autism 8:141–161 Castermans D. Research Units on Pediatric Psychopharmacology. 24. Bailey A. Boyd S. Eur J Hum Genet (in press) Chakrabarti S. McCracken JT. Frost LA (1998) The picture exchange communication system. GatesUlanet P. May 2007 Canitano R (2007) Epilepsy in autism spectrum disorders. MMWR Surveill Summ 56:12–28 9. Br J Psychiatry 161:839–843 Baron-Cohen S. Zappella M (2005) Epilepsy. Van de Ven WJ. Steyaert J. 22. Baird G. Though most physicians are not so tempted to read the alternative literature. and the limitations of behavioural treatments may boost the hotchpotch of socalled complementary and alternative treatments towards which desperate parents have a tendency to turn. Steyaert JG. Shah B. Epilepsy Behav 5(Suppl 1):S3–S13 Bethea TC. Volkmar FR (2000) Assessment in multisite randomized clinical trials of patients with autistic disorder: the Autism RUPP Network. Am J Hum Genet 82:150–159 2. Vermeesch JR.2 deletion). In: Frith U (ed) (1991) Autism and Asperger syndrome. Posey DJ. J Med Genet 40:352–356 Castermans D. Geschwind DH (2008) Linkage. Freeman BJ. Devriendt K (2003) The neurobeachin gene is disrupted by a translocation in a patient with idiopathic autism. 30. Vitiello B. Swiezy NB. Aneja A. Alarcón M. Chandler S. Robinson RO. Ashwood P. Swinnen L. Devriendt K (2004) Chromosomal anomalies in individuals with autism: a strategy towards the identification of genes involved in autism. Centers for Disease Control and Prevention (2007) Prevalence of autism spectrum disorders—autism and developmental disabilities monitoring network. Fryns JP. Steyaert JG. Huysmans C. the haystack. Asperger H (1944) “Autistic psychopathy” in childhood (translated and annotated). Am J Psychiatry 162:1133–1141 clinicians have to adopt heuristic thinking to evaluate the possible benefits of particular therapies. 20. Thienpont B. In: Proceedings of the 6th International Meeting for Autism Research (IFMAR). Am J Med Genet A 143:789–790 Battaglia A. Seattle. Autism and Developmental Disabilities Monitoring Network Surveillance Year 2002 Principal Investigators. Aman MG. 25. Loucas T. Swettenham J. Wilquet V. and gene-expression analyses identify CNTNAP2 as an autismsusceptibility gene. Ritz L. Tierney E. Cambridge UK. Allen J. Le Couteur A. Wheelwright S. Cox A. Biol Psychiatry 61:521–537 Bondy AS. Felce J (2007) The effects of PECS teaching to Phase III on the communicative interactions between children with autism and their teachers. Vitiello B (2007) Effects of short. Sikich L (2007) Early pharmacological treatment of autism: a rationale for developmental treatment. Luchetti A. a basic knowledge of it is essential in order to answer parents’ questions and help them differentiate between what’s really not recommendable and what might be acceptable. McDougle CJ. J Autism Dev Disord 37:1776– 1786 5. 29. Eur J Hum Genet 15:422–431 Castermans D. APA.3 as novel candidate genes for autism. Dev Med Child Neurol 48:604–608 Baird G. Sebat J. and regression in children with autism. Antshel KM. J Neurol Neurosurg Psychiatry 75:945–948 Baron-Cohen S. Fryns JP. Wilquet V. 26. Higgins AM. Stone JL. . Martin A. Pickles A. Robertson MM (1999) The prevalence of Gilles de la Tourette syndrome in children and adolescents with autism: a large scale study. Charman T (2006) Sleep electroencephalograms in young children with autism with and without regression. Scahill VL. Bomar JM. The absence of a robust aetiological theory. Abrahams BS. Vermeesch JR. 14. Peebles J. Lancet 368:210–215 Baron-Cohen S (2004) The cognitive neuroscience of autism. 23. Katsovich L. 18. Van de Ven W. American Psychiatric Association (2000) Diagnostic and statistical manual of mental disorders. Perederiy JV. Cantor RM. J Autism Dev Disord 30:99–111 6. J Am Acad Child Adolesc Psychiatry 39:694–702 Baird G. Bell-Bradshaw F. Fryns JP. References 1. Scahill L. Van de Ven W. Charman T (2006) Prevalence of disorders of the autism spectrum in a population cohort of children in South Thames: the Special Needs and Autism Project (SNAP). Psychol Med 25:63–77 10. 14 sites. Wigler M. 28. Martin CL. Martin A. Creemers JWM. Drew A (2000) A screening instrument for 17. Yuzda E. Scahill L. Asarnow R. Rutter M (1995) Autism as a strongly genetic disorder: evidence from a British twin study. Collier-Crespin A. Bolton P. Aman MG. Devriendt K (2008) Position effect leading to haploinsufficiency in a mosaic ring chromosome 14 in a boy with autism.

De Hert M. Crawford L. Aref-Adib M. Bourgeron T. State MW (2007) Recent advances in the genetics of autism. Hewson P. J Autism Dev Disord 30:475–479 60. Am J Psychiatry 160:636–645 59. Estes A. Nature 265:726–728 51. Wolf OT. Soderstrom H. Fadiga L. Bravaccio C. D’Agruma L. Todd RD (2006) Autistic social impairment in the siblings of children with pervasive developmental disorders. Convit A (2006) The ‘amygdala theory of autism’ revisited: linking structure to behavior. Akshoomoff N (2003) Evidence of brain overgrowth in the first year of life in autism. Pi D. Fogassi L. Rosen-Sheidley B (2001) Genetics of autism: complex aetiology for a heterogeneous disorder. Råstam M. Kalish LA. Biol Psychiatry 61:429–437 61. Munson J. Szatmari P. Puglisi-Allegra S. NJ 35. J Am Acad Child Adolesc Psychiatry 45:771–791 36. Madison DV (2007) Presynaptic FMR1 genotype influences the degree of synaptic connectivity in a mosaic mouse model of fragile X syndrome. J Paediatr Child Health 40:696–701 67. Dawson G. Nat Rev Genet 2:943–955 50. Brouwers M. Giros B. Wadsworth L (2007) Guidelines on the use of intravenous immune globulin for neurologic conditions. Bookheimer SY. Icasiano F. O’Bara M. Lajonchere C. Am J Psychiatry 163:294–296 34. Jesner O. Gadow KD. Horvath K. Paris Autism Research International Sibpair Study (2003) Mutations of the X-linked genes encoding neuroligins NLGN3 and NLGN4 are associated with autism. Schellenberg G. Georgiades S. Can J Neurol Sci 33:341–346 45. Gould TD (2003) The endophenotype concept in psychiatry: etymology and strategic intentions. Quach H. Poustka F (2007) Attention deficit hyperactivity disorder symptoms in pervasive developmental disorders: association with autistic behavior domains and coexisting psychopathology. Fombonne E. Bryson S. J Autism Dev Disord 34:543–556 47. Chawarska K. Bunce E. and behavioral perspectives. McKenna K. Rabinowitz D. Carr JE (2004) Secretin as a treatment for autism: a review of the evidence. Neuropsychologia 44:1891–1899 46. Ingersoll B. Hutton J. Psychopathology 40:172–177 64. Correll CU. Ware J. Int J Dev Neurosci 23:153–170 38. Hyman SL. Trends Cogn Sci 8:396–403 56. Carlson HE (2006) Endocrine and metabolic adverse effects of psychotropic medications in children and adolescents. Mol Psychiatry 12:2–22 54. Quattrone A. Stefanatos G. Freitag CM (2007) The genetics of autistic disorders and its clinical relevance: a review of the literature. Dawson G. Zelante L. Nat Neurosci 9:28–30 40. Goldberg J. Dapretto M. Roberts W (2006) Immunizations and autism: a review of the literature. Fombonne E (2005) Epidemiology of autistic disorder and other pervasive developmental disorders. Mahoney W (2007) Structure of the autism symptom phenotype: a proposed multidimensional model. Rutter M (2004) Adult outcome for children with autism. Holtmann M. Gallese V. Ment Retard Dev Disabil Res Rev 10:106–111 37. Feasby T. J Child Psychol Psychiatry 48:128– 138 32. J Neurosci 27:4014–4018 62. Rizzolatti G (1992) Understanding motor events: a neurophysiological study. Pascucci T. Abbott R (2007) Quantitative assessment of autism symptomrelated traits in probands and parents: Broader Phenotype Autism Symptom Scale. Wiley. Lutz M. Hanson E. Gillberg C.Eur J Pediatr (2008) 167:1091–1101 31. Klin A. Coonrod EE. Militerni R. Schneider C. Freedman M. and joint attention. Bolte S. Marshall A (2004) Childhood autism spectrum disorder in the Barwon region: a community based study. Reichelt KL. Roberts W. Biol Psychiatry 55:413–419 33. Gillberg IC. Curtis C. Rutter M (1977) Genetic influences and infantile autism. Hume H. Petry J (2007) Use of complementary and alternative medicine among children diagnosed with autism spectrum disorder. J Autism Dev Disord 34:379–393 55. Wachtel R. Dev Psychopathol 14:581–611 41. DeVincent CJ. Guarnieri V. Richards T (2002) Defining the broader phenotype of autism: genetic. Curr Opin Neurobiol 17:103–111 58. Nabors L. Courchesne E. Banwell B. Duku E. Colineaux C. Nat Genet 34:27–29 69. Iacoboni M (2006) Understanding emotions in others: mirror neuron dysfunction in children with autism spectrum disorders. Constantino JN. Singh D. Cohen DJ (eds) Handbook of autism and pervasive developmental disorders. Schreibman L (2006) Teaching reciprocal imitation skills to young children with autism using a naturalistic behavioral approach: effects on language. Levitt P (2007) Autism spectrum disorders: developmental disconnection syndromes. Machet P. J Child Psychol Psychiatry 45:212–229 66. Tildon JT (1998) Improved social and language skills after secretin administration in patients with autistic spectrum disorders. Paul R. Davies MS. Webb S. Doja A. Rizzolatti G (2004) A unifying view of the basis of social cognition. J Clin Psychiatry 66(Suppl 10):3–8 52. Spence SJ. Stodgell CJ. di Pellegrino G. van Eyck D. Gupta AR. Cooper C. Gray T. Int Clin Psychopharmacol 21:S11–S15 43. Quebec. Paul R. Bernier R. Hanson JE. Pomeroy J. Volkmar FR (2007) Autism spectrum disorder in the second year: stability and change in syndrome expression. Fleck S. Courchesne E (2004) Brain development in autism: early overgrowth followed by premature arrest of growth. Muscarella L. Geschwind DH. Scott AA. Gallese V. Courchesne E. Cochrane Database Syst Rev (1):CD005040 . Elia M. J Clin Psychiatry 66(Suppl 10):26–31 1099 49. Pierce K (2005) Brain overgrowth in autism during a critical time in development: implications for frontal pyramidal neuron and interneuron development and connectivity. Freedman J. 3rd edn. Zakarian R. J Autism Dev Disord 37:523–536 42. Howlin P. Pediatrics 118:E139–E150 53. Goode S. Melmed R. McDaniel S. Meng LY. Rogers K. In: Volkmar FR. Hahn A. Montecchi F. Zwaigenbaum L. Aylward E. Carper R. De Nayer A (2006) Metabolic abnormalities associated with second generation antipsychotics: fact or fiction? Development of guidelines for screening and monitoring. pretend play. Leboyer M. Bril V. J Am Acad Child Adolesc Psychiatry 46:188–196 57. Dziobek I. Folstein SE. Canada: prevalence and links with immunizations. Jamain S. Transfus Med Rev 21:S57–S107 48. JAMA 290:337–344 39. Friedman S. J Autism Dev Disord 36:487–505 68. J Autism Dev Disord 37:628–636 63. Azizian A (2004) Psychiatric symptoms in preschool children with PDD and clinic and comparison samples. Exp Brain Res 91:176–180 44. Trillo S. Sokolski KN. Findling RL (2005) Pharmacologic treatment of behavioral symptoms in autism and pervasive developmental disorders. Benstead T. Keysers C. Rodier PM. Conciatori M. J Assoc Acad Minor Phys 9:9–15 65. Sigman M. Gottesman II. Gupta S (2000) Immunological treatments for autism. Coren E (2007) Risperidone for autism spectrum disorder. Klin A. Betancur C. Folstein S. brain. McLeanHeywood D (2006) Pervasive developmental disorders in Montreal. Bennett A. Schellenberg GD. Stone WL (2005) Screening for autism in young children. Abbacchi A. Pfeifer JH. Hoboken. Persico AM (2004) Association between the HOXA1 A218G polymorphism and increased head circumference in patients with autism. Dager S. Esch BE.

Biol Psychiatry 61:492–497 86. Paul R. Rubin E. Ittenbach RF. Daly MJ. MacDonald ME. Van Engeland H (2006) No evidence for preferential involvement of medial temporal lobe structures in high-functioning autism. Lord C. Filipek P (2006) Absence of seizures despite high prevalence of epileptiform EEG abnormalities in children with autism monitored in a tertiary care center. Giardini O. Barbato M. J Clin Psychiatry 68:8–13 100. Chuang SZ. Scahill L. Laurent A (2005) Communication skills in individuals with high-functioning autism and Asperger syndrome. Klin A. Christian SL (2008) Recurrent 16p11. Shah B. Hyman SL (2005) Novel treatments for autistic spectrum disorders. Newcomer JW (2007) Antipsychotic medications: metabolic and cardiovascular risk. Kaplan L. Kanner L (1943) Autistic disturbances of affective contact. Paul R. Kolevzon A. Mawhood L. Rutter M. Paul R. Lord C (2007) Social and communication abilities and disabilities in higher functioning individuals with autism spectrum disorders: the Vineland and the ADOS. Neurology 64:A433–A434 95. Keen D. Moshe SL (2005) Clinical and EEG characteristics of children with language regression. J Autism Dev Disord 37:748–759 79. Persico AM. Bourgeron T (2006) Searching for ways out of the autism maze: genetic. Epilepsia 47:394–398 77. de Haan M. Cohen DJ (eds) . Johnson MH (2007) Developing a social brain. Badner JA. Newschaffer CJ.1100 70. Conrad DF. Johnson MH. Cohen DJ (eds) Handbook of autism and pervasive developmental disorders. Panminerva Med 37:137–141 91. McDougle CJ. In: Volkmar FR. Am J Psychiatry 162:1142–1148 94. Piven J. Seong IS. Hermon S. Higgins AW. Nederveen H. Levy SE. Najm J. Minshew N. Johnson CP. Ritz L. Mathewson KA. Childress D. Washington. Kosinovsky B. Brune C. Palmen SJ. Swiezy NB. Folstein S. Volkmar FR (2006) Head circumference and height in autism: a study by the Collaborative Program of Excellence in Autism. Koenig K. Stodgell CJ. Arndt S (1997) Broader autism phenotype: evidence from a family history study of multiple-incidence autism families. Trentacoste SV. Pickles A. Quintieri F. Tournay AE. Prizant BM. Am J Psychiatry 154: 185–190 105. Marans WD. American Academy of Pediatrics Council on Children With Disabilities (2007) Identification and evaluation of children with autism spectrum disorders. Cook EH Jr. Aman MG. Kramer U (2005) The yield of laboratory investigations in children with infantile autism. DiLavore PC. Hollander E (2006) Selective serotonin reuptake inhibitors in autism: a review of efficacy and tolerability. Myers SM. Goode S. Durston S. Yoran-Hegesh R.2 microdeletions in autism. J Autism Dev Disord 19:185–212 88. Vitiello B (2005) Risperidone for the core symptom domains of autism: results from the study by the autism network of the research units on pediatric psychopharmacology. Schopler E (1989) Autism diagnostic observation schedule: a standardized observation of communicative and social behavior. Souders MC. Le Couteur A. Griffin R. Csibra G. McVicar KA. Ozonoff S. National Research Council (NRC) Committee on Educational Interventions for Children with Autism (2001) Educating children with autism. Trends Neurosci 29:349–358 103. D’Eufemia P. Acta Paediatr 96:3–5 71. Risi S. Cardi E (1995) Food allergy and infantile autism. Bailey A. Estes A. Dinh E. Leventhal BL. Palmer P. Arnold LE. Hyman S. Farroni T. United States. Gottesman I. Senecky Y. Kim HL. Hollway J. Cohen DJ (eds) Handbook of autism and pervasive developmental disorders. Quade BJ. Gonzalez NM. Myers SM. Donnelly JH. Golomb A. Bailey A. Ghuman JK. Kim HG. Tsatsanis K. Posey DJ. Tager-Flusberg H. Jacobi D. J Autism Dev Disord 30:205–223 90. 3rd edn. McCracken JT. Lambrecht L. Papanikolaou K. Lucarelli S. Pauls DL. Troxell R. Martin A. McMahon W. Lainhart JE. Lord C. 3rd edn. Klin A. Dawson G. Munson J. Hepburn S. Rapin I (2004) The genetics of autism. Ruby A. DC 99. Bigler ED. Pickles A. Psychol Med 36:827–834 102. Lord C. Noens I. Saulnier CA. Gilliam TC. Hoboken. Rapin I. Am J Med Genet A 140:2257–2274 83. National Center for Health Statistics (2008) NCHS definitions. Health. In: Volkmar FR. Zingoni AM. NJ Eur J Pediatr (2008) 167:1091–1101 87. Pediatrics 120:1162–1182 97. Kazak S. Volkmar FR. Pediatrics 115:e277–e282 101. Mulberg AE. Ward S (2004) Autistic spectrum disorder: a child population profile. Pediatrics 120: 1183–1215 72. Reddy C. Hoboken. Dunn M. Volkmar FR. Osann K. Baron-Cohen S. Dev Psychopathol 17:599–619 73. Goode S. American Academy of Pediatrics Council on Children With Disabilities (2007) Management of children with autism spectrum disorders. Klin A. Wetherby AM (2005) Critical issues in enhancing communication abilities for persons with autism spectrum disorders. J Child Psychol Psychiatry 41:491–502 104. Morton CC. Frediani T. epigenetic and environmental clues. Starr E. Deutsch CK. Wiley. J Child Psychol Psychiatry 37:785–801 84. Tierney E. Klin A. Muhle R. Sudi J. Rutter M (2000) Variable expression of the autism broader phenotype: findings from extended pedigrees. Le Couteur A (1994) Autism Diagnostic Interview—Revised: a revised version of a diagnostic interview for caregivers of individuals with possible pervasive developmental disorders. Klin A. Geng L. Centers for Disease Control 98. Rodier P. National Academies Press. Kumar RA. McGough JJ. Heemsbergen J. Falb MD. Hum Mol Genet 17:628–638 82. Jordan H. Tucker LA. In: Volkmar FR. Ballaban-Gil K. Corsello C (2005) Diagnostic instruments in autistic spectrum disorders. Donovan DJ. Robertson S. Shen Y. McDonald BC (2002) Recent developments in the application of the nonverbal learning disabilities model. Rutter M (2000) The autism diagnostic observation schedule-generic: a standard measure of social and communication deficits associated with the spectrum of autism. Rogers S. Cook EH Jr. Davies M. Sigman M. Gurney JG (2005) National autism prevalence trends from United States special education data. Zimmerman-Bier B (2005) Evaluation of an association between gastrointestinal symptoms and cytokine production against common dietary proteins in children with autism spectrum disorders. Richards J (2005) The emergence of the social brain network: evidence from typical and atypical development. Holt L. Bolton P. J Clin Psychiatry 67:407–414 80. Levy SE. Pickles A. Pediatrics 113:e472–e486 96. Harris DJ. Weiss LA. Cicchetti DV. Lord C. Spence MA. Ment Retard Dev Disabil Res Rev 11:131–142 85. Goodman R. J Pediatr 146:605–610 74. Johnson CP. Bocian M. J Autism Dev Disord. Curr Psychiatry Rep 4:323–330 93. 24:659–685 89. Shinnar S. Sparrow SS. Kishikawa S. Descartes M. Lally E. Giarelli E. Kutsche K. KaraMohamed S. Book TM. Ferruzzi F. Goez H. Braddock S. Nerv Child 2:217–250 75. Gusella JF (2008) Disruption of neurexin 1 associated with autism spectrum disorder. Halit H. Wiley. Dobyns WB. NJ 92. J Neural Transm 112:587–596 81. Nowak NJ. Rutter M. Jyonouchi H. Pinto-Martin JA (2007) Relationship of dietary intake to gastrointestinal symptoms in children with autistic spectrum disorders. Autism 8:39–48 76. Rutter M (1996) A broader phenotype of autism: the clinical spectrum in twins. Am J Hum Genet 82:199–207 78. Coon H.

O’Hara T. Beemer FA. Fuerst DR (1992) Psychological dimensions of learning disability subtypes: neuropsychological studies in the windsor laboratory. Mandy W. Hepburn SL. Sweeney M. Am J Med Genet B Neuropsychiatr Genet 144B:581–588 1101 121. Pai D. Happé F. Tidmarsh L. Mendelsohn NJ (2008) Clinical genetics evaluation in identifying the etiology of autism spectrum disorders. Klee B. non-specific colitis. Schaefer GB. Steyaert J. Rourke BP. Klin A. Harvey P. Brierley LM.Eur J Pediatr (2008) 167:1091–1101 Handbook of autism and pervasive developmental disorders. Hicks J. Wijsman E (2007) Statistical genetic approaches for analysis of autism and autism endophenotypes. School Psych Rev 21:361–374 110. J Dev Behav Pediatr 7:324–329 125. Singh J. Yeates SR. Doernberg N. Arking DE. Butcher LM. Cohen H. Spence SJ. Illes J (2007) Interacting and paradoxical forces in neuroscience and society. Riddle MA. Schwab-Stone ME (2000) NIMH Diagnostic Interview Schedule for Children Version IV (NIMH DISC-IV): description. Lehtimäki T. McCracken J. Hallmayer J. Nat Rev Neurosci 8:153–160 118. Anthony A. WHO. NJ. Krasnitz A. Ment Retard Dev Disabil Res Rev 10:139–143 107. Washington. Gregersen PK. Williams. Klaassen PWJ. Jobanputra V. Chakravarti A. Sebat J. Roper M (2001) Fluvoxamine for the treatment of anxiety disorders in children and adolescents. Chowdhury U. Bolton P. Wiley. Rapin I. JAMA 289:49–55 134. Ingersoll B (2005) Behavioral interventions to promote learning in individuals with autism. Walkup JT. Eur Child Adolesc Psychiatry 11:201– 209 120. J Autism Dev Disord 37:466–480 . and reliability of some common diagnoses. In: Volkmar FR. Kustanovich V. Chung W. Sigman M (2007) Studying the emergence of autism spectrum disorders in high-risk infants: methodological and practical issues. Karapurkar T. Troge J. pp 882–896 114. Can J Psychiatry 48:517–525 122. J Child Neurol 19(Suppl 1):S49–S57 123. Kahn RS. Zwaigenbaum L. Lord C. Yeargin-Allsopp M. Ruderfer DM. Linnell J. Casson DM. Ferreira MA. 3rd edn. Science 316:445–449 115. Swaab H. and velocardiofacial syndromes: the NLD connection. Skuse D. Lord C. dimensional and diagnostic interview (3di): a novel computerized assessment for autism spectrum disorders. Yamrom B. Hoboken. Klin A. Dhillon AP. Plomin R (2006) Genetic heterogeneity between the three components of the autism spectrum: a twin study. Stone W. Malik M.2 and autism. van Engeland H (2006) The 22q11. Lau J. J Am Acad Child Adolesc Psychiatry 43:548–558 119. Gusella JF. 3rd edn. Law K. Ritz LA. Shen Y. N Engl J Med 358:667–675 129. Bergman L. Paul R. Wakefield AJ. Dulcan MK. Stefansson K. Bregman J. Seattle. Thomson MA. Labellarte MJ. Rourke BP (1998) Symposium: Asperger. Leotta A. Wiley. Geneva 133. Santangelo SL. Korn JM. Cohen DJ (eds) Handbook of autism and pervasive developmental disorders. J Am Acad Child Adolesc Psychiatry 39:28–38 116. Green T. World Health Organization (WHO) (1992) The ICD-10 Classification of Mental and Behavioural Disorders. Ye K. Sutcliffe JS. Lancet 351:637–641 127. Piacentini J. Walsh T. Fossdal R. Leotta A. Geschwind DH.2 deletion in children: high rate of autistic disorders and early onset of psychotic symptoms. Ledbetter D. Saemundsen E. Price TS. Walsh CA. Baron-Cohen S. Joober R. Hoboken. Boyle C. J Am Acad Child Adolesc Psychiatry 45:1104–1113 126. Wing L. Bishop D. Duijff SN. Shaffer D. Rogers SJ (2006) A two-year followup on risk status identified by the checklist for autism in toddlers. J Dev Behav Pediatr 27:S128–S136 124. NJ 106. Hoboken. Schreibman L. Heinemande Boer JA. Daly MJ (2008) Association between microdeletion and microduplication at 16p11. Warburton D. J Dev Behav Pediatr 27:S104–S110 112. Klin A. Skuse D. Gilliam TC. Law P. 3rd edn. Qiu S. Bryson S. Fisher P. Murch SH. Thurm A. J Am Acad Child Adolesc Psychiatry 45:691–699 108. Stefansson H. May 2007 130. March J. Psychol Med 6:89–100 132. Place M (2004) The developmental. Iverson J. Vorstman JAS. Pediatrics 117:1028–1037 117. Hack S. Morcus MEJ. Palmour R (2007) Informative phenotypes for genetic studies of psychiatric disorders. Volkmar FR. Robinson J. Potter D (2002) The epidemiology of autistic spectrum disorders: is the prevalence rising? Ment Retard Dev Disabil Res Rev 8:151–161 131. Cohen DJ (1986) Current concepts: infantile autism and the pervasive developmental disorders. Davies M. Gould J (1976) The prevalence of early childhood autism: comparison of administrative and epidemiological studies. Lee YH. Roy MA. Zhao X. Scahill L. Weiss LA. N Engl J Med 344:1279–1285 128. Zhang R. Yoon S. Volkmar FR (2003) Diagnosis and epidemiology of autism spectrum disorders. Davies SE. Landa R. Lucas CP. Mérette C. Walker-Smith JA (1998) Ileallymphoid-nodular hyperplasia. Martin A (2005) Psychopharmacology. Shinnar S (2006) Frequency of gastrointestinal symptoms in children with autistic spectrum disorders and association with family history of autoimmune disease. Rogers S. Malhotra D. Baranek G. Wheelwright S. Rice C. Sebat J. Greenhill L. Altshuler D. Lajonchere C. Scambler DJ. Kau A. Vitiello B. Ronald A. Baker S. Valentine A. Clin Neuropsychol 12:266 109. Wu BL. Genet Med 10:301–305 113. In: Volkmar FR. Rogers SJ (2004) Developmental regression in autism spectrum disorders. Wing L. King MC. Warrington R. McVicar K. Tanzi RE. NJ 111. Berelowitz M. Platt OS. Trevathan E (2004) Seizures and epilepsy among children with language regression and autistic spectrum disorders. Paul R. Puura K. Lakshmi B. Maziade M. Szatmari P. Klein R. differences from previous versions. Pine DS. Proc Natl Acad Sci U S A 104:12831–12836 135. Geschwind DH. Lese-Martin C. Murphy C (2003) Prevalence of autism in a US metropolitan area. Wigler M (2007) Strong association of de novo copy number mutations with autism. Fryns JP (2002) Psychiatric genetics: the case of single gene disorders. Zwaigenbaum L. Abikoff H. Miller DT. Shattuck PT (2006) The contribution of diagnostic substitution to the growing administrative prevalence of autism in US special education. Cohen DJ (eds) Handbook of autism and pervasive developmental disorders. Wershil BK. Compton S. Sklar P. Kendall J. Ye K. In: Proceedings of the 6th International Meeting for Autism Research (IFMAR). and pervasive developmental disorder in children. Wigler M (2007) A unified genetic theory for sporadic and inherited autism. Wiley. Lee AT. Valicenti-McDermott M.