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1.  Klinefelter syndrome as a window on the aetiology of language and communication impairments in children: the neuroligin–neurexin hypothesis 
To compare the phenotype in Klinefelter syndrome (KS) with (i) specific language impairment (SLI) and (ii) XXX and XYY trisomies.
Phenotypes of KS, XXX and XYY were based on data from a systematic review of neurodevelopmental outcomes plus a recent parent survey. Phenotype of SLI was based on a published survey of children attending a special school.
There are close similarities between the KS phenotype and SLI. Furthermore, a minority of children with KS have features of autistic spectrum disorder. Similar language and communication problems are seen in the other two sex chromosome trisomies (SCTs), XXX and XYY.
We propose the neurexin–neuroligin hypothesis, based on the observation that neuroligin genes, which occur on both X and Y chromosomes, are involved in the same synaptic networks as neurexin genes with common variants that affect risk for SLI and autism. According to our hypothesis, the effect of a triple dose of neuroligin gene product will be particularly detrimental when it occurs in conjunction with specific variants of neurexin genes on other chromosomes. This speculative proposal demonstrates the potential of illuminating the aetiology of common neurodevelopmental disorders by studying children with SCTs.
PMCID: PMC3107947  PMID: 21418292
Autism; Klinefelter syndrome; Language impairment; Neurexin; Neuroligin; Sex chromosome trisomy
2.  Neurocognitive outcomes of individuals with a sex chromosome trisomy: XXX, XYY, or XXY: a systematic review* 
To review systematically the neurodevelopmental characteristics of individuals with sex chromosome trisomies (SCTs).
A bibliographic search identified English-language articles on SCTs. The focus was on studies unbiased by clinical referral, with power of at least 0.69 to detect an effect size of 1.0.
We identified 35 articles on five neonatally identified samples that had adequate power for our review. An additional 11 studies were included where cases had been identified for reasons other than neurodevelopmental concerns. Individuals with an additional X chromosome had mean IQs that were within broadly normal limits but lower than the respective comparison groups, with verbal IQ most affected. Cognitive outcomes were poorest for females with XXX. Males with XYY had normal-range IQs, but all three SCT groups (XXX, XXY, and XYY) had marked difficulties in speech and language, motor skills, and educational achievement. Nevertheless, most adults with SCTs lived independently. Less evidence was available for brain structure and for attention, social, and psychiatric outcomes. Within each group there was much variation.
Individuals with SCTs are at risk of cognitive and behavioural difficulties. However, the evidence base is slender, and further research is needed to ascertain the nature, severity, and causes of these difficulties in unselected samples.
PMCID: PMC2820350  PMID: 20059514
3.  Sex chromosome trisomies in Europe: prevalence, prenatal detection and outcome of pregnancy 
This study aims to assess prevalence and pregnancy outcome for sex chromosome trisomies (SCTs) diagnosed prenatally or in the first year of life. Data held by the European Surveillance of Congenital Anomalies (EUROCAT) database on SCT cases delivered 2000–2005 from 19 population-based registries in 11 European countries covering 2.5 million births were analysed. Cases included were livebirths diagnosed to 1 year of age, fetal deaths from 20 weeks gestation and terminations of pregnancy for fetal anomaly (TOPFA). In all, 465 cases of SCT were diagnosed between 2000 and 2005, a prevalence of 1.88 per 10,000 births (95% CI 1.71–2.06). Prevalence of XXX, XXY and XYY were 0.54 (95% CI 0.46–0.64), 1.04 (95% CI 0.92–1.17) and 0.30 (95% CI 0.24–0.38), respectively. In all, 415 (89%) were prenatally diagnosed and 151 (36%) of these resulted in TOPFA. There was wide country variation in prevalence (0.19–5.36 per 1000), proportion prenatally diagnosed (50–100%) and proportion of prenatally diagnosed resulting in TOPFA (13–67%). Prevalence of prenatally diagnosed cases was higher in countries with high prenatal detection rates of Down syndrome. The EUROCAT prevalence rate for SCTs diagnosed prenatally or up to 1 year of age represents 12% of the prevalence expected from cytogenetic studies of newborn babies, as the majority of cases are never diagnosed or are diagnosed later in life. There is a wide variation between European countries in prevalence, prenatal detection and TOPFA proportions, related to differences in screening policies as well as organizational and cultural factors.
PMCID: PMC3025783  PMID: 20736977
sex chromosome trisomies; prenatal diagnosis; termination of pregnancy
4.  The Sex Chromosome Trisomy mouse model of XXY and XYY: metabolism and motor performance 
Klinefelter syndrome (KS), caused by XXY karyotype, is characterized by low testosterone, infertility, cognitive deficits, and increased prevalence of health problems including obesity and diabetes. It has been difficult to separate direct genetic effects from hormonal effects in human studies or in mouse models of KS because low testosterone levels are confounded with sex chromosome complement.
In this study, we present the Sex Chromosome Trisomy (SCT) mouse model that produces XXY, XYY, XY, and XX mice in the same litters, each genotype with either testes or ovaries. The independence of sex chromosome complement and gonadal type allows for improved recognition of sex chromosome effects that are not dependent on levels of gonadal hormones. All mice were gonadectomized and treated with testosterone for 3 weeks. Body weight, body composition, and motor function were measured.
Before hormonal manipulation, XXY mice of both sexes had significantly greater body weight and relative fat mass compared to XY mice. After gonadectomy and testosterone replacement, XXY mice (both sexes) still had significantly greater body weight and relative fat mass, but less relative lean mass compared to XY mice. Liver, gonadal fat pad, and inguinal fat pad weights were also higher in XXY mice, independent of gonadal sex. In several of these measures, XX mice also differed from XY mice, and gonadal males and females differed significantly on almost every metabolic measure. The sex chromosome effects (except for testis size) were also seen in gonadally female mice before and after ovariectomy and testosterone treatment, indicating that they do not reflect group differences in levels of testicular secretions. XYY mice were similar to XY mice on body weight and metabolic variables but performed worse on motor tasks compared to other groups.
We find that the new SCT mouse model for XXY and XYY recapitulates features found in humans with these aneuploidies. We illustrate that this model has significant promise for unveiling the role of genetic effects compared to hormonal effects in these syndromes, because many phenotypes are different in XXY vs. XY gonadal female mice which have never been exposed to testicular secretions.
PMCID: PMC3751353  PMID: 23926958
Klinefelter; Sex chromosome trisomy; XXY; XYY; Mouse; X chromosome; Y chromosome; Body weight; Obesity
5.  Attention-Deficit Hyperactivity Disorder Symptoms in Children and Adolescents with Sex Chromosome Aneuploidy: XXY, XXX, XYY, and XXYY 
Attentional problems, hyperactivity, and impulsivity have been described as behavioral features associated with sex chromosome aneuploidy (SCA). In this study, the authors compare attention-deficit hyperactivity disorder (ADHD) symptoms in 167 participants aged 6 to 20 years with 4 types of SCA (XXY n = 56, XYY n = 33, XXX n = 25, and XXYY n = 53). They also evaluate factors associated with ADHD symptomatology (cognitive and adaptive scores, prenatal vs postnatal ascertainment) and describe the clinical response to psychopharmacologic medications in a subset of patients treated for ADHD.
Evaluation included medical and developmental history, cognitive and adaptive functioning assessment, and parent and teacher ADHD questionnaires containing DSM-IV criteria.
In the total study group, 58% (96/167) met DSM-IV criteria for ADHD on parent-report questionnaires (36% in XXY, 52% in XXX, 76% in XYY, and 72% in XXYY). The Inattentive subtype was most common in XXY and XXX, whereas the XYY and XXYY groups were more likely to also have hyperactive/impulsive symptoms. There were no significant differences in Verbal, Performance, or Full Scale IQ between children with symptom scores in the ADHD range compared with those below the ADHD range. However, adaptive functioning scores were significantly lower in the group whose scores in the ADHD range were compared with those of the group who did not meet ADHD DSMIV criteria. Those with a prenatal diagnosis of XXY were less likely to meet criteria for ADHD compared with the postnatally diagnosed group. Psychopharmacologic treatment with stimulants was effective in 78.6% (66/84).
Children and adolescents with SCA are at increased risk for ADHD symptoms. Recommendations for ADHD evaluation and treatment in consideration of other aspects of the SCA medical and behavioral phenotype are provided.
PMCID: PMC3348431  PMID: 22333574
attention-deficit hyperactivity disorder (ADHD); XXY; Klinefelter syndrome; XYY; XXYY; sex chromosome aneuploidy
6.  Behavioral and Social Phenotypes in Boys With 47,XYY Syndrome or 47,XXY Klinefelter Syndrome 
Pediatrics  2012;129(4):769-778.
To contrast the behavioral and social phenotypes including a screen for autistic behaviors in boys with 47,XYY syndrome (XYY) or 47,XXY Klinefelter syndrome (KS) and controls and investigate the effect of prenatal diagnosis on the phenotype.
Patients included 26 boys with 47,XYY, 82 boys with KS, and 50 control boys (ages 4–15 years). Participants and parents completed a physical examination, behavioral questionnaires, and intellectual assessments.
Most boys with XYY or KS had Child Behavior Checklist parental ratings within the normal range. On the Child Behavior Checklist, mean problem behaviors t scores were higher in the XYY versus KS groups for the Problem Behavior, Externalizing, Withdrawn, Thought Problems, and Attention Problems subscales. On the Conners’ Parent Rating Scale–Revised, the XYY versus KS group had increased frequency of hyperactive/impulsive symptoms (P < .006). In addition, 50% and 12% of the XYY and KS groups, respectively, had scores >15 for autism screening from the Social Communication Questionnaire. For the boys with KS, prenatal diagnosis was associated with fewer problem behaviors.
A subset of the XYY and KS groups had behavioral difficulties that were more severe in the XYY group. These findings could guide clinical practice and inform patients and parents. Boys diagnosed with XYY or KS should receive a comprehensive psychoeducational evaluation and be screened for learning disabilities, attention-deficit/hyperactivity disorder, and autism spectrum disorders.
PMCID: PMC3356148  PMID: 22412026
XXY; XYY; Klinefelter syndrome; autism; ADHD
7.  Early manifestations in a cohort of children prenatally diagnosed with 47,XYY. Role of multidisciplinary counseling for parental guidance and prevention of aggressive behavior 
An increasing number of foetuses are recognized as having double Y because of the widespread use of prenatal screening using chorionic villus sampling and amniocentesis. 47, XYY karyotype occurs in about one out of 1,000 newborn males, but it is not often detected unless it is diagnosed during prenatal testing. Despite the fact that unbiased follow-up studies demonstrate largely normal post-natal development of young men with 47, XYY, there is a scarcity of controlled studies about the neurological, cognitive and behavioural phenotype which remains the main reason for anxiety and anticipatory negative attitudes of parents. Furthermore, prejudices still exist among professionals and the general population concerning the relationship between this sex chromosome aneuploidy and aggressive and antisocial behaviours.
We report on the clinical follow-up of children diagnosed prenatally with a 47,XYY karyotype, whose parents received multidisciplinary counselling and support at time of diagnosis. The specific focus of our study is on auxology, facial features, developmental milestones, behaviour, detection of aggressiveness as well as the evaluation of parental attitudes toward prenatal counselling. Clinical evaluations including auxological measurements and dysmorphological descriptions were as conducted on 13 boys aged 9 month -7 years. The Child Behavior Check List test specific for age and a 15 item questionnaire were administered to both parents. An update of ongoing problems was carried out by means of a telephone interview two years later.
Our results show that, from birth, weight, height and head circumference were above average values while some facial features such mild hypertelorism are overrepresented when compared to parents' facial features. Language delay was detected in 8 out of 11 children older than 20 months. Parental attitudes were found to be favourable toward prenatal diagnoses of sexual chromosome aneuploidies.
Our data, although limited, is similar to other observational studies, and serves to alert clinicians about opportunities to delineate new and appropriate educational interventions that target the specific learning challenges of XYY boys. Our experience better defines the early manifestation of XYY and should aid those involved in prenatal counselling and paediatric surveillance.
PMCID: PMC3523010  PMID: 23034220
8.  Criminality in men with Klinefelter's syndrome and XYY syndrome: a cohort study 
BMJ Open  2012;2(1):e000650.
To investigate the criminal pattern in men between 15 and 70 years of age diagnosed with 47,XXY (Klinefelter's syndrome (KS)) or 47,XYY compared to the general population.
Register-based cohort study comparing the incidence of convictions among men with KS and with 47,XYY with age- and calendar-matched samples of the general population. Crime was classified into eight types (sexual abuse, homicide, burglary, violence, traffic, drug-related, arson and ‘others’).
Denmark 1978–2006.
All men diagnosed with KS (N=934) or 47,XYY (N=161) at risk and their age- and calendar-time-matched controls (N=88 979 and 15 356, respectively).
The incidence of convictions was increased in men with KS (omitting traffic offenses) compared to controls with a HR of 1.40 (95% CI 1.23 to 1.59, p<0.001), with significant increases in sexual abuse, burglary, arson and ‘others’, but with a decreased risk of traffic and drug-related offenses. The incidence of convictions was significantly increased among men with 47,XYY compared to controls with a HR of 1.42 (95% CI 1.14 to 1.77, p<0.005) in all crime types, except drug-related crimes and traffic. Adjusting for socioeconomic variables (education, fatherhood, retirement and cohabitation) reduced the total HR for both KS and 47,XYY to levels similar to controls, while some specific crime types (sexual abuse, arson, etc) remained increased.
The overall risk of conviction (excluding traffic offenses) was moderately increased in men with 47,XYY or KS; however, it was similar to controls when adjusting for socioeconomic parameters. Convictions for sexual abuse, burglary, arson and ‘others’ were significantly increased. The increased risk of convictions may be partly or fully explained by the poor socioeconomic conditions related to the chromosome aberrations.
Article summary
Article focus
To investigate crime rates of men with an extra sex chromosome (47,XXY and 47,XYY). Based on previous small studies, we hypothesised that an increased crime rate would be present in men with an extra sex chromosome and investigated this in a nationwide registry study.
Key messages
Using a nationwide approach, we show that men diagnosed with KS (47,XXY) and 47,XYY are more frequently convicted for sexual abuse, burglary, arson and other reasons. Traffic offenses are seen less frequently in both groups.
Whether early diagnosis and improved clinical care can lead to a decrease in convictions is not clear.
The increased crime rate may be partly or fully mediated by poor socioeconomic conditions.
Strengths and limitations of this study
The study clearly delineates a pattern of increased crime rates among men diagnosed with an extra sex chromosome. The strength of the present study is the large number of men with sex chromosomes and the large control group and the merging of several registries.
The limitations are that we were not able to control for concomitant medicinal use, especially testosterone use in KS, nor to include clinical data.
PMCID: PMC3289987  PMID: 22357573
9.  The Importance of Screening and Prenatal Diagnosis in the Identification of the Numerical Chromosomal Abnormalities 
Mædica  2011;6(3):179-184.
Background and aims: The obstetric care of a pregnancy, as it is practiced today, includes non-invasive screening approaches as well as invasive procedures for the definitive prenatal diagnosis of fetal disorders correlations between indications for prenatal cytogenetic diagnosis and results of the chromosomal analysis made upon fetal cells. The aim of our study was to evaluate the correlations between the screening test results and results of chromosomal analysis on fetal cells.
Methods: Amniotic fluid samples from 1159 pregnant women were studied with the rapid FISH method and the cytogenetic analysis (karyotype). The results from both methods were compared.
Results: The indications to perform prenatal cytogenetic diagnosis for numerical chromosomal abnormalities were: abnormal results of double or triple test, advanced maternal age, fetal abnormality detected through ultrasound examination, and positive family history for chromosomal anomalies. In our study we identified 30 cases with abnormal numeric chromosomes (18 cases of trisomy 21, 4 cases of trisomy 18, 3 cases of trisomy X, 1 case of monosomy, 2 cases of trisomy XYY, 1 case of trisomy XXY and 1 case of triploidy).
Conclusions: This report confirms the importance of screening and the cytogenetic diagnosis in the identification of the numerical chromosomal abnormalities.
PMCID: PMC3282538  PMID: 22368694
aneuploidy; prenatal screening; prenatal diagnosis; amniotic fluid
10.  Noninvasive Fetal Trisomy (NIFTY) test: an advanced noninvasive prenatal diagnosis methodology for fetal autosomal and sex chromosomal aneuploidies 
BMC Medical Genomics  2012;5:57.
Conventional prenatal screening tests, such as maternal serum tests and ultrasound scan, have limited resolution and accuracy.
We developed an advanced noninvasive prenatal diagnosis method based on massively parallel sequencing. The Noninvasive Fetal Trisomy (NIFTY) test, combines an optimized Student’s t-test with a locally weighted polynomial regression and binary hypotheses. We applied the NIFTY test to 903 pregnancies and compared the diagnostic results with those of full karyotyping.
16 of 16 trisomy 21, 12 of 12 trisomy 18, two of two trisomy 13, three of four 45, X, one of one XYY and two of two XXY abnormalities were correctly identified. But one false positive case of trisomy 18 and one false negative case of 45, X were observed. The test performed with 100% sensitivity and 99.9% specificity for autosomal aneuploidies and 85.7% sensitivity and 99.9% specificity for sex chromosomal aneuploidies. Compared with three previously reported z-score approaches with/without GC-bias removal and with internal control, the NIFTY test was more accurate and robust for the detection of both autosomal and sex chromosomal aneuploidies in fetuses.
Our study demonstrates a powerful and reliable methodology for noninvasive prenatal diagnosis.
PMCID: PMC3544640  PMID: 23198897
Noninvasive Fetal Trisomy (NIFTY) test; Massively parallel sequencing; Autosomal aneuploidies; Sex chromosomal aneuploidies
11.  A review of trisomy X (47,XXX) 
Trisomy X is a sex chromosome anomaly with a variable phenotype caused by the presence of an extra X chromosome in females (47,XXX instead of 46,XX). It is the most common female chromosomal abnormality, occurring in approximately 1 in 1,000 female births. As some individuals are only mildly affected or asymptomatic, it is estimated that only 10% of individuals with trisomy X are actually diagnosed. The most common physical features include tall stature, epicanthal folds, hypotonia and clinodactyly. Seizures, renal and genitourinary abnormalities, and premature ovarian failure (POF) can also be associated findings. Children with trisomy X have higher rates of motor and speech delays, with an increased risk of cognitive deficits and learning disabilities in the school-age years. Psychological features including attention deficits, mood disorders (anxiety and depression), and other psychological disorders are also more common than in the general population. Trisomy X most commonly occurs as a result of nondisjunction during meiosis, although postzygotic nondisjunction occurs in approximately 20% of cases. The risk of trisomy X increases with advanced maternal age. The phenotype in trisomy X is hypothesized to result from overexpression of genes that escape X-inactivation, but genotype-phenotype relationships remain to be defined. Diagnosis during the prenatal period by amniocentesis or chorionic villi sampling is common. Indications for postnatal diagnoses most commonly include developmental delays or hypotonia, learning disabilities, emotional or behavioral difficulties, or POF. Differential diagnosis prior to definitive karyotype results includes fragile X, tetrasomy X, pentasomy X, and Turner syndrome mosaicism. Genetic counseling is recommended. Patients diagnosed in the prenatal period should be followed closely for developmental delays so that early intervention therapies can be implemented as needed. School-age children and adolescents benefit from a psychological evaluation with an emphasis on identifying and developing an intervention plan for problems in cognitive/academic skills, language, and/or social-emotional development. Adolescents and adult women presenting with late menarche, menstrual irregularities, or fertility problems should be evaluated for POF. Patients should be referred to support organizations to receive individual and family support. The prognosis is variable, depending on the severity of the manifestations and on the quality and timing of treatment.
PMCID: PMC2883963  PMID: 20459843
12.  Non-Specialist Psychosocial Interventions for Children and Adolescents with Intellectual Disability or Lower-Functioning Autism Spectrum Disorders: A Systematic Review 
PLoS Medicine  2013;10(12):e1001572.
In a systematic review, Brian Reichow and colleagues assess the evidence that non-specialist care providers in community settings can provide effective interventions for children and adolescents with intellectual disabilities or lower-functioning autism spectrum disorders.
Please see later in the article for the Editors' Summary
The development of effective treatments for use by non-specialists is listed among the top research priorities for improving the lives of people with mental illness worldwide. The purpose of this review is to appraise which interventions for children with intellectual disabilities or lower-functioning autism spectrum disorders delivered by non-specialist care providers in community settings produce benefits when compared to either a no-treatment control group or treatment-as-usual comparator.
Methods and Findings
We systematically searched electronic databases through 24 June 2013 to locate prospective controlled studies of psychosocial interventions delivered by non-specialist providers to children with intellectual disabilities or lower-functioning autism spectrum disorders. We screened 234 full papers, of which 34 articles describing 29 studies involving 1,305 participants were included. A majority of the studies included children exclusively with a diagnosis of lower-functioning autism spectrum disorders (15 of 29, 52%). Fifteen of twenty-nine studies (52%) were randomized controlled trials and just under half of all effect sizes (29 of 59, 49%) were greater than 0.50, of which 18 (62%) were statistically significant. For behavior analytic interventions, the best outcomes were shown for development and daily skills; cognitive rehabilitation, training, and support interventions were found to be most effective for improving developmental outcomes, and parent training interventions to be most effective for improving developmental, behavioral, and family outcomes. We also conducted additional subgroup analyses using harvest plots. Limitations include the studies' potential for performance bias and that few were conducted in lower- and middle-income countries.
The findings of this review support the delivery of psychosocial interventions by non-specialist providers to children who have intellectual disabilities or lower-functioning autism spectrum disorders. Given the scarcity of specialists in many low-resource settings, including many lower- and middle-income countries, these findings may provide guidance for scale-up efforts for improving outcomes for children with developmental disorders or lower-functioning autism spectrum disorders.
Protocol Registration
PROSPERO CRD42012002641
Please see later in the article for the Editors' Summary
Editors' Summary
Newborn babies are helpless, but over the first few years of life, they acquire motor (movement) skills, language (communication) skills, cognitive (thinking) skills, and social (interpersonal interaction) skills. Individual aspects of these skills are usually acquired at specific ages, but children with a development disorder such as an autism spectrum disorder (ASD) or intellectual disability (mental retardation) fail to reach these “milestones” because of impaired or delayed brain maturation. Autism, Asperger syndrome, and other ASDs (also called pervasive developmental disorders) affect about 1% of the UK and US populations and are characterized by abnormalities in interactions and communication with other people (reciprocal socio-communicative interactions; for example, some children with autism reject physical affection and fail to develop useful speech) and a restricted, stereotyped, repetitive repertoire of interests (for example, obsessive accumulation of facts about unusual topics). About half of individuals with an ASD also have an intellectual disability—a reduced overall level of intelligence characterized by impairment of the skills that are normally acquired during early life. Such individuals have what is called lower-functioning ASD.
Why Was This Study Done?
Most of the children affected by developmental disorders live in low- and middle-income countries where there are few services available to help them achieve their full potential and where little research has been done to identify the most effective treatments. The development of effective treatments for use by non-specialists (for example, teachers and parents) is necessary to improve the lives of people with mental illnesses worldwide, but particularly in resource-limited settings where psychiatrists, psychologists, and other specialists are scarce. In this systematic review, the researchers investigated which psychosocial interventions for children and adolescents with intellectual disabilities or lower-functioning ASDs delivered by non-specialist providers in community settings produce improvements in development, daily skills, school performance, behavior, or family outcomes when compared to usual care (the control condition). A systematic review identifies all the research on a given topic using predefined criteria; psychosocial interventions are defined as therapy, education, training, or support aimed at improving behavior, overall development, or specific life skills without the use of drugs.
What Did the Researchers Do and Find?
The researchers identified 29 controlled studies (investigations with an intervention group and a control group) that examined the effects of various psychosocial interventions delivered by non-specialist providers to children (under 18 years old) who had a lower-functioning ASD or intellectual disability. The researchers retrieved information on the participants, design and methods, findings, and intervention characteristics for each study, and calculated effect sizes—a measure of the effectiveness of a test intervention relative to a control intervention—for several outcomes for each intervention. Across the studies, three-quarters of the effect size estimates were positive, and nearly half were greater than 0.50; effect sizes of less than 0.2, 0.2–0.5, and greater than 0.5 indicate that an intervention has no, a small, or a medium-to-large effect, respectively. For behavior analytic interventions (which aim to improve socially significant behavior by systematically analyzing behavior), the largest effect sizes were seen for development and daily skills. Cognitive rehabilitation, training, and support (interventions that facilitates the relearning of lost or altered cognitive skills) produced good improvements in developmental outcomes such as standardized IQ tests in children aged 6–11 years old. Finally, parental training interventions (which teach parents how to provide therapy services for their child) had strong effects on developmental, behavioral, and family outcomes.
What Do These Findings Mean?
Because few of the studies included in this systematic review were undertaken in low- and middle-income countries, the review's findings may not be generalizable to children living in resource-limited settings. Moreover, other characteristics of the included studies may limit the accuracy of these findings. Nevertheless, these findings support the delivery of psychosocial interventions by non-specialist providers to children who have intellectual disabilities or a lower-functioning ASD, and indicate which interventions are likely to produce the largest improvements in developmental, behavioral, and family outcomes. Further studies are needed, particularly in low- and middle-income countries, to confirm these findings, but given that specialists are scarce in many resource-limited settings, these findings may help to inform the implementation of programs to improve outcomes for children with intellectual disabilities or lower-functioning ASDs in low- and middle-income countries.
Additional Information
Please access these websites via the online version of this summary at
This study is further discussed in a PLOS Medicine Perspective by Bello-Mojeed and Bakare
The US Centers for Disease Control and Prevention provides information (in English and Spanish) on developmental disabilities, including autism spectrum disorders and intellectual disability
The US National Institute of Mental Health also provides detailed information about autism spectrum disorders, including the publication “A Parent's Guide to Autism Spectrum Disorder”
Autism Speaks, a US non-profit organization, provides information about all aspects of autism spectrum disorders and includes information on the Autism Speaks Global Autism Public Health Initiative
The National Autistic Society, a UK charity, provides information about all aspects of autism spectrum disorders and includes personal stories about living with these conditions
The UK National Health Service Choices website has an interactive guide to child development and information about autism and Asperger syndrome, including personal stories, and about learning disabilities
The UK National Institute for Health and Care Excellence provides clinical guidelines for the management and support of children with autism spectrum disorders
The World Health Organization provides information on its Mental Health Gap Action Programme (mhGAP), which includes recommendations on the management of developmental disorders by non-specialist providers; the mhGAP Evidence Resource Center provides evidence reviews for parent skills training for management of children with intellectual disabilities and pervasive developmental disorders and interventions for management of children with intellectual disabilities
PROSPERO, an international prospective register of systematic reviews, provides more information about this systematic review
PMCID: PMC3866092  PMID: 24358029
13.  Heavy Metals and Trace Elements in Hair and Urine of a Sample of Arab Children with Autistic Spectrum Disorder 
Mædica  2011;6(4):247-257.
General information: Autism is a severe developmental disorder which involves social withdrawal, communication deficits, and stereotypic/repetitive behavior. The pathophysiological etiologies which precipitate autism symptoms remain elusive and controversial in many cases, but both genetic and environmental factors (and their interactions) have been implicated. While autism is considered multicausal, environmental factors have received significant attention. International discussion has ocused on neurotoxins such as mercury and lead, suggesting that these and other toxic metals contribute to the development of the disorder. An epidemiological study released in 2006 (Palmer et al.) linking Toxic Release Inventory (TRI) data on mercury to special education data in Texas reported a 61% increase in autism prevalence rates (or 17% adjusted) per 1000 pounds of mercury released into the environment (1). We attempted to further evaluate whether exposure to variable environmental contributes to the genesis of autistic spectrum disorder, and thus is a factor increasing the risk for developing autism symptoms in utero or in early childhood.
Purpose: The purpose of this study is to examine possible environmental risk factors and sources of exposure to mercury and other heavy metals in children with autism spectrum disorder versus controls. Through laboratory diagnostics we are able to distinguish between present and past exposure (i.e. hair analysis measurements reflect past exposure), urinary excretion levels of unprovoked urine represent immediate exposure. By assessing a spectrum of trace elements and heavy metals in hair and urine of both autistic and control groups, we focused on the participants≈ past and present exposure.
Methodology: The participants were 25 Autistic Spectrum Disorder (ASD) children (22 boys and 3 girls) between the age of 3 and 9 years. They were either diagnosed previously by other psychiatrist, psychologist, and developmental pediatrician or suspected by their parents as being autistic. All children were attendants to the Child Psychiatric Clinic in Erfan Psychiatric Hospital in Jeddah, KSA. Samples were collected during the period of June 2006 to March 2008. A control group of 25 children without any psychiatric or medical disorders was age-matched and sex-matched. All parents signed informed consent forms. All autistic children were subjected to a full clinical child psychiatric sheet for the diagnosis of autism spectrum disorder and exclusion of other psychiatric disorders according to the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (DSM IV). The severity of autistic symptomatology was measured by the Childhood Autism Rating Scale (CARS) and Autism Behavior Checklist (ABC) using the Arabic versions. Both groups were subjected to the Questionnaire on Exposure to Heavy Metals, Physical Symptoms, and Child Development. Hair and baseline urine samples (i.e. unprovoked urine) were taken from both groups and sent to the German clinical and environmental laboratory Micro Trace Minerals Gmbh, for the detection of heavy metals and trace elements levels where metal testing was performed via ICP-MS spectroscopy utilizing cell technique.
Results: By comparing the ASD Group to the Control Group, we found a statistically significant difference in the mean hair levels of arsenic, cadmium, barium, cerium and lead (p=0.01, 0.03, 0.003, 0.003, and 0.03 respectively), and in the mean hair levels of magnesium and zinc (p=0.001 and 0.003 respectively). There were also statistically significant differences in the mean urine levels of aluminum, barium, cerium, mercury, and lead (p=0.004, 002, 0.014, 0.006 and 0.004 respectively), and in the mean urine levels of copper and germanium (p=0.049 and 0.02 respectively). An agreement was found in both specimen (hair and urine) for barium and lead. The statistically significant differences in mean hair levels of arsenic, cadmium, and cerium were not supported by urine baseline levels. Also, the statistically significant magnesium and zinc levels of hair were not supported by urine levels. A disagreement was also found with copper and germanium concentrations.
PMCID: PMC3391939  PMID: 22879836
micronucleus; nucleoplasmic bridges; colon cancer
14.  SNP-based non-invasive prenatal testing detects sex chromosome aneuploidies with high accuracy 
Prenatal diagnosis  2013;33(7):643-649.
To develop a single nucleotide polymorphism- and informatics-based non-invasive prenatal test that detects sex chromosome aneuploidies early in pregnancy.
Fifteen aneuploid samples, including thirteen 45,X, two 47,XXY, and one 47,XYY, along with 185 euploid controls, were analyzed. Cell-free DNA was isolated from maternal plasma, amplified in a single multiplex PCR assay that targeted 19,488 polymorphic loci covering chromosomes 13, 18, 21, X, and Y, and sequenced. Sequencing results were analyzed using a Bayesian-based maximum likelihood statistical method to determine copy number of interrogated chromosomes, calculating sample-specific accuracies.
Of the samples that passed a stringent quality control metric (93%), the algorithm correctly identified copy number at all five chromosomes in all 187 samples, for 934/935 correct calls as early as 9.4 weeks of gestation. We detected 45,X with 91.7% sensitivity (CI: 61.5-99.8%) and 100% specificity (CI: 97.9-100%), and 47,XXY and 47,XYY. The average calculated accuracy was 99.78%.
This method non-invasively detected 45,X, 47,XXY, and 47,XYY fetuses from cfDNA isolated from maternal plasma with high calculated accuracies, and thus offers a non-invasive method with the potential to function as a routine screen allowing for early prenatal detection of rarely diagnosed yet commonly occurring sex aneuploidies.
PMCID: PMC3764608  PMID: 23712453
15.  Volumetric magnetic resonance imaging study of the brain in subjects with sex chromosome aneuploidies 
OBJECTIVES—Cognitive impairment has been reported in people with sex chromosome aneuploides (SCAs) and it has been proposed that the presence of an extra sex chromosome may have an adverse effect on neurodevelopment. This study examines the hypothesis with structural MRI of the brain.
METHODS—Thirty two subjects with SCA (XXX (n=12), XYY (n=10), and XXY (n=10)) from a birth cohort study were matched groupwise for age, parental social class, and height with normal controls (13female, 26 male). Brain MRI , measurements of IQ, and a structured psychiatric interview were performed.
RESULTS—The XXX females and XXY males had significantly smaller whole brain volumes than controls of the same phenotypic sex (p=0.003 and p⩽0.05 respectively). The XXY group also had bilaterally enlarged lateral ventricles (p⩽0.05). No significant differences were found between the XYY group and controls. IQ scores in all SCA groups were lower than in the control groups.
CONCLUSIONS—The main result of reduced brain volumes in XXX and XXY subjects, but not in XYY subjects, indicates that the presence of a supernumerary X chromosome has a demonstrable effect on brain development.

PMCID: PMC1736357  PMID: 10209175
16.  Broader Autism Phenotype in Iranian Parents of Children with Autism Spectrum Disorders vs. Normal Children 
Iranian Journal of Psychiatry  2012;7(4):157-163.
The aim of the present study was to compare the broader autism phenotype in Iranian parents of children with autism spectrum disorders and parents of typically developing children.
Parents of children with ASD and parents of typically developing children were asked to complete the Persian version of the Autism Spectrum Quotient (AQ). In the ASD group, families included 204 parents (96 fathers and 108 mothers) of children diagnosed as having autism (Autistic Disorder, or AD) (n=124), Asperger Syndrome (AS) or High Functioning Autism (HFA) (n=48) and Pervasive Developmental Disorder Not Otherwise Specified (PDD-NOS) (n=32) by psychiatrists based on the Diagnostic and Statistical Manual of Mental Disorders-4thedition (DSM-IV-TR) criteria. In the control group, 210 (108 fathers and 102 mothers) parents of typically developing children. Parents of typically developing children were selected from four primary schools. Based on family reports, their children did not have any psychiatric problems. Total AQ score and each of the 5 subscales were analyzed using two-way ANOVAs with sex and group as factors.
The mean age of ASD fathers was 40.6 years (SD=5.96; range 31-54), and of ASD mothers was 34.7 years (SD=4.55; range 28-45). The mean age of control fathers was 37 years (SD=4.6; range 29-45) and of control mothers was 34.11 years (SD=4.86; range 28-45). Group differences were found in age (p ‹ 0/001). On total AQ, a main effect for group and sex was found. ASD parents scored higher than controls (F(1,410)=77.876, P ‹ 0/001) and males scored higher than females (F(1,410)=23.324, P ‹ 0/001). Also, Group by Sex interaction was significant (F(1,410)=4.986, P ‹ 0/05). Results of MANOVA analysis displayed significant differences between ASD's subgroups on total AQ and subscales scores (F (15, 1121)=13.924, p < 0.0005; Wilk's Lambda= 0.624, partial =0.145). Pairwise comparisons between ASD's subgroups and Normal group showed that mean scores for the Asperger group are significantly more than other groups in total AQ, attention switching and communication subscales (p < 0.05). The frequencies of BAP (X^2=52.721 (DF=1), P ‹ 0/001), MAP (X^2=17.133 (DF=1), P ‹ 0/001) and NAP (X^2=12.722 (DF=1), P ‹ 0/001) in ASD parents were significantly more than control parents. The frequencies of Broader Autism Phenotype (BAP) (X^2=3.842 (DF=1), P›0/05) and Medium Autism phenotype (MAP) (X^2=0.060 (DF=1), P›0/05) did not significantly differ in ASD fathers and mothers, but the proportion of fathers in Narrow Autism Phenotype(NAP) range was more than mothers (X2=14.344, P ‹ 0/001).
Results of the present study revealed that parents of children with ASD scored significantly higher than control parents on total AQ and its subscales and the rates of BAP, MAP and NAP were higher in ASD parents than in controls. In addition, in ASD's subgroups, the parents of Asperger children scored significantly more than other subgroups (Autism and PDD-nos) and the normal group on total AQ and some subscales.
PMCID: PMC3570573  PMID: 23408558
Autistic disorder; Child; Iran; Parents
17.  Gastrointestinal Dysfunction in Autism: Parental Report, Clinical Evaluation, & Associated Factors 
Autism Research  2012;5(2):101-108.
Lay Abstract
Gastrointestinal dysfunction (GID) in children with autism spectrum disorder (ASD) is not well understood. Differences in factors associated with GID, such as eating habits, have been reported between ASD and non-ASD populations, but relationships between these factors and GID have not been examined. There is also the possibility that what we do know about GID in ASD is influenced by parents’ perceptions of GID in their children. Although parents know their children best, they are not necessarily experts in determining GID. This study examined how well parents and pediatric gastrointestinal clinicians agree on GID in children, and how factors thought to relate to GID in ASD, actually do relate to GID. 121 children were studied, in three groups: co-occurring ASD and GID, ASD without GID, and GID without ASD. Clinical evaluations by pediatric gastroenterologists validated parental reports of GID in ASD, with constipation the leading type of GID in ASD. Presence of GID in ASD was not associated with differences in diet or medications, but was associated with language and social impairments. These findings suggest that healthcare providers of children with ASD should be vigilant for GID, particularly in children who lack the ability to communicate verbally.
Scientific Abstract
The objectives of this study were to characterize gastrointestinal dysfunction (GID) in autism spectrum disorder (ASD), to examine parental reports of GID relative to evaluations by pediatric gastroenterologists, and to explore factors associated with GID in ASD. 121 children were recruited into three groups: co-occurring ASD and GID, ASD without GID, and GID without ASD. A pediatric gastroenterologist evaluated both GID groups. Parents in all three groups completed questionnaires about their child’s behavior and GI symptoms, and a dietary journal. Functional constipation was the most common type of GID in children with ASD (85.0%). Parental report of any GID was highly concordant with a clinical diagnosis of any GID (92.1%). Presence of GID in children with ASD was not associated with distinct dietary habits or medication status. Odds of constipation were associated with younger age, increased social impairment, and lack of expressive language (adjusted odds ratio in nonverbal children: 11.98, 95% CI 2.54 – 56.57). This study validates parental concerns for GID in children with ASD, as parents were sensitive to the existence, although not necessarily the nature, of GID. The strong association between constipation and language impairment highlights the need for vigilance by healthcare providers to detect and treat GID in children with ASD. Medications and diet, commonly thought to contribute to GID in ASD, were not associated with GID status. These findings are consistent with a hypothesis that GID in ASD represents pleiotropic expression of genetic risk factors.
PMCID: PMC3335766  PMID: 22511450
Autism; Constipation; Diet; Functional Gastrointestinal Disorders; Nonverbal Communication; Social Behavior
18.  Redox metabolism abnormalities in autistic children associated with mitochondrial disease 
Translational Psychiatry  2013;3(6):e273-.
Research studies have uncovered several metabolic abnormalities associated with autism spectrum disorder (ASD), including mitochondrial disease (MD) and abnormal redox metabolism. Despite the close connection between mitochondrial dysfunction and oxidative stress, the relation between MD and oxidative stress in children with ASD has not been studied. Plasma markers of oxidative stress and measures of cognitive and language development and ASD behavior were obtained from 18 children diagnosed with ASD who met criteria for probable or definite MD per the Morava et al. criteria (ASD/MD) and 18 age and gender-matched ASD children without any biological markers or symptoms of MD (ASD/NoMD). Plasma measures of redox metabolism included reduced free glutathione (fGSH), oxidized glutathione (GSSG), the fGSH/GSSG ratio and 3-nitrotyrosine (3NT). In addition, a plasma measure of chronic immune activation, 3-chlorotyrosine (3CT), was also measured. Language was measured using the preschool language scale or the expressive one-word vocabulary test (depending on the age), adaptive behaviour was measured using the Vineland Adaptive Behavior Scale (VABS) and core autism symptoms were measured using the Autism Symptoms Questionnaire and the Social Responsiveness Scale. Children with ASD/MD were found to have lower scores on the communication and daily living skill subscales of the VABS despite having similar language and ASD symptoms. Children with ASD/MD demonstrated significantly higher levels of fGSH/GSSG and lower levels of GSSG as compared with children with ASD/NoMD, suggesting an overall more favourable glutathione redox status in the ASD/MD group. However, compare with controls, both ASD groups demonstrated lower fGSH and fGSH/GSSG, demonstrating that both groups suffer from redox abnormalities. Younger ASD/MD children had higher levels of 3CT than younger ASD/NoMD children because of an age-related effect in the ASD/MD group. Both ASD groups demonstrated significantly higher 3CT levels than control subjects, suggesting that chronic inflammation was present in both groups of children with ASD. Interestingly, 3NT was found to correlate positively with several measures of cognitive function, development and behavior for the ASD/MD group, but not the ASD/NoMD group, such that higher 3NT concentrations were associated with more favourable adaptive behaviour, language and ASD-related behavior. To determine whether difference in receiving medications and/or supplements could account for the differences in redox and inflammatory biomarkers across ASD groups, we examined differences in medication and supplements across groups and their effect of redox and inflammatory biomarkers. Overall, significantly more participants in the ASD/MD group were receiving folate, vitamin B12, carnitine, co-enzyme Q10, B vitamins and antioxidants. We then determined whether folate, carnitine, co-enzyme Q10, B vitamins and/or antioxidants influenced redox or inflammatory biomarkers. Antioxidant supplementation was associated with a significantly lower GSSG, whereas antioxidants, co-enzyme Q10 and B vitamins were associated with a higher fGSH/GSSG ratio. There was no relation between folate, carnitine, co-enzyme Q10, B vitamins and antioxidants with 3NT, 3CT or fGSH. Overall, our findings suggest that ASD/MD children with a more chronic oxidized microenvironment have better development. We interpret this finding in light of the fact that more active mitochondrial can create a greater oxidized microenvironment especially when dysfunctional. Thus, compensatory upregulation of mitochondria which are dysfunctional may both increase activity and function at the expense of a more oxidized microenvironment. Although more ASD/MD children were receiving certain supplements, the use of such supplements were not found to be related to the redox biomarkers that were related to cognitive development or behavior in the ASD/MD group but could possibly account for the difference in glutathione metabolism noted between groups. This study suggests that different subgroups of children with ASD have different redox abnormalities, which may arise from different sources. A better understanding of the relationship between mitochondrial dysfunction in ASD and oxidative stress, along with other factors that may contribute to oxidative stress, will be critical to understanding how to guide treatment and management of ASD children. This study also suggests that it is important to identify ASD/MD children as they may respond differently to specific treatments because of their specific metabolic profile.
PMCID: PMC3693408  PMID: 23778583
autism; inflammation; endophenotypes; mitochondrial disease; oxidative stress
19.  Lack of Infection with XMRV or Other MLV-Related Viruses in Blood, Post-Mortem Brains and Paternal Gametes of Autistic Individuals 
PLoS ONE  2011;6(2):e16609.
Autistic spectrum disorder (ASD) is characterized by impaired language, communication and social skills, as well as by repetitive and stereotypic patterns of behavior. Many autistic subjects display a dysregulation of the immune system which is compatible with an unresolved viral infection with prenatal onset, potentially due to vertical viral transmission. Recently, the xenotropic murine leukemia virus-related virus (XMRV) has been implicated in chronic fatigue syndrome (CFS) and in prostate cancer by several, though not all studies.
Methodology/Principal Findings
We assessed whether XMRV or other murine leukemia virus (MLV)-related viruses are involved in autistic disorder. Using nested PCR targeted to gag genomic sequences, we screened DNA samples from: (i) peripheral blood of 102 ASD patients and 97 controls, (ii) post-mortem brain samples of 20 ASD patients and 17 sex- and age-matched controls, (iii) semen samples of 11 fathers of ASD children, 25 infertile individuals and 7 fertile controls. No XMRV gag DNA sequences were detected, whereas peripheral blood samples of 3/97 (3.1%) controls were positive for MLV.
No MLV-related virus was detected in blood, brain, and semen samples of ASD patients or fathers. Hence infection with XMRV or other MLV-related viruses is unlikely to contribute to autism pathogenesis.
PMCID: PMC3043069  PMID: 21373179
20.  Prenatal fetal karyotyping and maternal serum alpha-fetoprotein screening. 
Prenatal karyotyping was undertaken in 569 consecutive amniotic fluid samples where the indication for amniocentesis was two sequential raised maternal serum alpha-fetoprotein concentrations. In 475 successful cultures five chromosome abnormalities were found--four constitutional anomalies (47,XXY; 47,XYY; an inherited inv(8) (p23q11); and a de-novo translocation t(6;7) (p11;p22) and a culture-derived anomaly (trisomy 2) found in amniotic fluid cells but not in the fetus aborted because it had spina bifida. Of the pregnancies complicated by constitutional abnormalities, only the pregnancy in which the de-novo translocation was detected was terminated. No chromosome abnormalities were detected in the 17 pregnancies which miscarried after amniocentesis. These results provide little justification for including fetal karyotyping as an essential part of maternal serum alpha-fetoprotein screening programmes.
PMCID: PMC1504099  PMID: 6161673
21.  Adult psychosocial outcomes of children with specific language impairment, pragmatic language impairment and autism 
Background: The few studies that have tracked children with developmental language disorder to adulthood have found that these individuals experience considerable difficulties with psychosocial adjustment (for example, academic, vocational and social aptitude). Evidence that some children also develop autistic symptomatology over time has raised suggestions that developmental language disorder may be a high-functioning form of an autism spectrum disorder (ASD). It is not yet clear whether these outcomes vary between individuals with different subtypes of language impairment.
Aims: To compare the adult psychosocial outcomes of children with specific language impairment (SLI), pragmatic language impairment (PLI) and ASD.
Methods & Procedures: All participants took part in research as children. In total, there were 19 young adults with a childhood history of Specific Language Impairment (M age = 24;8), seven with PLI (M age = 22;3), 11 with high functioning ASD (M age = 21;9) and 12 adults with no history of developmental disorder (Typical; n = 12; M age = 21;6). At follow-up, participants and their parents were interviewed to elicit information about psychosocial outcomes.
Outcomes & Results: Participants in the SLI group were most likely to pursue vocational training and work in jobs not requiring a high level of language/literacy ability. The PLI group tended to obtain higher levels of education and work in ‘skilled’ professions. The ASD participants had lower levels of independence and more difficulty obtaining employment than the PLI and SLI participants. All groups had problems establishing social relationships, but these difficulties were most prominent in the PLI and ASD groups. A small number of participants in each group were found to experience affective disturbances. The PLI and SLI groups showed lower levels of autistic symptomatology than the ASD group.
Conclusions & Implications: The between-group differences in autistic symptomatology provide further evidence that SLI, PLI, and ASD are related disorders that vary along qualitative dimensions of language structure, language use and circumscribed interests. Childhood diagnosis showed some relation to adult psychosocial outcome. However, within-group variation highlights the importance of evaluating children on a case-by-case basis.
PMCID: PMC2835860  PMID: 19340628
specific language impairment; pragmatic language impairment; autism; longitudinal; psychosocial; outcome
22.  Adult psychosocial outcomes of children with specific language impairment, pragmatic language impairment and autism 
The few studies that have tracked children with developmental language disorder to adulthood have found that these individuals experience considerable difficulties with psychosocial adjustment (for example, academic, vocational and social aptitude). Evidence that some children also develop autistic symptomatology over time has raised suggestions that developmental language disorder may be a high-functioning form of an autism spectrum disorder (ASD). It is not yet clear whether these outcomes vary between individuals with different subtypes of language impairment.
To compare the adult psychosocial outcomes of children with specific language impairment (SLI), pragmatic language impairment (PLI) and ASD.
Methods & Procedures:
All participants took part in research as children. In total, there were 19 young adults with a childhood history of Specific Language Impairment (M age=24;8), seven with PLI (M age=22;3), 11 with high functioning ASD (M age=21;9) and 12 adults with no history of developmental disorder (Typical; n=12; M age=21;6). At follow-up, participants and their parents were interviewed to elicit information about psychosocial outcomes.
Outcomes & Results:
Participants in the SLI group were most likely to pursue vocational training and work in jobs not requiring a high level of language/literacy ability. The PLI group tended to obtain higher levels of education and work in ‘skilled’ professions. The ASD participants had lower levels of independence and more difficulty obtaining employment than the PLI and SLI participants. All groups had problems establishing social relationships, but these difficulties were most prominent in the PLI and ASD groups. A small number of participants in each group were found to experience affective disturbances. The PLI and SLI groups showed lower levels of autistic symptomatology than the ASD group.
Conclusions & Implications:
The between-group differences in autistic symptomatology provide further evidence that SLI, PLI, and ASD are related disorders that vary along qualitative dimensions of language structure, language use and circumscribed interests. Childhood diagnosis showed some relation to adult psychosocial outcome. However, within-group variation highlights the importance of evaluating children on a case-by-case basis.
PMCID: PMC2835860  PMID: 19340628
specific language impairment; pragmatic language impairment; autism; longitudinal; psychosocial; outcome
23.  Exploratory study describing 6 month outcomes for young children with autism who receive treatment as usual in Italy 
In the last few years, the results of different studies have confirmed, in different ways, the importance of early intervention for autism. This study aims to evaluate the role of early “as usual” interventions in the outcome of toddlers diagnosed with autism spectrum disorder (ASD).
Seventy children with ASD aged between 24 and 48 months were recruited at different centers in Italy. They were evaluated by blind researchers at baseline and after 6 months of using Autism Diagnostic Observation Schedule-Generic (ADOS-G), Griffiths Mental Developmental Scales, and Vineland Adaptive Behavior scales. Parents filled out the MacArthur Inventory, Social Communication Questionnaire, and Child Behavior Check List. All children were referred to community providers for available interventions.
At the endpoint, most of the children were still classified as having an ADOS-G classification of ASD. However, 21 (34.2%) passed from autism to autism spectrum, and 3 (4.2%) passed from autism spectrum to no spectrum. Treatment effects were obtained for cognitive functioning, language, adaptive behavior, and child behavior without differences between development-oriented and behavior-oriented interventions. Parent involvement was a mediator for the best clinical outcome. Baseline low impairments of communication, language comprehension, and gesture were predictors of positive outcome.
Treatment as usual, composed of individual therapy plus school-supported inclusion, may be an effective intervention in ASD. Better initial levels of communication in child and parent involvement during treatment have an important role for a positive outcome.
PMCID: PMC3986291  PMID: 24748794
autism; preschoolers; treatment as usual; early intervention
24.  Perinatal testosterone exposure and autistic-like traits in the general population: a longitudinal pregnancy-cohort study 
Increased prenatal testosterone exposure has been hypothesized as a mechanism underlying autism spectrum disorders (ASD). However, no studies have prospectively measured prenatal testosterone exposure and ASD. The current study sought to determine whether testosterone concentrations in umbilical cord blood are associated with a clinical diagnosis of ASD in a small number of children and with autistic-like traits in the general population.
Umbilical cord blood was collected from 707 children. Samples were analyzed for total (TT) and bioavailable (BioT) testosterone concentrations. Parent report indicated that five individuals had a clinical diagnosis of ASD. Those participants without a diagnosis were approached in early adulthood to complete the Autism-Spectrum Quotient (AQ), a self-report measure of autistic-like traits, with 184 males (M = 20.10 years; SD= 0.65 years) and 190 females (M = 19.92 years; SD=0.68 years) providing data.
The BioT and TT concentrations of the five children diagnosed with ASD were within one standard-deviation of the sex-specific means. Spearman’s rank-order coefficients revealed no significant correlations between TT levels and scores on any AQ scale among males (rho range: -.01 to .06) or females (rho value range: -.07 to .01). There was also no significant association between BioT or TT concentrations and AQ scores among males (rho value range: -.07 to .08) or females (rho value range: -.06 to .12). Males were more likely than females to have ‘high’ scores (upper decile) on the AQ scale relating pattern and detail processing. However, the likelihood of a high score on this scale was unrelated to BioT and TT concentrations in both males and females.
These findings indicate that testosterone concentrations from umbilical cord blood are unrelated to autistic-like traits in the general population. However, the findings do not exclude an association between testosterone exposure in early intrauterine life and ASD.
PMCID: PMC3500651  PMID: 23110806
Autism; Testosterone; Prenatal; Perinatal; Autistic-like traits
25.  Diagnosis of autism spectrum disorders in two year-olds: A study of community practice 
Longitudinal research studies have demonstrated that experienced clinicians using standardized assessment measures can make a reliable diagnosis of Autism Spectrum Disorders (ASDs) in children under age 3. Limited data are available regarding the sensitivity and specificity of these measures in community settings. The aims of this study were to determine how well a standardized diagnostic observational measure (Autism Diagnostic Observation Schedule; ADOS) functions alone, and with a brief parent measure within a community setting when administered by community clinicians.
Clinical records for 138 children between the ages of 24 and 36 months of age who were evaluated for possible ASD or social/language concerns at a hospital based developmental evaluation clinic were examined. Evaluations were conducted by community based clinical psychologists. Classification results obtained from standardized diagnostic measures were compared with case reviewer diagnosis, by reviewers blind to scores on diagnostic measures, using The Records-based Methodology for ASD Case Definitionthat was developed by the Metropolitan Atlanta Developmental Disabilities Surveillance Program (MADDSP).
When compared with case review diagnosis, the ADOS demonstrated strong sensitivity and specificity for both Autism vs. Not Autism and ASD vs. Non-spectrum (NS) diagnoses in this young sample. The Social Communication Questionnaire (SCQ), using the lower cut-off of ≥12, had adequate sensitivity when differentiating Autism from Not Autism, but weak sensitivity when differentiating ASD from NS, missing about 80% of the children with Pervasive Developmental Disorder – Not Otherwise Specified (PDD-NOS). Using either the Modified Checklist for Autism in Toddlers(M-CHAT) or the SCQ in combination with the ADOS did not result in improved specificity over the ADOS alone and led to a drop in sensitivity when differentiating ASD from NS disorders.
These results demonstrate that following best practice guidelines, the ADOS can be successfully incorporated into clinical practicewith relatively good sensitivity and specificity, and worked well with a referred sample of two-year-olds. A parent questionnaire did not lead to any improvement in diagnostic classification above the ADOS used in isolation.
PMCID: PMC3505251  PMID: 22905987

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