1. {{A framework for interpreting genome-wide association studies of psychiatric disorders}}. {Mol Psychiatry};2009 (Jan);14(1):10-17.Psychiatric GWAS Consortium Steering Committee
Genome-wide association studies (GWAS) have yielded a plethora of new findings in the past 3 years. By early 2009, GWAS on 47 samples of subjects with attention-deficit hyperactivity disorder, autism, bipolar disorder, major depressive disorder and schizophrenia will be completed. Taken together, these GWAS constitute the largest biological experiment ever conducted in psychiatry (59 000 independent cases and controls, 7700 family trios and >40 billion genotypes). We know that GWAS can work, and the question now is whether it will work for psychiatric disorders. In this review, we describe these studies, the Psychiatric GWAS Consortium for meta-analyses of these data, and provide a logical framework for interpretation of some of the conceivable outcomes.
2. Adamson LB, Bakeman R, Deckner DF, Romski M. {{Joint engagement and the emergence of language in children with autism and down syndrome}}. {J Autism Dev Disord};2009 (Jan);39(1):84-96.
Systematic longitudinal observations were made as typically developing toddlers and young children with autism and with Down syndrome interacted with their caregivers in order to document how joint engagement developed over a year-long period and how variations in joint engagement experiences predicted language outcome. Children with autism displayed a persistent deficit in coordinated joint attention; children with Down syndrome were significantly less able to infuse symbols into joint engagement. For all groups, variations in amount of symbol-infused supported joint engagement, a state in which the child attended to a shared object and to language but not actively to the partner, contributed to differences in expressive and receptive language outcome, over and above initial language capacity.
3. Adegbola AA, Gonzales ML, Chess A, LaSalle JM, Cox GF. {{A novel hypomorphic MECP2 point mutation is associated with a neuropsychiatric phenotype}}. {Hum Genet};2009 (Jan);124(6):615-623.
The MECP2 gene on Xq28 encodes a transcriptional repressor, which binds to and modulates expression of active genes. Mutations in MECP2 cause classic or preserved speech variant Rett syndrome and intellectual disability in females and early demise or marked neurodevelopmental handicap in males. The consequences of a hypomorphic Mecp2 allele were recently investigated in a mouse model, which developed obesity, motor, social, learning, and behavioral deficits, predicting a human neurobehavioral syndrome. Here, we describe mutation analysis of a nondysmorphic female proband and her father who presented with primarily neuropsychiatric manifestations and obesity with relative sparing of intelligence, language, growth, and gross motor skills. We identified and characterized a novel missense mutation (c.454C>G; p.P152A) in the critical methyl-binding domain of MeCP2 that disrupts MeCP2 functional activity. We show that a gradient of impairment is present when the p.P152A mutation is compared with an allelic p.P152R mutation, which causes classic Rett syndrome and another Rett syndrome-causing mutation, such that protein-heterochromatin binding observed by immunofluorescence and immunoblotting is wild-type > P152A > P152R > T158 M, consistent with the severity of the observed phenotype. Our findings provide evidence for very mild phenotypes in humans associated with partial reduction of MeCP2 function arising from subtle variation in MECP2.
4. Ashwin E, Ashwin C, Rhydderch D, Howells J, Baron-Cohen S. {{Eagle-eyed visual acuity: an experimental investigation of enhanced perception in autism}}. {Biol Psychiatry};2009 (Jan 1);65(1):17-21.
BACKGROUND: Anecdotal accounts of sensory hypersensitivity in individuals with autism spectrum conditions (ASC) have been noted since the first reports of the condition. Over time, empirical evidence has supported the notion that those with ASC have superior visual abilities compared with control subjects. However, it remains unclear whether these abilities are specifically the result of differences in sensory thresholds (low-level processing), rather than higher-level cognitive processes. METHODS: This study investigates visual threshold in n = 15 individuals with ASC and n = 15 individuals without ASC, using a standardized optometric test, the Freiburg Visual Acuity and Contrast Test, to investigate basic low-level visual acuity. RESULTS: Individuals with ASC have significantly better visual acuity (20:7) compared with control subjects (20:13)-acuity so superior that it lies in the region reported for birds of prey. CONCLUSIONS: The results of this study suggest that inclusion of sensory hypersensitivity in the diagnostic criteria for ASC may be warranted and that basic standardized tests of sensory thresholds may inform causal theories of ASC.
5. Banach R, Thompson A, Szatmari P, Goldberg J, Tuff L, Zwaigenbaum L, Mahoney W. {{Brief Report: Relationship Between Non-verbal IQ and Gender in Autism}}. {J Autism Dev Disord};2009 (Jan);39(1):188-193.
It has been proposed that females at risk for autism are protected in some way, so that only those with the greatest genetic liability are affected. Consequently, affected male siblings of females with autism should be more impaired than affected male siblings of male probands. One hundred and ninety-four (194) families with a single child with autism (simplex, SPX) and 154 families with more than one child with autism (multiplex, MPX) were examined on measures of severity, including non-verbal IQ. Among SPX families, girls had lower IQ than boys, but no such differences were seen among MPX families. Similarly, the affected brothers of girls with autism were no different from affected brothers of male probands. These data suggest that MPX and SPX families differ with respect to the relationship between gender and IQ.
6. Basu SN, Kollu R, Banerjee-Basu S. {{AutDB: a gene reference resource for autism research}}. {Nucleic Acids Res};2009 (Jan);37(Database issue):D832-836.
Recent advances in studies of Autism Spectrum Disorders (ASD) has uncovered many new candidate genes and continues to do so at an accelerated pace. To address the genetic complexity of ASD, we have developed AutDB (http://www.mindspec.org/autdb.html), a publicly available web-portal for on-going collection, manual annotation and visualization of genes linked to the disorder. We present a disease-driven database model in AutDB where all genes connected to ASD are collected and classified according to their genetic variation: candidates identified from genetic association studies, rare single gene mutations and genes linked to syndromic autism. Gene entries are richly annotated for their relevance to autism, along with an in-depth view of their molecular functions. The content of AutDB originates entirely from the published scientific literature and is organized to optimize its use by the research community. The main focus of this resource is to provide an up-to-date, annotated list of ASD candidate genes in the form of reference dataset for interrogating molecular mechanisms underlying the disorder. Our model for consolidated knowledge representation in genetically complex disorders could be replicated to study other such disorders.
7. Begeer S, Bouk SE, Boussaid W, Terwogt MM, Koot HM. {{Underdiagnosis and referral bias of autism in ethnic minorities}}. {J Autism Dev Disord};2009 (Jan);39(1):142-148.
This study examined (1) the distribution of ethnic minorities among children referred to autism institutions and (2) referral bias in pediatric assessment of autism in ethnic minorities. It showed that compared to the known community prevalence, ethnic minorities were under-represented among 712 children referred to autism institutions. In addition, pediatricians (n = 81) more often referred to autism when judging clinical vignettes of European majority cases (Dutch) than vignettes including non-European minority cases (Moroccan or Turkish). However, when asked explicitly for ratings of the probability of autism, the effect of ethnic background on autism diagnosis disappeared. We conclude that the use of structured ratings may decrease the likelihood of ethnic bias in diagnostic decisions of autism.
8. Ben-Sasson A, Hen L, Fluss R, Cermak SA, Engel-Yeger B, Gal E. {{A meta-analysis of sensory modulation symptoms in individuals with autism spectrum disorders}}. {J Autism Dev Disord};2009 (Jan);39(1):1-11.
Sensory modulation symptoms are common in persons with autism spectrum disorders (ASD); however have a heterogeneous presentation. Results from 14 studies indicated a significant high difference between ASD and typical groups in the presence/frequency of sensory symptoms, with the greatest difference in under-responsivity, followed by over-responsivity and sensation seeking. Three moderators that reduced the variability in findings among studies were: chronological age, severity of autism, and type of control group. Sensory differences were highest for studies of children ages 6-9 years, samples with more than 80% with an autism diagnosis, and compared to a CA matched versus a MA or DD matched group. It is important to consider these moderators in the design of studies and interventions addressing sensory symptoms.
9. Bent S, Bertoglio K, Hendren RL. {{Regarding omega-3 fatty acids in severe autism}}. {Arch Med Res};2009 (Jan);40(1):64; author reply 65.
10. Brosnan M, Walker I. {{A Preliminary Investigation into the Potential Role of Waist Hip Ratio (WHR) Preference within the Assortative Mating Hypothesis of Autistic Spectrum Disorders}}. {J Autism Dev Disord};2009 (Jan);39(1):164-171.
Of particular interest to studying the etiology of Autistic Spectrum Disorders (ASDs) is the potential for multiple risk factors to combine through non-random mechanisms-assortative mating. Both genetic influences and a high-testosterone prenatal environment have been implicated in the etiology of ASDs, and given that waist-hip ratio (WHR) is indicative of a woman’s circulating testosterone level, a man attracted to higher-than-average WHR women is likely to have a higher-than-average prenatal testosterone exposure for their offspring. We show that whereas fathers of children without ASD show a statistically reliable preference for WHRs at the low end of the normal range, indicative of women with low testosterone levels, fathers of children diagnosed with ASD do not consistently show this preference.
11. Brown JS, Jr. {{Effects of bisphenol-a and other endocrine disruptors compared with abnormalities of schizophrenia: an endocrine-disruption theory of schizophrenia}}. {Schizophr Bull};2009 (Jan);35(1):256-278.
In recent years, numerous substances have been identified as so-called « endocrine disruptors » because exposure to them results in disruption of normal endocrine function with possible adverse health outcomes. The pathologic and behavioral abnormalities attributed to exposure to endocrine disruptors like bisphenol-A (BPA) have been studied in animals. Mental conditions ranging from cognitive impairment to autism have been linked to BPA exposure by more than one investigation. Concurrent with these developments in BPA research, schizophrenia research has continued to find evidence of possible endocrine or neuroendocrine involvement in the disease. Sufficient information now exists for a comparison of the neurotoxicological and behavioral pathology associated with exposure to BPA and other endocrine disruptors to the abnormalities observed in schizophrenia. This review summarizes these findings and proposes a theory of endocrine disruption, like that observed from BPA exposure, as a pathway of schizophrenia pathogenesis. The review shows similarities exist between the effects of exposure to BPA and other related chemicals with schizophrenia. These similarities can be observed in 11 broad categories of abnormality: physical development, brain anatomy, cellular anatomy, hormone function, neurotransmitters and receptors, proteins and factors, processes and substances, immunology, sexual development, social behaviors or physiological responses, and other behaviors. Some of these similarities are sexually dimorphic and support theories that sexual dimorphisms may be important to schizophrenia pathogenesis. Research recommendations for further elaboration of the theory are proposed.
12. Di Martino A, Ross K, Uddin LQ, Sklar AB, Castellanos FX, Milham MP. {{Functional brain correlates of social and nonsocial processes in autism spectrum disorders: an activation likelihood estimation meta-analysis}}. {Biol Psychiatry};2009 (Jan 1);65(1):63-74.
BACKGROUND: Functional neuroimaging studies of autism spectrum disorders (ASD) have examined social and nonsocial paradigms, although rarely in the same study. Here, we provide an objective, unbiased survey of functional brain abnormalities in ASD, related to both social and nonsocial processing. METHODS: We conducted two separate voxel-wise activation likelihood estimation meta-analyses of 39 functional neuroimaging studies consisting of 24 studies examining social processes (e.g., theory of mind, face perception) and 15 studies examining nonsocial processes (e.g., attention control, working memory). Voxel-wise significance threshold was p<.05, corrected by false discovery rate. RESULTS: Compared with neurotypical control (NC) subjects, ASD showed greater likelihood of hypoactivation in two medial wall regions: perigenual anterior cingulate cortex (ACC) in social tasks only and dorsal ACC in nonsocial studies. Further, right anterior insula, recently linked to social cognition, was more likely to be hypoactivated in ASD in the analyses of social studies. In nonsocial studies, group comparisons showed greater likelihood of activation for the ASD group in the rostral ACC region that is typically suppressed during attentionally demanding tasks. CONCLUSIONS: Despite substantial heterogeneity of tasks, the rapidly increasing functional imaging literature showed ASD-related patterns of hypofunction and aberrant activation that depended on the specific cognitive domain, i.e., social versus nonsocial. These results provide a basis for targeted extensions of these findings with younger subjects and a range of paradigms, including analyses of default mode network regulation in ASD.
13. Eikeseth S. {{Outcome of comprehensive psycho-educational interventions for young children with autism}}. {Res Dev Disabil};2009 (Jan-Feb);30(1):158-178.
This paper evaluates comprehensive psycho-educational research on early intervention for children with autism. Twenty-five outcome studies were identified. Twenty studies evaluated behavioral treatment, 3 studies evaluated TEACCH and 2 studies evaluated the Colorado Health Sciences Project. Outcome studies are graded according to their scientific value, and subsequently graded according to the magnitude of results documented in the studies. Based on the available evidence, treatment recommendations are made and practice parameters are suggested.
14. Elsabbagh M, Volein A, Csibra G, Holmboe K, Garwood H, Tucker L, Krljes S, Baron-Cohen S, Bolton P, Charman T, Baird G, Johnson MH. {{Neural correlates of eye gaze processing in the infant broader autism phenotype}}. {Biol Psychiatry};2009 (Jan 1);65(1):31-38.
BACKGROUND: Studies of infant siblings of children diagnosed with autism have allowed for a prospective approach to study the emergence of autism in infancy and revealed early behavioral characteristics of the broader autism phenotype. In view of previous findings of atypical eye gaze processing in children and adults with autism, the aim of this study was to examine the early autism phenotype in infant siblings of children diagnosed with autism spectrum disorder (sib-ASD), focusing on the neural correlates of direct compared with averted gaze. METHODS: A group of 19 sib-ASD was compared with 17 control infants with no family history of ASD (mean age=10 months) on their response to direct versus averted gaze in static stimuli. RESULTS: Relative to the control group, the sib-ASD group showed prolonged latency of the occipital P400 event-related potentials component in response to direct gaze, but they did not differ in earlier components. Similarly, time-frequency analysis of high-frequency oscillatory activity in the gamma band showed group differences in response to direct gaze, where induced gamma activity was late and less persistent over the right temporal region in the sib-ASD group. CONCLUSION: This study suggests that a broader autism phenotype, which includes an atypical response to direct gaze, is manifest early in infancy.
15. Enstrom AM, Lit L, Onore CE, Gregg JP, Hansen RL, Pessah IN, Hertz-Picciotto I, Van de Water JA, Sharp FR, Ashwood P. {{Altered gene expression and function of peripheral blood natural killer cells in children with autism}}. {Brain Behav Immun};2009 (Jan);23(1):124-133.
Immune related abnormalities have repeatedly been reported in autism spectrum disorders (ASD), including evidence of immune dysregulation and autoimmune phenomena. NK cells may play an important role in neurodevelopmental disorders such as ASD. Here we performed a gene expression screen and cellular functional analysis on peripheral blood obtained from 52 children with ASD and 27 typically developing control children enrolled in the case-control CHARGE study. RNA expression of NK cell receptors and effector molecules were significantly upregulated in ASD. Flow cytometric analysis of NK cells demonstrated increased production of perforin, granzyme B, and interferon gamma (IFNgamma) under resting conditions in children with ASD (p<0.01). Following NK cell stimulation in the presence of K562 target cells, the cytotoxicity of NK cells was significantly reduced in ASD compared with controls (p<0.02). Furthermore, under similar stimulation conditions the presence of perforin, granzyme B, and IFNgamma in NK cells from ASD children was significantly lower compared with controls (p<0.001). These findings suggest possible dysfunction of NK cells in children with ASD. Abnormalities in NK cells may represent a susceptibility factor in ASD and may predispose to the development of autoimmunity and/or adverse neuroimmune interactions during critical periods of development.
16. Esbensen AJ, Seltzer MM, Lam KS, Bodfish JW. {{Age-related differences in restricted repetitive behaviors in autism spectrum disorders}}. {J Autism Dev Disord};2009 (Jan);39(1):57-66.
Restricted repetitive behaviors (RRBs) were examined in a large group of children, adolescents and adults with ASD in order to describe age-related patterns of symptom change and association with specific contextual factors, and to examine if the patterns of change are different for the various types of RRBs. Over 700 individuals with ASD were rated on the Repetitive Behavior Scale-Revised. RRBs were less frequent and less severe among older than younger individuals, corroborating that autism symptoms abate with age. Our findings further suggest that repetitive behaviors are a heterogeneous group of behaviors, with the subtypes of RRBs having their own individual patterns across the lifespan, and in some cases, a differential association with age depending on intellectual functioning.
17. Fabbri-Destro M, Cattaneo L, Boria S, Rizzolatti G. {{Planning actions in autism}}. {Exp Brain Res};2009 (Jan);192(3):521-525.
It has been suggested that the deficit in understanding others’ intention in autism depends on a malfunctioning of the mirror system. This malfunction could be due either to a deficit of the basic mirror mechanism or to a disorganization of chained action organization on which the mirror understanding of others’ intention is based. Here we tested this last hypothesis investigating the kinematics of intentional actions. Children with autism and typically developing children (TD) were asked to execute two actions consisting each of three motor acts: the first was identical in both actions while the last varied for its difficulty. The result showed that, unlike in TD children, in children with autism the kinematics of the first motor act was not modulated by the task difficulty. This finding strongly supports the notion that children with autism have a deficit in chaining motor acts into a global action.
18. Fabio RA, Giannatiempo S, Antonietti A, Budden S. {{The role of stereotypies in overselectivity process in Rett syndrome}}. {Res Dev Disabil};2009 (Jan-Feb);30(1):136-145.
Ten Rett syndrome (RS) girls and 10 control girls executed an attentional task in which a complex stimulus was shown followed by individual stimuli presented with distractors. Participants had to discriminate previously presented stimuli from distractors. RS girls carried out the task both in a condition with the containment of stereotypies and in a no-containment condition. Overselectivity occurred in RS since patients failed to discriminate about 1/3 of the individual stimuli. There were no statistical differences with respect to the number of correct responses in the two conditions; RS girls learned quickly when their stereotypies were contained as opposed to when the containment of stereotypies was lacking.
19. Fletcher-Watson S, Leekam SR, Benson V, Frank MC, Findlay JM. {{Eye-movements reveal attention to social information in autism spectrum disorder}}. {Neuropsychologia};2009 (Jan);47(1):248-257.
Autism spectrum disorder (ASD) is a neurodevelopmental condition in which children show reduced attention to social aspects of the environment. However in adults with ASD, evidence for social attentional deficits is equivocal. One problem is that many paradigms present social information in an unrealistic, isolated way. This study presented adults and adolescents, with and without ASD, with a complex social scene alongside another, non-social scene, and measured eye-movements during a 3-s viewing period. Analyses first identified viewing time to different regions and then investigated some more complex issues. These were: the location of the very first fixation in a trial (indicating attentional priority); the effect of a task instruction on scan paths; the extent to which gaze-following was evident; and the degree to which participants’ scan paths were influenced by the low-level properties of a scene. Results indicate a superficially normal attentional preference for social information in adults with ASD. However, more sensitive measures show that ASD does entail social attention problems across the lifespan, supporting accounts of the disorder which emphasise lifelong neurodevelopmental atypicalities. These subtle abnormalities may be sufficient to produce serious difficulties in real-life scenarios.
20. Ganz JB, Flores MM. {{The effectiveness of direct instruction for teaching language to children with autism spectrum disorders: identifying materials}}. {J Autism Dev Disord};2009 (Jan);39(1):75-83.
Students with autism spectrum disorders (ASD) frequently demonstrate language delays (American Psychiatric Association 2000). This study investigated the effects of a Direct Instruction (DI) language program implemented with elementary students with ASD. There is little research in the area of DI as a language intervention for students with ASD. This study examined the effectiveness of DI with regard to students’ oral language skills, specifically the identification of materials of which objects were made. A single-subject changing criterion design was employed. A functional relation between DI and oral language skills was demonstrated through replication of skill increase over three criterion changes and across three students. The results and their implications are discussed further.
21. Gitiaux C, Ceballos-Picot I, Marie S, Valayannopoulos V, Rio M, Verrieres S, Benoist JF, Vincent MF, Desguerre I, Bahi-Buisson N. {{Misleading behavioural phenotype with adenylosuccinate lyase deficiency}}. {Eur J Hum Genet};2009 (Jan);17(1):133-136.
Adenylosuccinate lyase deficiency is a rare autosomal disorder of de novo purine synthesis, which results in the accumulation of succinylpurines in body fluids. Patients with adenylosuccinate lyase deficiency show a variable combination of mental retardation, epilepsy and autistic features and are usually discovered during screens for unexplained encephalopathy using the Bratton-Marshall assay that reveals the excretion of the succinylaminoimidazolecarboxamide riboside (SAICAr). Here, we report on two sisters aged 11 and 12 years presented with global developmental delay, motor apraxia, severe speech deficits, seizures and behavioural features, which combined excessive laughter, a very happy disposition, hyperactivity, a short attention span, the mouthing of objects, tantrums and stereotyped movements that gave a behavioural profile mimicking Angelman syndrome. Both patients had an increased succinyladenosine/SAICAr ratio of 1.6, and exhibited a novel homozygous missense mutation (c.674T>C; p.Met225Thr) in the exon 6 of the ADSL gene. We suggest that these clinical features might be a new presentation of adenylosuccinate lyase deficiency. On the basis of this observation, although adenylosuccinate lyase deficiency is a rare disorder, this diagnosis should be considered in patients with mental retardation and a behavioural profile suggestive of Angelman syndrome.European Journal of Human Genetics (2009) 17, 133-136; doi:10.1038/ejhg.2008.174; published online 1 October 2008.
22. Glancy M, Barnicoat A, Vijeratnam R, de Souza S, Gilmore J, Huang S, Maloney VK, Thomas NS, Bunyan DJ, Jackson A, Barber JC. {{Transmitted duplication of 8p23.1-8p23.2 associated with speech delay, autism and learning difficulties}}. {Eur J Hum Genet};2009 (Jan);17(1):37-43.
Duplications of distal 8p with and without significant clinical phenotypes have been reported and are often associated with an unusual degree of structural complexity. Here, we present a duplication of 8p23.1-8p23.2 ascertained in a child with speech delay and a diagnosis of ICD-10 autism. The same duplication was found in his mother who had epilepsy and learning problems. A combination of cytogenetic, FISH, microsatellite, MLPA and oaCGH analysis was used to show that the duplication extended over a minimum of 6.8 Mb between 3 539 893 and 10 323 426 bp. This interval contains 32 novel and 41 known genes, of which only microcephalin (MCPH1) is a plausible candidate gene for autism at present. The distal breakpoint of the duplicated region interrupts the CSMD1 gene in 8p23.2 and the medial breakpoint lies between the MSRA and RP1L1 genes in 8p23.1.An interchromosomal insertion between a normal and polymorphically inverted chromosome 8 is proposed to explain the origin of this duplication. Further mapped imbalances of distal 8p are needed to determine whether the autistic component of the phenotype in this family results from the cumulative imbalance of many genes or dosage imbalance of an individual susceptibility gene.European Journal of Human Genetics (2009) 17, 37-43; doi:10.1038/ejhg.2008.133; published online 20 August 2008.
23. Goldberg J, Anderson GM, Zwaigenbaum L, Hall GB, Nahmias C, Thompson A, Szatmari P. {{Cortical serotonin type-2 receptor density in parents of children with autism spectrum disorders}}. {J Autism Dev Disord};2009 (Jan);39(1):97-104.
Parents (N = 19) of children with autism spectrum disorders (ASD) and adult controls (N = 17) underwent positron emission tomography (PET) using [(18)F]setoperone to image cortical serotonin type-2 (5-HT2) receptors. The 5-HT2 binding potentials (BPs) were calculated by ratioing [(18)F]setoperone intensity in regions of interest (ROI) to cerebellar intensity. Cortical 5-HT2 BPs were significantly lower in parents compared to controls and platelet 5-HT levels were significantly negatively correlated with cortical 5-HT2 BP in parents. Lower cortical 5-HT2 receptor density in parents of children with ASD is consistent with reports of diminished 5-HT2 expression and functioning in individuals with ASD. Further research should examine the relationship of reduced 5-HT2 receptor expression to underlying causation and to clinical and neurochemical correlates of autistic behavior.
24. Goldman S, Wang C, Salgado MW, Greene PE, Kim M, Rapin I. {{Motor stereotypies in children with autism and other developmental disorders}}. {Dev Med Child Neurol};2009 (Jan);51(1):30-38.
The purpose of the study was to count and characterize the range of stereotypies – repetitive rhythmical, apparently purposeless movements – in developmentally impaired children with and without autism, and to determine whether some types are more prevalent and diagnostically useful in children with autism. We described each motor stereotypy recorded during 15 minutes of archived videos of standardized play sessions in 277 children (209 males, 68 females; mean age 4y 6mo [SD 1y 5mo], range 2y 11mo-8y 1mo), 129 with autistic disorder (DSM-III-R), and 148 cognitively-matched non-autistic developmentally disordered (NADD) comparison children divided into developmental language disorder and non-autism, low IQ (NALIQ) sub-groups. The parts of the body involved and characteristics of all stereotypies were scored blind to diagnosis. More children with autism had stereotypies than the NADD comparison children. Autism and, to a lesser degree, nonverbal IQ (NVIQ) <80, especially in females contributed independently to the occurrence, number, and variety of stereotypies, with non-autistic children without cognitive impairment having the least number of stereotypies and children with autism and low NVIQ the most. Autism contributed independently to gait and hand/finger stereotypies and NVIQ <80 to head/trunk stereotypies. Atypical gazing at fingers and objects was rare but virtually limited to autism. Stereotypies are environmentally modulated movement disorders, some highly suggestive, but not pathognomonic, of autism. Their underlying brain basis and genetic correlates need investigation.
25. Grandin T. Visual abilities and sensory differences in a person with autism. Biol Psychiatry;2009 (Jan 1);65(1):15-16.
26. Grindle CF, Kovshoff H, Hastings RP, Remington B. {{Parents’ experiences of home-based applied behavior analysis programs for young children with autism}}. {J Autism Dev Disord};2009 (Jan);39(1):42-56.
Although much research has documented the benefits to children with autism of early intensive behavioral intervention (EIBI), little has focused on the impact of EIBI on families. Using a semi-structured format, we interviewed 53 parents whose children had received 2 years of EIBI to obtain detailed first person accounts of the perceived benefits and pitfalls of running a home program, and the impact of EIBI on family life and support systems. In general, parents were positive about EIBI, its benefits for them, their child, and the broader family. Interviews also, however, revealed some of the more challenging aspects of managing home-based EIBI. The implications of these findings for more supportive interventions for families on home programs are discussed.
27. Hagerman RJ, Berry-Kravis E, Kaufmann WE, Ono MY, Tartaglia N, Lachiewicz A, Kronk R, Delahunty C, Hessl D, Visootsak J, Picker J, Gane L, Tranfaglia M. {{Advances in the treatment of fragile x syndrome}}. {Pediatrics};2009 (Jan);123(1):378-390.
The FMR1 mutations can cause a variety of disabilities, including cognitive deficits, attention-deficit/hyperactivity disorder, autism, and other socioemotional problems, in individuals with the full mutation form (fragile X syndrome) and distinct difficulties, including primary ovarian insufficiency, neuropathy and the fragile X-associated tremor/ataxia syndrome, in some older premutation carriers. Therefore, multigenerational family involvement is commonly encountered when a proband is identified with a FMR1 mutation. Studies of metabotropic glutamate receptor 5 pathway antagonists in animal models of fragile X syndrome have demonstrated benefits in reducing seizures, improving behavior, and enhancing cognition. Trials of metabotropic glutamate receptor 5 antagonists are beginning with individuals with fragile X syndrome. Targeted treatments, medical and behavioral interventions, genetic counseling, and family supports are reviewed here.
28. Hobson RP, Lee A, Hobson JA. {{Qualities of symbolic play among children with autism: a social-developmental perspective}}. {J Autism Dev Disord};2009 (Jan);39(1):12-22.
We hypothesized that the qualities of play shown by children with autism reflect their impoverished experience of identifying with other people’s attitudes and moving among person-anchored perspectives. On this basis, we predicted their play should manifest a relative lack of the social-developmental hallmarks that typify creative symbolic functioning. We videotaped the spontaneous and modelled symbolic play of matched groups of children with and without autism. The two groups were similar in the mechanics of play, for example in making one thing stand for another and using materials flexibly. By contrast, and as predicted, children with autism were rated as showing less playful pretend involving self-conscious awareness of pretending, investment in the symbolic meanings given to play materials, creativity, and fun.
29. Johnston MV, Ishida A, Ishida WN, Matsushita HB, Nishimura A, Tsuji M. {{Plasticity and injury in the developing brain}}. {Brain Dev};2009 (Jan);31(1):1-10.
The child’s brain is more malleable or plastic than that of adults and this accounts for the ability of children to learn new skills quickly or recovery from brain injuries. Several mechanisms contribute to this ability including overproduction and deletion of neurons and synapses, and activity-dependent stabilization of synapses. The molecular mechanisms for activity-dependent synaptic plasticity are being discovered and this is leading to a better understanding of the pathogenesis of several disorders including neurofibromatosis, tuberous sclerosis, Fragile X syndrome and Rett syndrome. Many of the same pathways involved in synaptic plasticity, such as glutamate-mediated excitation, can also mediate brain injury when the brain is exposed to stress or energy failure such as hypoxia-ischemia. Recent evidence indicates that cell death pathways activated by injury differ between males and females. This new information about the molecular pathways involved in brain plasticity and injury are leading to insights that will provide better therapies for pediatric neurological disorders.
30. Law LW, Lau TK, Fung TY, Leung TY, Wang CC, Choy KW. {{De novo 16p13.11 microdeletion identified by high-resolution array CGH in a fetus with increased nuchal translucency}}. {Bjog};2009 (Jan);116(2):339-343.
OBJECTIVE: We investigated the application of high-resolution microarray-based comparative genomic hybridisation (array CGH) on a fetus showing increased nuchal translucency (NT). DESIGN: Case study. SETTING: Tertiary referral obstetrics unit. SAMPLE: Pregnant woman attended the antenatal clinic. METHODS: Conventional karyotyping and genetic test was carried out for the alpha-globin gene. High-resolution array CGH using the high-density 244K Agilent microarray was performed on fetal blood sample by cordocentesis to investigate the possibility of any genomic imbalance. MAIN OUTCOME MEASURES: Detection of chromosomal abnormality. RESULTS: Karyotyping analysis showed 46,XY. Molecular genetic diagnosis confirms the fetus has Hb-H constant spring disease but cannot explain the increased NT to 3.2 mm. Array CGH analysis discovered a 1.32-Mb microdeletion on chromosome 16p13.11. Deletion at 16p13.11 has been implicated to predispose to autism and/or mental retardation. Baby was delivered at 40 weeks of gestation, and follow up was carried out at 3 months of age without sign of mental retardation/developmental delay. CONCLUSIONS: This case study demonstrated that array CGH can accurately calibrate the size and identify de novo interstitial chromosome imbalances. However, the presence of chromosome copy variants with unknown clinical significance currently limits its wider scale application in prenatal diagnosis and needs further investigations.
31. Mancil GR, Conroy MA, Haydon TF. {{Effects of a modified milieu therapy intervention on the social communicative behaviors of young children with autism spectrum disorders}}. {J Autism Dev Disord};2009 (Jan);39(1):149-163.
The purpose of the current study was to evaluate the effectiveness of combining milieu therapy and functional communication training (FCT)] to replace aberrant behavior with functional communicative skills in 3 male preschool or elementary aged children with Autism Spectrum Disorders (ASD). Study activities were conducted in the natural environments of the participants and parents acted as change agents. A concurrent multiple baseline design across participants was used to evaluate the effectiveness of the modified milieu therapy intervention. Results indicate that aberrant behavior decreased concurrent with an increase in total percentage of communication responses (PCR). The children maintained communication and low rates of aberrant behavior, and generalized their communication from the home to the classroom. A discussion of limitations and future research directions is included.
32. Markiewicz K, MacQueen BD. {{The autistic mind: a case study}}. {Med Sci Monit};2009 (Jan);15(1):CS5-13.
BACKGROUND: Despite years of intensive research, there is much about autism that remains theoretically and practically difficult to understand. There are presently three main theories: (1) defect of theory of mind, (2) executive dysfunction, and (3) lack of central coherence, i.e. an inability to integrate sensation and behavior into complex and sensible wholes. CASE REPORT: The patient, Damian S, born 1993, was diagnosed in early childhood with profound autism. He has been closely observed longitudinally by the first author, who is his therapist. Despite the absence of noticeable improvement in standard psychometric tests, he has shown considerable clinical progress. However, he continues to have difficulty in making and maintaining contact with others: he converses spontaneously only with his father and his teacher, and interacts with other persons (including his mother) only in the presence of one of these two persons. However, he has learned to use a computer to communicate. Samples of dialogue are provided to help illuminate how he thinks. CONCLUSIONS: Despite his profound autism, Damian displays awareness of and concern for the thoughts and feelings of others. He is also able to solve problems. On the basis of this and other observations, the authors suggest that the « central coherence » theory better explains the available observations and data.
33. Matarazzo MR, De Bonis ML, Vacca M, Della Ragione F, D’Esposito M. {{Lessons from two human chromatin diseases, ICF syndrome and Rett syndrome}}. {Int J Biochem Cell Biol};2009;41(1):117-126.
Spatial organisation of DNA into chromatin profoundly affects gene expression and function. The recent association of genes controlling chromatin structure to human pathologies resulted in a better comprehension of the interplay between regulation and function. Among many chromatin disorders we will discuss Rett and immunodeficiency, centromeric instability and facial anomalies (ICF) syndromes. Both diseases are caused by defects related to DNA methylation machinery, with Rett syndrome affecting the transduction of the repressive signal from the methyl CpG binding protein prototype, MeCP2, and ICF syndrome affecting the genetic control of DNA methylation, by the DNA methyltransferase DNMT3B. Rather than listing survey data, our aim is to highlight how a deeper comprehension of gene regulatory web may arise from studies of such pathologies. We also maintain that fundamental studies may offer chances for a therapeutic approach focused on these syndromes, which, in turn, may become paradigmatic for this increasing class of diseases.
34. Matijevic T, Knezevic J, Slavica M, Pavelic J. {{Rett syndrome: from the gene to the disease}}. {Eur Neurol};2009;61(1):3-10.
Rett syndrome (RTT, MIM No. 312750) is a progressive neurodevelopmental disorder and one of the most common causes of mental retardation. It is transmitted as an X-linked dominant trait, therefore almost exclusively affecting females. About 80% of RTT cases are sporadic caused by mutations in the MECP2 gene located on Xq28. The gene codes for two isoforms of the methyl-CpG-binding protein (MeCP2, MeCP2B) which are involved in transcriptional silencing through DNA methylation. The gene has 4 exons. The fourth one is the largest. Almost all mutations in MECP2 occur de novo. Although mutations are dispersed throughout the gene, about 67% of all MECP2 mutations, caused by C>T transitions at 8 CpG dinucleotides, are located in the third and fourth exon. The most common mutation is R168X. So far, there is no clear evidence on genotype-phenotype correlations. There are also reports claiming that the same mutation can provoke different phenotypes. It was shown that MeCP2 can silence certain genes. One of them, brain-derived neurotrophic factor, is essential for neural plasticity, learning and memory. This discovery revealed the role of MeCP2 in the control of neuronal activity-dependent gene regulation and suggested that the pathology of RTT may result from deregulation of this process.
35. Mawson AR. {{Bone pain, growth failure, and skin rash after an upper respiratory illness in a boy with autism: possible association with altered retinoid metabolism}}. {Clin Pediatr} (Phila);2009 (Jan);48(1):21-25.
Symptoms of bone pain and skin rashes are not uncommon following a variety of infectious illnesses, but the underlying mechanisms are not well understood. The case of a 9-year-old boy with autism was recently described, who was hospitalized because of pain in the right hip, refusal to walk, fatigue, irritability, skin rash, and subsequent gingival swelling after an unspecified upper respiratory illness. The boy was diagnosed with scurvy. However, the gingival symptoms occurred after treatment with indomethacin, which lowers vitamin C levels; severe bone pain and fatigue are also well-documented symptoms of hypervitaminosis A. This review of a case report of a boy with autism provides an opportunity to present a new hypothesis of the mechanism of these postinfection symptoms in the context of an increasingly common condition of childhood.
36. McConachie H, Barry R, Spencer A, Parker L, Le Couteur A, Colver A. Dasl(n)e: {{the challenge of developing a regional database for autism spectrum disorder}}. {Arch Dis Child};2009 (Jan);94(1):38-41.
The setting up of a database of children with autism spectrum disorder (ASD) in the north east of England is described. Best practice has been followed and included involving parents in planning and implementation at all stages, oversight by a multi-agency group, management by a multidisciplinary steering group, and independent administration of the database. From a potential listing of 986 children with ASD aged 3-12 years, the parents of 511 have so far responded (51.8%), although response rate varies considerably by local authority. Data checking has shown the information to be valid and case ascertainment broadly representative. The uses to which the data are being put and the continuing challenges are outlined.
37. Milne E, Scope A, Pascalis O, Buckley D, Makeig S. {{Independent component analysis reveals atypical electroencephalographic activity during visual perception in individuals with autism}}. {Biol Psychiatry};2009 (Jan 1);65(1):22-30.
BACKGROUND: Individuals with autistic spectrum disorder (ASD) experience atypical visual perception, yet the etiology of this remains unknown. The aim of this study was to investigate the neural correlates of visual perception in individuals with and without ASD by carrying out a detailed analysis of the dynamic brain processes elicited by perception of a simple visual stimulus. METHODS: We investigated perception in 20 individuals with ASD and 20 control subjects with electroencephalography (EEG). Visual evoked potentials elicited by Gabor patches of varying spatial frequency and stimulus-induced changes in alpha- and gamma-frequency bands of independent components were compared in those with and without ASD. RESULTS: By decomposing the EEG data into independent components, we identified several processes that contributed to the average event related potential recorded at the scalp. Differences between the ASD and control groups were found only in some of these processes. Specifically, in those components that were in or near the striate or extrastriate cortex, stimulus spatial frequency exerted a smaller effect on induced increases in alpha- and gamma-band power, and time to peak alpha-band power was reduced, in the participants with ASD. Induced alpha-band power of components that were in or near the cingulate gyrus was increased in the participants with ASD, and the components that were in or near the parietal cortex did not differ between the two groups. CONCLUSIONS: Atypical processing is evident in individuals with ASD during perception of simple visual stimuli. The implications of these data for existing theories of atypical perception in ASD are discussed.
38. Mineo BA, Ziegler W, Gill S, Salkin D. {{Engagement with electronic screen media among students with autism spectrum disorders}}. {J Autism Dev Disord};2009 (Jan);39(1):172-187.
This study investigated the relative engagement potential of four types of electronic screen media (ESM): animated video, video of self, video of a familiar person engaged with an immersive virtual reality (VR) game, and immersion of self in the VR game. Forty-two students with autism, varying in age and expressive communication ability, were randomly assigned to the experimental conditions. Gaze duration and vocalization served as dependent measures of engagement. The results reveal differential responding across ESM, with some variation related to the engagement metric employed. Preferences for seeing themselves on the screen, as well as for viewing the VR scenarios, emerged from the data. While the study did not yield definitive data about the relative engagement potential of ESM alternatives, it does provide a foundation for future research, including guidance related to participant profiles, stimulus characteristics, and data coding challenges.
39. Minio-Paluello I, Baron-Cohen S, Avenanti A, Walsh V, Aglioti SM. {{Absence of embodied empathy during pain observation in Asperger syndrome}}. {Biol Psychiatry};2009 (Jan 1);65(1):55-62.
BACKGROUND: Asperger syndrome (AS) is a neurodevelopmental condition within the autism spectrum conditions (ASC) characterized by specific difficulties in communication, social interaction, and empathy that is essential for sharing and understanding others’ feelings and emotions. Although reduced empathy is considered a core feature of ASC, neurophysiological evidence of empathic deficits before and below mentalizing and perspective taking is lacking. We explored whether people with AS differ from neurotypical control participants in their empathic corticospinal response to the observation of others’ pain and the modulatory role played by phenomenal experience of observed pain and personality traits. METHODS: Sixteen right-handed men with AS (aged 28.0+/-7.2 years) and 20 neurotypical controls (aged 25.3+/-6.7 years) age, sex, and IQ matched, underwent single-pulse transcranial magnetic stimulation during observation of painful and nonpainful stimuli affecting another individual. RESULTS: When observing other’s pain, participants with AS, in contrast to neurotypical control participants, did not show any amplitude reduction of motor-evoked potentials recorded from the muscle vicariously affected by pain, nor did their neurophysiological response correlate with imagined pain sensory qualities. Participants with AS represented others’ pain in relation to the self-oriented arousal experienced while watching pain videos. CONCLUSIONS: Finding no embodiment of others’ pain provides neurophysiological evidence for reduced empathic resonance in people with AS and indicates that their empathic difficulties involve not only cognitive dimensions but also sensorimotor resonance with others. We suggest that absence of embodied empathy may be linked to changes at very basic levels of neural processing.
40. Moser D, Ekawardhani S, Kumsta R, Palmason H, Bock C, Athanassiadou Z, Lesch KP, Meyer J. {{Functional analysis of a potassium-chloride co-transporter 3 (SLC12A6) promoter polymorphism leading to an additional DNA methylation site}}. {Neuropsychopharmacology};2009 (Jan);34(2):458-467.
The human potassium-chloride co-transporter 3 (KCC3, SLC12A6) is involved in cell proliferation and in electro-neutral movement of ions across the cell membrane. The gene (SLC12A6) is located on chromosome 15q14, a region that has previously shown linkage with bipolar disorder, schizophrenia, rolandic epilepsy, idiopathic generalized epilepsy, autism and attention deficit/hyperactivity disorder. Furthermore, recessively inherited mutations of SLC12A6 cause Andermann syndrome, characterized by agenesis of the corpus callosum, which is associated with peripheral neuropathy and psychoses. Recently, we have demonstrated the association of two G/A promoter polymorphisms of SLC12A6 with bipolar disorder in a case-control study, and familial segregation of the rare variants as well as a trend toward association with schizophrenia. To investigate functional consequences of these polymorphisms, lymphocyte DNA was extracted, bisulfite modified, and subsequently sequenced. To investigate SLC12A6 promoter activity, various promoter constructs were generated and analyzed by luciferase reporter gene assays. We provide evidence that the G- allele showed a significant reduction of reporter gene expression. In human lymphocytes, the allele harboring the rare upstream G nucleotide was found to be methylated at the adjacent C position, possibly accountable for tissue-specific reduction in gene expression in vivo. Here we demonstrate functionality of an SNP associated with psychiatric disease and our results may represent a functional link between genetic variation and an epigenetic modification.
41. Paul R, Orlovski SM, Marcinko HC, Volkmar F. {{Conversational Behaviors in Youth with High-functioning ASD and Asperger Syndrome}}. {J Autism Dev Disord};2009 (Jan);39(1):115-125.
Twenty-nine youth with autism spectrum disorders and 26 with typical development between 12 and 18 years of age were engaged in structured interviews (ADOS). The interviews were videotaped and rated for atypical conversational behaviors by trained raters, using the Pragmatic Rating Scale (Landa et al. Psychol Med 22:245-254, 1992). The ASD group was divided into AS and HFA/PDD-NOS subgroups. Significant differences were found among groups on approximately one-third of the PRS items. These items involved primarily the management of topics and information, reciprocity, intonation, and gaze management. The only differences to reach significance between the AS and HFA/PDD-NOS group were a greater tendency for overly formal speech on the part of the AS group, and more difficulty with gaze management on the part of the group with HFA/PDD-NOS. The implications of these findings for understanding and treating conversational deficits in ASD are discussed.
42. Politi P, Marrone G, Emanuele E. {{Regarding Omega-3 Fatty Acids in Severe Autism: Reply to Bent and Co-workers}}. {Arch Med Res};2009 (Jan);40(1):65.
43. Posserud MB, Lundervold AJ, Gillberg C. {{Validation of the autism spectrum screening questionnaire in a total population sample}}. {J Autism Dev Disord};2009 (Jan);39(1):126-134.
There is a lack of instruments validated for screening of autism spectrum disorders (ASD) in general populations and primary care settings. The Autism Spectrum Screening Questionnaire (ASSQ) has previously been shown to have good screening properties in clinical settings. We used the ASSQ to screen a total population of 7-9 year-olds (N = 9430) for ASD in the Bergen Child Study. Parents and teachers filled in the ASSQ, and high-scorers were invited for clinical assessment, along with a large group of screen negative children. We found that the ASSQ was well suited as a general population screen. Combining parent and teacher ASSQ and using cut-off score of >/=17 provided the most efficient screen with sensitivity of 0.91 and specificity of 0.86.
44. Reichow B, Wolery M. {{Comprehensive synthesis of early intensive behavioral interventions for young children with autism based on the UCLA young autism project model}}. {J Autism Dev Disord};2009 (Jan);39(1):23-41.
A 3-part comprehensive synthesis of the early intensive behavioral intervention (EIBI) for young children with autism based on the University of California at Los Angeles Young Autism Project method (Lovaas in Journal of Consulting and Clinical Psychology, 55, 3-9, 1987) is presented. The three components of the synthesis were: (a) descriptive analyses, (b) effect size analyses, and (c) a meta-analysis. The findings suggest EIBI is an effective treatment, on average, for children with autism. The conditions under which this finding applies and the limitations and cautions that must be taken when interpreting the results are discussed within the contextual findings of the moderator analyses conducted in the meta-analysis.
45. Rinehart N. {{Motor stereotypies in children with autism and other developmental disorders}}. {Dev Med Child Neurol};2009 (Jan);51(1):2-3.
46. Roohi J, Devincent CJ, Hatchwell E, Gadow KD. {{Association of a monoamine oxidase-a gene promoter polymorphism with ADHD and anxiety in boys with autism spectrum disorder}}. {J Autism Dev Disord};2009 (Jan);39(1):67-74.
The aim of the present study was to examine the association between a variable number tandem repeat (VNTR) functional polymorphism in the promoter region of the MAO-A gene and severity of ADHD and anxiety in boys with ASD. Parents and teachers completed a DSM-IV-referenced rating scale for 5- to 14-year-old boys with ASD (n = 43). Planned comparisons indicated that children with the 4- versus 3-repeat allele had significantly (p < 05) more severe parent-rated ADHD inattention and impulsivity, and more severe teacher-rated symptoms of generalized anxiety. Our results support a growing body of research indicating that concomitant behavioral disturbances in children with ASD warrant consideration as clinical phenotypes, but replication with independent samples is necessary to confirm this preliminary finding.
47. Russell AJ, Mataix-Cols D, Anson MA, Murphy DG. {{Psychological treatment for obsessive-compulsive disorder in people with autism spectrum disorders–a pilot study}}. {Psychother Psychosom};2009;78(1):59-61.
48. Shi L, Smith SE, Malkova N, Tse D, Su Y, Patterson PH. {{Activation of the maternal immune system alters cerebellar development in the offspring}}. {Brain Behav Immun};2009 (Jan);23(1):116-123.
A common pathological finding in autism is a localized deficit in Purkinje cells (PCs). Cerebellar abnormalities have also been reported in schizophrenia. Using a mouse model that exploits a known risk factor for these disorders, maternal infection, we asked if the offspring of pregnant mice given a mid-gestation respiratory infection have cerebellar pathology resembling that seen in these disorders. We also tested the effects of maternal immune activation in the absence of virus by injection of the synthetic dsRNA, poly(I:C). We infected pregnant mice with influenza on embryonic day 9.5 (E9.5), or injected poly(I:C) i.p. on E12.5, and assessed the linear density of PCs in the cerebellum of adult or postnatal day 11 (P11) offspring. To study granule cell migration, we also injected BrdU on P11. Adult offspring of influenza- or poly(I:C)-exposed mice display a localized deficit in PCs in lobule VII of the cerebellum, as do P11 offspring. Coincident with this are heterotopic PCs, as well as delayed migration of granule cells in lobules VI and VII. The cerebellar pathology observed in the offspring of influenza- or poly(I:C)-exposed mice is strikingly similar to that observed in autism. The poly(I:C) findings indicate that deficits are likely caused by the activation of the maternal immune system. Finally, our data suggest that cerebellar abnormalities occur during embryonic development, and may be an early deficit in autism and schizophrenia.
49. Spreng RN, McKinnon MC, Mar RA, Levine B. {{The Toronto Empathy Questionnaire: scale development and initial validation of a factor-analytic solution to multiple empathy measures}}. {J Pers Assess};2009 (Jan);91(1):62-71.
To formulate a parsimonious tool to assess empathy, we used factor analysis on a combination of self-report measures to examine consensus and developed a brief self-report measure of this common factor. The Toronto Empathy Questionnaire (TEQ) represents empathy as a primarily emotional process. In 3 studies, the TEQ demonstrated strong convergent validity, correlating positively with behavioral measures of social decoding, self-report measures of empathy, and negatively with a measure of Autism symptomatology. Moreover, it exhibited good internal consistency and high test-retest reliability. The TEQ is a brief, reliable, and valid instrument for the assessment of empathy.
50. St Clair D. {{Copy number variation and schizophrenia}}. {Schizophr Bull};2009 (Jan);35(1):9-12.
Over the last 12 months, a series of major articles have reported associations with schizophrenia of copy number variants at 1q21, 15q11.2, 15q13.3, 16p11.2, 22q12, and Neurexin 1 loci. These are rare high-penetrant mutations that increase risk not only of schizophrenia but also of a range of other psychiatric disorders including autism and mental retardation. In some cases, the same phenotype can occur irrespective of whether the copy number variant causes a deletion or duplication. Some of these mutations occur at very high rates in human populations, but because of reduced fecundity associated with major psychiatric disorders the overall frequency in the population remains low. These new findings raise fundamental clinical and scientific questions concerning classification of major neuropsychiatric disorders, modes of inheritance, diagnostics, and genetic counseling. Although the loci identified so far account for only a small proportion of cases, many more are likely to be discovered over the next few years. A major focus of research will be to identify the key, the genetic and environmental determinants of schizophrenia risk in carriers of these copy number variants, and to discover whether their rates of mutation are unstable or fixed.
51. Stephenson J, Carter M. {{The use of weighted vests with children with autism spectrum disorders and other disabilities}}. {J Autism Dev Disord};2009 (Jan);39(1):105-114.
Therapists who use sensory integration therapy may recommend that children wear weighted vests as an intervention strategy that they claim may assist in remediating problems such as inattentiveness, hyperactivity, stereotypic behaviors and clumsiness. Seven studies examining weighted vests are reviewed. While there is only a limited body of research and a number of methodological weaknesses, on balance, indications are that weighted vests are ineffective. There may be an arguable case for continued research on this intervention but weighted vests cannot be recommended for clinical application at this point. Suggestions are offered for future research with regard to addressing methodological problems.
52. Temudo T, Rios M, Prior C, Carrilho I, Santos M, Maciel P, Sequeiros J, Fonseca M, Monteiro J, Cabral P, Vieira JP, Ormazabal A, Artuch R. {{Evaluation of CSF neurotransmitters and folate in 25 patients with Rett disorder and effects of treatment}}. {Brain Dev};2009 (Jan);31(1):46-51.
BACKGROUND: Rett disorder (RD) is a progressive neurodevelopmental entity caused by mutations in the MECP2 gene. It has been postulated that there are alterations in the levels of certain neurotransmitters and folate in the pathogenesis of this disease. Here we re-evaluated this hypothesis. PATIENTS AND METHODS: We evaluated CSF folate, biogenic amines and pterines in 25 RD patients. Treatment with oral folinic acid was started in those cases with low folate. Patients were clinically evaluated and videotaped up to 6 months after therapy. RESULTS: CSF folate was below the reference values in 32% of the patients. Six months after treatment no clinical improvement was observed. Three of the four patients with the R294X mutation had increased levels of a dopamine metabolite associated to a particular phenotype. Three patients had low levels of a serotonin metabolite. Two of them were treated with fluoxetine and one showed clinical improvement. No association was observed between CSF folate and these metabolites, after adjusting for the patients age and neopterin levels. CONCLUSION: Our results support that folinic acid supplementation has no significant effects on the course of the disease. We report discrete and novel neurotransmitter abnormalities that may contribute to the pathogenesis of RD highlighting the need for further studies on CSF neurotransmitters in clinically and genetically well characterized patients.
53. Volden J, Sorenson A. {{Bossy and nice requests: varying language register in speakers with autism spectrum disorder (ASD)}}. {J Commun Disord};2009 (Jan-Feb);42(1):58-73.
The ability to vary language style or register is important for successfully navigating social situations. For example, we speak differently to our boss than we do to our children. This project examined whether high-functioning speakers with ASD were able to vary the language used for requests along continua of « politeness/bossiness », whether any such adjustments were similar to those made by appropriately matched controls, and whether speakers with ASD were able to accurately interpret politeness/bossiness registers. High-functioning children and adolescents (aged 6-16) with ASD were compared to matched typically developing children and adolescents on ability to (1) produce both « nice » and « bossy » requests to puppet listeners and, (2) to judge which of two requests was more polite. Contrary to expectations, participants with ASD were as adept as controls in both producing and judging polite and bossy requests. These results suggest that, at least for high-functioning children and adolescents with ASD, some skill at adjusting language register exists in their repertoire. Future research should examine whether this skill is also present in younger children and in unstructured interactions. If these results hold, clinicians may be able to focus their intervention on teaching strategies for successful use of behaviours that already exist rather than training the responses themselves. Learning outcomes: The reader will become familiar with the functional importance of varying language registers or style according to situational demands. In addition, teaching a strategy for how to determine when a particular language behaviour should be used may sometimes be more effective than training the specific language response.
54. Ward BC, Kolodny NH, Nag N, Berger-Sweeney JE. {{Neurochemical changes in a mouse model of Rett syndrome: changes over time and in response to perinatal choline nutritional supplementation}}. {J Neurochem};2009 (Jan);108(2):361-371.
Rett syndrome (RTT), the second leading cause of mental retardation in girls, is caused by mutations in the X-linked gene for methyl-CpG-binding protein 2 (MeCP2), a transcriptional repressor. In addition to well-documented neuroanatomical and behavioral deficits, RTT is characterized by reduced markers of cholinergic activity and general neuronal health. Previously, we have shown that early postnatal choline (Cho) supplementation improves behavioral and neuroanatomical symptoms in a mouse model of RTT (Mecp2(1lox) mice). In this study, we use NMR spectroscopy to quantify the relative amounts of Cho, Glutamate (Glu), Glutamine (Gln), and N-acetyl aspartate (NAA) in the brains of wild type and mutant mice at 21, 35, and 42 days of age and in mice receiving postnatal Cho supplementation. We find that the mutant mice have reduced levels of Cho, Glu, and NAA, but elevated Gln levels, compared with their wild type littermates. These differences emerge at different developmental ages. Cho supplementation increases NAA levels, a marker of neuronal integrity, but has no effect on Cho, Glu, or Gln. These data suggest that postnatal nutritional supplementation may
