1. Artigas-Pallares J. {{[Autism and attention deficit hyperactivity disorder: convergences and divergences. Genetics]}}. {Rev Neurol};2013 (Sep 6);57 Suppl:S155-161.
According to the DSM-5, attention deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) are different conditions that earlier versions of the DSM stated could not be diagnosed together in the same individual. Yet, over the last few decades the debate on the limits between the two disorders has continued, even though ADHD and ASD are undoubtedly clinically and cognitively different phenotypes, as demonstrated by the simple fact that they have been defined in clearly different ways. Thus, from a perspective anchored in a purely phenomenological view, there would be no grounds whatsoever on which to question the independence between the two disorders. Since, at the present time, the discussion on the convergence between ADHD and ASD cannot be considered to have been solved, this study aims to take the data available from genetics as the basis on which to review the nosological position of the two disorders. The main studies that have addressed this issue are reviewed. The data collected agree on a genetic overlap between ADHD and ASD, which is influenced by common molecular mechanisms that affect the two disorders at the same time. The conclusions that can be drawn from the data collected suggest a new conceptual model not only for ADHD and ASD, but also for complex mental disorders in general. This line of research will transform the way of understanding the treatment of mental disorders and will almost certainly open up new perspectives in this area.
2. Chaidez V, Hansen RL, Hertz-Picciotto I. {{Gastrointestinal Problems in Children with Autism, Developmental Delays or Typical Development}}. {J Autism Dev Disord};2013 (Nov 6)
To compare gastrointestinal (GI) problems among children with: (1) autism spectrum disorder (ASD), (2) developmental delay (DD) and (3) typical development (TD), GI symptom frequencies were obtained for 960 children from the CHildhood Autism Risks from Genetics and Environment (CHARGE) study. We also examined scores on five Aberrant Behavior Checklist (ABC) subscales comparing ASD children with high versus low frequency GI symptoms. Compared to TD children, those with ASD [aOR 7.92 (4.89-12.85)] and DD [aOR 4.55 (2.51-8.24)] were more likely to have at least one frequent GI symptom. Restricting to ASD children, those with frequent abdominal pain, gaseousness, diarrhea, constipation or pain on stooling scored worse on irritability, social withdrawal, stereotypy, and hyperactivity compared with children having no frequent GI symptoms. Frequent GI problems affect young children with ASD and DD more commonly than those with TD. Maladaptive behaviors correlate with GI problems, suggesting these comorbidities require attention.
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3. Duvall MG, Pikman Y, Kantor DB, Ariagno K, Summers L, Sectish TC, Mullen MP. {{Pulmonary Hypertension Associated With Scurvy and Vitamin Deficiencies in an Autistic Child}}. {Pediatrics};2013 (Nov 4)
Restricted dietary intake is common among children with behavioral issues. Here we report a case of a severely autistic child who presented initially with limp but who soon developed cough, tachypnea, hypoxia, and tachycardia. An echocardiogram revealed evidence of pulmonary hypertension (PH) with severely dilated right ventricle and elevated right-sided pressures. The etiology of his PH was unclear but further laboratory evaluation demonstrated severe nutritional deficiencies, in particular an undetectable ascorbic acid (vitamin C) level as well as deficient levels of thiamine (vitamin B1), pyridoxine (vitamin B6), cobalamin (vitamin B12), and vitamin D. Repletion of these vitamins was associated with resolution of his PH and his musculoskeletal complaints. We report this case and a review of the relevant literature as a clinical lesson to expand the differential diagnosis of limp in children who may be difficult to assess as well as to report on an unusual association between severe vitamin deficiencies and PH.
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4. Fernandez-Jaen A, Martin Fernandez-Mayoralas D, Fernandez-Perrone AL, Calleja-Perez B, Munoz-Jareno N, Lopez-Arribas S. {{[Autism and attention deficit hyperactivity disorder: pharmacological intervention]}}. {Rev Neurol};2013 (Sep 6);57 Suppl:S205-210.
The cardinal symptoms of attention deficit hyperactivity disorder (ADHD) -inattention, hyperactivity and impulsiveness- are not specific and may be found in the general population and in other disorders. These symptoms are present in over 50% of patients with autism spectrum disorders (ASD). It thus seems quite clear that both problems can coexist in these patients. The usual pharmacological treatments for ADHD, methylphenidate and atomoxetine, appear to be useful in reducing the above-mentioned symptoms in patients with ADHD and ASD. Effectiveness seems to be lower in patients with ASD and tolerance is slightly poorer. This may be conditioned by a number of variables, including: the complexity of ASD, association with mental retardation, polypharmacotherapy, and so on. Given the long-term tolerance profile of methylphenidate and atomoxetine, these treatments appear to be a good alternative with which to improve the problems of attention and self-control these patients have. Nevertheless, further controlled studies are needed to confirm this proposition.
5. Garg S, Green J, Leadbitter K, Emsley R, Lehtonen A, Evans DG, Huson SM. {{Neurofibromatosis Type 1 and Autism Spectrum Disorder}}. {Pediatrics};2013 (Nov 4)
OBJECTIVE:To determine the prevalence of autism spectrum disorder (ASD) in Neurofibromatosis Type 1 (NF1).METHODS:Second-phase population-based epidemiologic study using an allcase NF1 registry in a defined UK 4.1 million population area. A total of 109 (52.7%) of 207 responders from the initial screening phase were grouped by using the parent-rated Social Responsiveness Scale (SRS) as significant ASD (SRS>/=76; n = 32), moderate ASD (SRS >/= 60<76; n = 29), or non-ASD (SRS <60, n = 48). Twenty-three cases from the significant ASD group, 16 from moderate ASD, and 8 from non-ASD (total n = 47), invited proportionately by random selection, were seen for detailed confirmatory ascertainment. Assessments on Autism Diagnostic Interview-Revised, Autism Diagnostic Observation Scale-Generic, and verbal IQ were combined by using standard Collaborative Program for Excellence in Autism criteria into an ASD categorization for each case (ASD, broad ASD with partial features, non-ASD). A preplanned weighted analysis was used to derive prevalence estimates for the whole population.RESULTS:Fourteen (29.5%) of 47 showed ASD, 13 (27.7%) broad ASD, and 20 (42.5%) non-ASD. The ASD/broad ASD group showed male predominance (1.7:1.0), but did not differ significantly from the non-ASD group on IQ, age, socioeconomic status, inheritance, physical severity, or education. The population prevalence estimate is 24.9% ASD (95% confidence interval 13.1%-42.1%) and 20.8% broad ASD (95% confidence interval 10.0%-38.1%); a total of 45.7% showing some ASD spectrum phenotype.CONCLUSIONS:Findings indicate high prevalence of ASD in NF1, with implications for clinical practice and further research into NF1 as a single-gene model for autism.
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6. Grainger C, Williams DM, Lind SE. {{Online Action Monitoring and Memory for Self-Performed Actions in Autism Spectrum Disorder}}. {J Autism Dev Disord};2013 (Nov 6)
This study explored whether individuals with autism spectrum disorder (ASD) experience difficulties with action monitoring. Two experimental tasks examined whether adults with ASD are able to monitor their own actions online, and whether they also show a typical enactment effects in memory (enhanced memory for actions they have performed compared to actions they have observed being performed). Individuals with ASD and comparison participants showed a similar pattern of performance on both tasks. In a task which required individuals to distinguish person-caused from computer-caused changes in phenomenology both groups found it easier to monitor their own actions compared to those of an experimenter. Both groups also showed typical enactment effects. Despite recent suggestions to the contrary, these results support suggestions that action monitoring is unimpaired in ASD.
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7. Kratovac S, Corbin JG. {{Developmental changes in expression of inhibitory neuronal proteins in the Fragile X Syndrome mouse basolateral amygdala}}. {Brain Res};2013 (Nov 6);1537:69-78.
In humans, Fragile X Syndrome (FXS) is characterized by enhanced fear, hyperactivity, social anxiety, and, in a subset of individuals, autism. Many of the emotional and social deficits point to defects in the amygdala. We have previously shown defects in inhibitory neuron drive onto excitatory projection neurons in the basolateral amygdala (BLA) of juvenile Fmr1(-/y) knockout (KO) mice. Using pharmacological approaches, we have also previously revealed dynamic functional deficits in alpha1, alpha2, and alpha3 subunit-containing GABAA receptors (GABAARs alpha1, alpha2, and alpha3) during early postnatal development. In this study, we sought to determine whether these defects in GABAAR function are accompanied by changes in protein expression of GABAARs alpha1, alpha2, and alpha3 and the post-synaptic GABAAR-clustering protein gephyrin. Interestingly, we found that while the expression of these proteins did not significantly differ between wildtype (WT) and KO mice at each time point, the timing of developmental expression of GABAAR alpha1, alpha2, and gephyrin was altered. Collectively, these data reveal novel defects in inhibitory synapse protein expression during critical periods of early postnatal development that could contribute to observed inhibitory neurotransmission deficits in the KO mouse BLA.
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8. Martos-Perez J, Llorente-Comi M. {{[Treatment of autism spectrum disorders: union between understanding and evidence-based practice]}}. {Rev Neurol};2013 (Sep 6);57 Suppl:S185-191.
INTRODUCTION. Synthetically realizes heterogeneous operating characteristics of people with autism spectrum disorders (ASD) and how these features can also be based on the variability in response to treatment. It emphasizes the need to combine, in treatment, evidence-based practice with a deep understanding of ASD. DEVELOPMENT. It explains some of the key principles that should guide the treatment from the standpoint of quality indicators should include intervention programs, to then influence the features and content that are part of the programs carried out in the field early intervention, briefly explaining some of these programs and then characterize the intervention, with the use of techniques and strategies, which is usually carried out with children and adolescents in high-functioning. CONCLUSION. Research and accumulated knowledge and the increasing experimental evidence configure the features to be taken by intervention and treatment programs that are used with people with ASD. Such treatment should begin early, as soon as possible and spread over the life cycle.
9. Miranda-Casas A, Baixauli-Fortea I, Colomer-Diago C, Rosello-Miranda B. {{[Autism and attention deficit hyperactivity disorder: similarities and differences in executive functioning and theory of mind]}}. {Rev Neurol};2013 (Sep 6);57 Suppl:S177-184.
INTRODUCTION. Although the DSM-IV-TR diagnostic criteria do not overlap, the presence of attention deficit hyperactivity disorder (ADHD) symptoms in individuals with a clinical diagnosis of autism is quite high. At the same time, children with ADHD can have autistic traits, the most prevalent being social and communication difficulties. The analysis of the combination of executive functions and theory of mind (ToM) deficits could help to explain the overlap and differentiation between the two disorders. AIM. To review the findings of empirical studies in which children with ADHD and autism have been compared on indicators of executive functions and ToM. DEVELOPMENT. The literature review suggests the existence of distinct patterns in autism spectrum disorders (ASD) and ADHD when the executive functioning is segmented by components. Children with ADHD experience deficits in inhibitory control, while children with ASD have problems with cognitive flexibility and planning. Regarding the domain of the mentalist skills, there are developmental differences, as well as differences in their severity. Younger children with ASD have greater deficiencies in the ToM compared to children with ADHD, and a primary deficit in social orientation. CONCLUSION. Although important progress has been made, some issues remain to be clarified, among which we can highlight the analysis of how ToM development affects poor executive functions development, using longitudinal studies that analyze the developmental paths of children with ASD and children with ADHD.
10. Nuytens K, Tuand K, Di Michele M, Boonen K, Waelkens E, Freson K, Creemers JW. {{Platelets of mice heterozygous for neurobeachin, a candidate gene for autism spectrum disorder, display protein changes related to aberrant protein kinase A activity}}. {Mol Autism};2013 (Nov 4);4(1):43.
BACKGROUND: Neurobeachin (NBEA) has been identified as a candidate gene for autism spectrum disorders (ASD) in several unrelated patients with alterations in the NBEA gene. The exact function of NBEA, a multidomain scaffolding protein, is currently unknown. It contains an A-kinase anchoring protein (AKAP) domain which binds the regulatory subunit of protein kinase A (PKA) thereby confining its activity to specific subcellular regions. NBEA has been implicated in post-Golgi membrane trafficking and in regulated secretion. The mechanism of regulated secretion is largely conserved between neurons and platelets, and the morphology of platelet dense granules was found to be abnormal in several ASD patients, including one with NBEA haploinsufficiency. Platelet dense granules are secreted upon vascular injury when platelets are exposed to for instance collagen. Dense granules contain serotonin, ATP and ADP, which are necessary for platelet plug formation and vascular contraction. METHODS: To further investigate possible roles for NBEA in secretion or dense granule morphology, platelets from Nbea+/- mice were analyzed morphometrically, functionally and biochemically. A differential proteomics and peptidomics screen was performed between Nbea+/- and Nbea+/+ mice, in which altered Talin-1 cleavage was further investigated and validated in brain samples. Finally, the phosphorylation pattern of PKA substrates was analyzed. RESULTS: Platelet dense granules of Nbea+/- mice had a reduced surface area and abnormal dense-core halo, but normal serotonin-content. Nbea haploinsufficiency did not affect platelet aggregation and ATP secretion after collagen stimulation, although the platelet shape change was more pronounced. Furthermore, peptidomics revealed that Nbea+/- platelets contain significantly reduced levels of several actin-interacting peptides. Decreased levels were detected of the actin-binding head and rod domain of Talin-1, which are cleavage products of Calpain-2. This is most likely due to increased PKA-mediated phosphorylation of Calpain-2, which renders the enzyme less active. Analysis of other PKA substrates revealed both increased and reduced phosphorylation. CONCLUSION: Our results show the pleiotropic effects of alterations in PKA activity due to Nbea haploinsufficiency, highlighting the important function of the AKAP domain in Nbea in regulating and confining PKA activity. Furthermore, these results suggest a role for Nbea in remodeling the actin cytoskeleton of platelets.
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11. Proal E, Gonzalez-Olvera J, Blancas AS, Chalita PJ, Castellanos FX. {{[Neurobiology of autism and attention deficit hyperactivity disorder by means of neuroimaging techniques: convergences and divergences]}}. {Rev Neurol};2013 (Sep 6);57 Suppl:S163-175.
In the clinical area, some symptoms of attention deficit hyperactivity disorder (ADHD) also present in patients with autism spectrum disorders (ASD). Research has shown that there are alterations in brain circuits that have an impact upon specific cognitive and behavioural failures in each of these disorders. Yet, little research has been conducted on the brain correlates underlying both the similarities and the differences in the symptoms. In this review, the structural and functional meta-analytical studies that have been carried out to date on ADHD and ASD have been analysed. On the one hand, there are convergences in the attentional dorsal, executive functions, visual, somatomotor circuits and the default activation circuit. These similarities can account for the comorbid manifestations between the disorders, such as failure in the integration of information, fine motor control and specific attention processes. On the other hand, specifically in ADHD, there is a deficit in the reward circuit and in the attentional ventral, which are systems involved in the measurement of the effects of reinforcement and monitoring of attention. In ASD, the circuits that are most strongly affected are those involved in social cognition and language processes. In conclusion, there are neuronal correlates in both disorders that explain both the convergent and divergent clinical and behavioural manifestations.
12. Reser JE. {{Solitary Mammals Provide an Animal Model for Autism Spectrum Disorders}}. {J Comp Psychol};2013 (Nov 4)
Species of solitary mammals are known to exhibit specialized, neurological adaptations that prepare them to focus working memory on food procurement and survival rather than on social interaction. Solitary and nonmonogamous mammals, which do not form strong social bonds, have been documented to exhibit behaviors and biomarkers that are similar to endophenotypes in autism. Both individuals on the autism spectrum and certain solitary mammals have been reported to be low on measures of affiliative need, bodily expressiveness, bonding and attachment, direct and shared gazing, emotional engagement, conspecific recognition, partner preference, separation distress, and social approach behavior. Solitary mammals also exhibit certain biomarkers that are characteristic of autism, including diminished oxytocin and vasopressin signaling, dysregulation of the endogenous opioid system, increased Hypothalamic-pituitary-adrenal axis (HPA) activity to social encounters, and reduced HPA activity to separation and isolation. The extent of these similarities suggests that solitary mammals may offer a useful model of autism spectrum disorders and an opportunity for investigating genetic and epigenetic etiological factors. If the brain in autism can be shown to exhibit distinct homologous or homoplastic similarities to the brains of solitary animals, it will reveal that they may be central to the phenotype and should be targeted for further investigation. Research of the neurological, cellular, and molecular basis of these specializations in other mammals may provide insight for behavioral analysis, communication intervention, and psychopharmacology for autism. (PsycINFO Database Record (c) 2013 APA, all rights reserved).
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13. Roberts JL, Hovanes K, Dasouki M, Manzardo AM, Butler MG. {{Chromosomal Microarray Analysis of Consecutive Individuals with Autism Spectrum Disorders or Learning Disability Presenting for Genetic Services}}. {Gene};2013 (Nov 1)
Chromosomal microarray analysis is now commonly used in clinical practice to identify copy number variants (CNVs) in the human genome. We report our experience with the use of the 105K and 180K oligonucleotide microarrays in 215 consecutive patients referred with either autism or autism spectrum disorders (ASD) or developmental delay/learning disability for genetic services at the University of Kansas Medical Center during the past 4years (2009-2012). Of the 215 patients [140 males and 75 females (male/female ratio=1.87); 65 with ASD and 150 with learning disability], abnormal microarray results were seen in 45 individuals (21%) with a total of 49 CNVs. Of these findings, 32 represented a known diagnostic CNV contributing to the clinical presentation and 17 represented non-diagnostic CNVs (variants of unknown significance). Thirteen patients with ASD had a total of 14 CNVs, 6 CNVs recognized as diagnostic and 8 as non-diagnostic. The most common chromosome involved in the ASD group was chromosome 15. For those with a learning disability, 32 patients had a total of 35 CNVs. Twenty-six of the 35 CNVs were classified as a known diagnostic CNV, usually a deletion (n=20). Nine CNVs were classified as an unknown non-diagnostic CNV, usually a duplication (n=8). For the learning disability subgroup, chromosomes 2 and 22 were most involved. Thirteen out of 65 patients (20%) with ASD had a CNV compared with 32 out of 150 patients (21%) with a learning disability. The frequency of chromosomal microarray abnormalities compared by subject group or gender was not statistically different. A higher percentage of individuals with a learning disability had clinical findings of seizures, dysmorphic features and microcephaly, but not statistically significant. While both groups contained more males than females, a significantly higher percentage of males were present in the ASD group.
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14. Roberts TP, Lanza MR, Dell J, Qasmieh S, Hines K, Blaskey L, Zarnow DM, Levy SE, Edgar JC, Berman JI. {{Maturational differences in thalamocortical white matter microstructure and auditory evoked response latencies in autism spectrum disorders}}. {Brain Res};2013 (Nov 6);1537:79-85.
White matter diffusion anisotropy in the acoustic radiations was characterized as a function of development in autistic and typically developing children. Auditory-evoked neuromagnetic fields were also recorded from the same individuals and the latency of the left and right middle latency superior temporal gyrus auditory ~50ms response (M50)(1) was measured. Group differences in structural and functional auditory measures were examined, as were group differences in associations between white matter pathways, M50 latency, and age. Acoustic radiation white matter fractional anisotropy did not differ between groups. Individuals with autism displayed a significant M50 latency delay. Only in typically developing controls, white matter fractional anisotropy increased with age and increased white matter anisotropy was associated with earlier M50 responses. M50 latency, however, decreased with age in both groups. Present findings thus indicate that although there is loss of a relationship between white matter structure and auditory cortex function in autism spectrum disorders, and although there are delayed auditory responses in individuals with autism than compared with age-matched controls, M50 latency nevertheless decreases as a function of age in autism, parallel to the observation in typically developing controls (although with an overall latency delay). To understand auditory latency delays in autism and changes in auditory responses as a function of age in controls and autism, studies examining white matter as well as other factors that influence auditory latency, such as synaptic transmission, are of interest.
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15. Sowers LP, Loo L, Wu Y, Campbell E, Ulrich JD, Wu S, Paemka L, Wassink T, Meyer K, Bing X, El-Shanti H, Usachev YM, Ueno N, Manak RJ, Shepherd AJ, Ferguson PJ, Darbro BW, Richerson GB, Mohapatra DP, Wemmie JA, Bassuk AG. {{Disruption of the non-canonical Wnt gene PRICKLE2 leads to autism-like behaviors with evidence for hippocampal synaptic dysfunction}}. {Mol Psychiatry};2013 (Nov 5)
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16. Wang L, Christophersen CT, Sorich MJ, Gerber JP, Angley MT, Conlon MA. {{Increased abundance of Sutterella spp. and Ruminococcus torques in feces of children with autism spectrum disorder}}. {Mol Autism};2013 (Nov 4);4(1):42.
BACKGROUND: A recent report indicated that numbers of Sutterella spp. are elevated in gastrointestinal biopsies taken from children with autism spectrum disorder (ASD). We have recently reported changes in the numbers of some bacteria within the stool of ASD children, and now examine whether numbers of Sutterella spp. and some other mucosa-associated bacteria linked with gastrointestinal disease (Ruminococcus gnavus and Ruminococcus torques) are also altered in the stool of these children. FINDINGS: We show that numbers of Sutterella spp. are elevated in feces of ASD children relative to controls, and that numbers of R. torques are higher in the children with ASD with a reported functional gastrointestinal disorder than those without such a disorder. CONCLUSIONS: We show further evidence of changes in the gut microbiota of children with ASD and confirm that the abundance of Sutterella spp. is altered in stool.
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17. Xia K, Guo H, Hu Z, Xun G, Zuo L, Peng Y, Wang K, He Y, Xiong Z, Sun L, Pan Q, Long Z, Zou X, Li X, Li W, Xu X, Lu L, Liu Y, Hu Y, Tian D, Long L, Ou J, Zhang L, Pan Y, Chen J, Peng H, Liu Q, Luo X, Su W, Wu L, Liang D, Dai H, Yan X, Feng Y, Tang B, Li J, Miedzybrodzka Z, Xia J, Zhang Z, Zhang X, St Clair D, Zhao J, Zhang F. {{Common genetic variants on 1p13.2 associate with risk of autism}}. {Mol Psychiatry};2013 (Nov 5)
Autism is a highly heritable neurodevelopmental disorder, and known genetic variants, mostly rare, account only for a small proportion of cases. Here we report a genome-wide association study on autism using two Chinese cohorts as gene discovery (n=2150) and three data sets of European ancestry populations for replication analysis of top association signals. Meta-analysis identified three single-nucleotide polymorphisms, rs936938 (P=4.49 x 10-8), non-synonymous rs6537835 (P=3.26 x 10-8) and rs1877455 (P=8.70 x 10-8), and related haplotypes, AMPD1-NRAS-CSDE1, TRIM33 and TRIM33-BCAS2, associated with autism; all were mapped to a previously reported linkage region (1p13.2) with autism. These genetic associations were further supported by a cis-acting regulatory effect on the gene expressions of CSDE1, NRAS and TRIM33 and by differential expression of CSDE1 and TRIM33 in the human prefrontal cortex of post-mortem brains between subjects with and those without autism. Our study suggests TRIM33 and NRAS-CSDE1 as candidate genes for autism, and may provide a novel insight into the etiology of autism.Molecular Psychiatry advance online publication, 5 November 2013; doi:10.1038/mp.2013.146.
