pubmed: autism and genetics

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Neurodevelopmental and neuropsychiatric disorders represent an interconnected molecular system.

October 28, 2014 - 7:55am
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Neurodevelopmental and neuropsychiatric disorders represent an interconnected molecular system.

Mol Psychiatry. 2014 Mar;19(3):294-301

Authors: Cristino AS, Williams SM, Hawi Z, An JY, Bellgrove MA, Schwartz CE, Costa Lda F, Claudianos C

Abstract
Many putative genetic factors that confer risk to neurodevelopmental disorders such as autism spectrum disorders (ASDs) and X-linked intellectual disability (XLID), and to neuropsychiatric disorders including attention deficit hyperactivity disorder (ADHD) and schizophrenia (SZ) have been identified in individuals from diverse human populations. Although there is significant aetiological heterogeneity within and between these conditions, recent data show that genetic factors contribute to their comorbidity. Many studies have identified candidate gene associations for these mental health disorders, albeit this is often done in a piecemeal fashion with little regard to the inherent molecular complexity. Here, we sought to abstract relationships from our knowledge of systems level biology to help understand the unique and common genetic drivers of these conditions. We undertook a global and systematic approach to build and integrate available data in gene networks associated with ASDs, XLID, ADHD and SZ. Complex network concepts and computational methods were used to investigate whether candidate genes associated with these conditions were related through mechanisms of gene regulation, functional protein-protein interactions, transcription factor (TF) and microRNA (miRNA) binding sites. Although our analyses show that genetic variations associated with the four disorders can occur in the same molecular pathways and functional domains, including synaptic transmission, there are patterns of variation that define significant differences between disorders. Of particular interest is DNA variations located in intergenic regions that comprise regulatory sites for TFs or miRNA. Our approach provides a hypothetical framework, which will help discovery and analysis of candidate genes associated with neurodevelopmental and neuropsychiatric disorders.

PMID: 23439483 [PubMed - indexed for MEDLINE]

A Neural Model to Study Sensory Abnormalities and Multisensory Effects in Autism.

October 25, 2014 - 4:11pm

A Neural Model to Study Sensory Abnormalities and Multisensory Effects in Autism.

IEEE Trans Neural Syst Rehabil Eng. 2014 Oct 16;

Authors: Noriega G

Abstract
Computational modeling plays an increasingly prominent role in complementing critical research in the genetics, neuroscience, and psychology of autism. This paper presents a model that supports the notion that weak central coherence, a processing bias for features and local information, may be responsible for perception abnormalities by failing to "control" sensory issues in autism. The model has a biologically-plausible architecture based on a self-organizing map. It incorporates temporal information in input stimuli, with emphasis on real auditory signals, and provides a mechanism to model multisensory effects. Through comprehensive simulations the paper studies the effect of a control mechanism (akin to central coherence) in compensating the effects of temporal information in the presentation of stimuli, sensory abnormalities, and crosstalk between domains. The mechanism is successful in balancing out timing effects, basic hypersensitivities and, to a lesser degree, multisensory effects. An analysis of the effect of the control mechanism's onset time on performance, suggests that most of the potential benefits are still attainable even when started rather late in the learning process. This high level of adaptability shown by the neural network highlights the importance of appropriate teaching and intervention throughout the lifetime of persons with autism and other neurological disorders.

PMID: 25343764 [PubMed - as supplied by publisher]

Repeated positive fighting experience in male inbred mice.

October 24, 2014 - 8:08am

Repeated positive fighting experience in male inbred mice.

Nat Protoc. 2014 Nov;9(11):2705-2717

Authors: Kudryavtseva NN, Smagin DA, Kovalenko IL, Vishnivetskaya GB

Abstract
Repeated aggression is a frequent symptom of many psychiatric and neurological disorders, including obsessive-compulsive and attention deficit hyperactivity disorders, bipolar and post-traumatic stress disorders, epilepsy, autism, schizophrenia and drug abuse. However, repeated aggression is insufficiently studied because there is a lack of adequate models in animals. The sensory contact model (SCM), widely used to study the effects of chronic social defeat stress, can also be used to investigate the effects of repeated aggression. Mice with repeated positive fighting experience in daily agonistic interactions in this model develop pronounced aggressiveness, anxiety and impulsivity, disturbances in motivated and cognitive behaviors, and impairments of sociability; they also demonstrate hyperactivity, attention-deficit behavior, motor dysfunctions and repetitive stereotyped behaviors, such as jerks, rotations and head twitches. In this protocol, we describe how to apply the SCM to study repeated aggression in mice. Severe neuropathology develops in male mice after 20-21 d of agonistic interactions.

PMID: 25340443 [PubMed - as supplied by publisher]

Complex de novo chromosomal rearrangement at 15q11-q13 involving an intrachromosomal triplication in a patient with a severe neuropsychological phenotype: Clinical report and review of the literature.

October 24, 2014 - 8:08am

Complex de novo chromosomal rearrangement at 15q11-q13 involving an intrachromosomal triplication in a patient with a severe neuropsychological phenotype: Clinical report and review of the literature.

Am J Med Genet A. 2014 Oct 22;

Authors: Castronovo C, Crippa M, Bestetti I, Rusconi D, Russo S, Larizza L, Sangermani R, Bonati MT, Finelli P

Abstract
Interstitial triplications of 15q11-q13, leading to tetrasomy of the involved region, are very rare, with only 11 cases reported to date. Their pathogenicity is independent of the parental origin of the rearranged chromosome. The associated phenotype resembles, but is less severe, than that of patients bearing inv dup(15) marker chromosomes. Here, we describe a boy of 3 years and 9 months of age who exhibited very mild craniofacial dysmorphism (arched eyebrows, hypertelorism, and a wide mouth), developmental delay, generalized hypotonia, ataxic gait, severe intellectual disability, and autism. Array comparative genomic hybridization (CGH) analysis identified a heterozygous duplication of 1.1 Mb at 15q11.2 (between low-copy repeats BP1 and BP2), and a heterozygous triplication of 6.8 Mb at 15q11.2-q13.1 (BP2-BP4). Both acquisitions were de novo and contiguous. Microsatellite polymorphism analysis revealed the maternal origin of the triplication and the involvement of both maternal chromosomes 15. Furthermore, fluorescence in situ hybridization (FISH) analysis using BAC clones revealed that the rearrangement was complex, containing three differently sized tandem repeats of which the middle one was inverted. Our study confirms and extends the model proposed to explain the formation of intrachromosomal triplications through recombination events between non-allelic duplicons. The comparison of the proband's clinical presentation with those of previously described cases attests the existence of endophenotypes due to the parental origin of the 15q11-q13 triplicated segment and suggests a timetable for achievement of developmental milestones, thereby contributing to improved genotype-phenotype correlations. © 2014 Wiley Periodicals, Inc.

PMID: 25339188 [PubMed - as supplied by publisher]

Neural cell adhesion molecules belonging to the family of leucine-rich repeat proteins.

October 24, 2014 - 8:08am
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Neural cell adhesion molecules belonging to the family of leucine-rich repeat proteins.

Adv Neurobiol. 2014;8:315-95

Authors: Winther M, Walmod PS

Abstract
Leucine-rich repeats (LRRs) are motifs that form protein-ligand interaction domains. There are approximately 140 human genes encoding proteins with extracellular LRRs. These encode cell adhesion molecules (CAMs), proteoglycans, G-protein-coupled receptors, and other types of receptors. Here we give a brief description of 36 proteins with extracellular LRRs that all can be characterized as CAMs or putative CAMs expressed in the nervous system. The proteins are involved in multiple biological processes in the nervous system including the proliferation and survival of cells, neuritogenesis, axon guidance, fasciculation, myelination, and the formation and maintenance of synapses. Moreover, the proteins are functionally implicated in multiple diseases including cancer, hearing impairment, glaucoma, Alzheimer's disease, multiple sclerosis, Parkinson's disease, autism spectrum disorders, schizophrenia, and obsessive-compulsive disorders. Thus, LRR-containing CAMs constitute a large group of proteins of pivotal importance for the development, maintenance, and regeneration of the nervous system.

PMID: 25300143 [PubMed - indexed for MEDLINE]

The L1 family of cell adhesion molecules: a sickening number of mutations and protein functions.

October 24, 2014 - 8:08am
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The L1 family of cell adhesion molecules: a sickening number of mutations and protein functions.

Adv Neurobiol. 2014;8:195-229

Authors: Hortsch M, Nagaraj K, Mualla R

Abstract
L1-type proteins are transmembrane cell adhesion molecules with an evolutionary well-conserved protein domain structure of usually six immunoglobulin and five fibronectin type III domains. By engaging in many different protein-protein interactions they are involved in a multitude of molecular functions and are important players during the formation and maintenance of metazoan nervous systems. As a result, mutations in L1-type genes cause a great variety of phenotypes, most of which are neurological in nature. In humans, mutations in the L1CAM gene are responsible for L1 syndrome and other L1-type genes have been implicated in conditions as varied as mental retardation, autism, schizophrenia, multiple sclerosis, and other disorders. Equally, the overexpression of L1-type proteins appears to have deleterious effects in various types of human tumor cells, where they generally contribute to an increase in cell mobility and metastatic potential.

PMID: 25300138 [PubMed - indexed for MEDLINE]

A novel (paternally inherited) duplication 13q31.3q32.3 in a 12-year-old patient with facial dysmorphism and developmental delay.

October 23, 2014 - 7:49am

A novel (paternally inherited) duplication 13q31.3q32.3 in a 12-year-old patient with facial dysmorphism and developmental delay.

Mol Syndromol. 2014 Aug;5(5):245-50

Authors: Atack E, Fairtlough H, Smith K, Balasubramanian M

Abstract
We report a 12-year-old boy referred to the Clinical Genetics service in view of facial dysmorphism, learning difficulties and autistic spectrum disorder. 60K arrayCGH revealed an 8.2-Mb duplication on chromosome 13q31.3q32.3, which was paternally inherited. This specific duplication on chromosome 13 has not been previously reported in the medical literature, and there are no familial or de novo patients with the same duplication breakpoints. This region contains 24 OMIM genes, including the glypicans GPC5 and GPC6, and the ZIC2 gene. We discuss the relevance of this chromosome imbalance and discuss the impact of this duplication on our patient's phenotype. Given that the duplication on 13q was paternally inherited, and although initially thought to be of uncertain significance, on exploring the family history further, it became apparent that the father had learning difficulties as a child and previous surgery for congenital diaphragmatic hernia. Here we explore the phenotype in association with this novel duplication on chromosome 13q and add to the existing literature on array findings within this region.

PMID: 25337073 [PubMed]

A candidate gene association study further corroborates involvement of contactin genes in autism.

October 23, 2014 - 7:49am

A candidate gene association study further corroborates involvement of contactin genes in autism.

Mol Syndromol. 2014 Aug;5(5):229-35

Authors: Poot M

Abstract
Although autism spectrum disorder (ASD) shows a high degree of heritability, only a few mutated genes and mostly de novo copy number variations (CNVs) with a high phenotypic impact have as yet been identified. In families with multiple ASD patients, transmitted CNVs often do not appear to cosegregate with disease. Therefore, also transmitted single nucleotide variants which escape detection if genetic analyses were limited to CNVs may contribute to disease risk. In several studies of ASD patients, CNVs covering at least one gene of the contactin gene family were found. To determine whether there is evidence for a contribution of transmitted variants in contactin genes, a cohort of 67 ASD patients and a population-based reference of 117 healthy individuals, who were not related to the ASD families, were compared. In total, 1,648 SNPs, spanning 12.1 Mb of genomic DNA, were examined. After Bonferroni correction for multiple testing, the strongest signal was found for a SNP located within the CNTN5 gene (rs6590473 [G], p = 4.09 × 10(-7); OR = 3.117; 95% CI = 1.603-6.151). In the ASD cohort, a combination of risk alleles of SNPs in CNTN6 (rs9878022 [A]; OR = 3.749) and in CNTNAP2 (rs7804520 [G]; OR = 2.437) was found more frequently than would be expected under random segregation, albeit this association was not statistically significant. The latter finding is consistent with a polygenic disease model in which multiple mutagenic mechanisms, operating concomitantly, elicit the ASD phenotype. Altogether, this study corroborates the possible involvement of contactins in ASD, which has been indicated by earlier studies of CNVs.

PMID: 25337070 [PubMed]

The developmental transcriptome of the human brain: implications for neurodevelopmental disorders.

October 23, 2014 - 7:49am
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The developmental transcriptome of the human brain: implications for neurodevelopmental disorders.

Curr Opin Neurol. 2014 Apr;27(2):149-56

Authors: Tebbenkamp AT, Willsey AJ, State MW, Sestan N

Abstract
PURPOSE OF REVIEW: Recent characterizations of the transcriptome of the developing human brain by several groups have generated comprehensive datasets on coding and noncoding RNAs that will be instrumental for illuminating the underlying biology of complex neurodevelopmental disorders. This review summarizes recent studies successfully utilizing these data to increase our understanding of the molecular mechanisms of pathogenesis.
RECENT FINDINGS: Several approaches have successfully integrated developmental transcriptome data with gene discovery to generate testable hypotheses about when and where in the developing human brain disease-associated genes converge. Specifically, these include the projection neurons in the prefrontal and primary motor--somatosensory cortex during mid-fetal development in autism spectrum disorder and the frontal cortex during fetal development in schizophrenia.
SUMMARY: Developmental transcriptome data is a key to interpreting disease-associated mutations and transcriptional changes. Novel approaches integrating the spatial and temporal dimensions of these data have increased our understanding of when and where disease occurs. Refinement of spatial and temporal properties and expanding these findings to other neurodevelopmental disorders will provide critical insights for understanding disease biology.

PMID: 24565942 [PubMed - indexed for MEDLINE]

Mood disorders in individuals with distal 18q deletions.

October 23, 2014 - 7:49am
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Mood disorders in individuals with distal 18q deletions.

Am J Med Genet B Neuropsychiatr Genet. 2013 Dec;162B(8):879-88

Authors: Daviss WB, O'Donnell L, Soileau BT, Heard P, Carter E, Pliszka SR, Gelfond JA, Hale DE, Cody JD

Abstract
We examined 36 participants at least 4 years old with hemizygous distal deletions of the long arm of Chromosome 18 (18q-) for histories of mood disorders and to characterize these disorders clinically. Since each participant had a different region of 18q hemizygosity, our goal was also to identify their common region of hemizygosity associated with mood disorders; thereby identifying candidate causal genes in that region. Lifetime mood and other psychiatric disorders were determined by semi-structured interviews of patients and parents, supplemented by reviews of medical and psychiatric records, and norm-referenced psychological assessment instruments, for psychiatric symptoms, cognitive problems, and adaptive functioning. Sixteen participants were identified with lifetime mood disorders (ages 12-42 years, 71% female, 14 having had unipolar depression and 2 with bipolar disorders). From the group of 20 who did not meet criteria for a mood disorder; a comparison group of 6 participants were identified who were matched for age range and deletion size. Mood-disordered patients had high rates of anxiety (75%) and externalizing behavior disorders (44%), and significant mean differences from comparison patients (P < 0.05), including higher overall and verbal IQs and lower autistic symptoms. A critical region was defined in the mood-disordered group that included a hypothetical gene, C18orf62, and two known genes, ZADH2 and TSHZ1. We conclude that patients having terminal deletions of this critical region of the long arm of Chromosome 18 are highly likely to have mood disorders, which are often comorbid with anxiety and to a lesser extent with externalizing disorders.

PMID: 24006251 [PubMed - indexed for MEDLINE]

A sociability gene? Meta-analysis of oxytocin receptor genotype effects in humans.

October 23, 2014 - 7:49am
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A sociability gene? Meta-analysis of oxytocin receptor genotype effects in humans.

Psychiatr Genet. 2014 Apr;24(2):45-51

Authors: Bakermans-Kranenburg MJ, van Ijzendoorn MH

Abstract
Variation in the oxytocin receptor (OXTR) gene may partly explain individual differences in oxytocin-related social behavior. Two single nucleotide polymorphisms (SNPs) have been suggested as promising candidates: rs53576 and rs2254298, although the results of studies were not consistent. We carried out meta-analyses for these two SNPs, covering five domains of outcomes: (a) biology, (b) personality, (c) social behavior, (d) psychopathology, and (e) autism, on the basis of 82 pertinent effect sizes, 48 for OXTR rs53576 (N=17 559) and 34 for OXTR rs2254298 (N=13 547). Combined effect sizes did not differ from zero in any of the domains, nor for all domains combined. Clinical status, age, and sex did not moderate the effect sizes. Minor allele frequency was related to ethnicity, with significantly lower minor allele frequencies in samples with predominantly Caucasian participants. The domain of biological functioning seemed most promising, but comprised few studies. We conclude that so far two of the most intensively studied OXTR SNPs (rs53576 and rs2254298) failed to explain a significant part of human social behavior.

PMID: 23921259 [PubMed - indexed for MEDLINE]

Microduplication of 15q13.3 and Xq21.31 in a family with Tourette syndrome and comorbidities.

October 23, 2014 - 7:49am
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Microduplication of 15q13.3 and Xq21.31 in a family with Tourette syndrome and comorbidities.

Am J Med Genet B Neuropsychiatr Genet. 2013 Dec;162B(8):825-31

Authors: Melchior L, Bertelsen B, Debes NM, Groth C, Skov L, Mikkelsen JD, Brøndum-Nielsen K, Tümer Z

Abstract
Tourette syndrome (TS) is a childhood onset neurodevelopmental disorder. Although it is widely accepted that genetic factors play a significant role in TS pathogenesis the etiology of this disorder is largely unknown. Identification of rare copy number variations (CNVs) as susceptibility factors in several neuropsychiatric disorders such as attention deficit-hyperactivity disorder (ADHD), autism and schizophrenia, suggests involvement of these rare structural changes also in TS etiology. In a male patient with TS, ADHD, and OCD (obsessive compulsive disorder) we identified two microduplications (at 15q13.3 and Xq21.31) inherited from a mother with subclinical ADHD. The 15q duplication included the CHRNA7 gene; while two genes, PABPC5 and PCDH11X, were within the Xq duplication. The Xq21.31 duplication was present in three brothers with TS including the proband, but not in an unaffected brother, whereas the 15q duplication was present only in the proband and his mother. The structural variations observed in this family may contribute to the observed symptoms, but further studies are necessary to investigate the possible involvement of the described variations in the TS etiology.

PMID: 23894120 [PubMed - indexed for MEDLINE]

Serotonin 2A receptor gene (HTR2A) regulatory variants: possible association with severity of depression symptoms in children with autism spectrum disorder.

October 22, 2014 - 7:38am
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Serotonin 2A receptor gene (HTR2A) regulatory variants: possible association with severity of depression symptoms in children with autism spectrum disorder.

Cogn Behav Neurol. 2014 Jun;27(2):107-16

Authors: Gadow KD, Smith RM, Pinsonneault JK

Abstract
OBJECTIVE AND BACKGROUND: Our aim was to characterize the association of 2 functional single nucleotide polymorphisms (rs6311 and rs6314) in the serotonin 2A receptor gene (HTR2A) with severity of depression symptoms in children with autism spectrum disorder. These polymorphisms have been shown to be associated with depression symptom severity and response to selective serotonin reuptake inhibitor drugs in adults with diagnosed depressive disorder.
METHODS: Parents of 104 children with autism spectrum disorder rated their children's depressive symptoms using a validated scale based on criteria from the Diagnostic and Statistical Manual of Mental Disorders, 4th edition. We compared severity of depression symptoms across the rs6311 and rs6314 genotypes, measured from the children's genomic DNA.
RESULTS: Children homozygous for the G allele of rs6311 had significantly more severe depression symptoms than those with G/A or A/A genotypes (P=0.025). The effect size (partial eta-squared) was small (ηp=0.047) but was somewhat larger when we controlled for severity of generalized anxiety disorder symptoms (P=0.006, ηp=0.072). When we restricted our analyses to white participants, our results were essentially the same as for the entire sample (P=0.004, ηp=0.086). There was no significant association between rs6314 (C/C versus T carriers) and severity of depression.
CONCLUSIONS: Our findings suggest that the HTR2A functional rs6311 polymorphism, which other studies have associated with differential HTR2A mRNA expression, may modulate the severity of depression symptoms in children with autism spectrum disorder. These tentative, hypothesis-generating findings need replication with larger, independent samples.

PMID: 24968012 [PubMed - indexed for MEDLINE]

A girl with tuberous sclerosis complex presenting with severe epilepsy and electrical status epilepticus during sleep, and with high-functioning autism and mutism.

October 22, 2014 - 7:38am
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A girl with tuberous sclerosis complex presenting with severe epilepsy and electrical status epilepticus during sleep, and with high-functioning autism and mutism.

Cogn Behav Neurol. 2014 Jun;27(2):88-95

Authors: Pacheva I, Panov G, Gillberg C, Neville B

Abstract
Most patients with tuberous sclerosis complex (TSC) suffer from epilepsy, and many have cognitive and behavioral problems like severe intellectual disability, autism, and hyperactivity. Only rare patients with TSC and autism have a normal intelligence quotient. We report a 13-year-old girl with definite TSC who had early-onset severe epilepsy, autistic behavior, and moderate developmental delay. By school age, however, she had normal intelligence; her intelligence quotient was at least 70 based on a Stanford-Binet test that she refused to complete. She showed good reading, writing, and language comprehension skills, and the special abilities of hyperlexia, hypermnesia, and hypercalculia. However, she did not speak. Criteria of the Diagnostic and Statistical Manual of Mental Disorders, 4th edition, and her Childhood Autism Rating Scale score of 36 indicated mild to moderate autism. She had severe electroencephalographic abnormalities: hypsarrhythmia, multifocal or generalized epileptiform discharges, and electrical status epilepticus during sleep, with a continuous left temporal focus. Magnetic resonance imaging showed many cortical tubers in all brain lobes, and subependymal nodules. We discuss possible explanations for her lack of speech. Considered as speech apraxia, her mutism could be either a symptom of her TSC or a component of her autism. Another possibility is that long-lasting electrical status epilepticus during sleep led to her autistic behavior and language arrest. Still another possibility is that a disinhibited mammalian target of rapamycin (mTOR) pathway was at the root of all of her neuropsychiatric symptoms.

PMID: 24968009 [PubMed - indexed for MEDLINE]

Altered expression of Alzheimer's disease-related genes in the cerebellum of autistic patients: a model for disrupted brain connectome and therapy.

October 22, 2014 - 7:38am
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Altered expression of Alzheimer's disease-related genes in the cerebellum of autistic patients: a model for disrupted brain connectome and therapy.

Cell Death Dis. 2014;5:e1250

Authors: Zeidán-Chuliá F, de Oliveira BH, Salmina AB, Casanova MF, Gelain DP, Noda M, Verkhratsky A, Moreira JC

Abstract
Autism and Alzheimer's disease (AD) are, respectively, neurodevelopmental and degenerative diseases with an increasing epidemiological burden. The AD-associated amyloid-β precursor protein-α has been shown to be elevated in severe autism, leading to the 'anabolic hypothesis' of its etiology. Here we performed a focused microarray analysis of genes belonging to NOTCH and WNT signaling cascades, as well as genes related to AD and apoptosis pathways in cerebellar samples from autistic individuals, to provide further evidence for pathological relevance of these cascades for autism. By using the limma package from R and false discovery rate, we demonstrated that 31% (116 out of 374) of the genes belonging to these pathways displayed significant changes in expression (corrected P-values <0.05), with mitochondria-related genes being the most downregulated. We also found upregulation of GRIN1, the channel-forming subunit of NMDA glutamate receptors, and MAP3K1, known activator of the JNK and ERK pathways with anti-apoptotic effect. Expression of PSEN2 (presinilin 2) and APBB1 (or F65) were significantly lower when compared with control samples. Based on these results, we propose a model of NMDA glutamate receptor-mediated ERK activation of α-secretase activity and mitochondrial adaptation to apoptosis that may explain the early brain overgrowth and disruption of synaptic plasticity and connectome in autism. Finally, systems pharmacology analyses of the model that integrates all these genes together (NOWADA) highlighted magnesium (Mg(2+)) and rapamycin as most efficient drugs to target this network model in silico. Their potential therapeutic application, in the context of autism, is therefore discussed.

PMID: 24853428 [PubMed - indexed for MEDLINE]

Recommendations for early diagnosis and intervention in autism spectrum disorders: an Italian-Israeli consensus conference.

October 22, 2014 - 7:38am
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Recommendations for early diagnosis and intervention in autism spectrum disorders: an Italian-Israeli consensus conference.

Eur J Paediatr Neurol. 2014 Mar;18(2):107-18

Authors: Zachor DA, Curatolo P, Participants of Italian-Israeli Consensus Conference

Abstract
On April 2013 experts in the field of autism from Italy and Israel convened in Jerusalem to discuss and finalize clinical recommendations for early diagnosis and intervention in Autism Spectrum Disorders (ASDs). In this paper, we summarize the results of this Italian-Israeli consensus conference. ASDs constitute a class of severe and heterogeneous neurodevelopmental conditions caused by atypical brain development beginning during early prenatal life, reflecting many genetic, neurobiological and environmental influences. The first clinical signs of ASDs begin to be evident in children between 12 and 18 months of age, often after a period of relatively typical postnatal development. Recent longitudinal studies reveal substantial diversity in developmental trajectories through childhood and adolescence. Some intervention approaches have been demonstrated to be effective in improving core symptoms of ASDs, even if the heterogeneity and developmental nature of the disorder make it implausible that only one specific treatment will be best for all children with ASDs. More randomized control trials (RCTs) on early intervention are needed to identify the most effective strategies and provide the most efficient allocation of resources during the critical early intervention time period. Future research should focus on linking biological phenotypes with specific genotypes, thus establishing a foundation for the development of diagnostic screening tools and individualization of treatments.

PMID: 24095105 [PubMed - indexed for MEDLINE]

Recurrence rates in autism spectrum disorders--reply.

October 21, 2014 - 7:17am
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Recurrence rates in autism spectrum disorders--reply.

JAMA. 2014 Sep 17;312(11):1155

Authors: Sandin S, Reichenberg A

PMID: 25226487 [PubMed - indexed for MEDLINE]

Recurrence rates in autism spectrum disorders.

October 21, 2014 - 7:17am
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Recurrence rates in autism spectrum disorders.

JAMA. 2014 Sep 17;312(11):1154-5

Authors: Constantino JN

PMID: 25226485 [PubMed - indexed for MEDLINE]

Downregulation of GABAA receptor protein subunits α6, β2, δ, ε, γ2, θ, and ρ2 in superior frontal cortex of subjects with autism.

October 21, 2014 - 7:17am
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Downregulation of GABAA receptor protein subunits α6, β2, δ, ε, γ2, θ, and ρ2 in superior frontal cortex of subjects with autism.

J Autism Dev Disord. 2014 Aug;44(8):1833-45

Authors: Fatemi SH, Reutiman TJ, Folsom TD, Rustan OG, Rooney RJ, Thuras PD

Abstract
We measured protein and mRNA levels for nine gamma-aminobutyric acid A (GABAA) receptor subunits in three brain regions (cerebellum, superior frontal cortex, and parietal cortex) in subjects with autism versus matched controls. We observed changes in mRNA for a number of GABAA and GABAB subunits and overall reduced protein expression for GABAA receptor alpha 6 (GABRα6), GABAA receptor beta 2 (GABRβ2), GABAA receptor delta (GABRδ), GABAA receptor epsilon (GABRε), GABAA receptor gamma 2 (GABRγ2), GABAA receptor theta (GABRθ), and GABAA receptor rho 2 (GABRρ2) in superior frontal cortex from subjects with autism. Our data demonstrate systematic changes in GABAA&B subunit expression in brains of subjects with autism, which may help explain the presence of cognitive abnormalities in subjects with autism.

PMID: 24668190 [PubMed - indexed for MEDLINE]

A twin study of heritable and shared environmental contributions to autism.

October 21, 2014 - 7:17am
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A twin study of heritable and shared environmental contributions to autism.

J Autism Dev Disord. 2014 Aug;44(8):2013-25

Authors: Frazier TW, Thompson L, Youngstrom EA, Law P, Hardan AY, Eng C, Morris N

Abstract
The present study examined genetic and shared environment contributions to quantitatively-measured autism symptoms and categorically-defined autism spectrum disorders (ASD). Participants included 568 twins from the Interactive Autism Network. Autism symptoms were obtained using the Social Communication Questionnaire and Social Responsiveness Scale. Categorically-defined ASD was based on clinical diagnoses. DeFries-Fulker and liability threshold models examined etiologic influences. Very high heritability was observed for extreme autism symptom levels ([Formula: see text]). Extreme levels of social and repetitive behavior symptoms were strongly influenced by common genetic factors. Heritability of categorically-defined ASD diagnosis was comparatively low (.21, 95 % CI 0.15-0.28). High heritability of extreme autism symptom levels confirms previous observations of strong genetic influences on autism. Future studies will require large, carefully ascertained family pedigrees and quantitative symptom measurements.

PMID: 24604525 [PubMed - indexed for MEDLINE]

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