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Microdeletion of the escape genes KDM5C and IQSEC2 in a girl with severe intellectual disability and autistic features.

April 11, 2015 - 8:35am

Microdeletion of the escape genes KDM5C and IQSEC2 in a girl with severe intellectual disability and autistic features.

Eur J Med Genet. 2015 Apr 6;

Authors: Fieremans N, Van Esch H, de Ravel T, Van Driessche J, Belet S, Bauters M, Froyen G

Abstract
Intellectual disability (ID) is a very heterogeneous disorder with over 100 ID genes located on the X chromosome alone. Of these, KDM5C and IQSEC2 are located adjacent to each other at the Xp11.22 locus. While mutations in either of these genes are associated with severe ID in males, female carriers are mostly unaffected. Here, we report on a female patient with severe ID and autistic features carrying a de novo 0.4 Mb deletion containing six coding genes including KDM5C and IQSEC2. X-inactivation analysis revealed skewing in a lymphocyte-derived cell line from this patient with preferential inactivation of the mutant X chromosome. As the brain-expressed KDM5C and IQSEC2 genes escape X-inactivation, deletion of these alleles could still be detrimental despite skewing of X-inactivation. Indeed, mutations in either of both genes have been reported in a few female ID patients. Expression analysis in the patients' cell line revealed decreased KDM5C mRNA levels compared to female controls. IQSEC2 levels could not be compared due to very low expression in blood. Overall, our data suggest that heterozygous loss-of-function of the escape genes KDM5C and/or IQSEC2 can contribute to severe ID in female patients and should be taken into account in diagnostics.

PMID: 25858702 [PubMed - as supplied by publisher]

Deficient tonic GABAergic conductance and synaptic balance in the fragile X syndrome amygdala.

April 11, 2015 - 8:35am
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Deficient tonic GABAergic conductance and synaptic balance in the fragile X syndrome amygdala.

J Neurophysiol. 2014 Aug 15;112(4):890-902

Authors: Martin BS, Corbin JG, Huntsman MM

Abstract
Fragile X syndrome (FXS) is the leading cause of inherited intellectual disability. Comorbidities of FXS such as autism are increasingly linked to imbalances in excitation and inhibition (E/I) as well as dysfunction in GABAergic transmission in a number of brain regions including the amygdala. However, the link between E/I imbalance and GABAergic transmission deficits in the FXS amygdala is poorly understood. Here we reveal that normal tonic GABAA receptor-mediated neurotransmission in principal neurons (PNs) of the basolateral amygdala (BLA) is comprised of both δ- and α5-subunit-containing GABAA receptors. Furthermore, tonic GABAergic capacity is reduced in these neurons in the Fmr1 knockout (KO) mouse model of FXS (1.5-fold total, 3-fold δ-subunit, and 2-fold α5-subunit mediated) as indicated by application of gabazine (50 μM), 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol (THIP, 1 μM), and α5ia (1.5 μM) in whole cell patch-clamp recordings. Moreover, α5-containing tonic GABAA receptors appear to preferentially modulate nonsomatic compartments of BLA PNs. Examination of evoked feedforward synaptic transmission in these cells surprisingly revealed no differences in overall synaptic conductance or E/I balance between wild-type (WT) and Fmr1 KO mice. Instead, we observed altered feedforward kinetics in Fmr1 KO PNs that supports a subtle yet significant decrease in E/I balance at the peak of excitatory conductance. Blockade of α5-subunit-containing GABAA receptors replicated this condition in WT PNs. Therefore, our data suggest that tonic GABAA receptor-mediated neurotransmission can modulate synaptic E/I balance and timing established by feedforward inhibition and thus may represent a therapeutic target to enhance amygdala function in FXS.

PMID: 24848467 [PubMed - indexed for MEDLINE]

Language laterality, handedness and empathy in a sample of parents of children with autism spectrum disorder.

April 11, 2015 - 8:35am
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Language laterality, handedness and empathy in a sample of parents of children with autism spectrum disorder.

Psicothema. 2014;26(1):17-20

Authors: Martínez-Sanchis S, Bernal Santacreu MC, Cortés Sancho R, Gadea Domenech M

Abstract
BACKGROUND: First-order relatives of persons with Autism Spectrum Disorder (ASD) exhibit a cognitive pattern which is part of a broader autism phenotype.
METHOD: The purpose of the present study was to evaluate whether some neuropsychological features related to the autism phenotype are present in parents of ASD children. To this end, the exploration included a dichotic listening task, handedness and the Empathy Quotient (EQ-60).
RESULTS: The scores obtained by the total sample (fathers plus mothers) were similar to those of the general population, although there were differences in some parameters of the dichotic listening task depending on the gender. Contrary to expectations, only in fathers, the negative correlation between data from both ears was not statistically significant, which could be evidence of a lack of hemispheric interdependence.
CONCLUSIONS: These results support the possible existence of a genetic susceptibility to an aberrant language asymmetry pattern. Moreover, possible unknown epigenetic factors could act on a vulnerable genotype in some ASD subjects. Nevertheless, due to the small sample size, the present research must be considered a pilot study.

PMID: 24444724 [PubMed - indexed for MEDLINE]

Age-dependent changes in the neural substrates of empathy in autism spectrum disorder.

April 11, 2015 - 8:35am
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Age-dependent changes in the neural substrates of empathy in autism spectrum disorder.

Soc Cogn Affect Neurosci. 2014 Aug;9(8):1118-26

Authors: Schulte-Rüther M, Greimel E, Piefke M, Kamp-Becker I, Remschmidt H, Fink GR, Herpertz-Dahlmann B, Konrad K

Abstract
In typical development, empathic abilities continue to refine during adolescence and early adulthood. Children and adolescents with autism spectrum disorders (ASD) show deficits in empathy, whereas adults with ASD may have developed compensatory strategies. We aimed at comparing developmental trajectories in the neural mechanisms underlying empathy in individuals with ASD and typically developing control (TDC) subjects. Using an explicit empathizing paradigm and functional magnetic resonance imaging, 27 participants with ASD and 27 TDC aged 12-31 years were investigated. Participants were asked to empathize with emotional faces and to either infer the face's emotional state (other-task) or to judge their own emotional response (self-task). Differential age-dependent changes were evident during the self-task in the right dorsolateral prefrontal cortex, right medial prefrontal cortex, right inferior parietal cortex, right anterior insula and occipital cortex. Age-dependent decreases in neural activation in TDC were paralleled by either increasing or unchanged age-dependent activation in ASD. These data suggest ASD-associated deviations in the developmental trajectories of self-related processing during empathizing. In TDC, age-dependent modulations of brain areas may reflect the 'fine-tuning' of cortical networks by reduction of task-unspecific brain activity. Increased age-related activation in individuals with ASD may indicate the development of compensatory mechanisms.

PMID: 23784073 [PubMed - indexed for MEDLINE]

A de novo microdeletion of ANKRD11 gene in a Korean patient with KBG syndrome.

April 10, 2015 - 8:17am
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A de novo microdeletion of ANKRD11 gene in a Korean patient with KBG syndrome.

Ann Lab Med. 2014 Sep;34(5):390-4

Authors: Lim JH, Seo EJ, Kim YM, Cho HJ, Lee JO, Cheon CK, Yoo HW

Abstract
KBG syndrome is a very rare genetic disorder characterized by macrodontia of upper central incisors, global developmental delay, distinctive craniofacial features, short stature, and skeletal anomalies. Ankyrin repeat domain 11 gene (ANKRD11) has recently been identified as a causal factor of this syndrome. We describe a 6-yr-old Korean boy with features of KBG syndrome. The patient had a short stature, macrodontia, dysmorphic facial features, speech and motor delay with intellectual disability, and partial seizures as indicated by the electroencephalogram, but he was neither autistic nor had autism spectrum disorders. Using high-resolution oligonucleotide array comparative genomic hybridization, we identified a heterozygous 240-kb deletion at 16q24.3 corresponding to ANKRD11. This patient provided additional evidence on the influence of ANKRD11 in KBG syndrome and suggested that deletion limited to ANKRD11 is unlikely to cause autism.

PMID: 25187894 [PubMed - indexed for MEDLINE]

Zinc finger protein 804A (ZNF804A) and verbal deficits in individuals with autism.

April 10, 2015 - 8:17am
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Zinc finger protein 804A (ZNF804A) and verbal deficits in individuals with autism.

J Psychiatry Neurosci. 2014 Sep;39(5):294-303

Authors: Anitha A, Thanseem I, Nakamura K, Vasu MM, Yamada K, Ueki T, Iwayama Y, Toyota T, Tsuchiya KJ, Iwata Y, Suzuki K, Sugiyama T, Tsujii M, Yoshikawa T, Mori N

Abstract
BACKGROUND: In a genome-wide association study of autism, zinc finger protein 804A (ZNF804A) single nucleotide polymorphisms (SNPs) were found to be nominally associated in verbally deficient individuals with autism. Zinc finger protein 804A copy number variations (CNVs) have also been observed in individuals with autism. In addition, ZNF804A is known to be involved in theory of mind (ToM) tasks, and ToM deficits are deemed responsible for the communication and social challenges faced by individuals with autism. We hypothesized that ZNF804A could be a risk gene for autism.
METHODS: We examined the genetic association and CNVs of ZNF804A in 841 families in which 1 or more members had autism. We compared the expression of ZNF804A in the postmortem brains of individuals with autism (n = 8) and controls (n = 13). We also assessed in vitro the effect of ZNF804A silencing on the expression of several genes known to be involved in verbal efficiency and social cognition.
RESULTS: We found that rs7603001 was nominally associated with autism (p = 0.018). The association was stronger (p = 0.008) in the families of individuals with autism who were verbally deficient (n = 761 families). We observed ZNF804A CNVs in 7 verbally deficient boys with autism. In ZNF804A knockdown cells, the expression of synaptosomal-associated protein, 25kDa (SNAP25) was reduced compared with controls (p = 0.009). The expression of ZNF804A (p = 0.009) and SNAP25 (p = 0.009) were reduced in the anterior cingulate gyrus (ACG) of individuals with autism. There was a strong positive correlation between the expression of ZNF804A and SNAP25 in the ACG (p < 0.001).
LIMITATIONS: Study limitations include our small sample size of postmortem brains.
CONCLUSION: Our results suggest that ZNF804A could be a potential candidate gene mediating the intermediate phenotypes associated with verbal traits in individuals with autism.

PMID: 24866414 [PubMed - indexed for MEDLINE]

Repetitive behaviors in the Shank1 knockout mouse model for autism spectrum disorder: developmental aspects and effects of social context.

April 10, 2015 - 8:17am
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Repetitive behaviors in the Shank1 knockout mouse model for autism spectrum disorder: developmental aspects and effects of social context.

J Neurosci Methods. 2014 Aug 30;234:92-100

Authors: Sungur AÖ, Vörckel KJ, Schwarting RK, Wöhr M

Abstract
BACKGROUND: Autism spectrum disorder (ASD) is characterized by persistent deficits in social behavior and communication, together with restricted and repetitive patterns of behavior. Several ASD candidate genes have been identified, including the SHANK gene family with its three family members SHANK1, SHANK2, and SHANK3.
METHODS: Typically, repetitive behavior in mouse models for ASD is assessed by measuring self-grooming behavior. The first aim of the current study was to assess repetitive behaviors in Shank1(-/-) null mutant, Shank1(+/-) heterozygous, and Shank1(+/+) wildtype littermate control mice by means of a comprehensive approach, including the assessment of self-grooming, digging behavior, and marble burying. The second aim was to establish a test paradigm that allows for assessing the effects of social context on the occurrence of repetitive behaviors in a genotype-dependent manner. To this aim, repetitive behaviors were repeatedly tested on three consecutive days in distinct social contexts, namely in presence or absence of social odors.
RESULTS: Shank1(+/-) heterozygous and to a lesser extent Shank1(-/-) null mutant mice displayed slightly elevated levels of self-grooming behavior as adults, but not as juveniles, with genotype differences being most prominent in the social context. In contrast to elevated self-grooming behavior, marble burying was strongly reduced in adult Shank1(+/-) heterozygous and Shank1(-/-) null mutant mice across social contexts, as compared to adult Shank1(+/+) wildtype littermate controls.
CONCLUSION: The opposite effects of the Shank1 deletion on the two types of repetitive behaviors are in line with a number of studies on repetitive behaviors in other genetic Shank models.

PMID: 24820912 [PubMed - indexed for MEDLINE]

A de novo FOXP1 variant in a patient with autism, intellectual disability and severe speech and language impairment.

April 9, 2015 - 6:35am

A de novo FOXP1 variant in a patient with autism, intellectual disability and severe speech and language impairment.

Eur J Hum Genet. 2015 Apr 8;

Authors: Lozano R, Vino A, Lozano C, Fisher SE, Deriziotis P

Abstract
FOXP1 (forkhead box protein P1) is a transcription factor involved in the development of several tissues, including the brain. An emerging phenotype of patients with protein-disrupting FOXP1 variants includes global developmental delay, intellectual disability and mild to severe speech/language deficits. We report on a female child with a history of severe hypotonia, autism spectrum disorder and mild intellectual disability with severe speech/language impairment. Clinical exome sequencing identified a heterozygous de novo FOXP1 variant c.1267_1268delGT (p.V423Hfs*37). Functional analyses using cellular models show that the variant disrupts multiple aspects of FOXP1 activity, including subcellular localization and transcriptional repression properties. Our findings highlight the importance of performing functional characterization to help uncover the biological significance of variants identified by genomics approaches, thereby providing insight into pathways underlying complex neurodevelopmental disorders. Moreover, our data support the hypothesis that de novo variants represent significant causal factors in severe sporadic disorders and extend the phenotype seen in individuals with FOXP1 haploinsufficiency.European Journal of Human Genetics advance online publication, 8 April 2015; doi:10.1038/ejhg.2015.66.

PMID: 25853299 [PubMed - as supplied by publisher]

Phenotypic and Molecular Convergence of 2q23.1 Deletion Syndrome with Other Neurodevelopmental Syndromes Associated with Autism Spectrum Disorder.

April 9, 2015 - 6:35am

Phenotypic and Molecular Convergence of 2q23.1 Deletion Syndrome with Other Neurodevelopmental Syndromes Associated with Autism Spectrum Disorder.

Int J Mol Sci. 2015;16(4):7627-7643

Authors: Mullegama SV, Alaimo JT, Chen L, Elsea SH

Abstract
Roughly 20% of autism spectrum disorders (ASD) are syndromic with a well-established genetic cause. Studying the genes involved can provide insight into the molecular and cellular mechanisms of ASD. 2q23.1 deletion syndrome (causative gene, MBD5) is a recently identified genetic neurodevelopmental disorder associated with ASD. Mutations in MBD5 have been found in ASD cohorts. In this study, we provide a phenotypic update on the prevalent features of 2q23.1 deletion syndrome, which include severe intellectual disability, seizures, significant speech impairment, sleep disturbance, and autistic-like behavioral problems. Next, we examined the phenotypic, molecular, and network/pathway relationships between nine neurodevelopmental disorders associated with ASD: 2q23.1 deletion Rett, Angelman, Pitt-Hopkins, 2q23.1 duplication, 5q14.3 deletion, Kleefstra, Kabuki make-up, and Smith-Magenis syndromes. We show phenotypic overlaps consisting of intellectual disability, speech delay, seizures, sleep disturbance, hypotonia, and autistic-like behaviors. Molecularly, MBD5 possibly regulates the expression of UBE3A, TCF4, MEF2C, EHMT1 and RAI1. Network analysis reveals that there could be indirect protein interactions, further implicating function for these genes in common pathways. Further, we show that when MBD5 and RAI1 are haploinsufficient, they perturb several common pathways that are linked to neuronal and behavioral development. These findings support further investigations into the molecular and pathway relationships among genes linked to neurodevelopmental disorders and ASD, which will hopefully lead to common points of regulation that may be targeted toward therapeutic intervention.

PMID: 25853262 [PubMed - as supplied by publisher]

Connecting the CNTNAP2 Networks with Neurodevelopmental Disorders.

April 9, 2015 - 6:35am

Connecting the CNTNAP2 Networks with Neurodevelopmental Disorders.

Mol Syndromol. 2015 Feb;6(1):7-22

Authors: Poot M

Abstract
Based on genomic rearrangements and copy number variations, the contactin-associated protein-like 2 gene (CNTNAP2) has been implicated in neurodevelopmental disorders such as Gilles de la Tourette syndrome, intellectual disability, obsessive compulsive disorder, cortical dysplasia-focal epilepsy syndrome, autism, schizophrenia, Pitt-Hopkins syndrome, and attention deficit hyperactivity disorder. To explain the phenotypic pleiotropy of CNTNAP2 alterations, several hypotheses have been put forward. Those include gene disruption, loss of a gene copy by a heterozygous deletion, altered regulation of gene expression due to loss of transcription factor binding and DNA methylation sites, and mutations in the amino acid sequence of the encoded protein which may provoke altered interactions of the CNTNAP2-encoded protein, Caspr2, with other proteins. Also exome sequencing, which covers <0.2% of the CNTNAP2 genomic DNA, has revealed numerous single nucleotide variants in healthy individuals and in patients with neurodevelopmental disorders. In some of these disorders, disruption of CNTNAP2 may be interpreted as a susceptibility factor rather than a directly causative mutation. In addition to being associated with impaired development of language, CNTNAP2 may turn out to be a central node in the molecular networks controlling neurodevelopment. This review discusses the impact of CNTNAP2 mutations on its functioning at multiple levels of the combinatorial genetic networks that govern brain development. In addition, recommendations for genomic testing in the context of clinical genetic management of patients with neurodevelopmental disorders and their families are put forward.

PMID: 25852443 [PubMed]

Microbiome Disturbances and Autism Spectrum Disorders.

April 9, 2015 - 6:35am

Microbiome Disturbances and Autism Spectrum Disorders.

Drug Metab Dispos. 2015 Apr 7;

Authors: Rosenfeld CS

Abstract
Autism spectrum disorders (ASD) are considered a heterogenous set of neurobehavioral diseases with the rates of diagnosis dramatically increasing in the past few decades. As genetics alone does not explain the underlying cause in many cases, attention has turned to other environmental factors as potential etiological agents. Gastrointestinal disorders are a common comorbidity in ASD patients. It was thus hypothesized that a gut-brain link may account for some autistic cases. With the characterization of the human microbiome, this concept has been expanded to include the microbiota-gut-brain axis. There are mounting reports in animal models and human epidemiological studies linking disruptive alterations in the gut microbiota or dysbiosis and ASD symptomology. In this review, we will explore the current evidence that gut dysbiosis in animal models and ASD patients correlates with disease risk and severity. The studies to date have surveyed how gut microbiome changes may affect these neurobehavioral disorders. However, we harbor other microbiomes reside in the body that might impact brain function. We will consider these other microbiomes in the oral cavity, vagina, and the most recently discovered one in the placenta. Based on the premise that gut microbiota alterations may be causative agents in ASD, several therapeutic options have been tested, such as diet modulations, prebiotics, probiotics, synbiotics, postbiotics, antibiotics, fecal transplantation, and activated charcoal. The potential benefits of these therapies will be considered. Lastly, the possible mechanisms by which changes in the gut bacterial communities may result in ASD and related neurobehavioral disorders will be examined.

PMID: 25852213 [PubMed - as supplied by publisher]

Neuroanatomical Diversity of Corpus Callosum and Brain Volume in Autism: Meta-analysis, Analysis of the Autism Brain Imaging Data Exchange Project, and Simulation.

April 9, 2015 - 6:35am

Neuroanatomical Diversity of Corpus Callosum and Brain Volume in Autism: Meta-analysis, Analysis of the Autism Brain Imaging Data Exchange Project, and Simulation.

Biol Psychiatry. 2015 Feb 17;

Authors: Lefebvre A, Beggiato A, Bourgeron T, Toro R

Abstract
BACKGROUND: Patients with autism have been often reported to have a smaller corpus callosum (CC) than control subjects.
METHODS: We conducted a meta-analysis of the literature, analyzed the CC in 694 subjects of the Autism Brain Imaging Data Exchange project, and performed computer simulations to study the effect of different analysis strategies.
RESULTS: Our meta-analysis suggested a group difference in CC size; however, the studies were heavily underpowered (20% power to detect Cohen's d = .3). In contrast, we did not observe significant differences in the Autism Brain Imaging Data Exchange cohort, despite having achieved 99% power. However, we observed that CC scaled nonlinearly with brain volume (BV): large brains had a proportionally smaller CC. Our simulations showed that because of this nonlinearity, CC normalization could not control for eventual BV differences, but using BV as a covariate in a linear model would. We also observed a weaker correlation of IQ and BV in cases compared with control subjects. Our simulations showed that matching populations by IQ could then induce artifactual BV differences.
CONCLUSIONS: The lack of statistical power in the previous literature prevents us from establishing the reality of the claims of a smaller CC in autism, and our own analyses did not find any. However, the nonlinear relationship between CC and BV and the different correlation between BV and IQ in cases and control subjects may induce artifactual differences. Overall, our results highlight the necessity for open data sharing to provide a more solid ground for the discovery of neuroimaging biomarkers within the context of the wide human neuroanatomical diversity.

PMID: 25850620 [PubMed - as supplied by publisher]

Genes with de novo mutations are shared by four neuropsychiatric disorders discovered from NPdenovo database.

April 8, 2015 - 11:47am

Genes with de novo mutations are shared by four neuropsychiatric disorders discovered from NPdenovo database.

Mol Psychiatry. 2015 Apr 7;

Authors: Li J, Cai T, Jiang Y, Chen H, He X, Chen C, Li X, Shao Q, Ran X, Li Z, Xia K, Liu C, Sun ZS, Wu J

Abstract
Currently, many studies on neuropsychiatric disorders have utilized massive trio-based whole-exome sequencing (WES) and whole-genome sequencing (WGS) to identify numerous de novo mutations (DNMs). Here, we retrieved 17 104 DNMs from 3555 trios across four neuropsychiatric disorders: autism spectrum disorder, epileptic encephalopathy, intellectual disability and schizophrenia, in addition to unaffected siblings (control), from 36 studies by WES/WGS. After eliminating non-exonic variants, we focused on 3334 exonic DNMs for evaluation of their association with these diseases. Our results revealed a higher prevalence of DNMs in the probands of all four disorders compared with the one in the controls (P<1.3 × 10(-7)). The elevated DNM frequency is dominated by loss-of-function/deleterious single-nucleotide variants and frameshift indels (that is, extreme mutations, P<4.5 × 10(-5)). With extensive annotation of these 'extreme' mutations, we prioritized 764 candidate genes in these four disorders. A combined analysis of Gene Ontology, microRNA targets and transcription factor targets revealed shared biological process and non-coding regulatory elements of candidate genes in the pathology of neuropsychiatric disorders. In addition, weighted gene co-expression network analysis of human laminar-specific neocortical expression data showed that candidate genes are convergent on eight shared modules with specific layer enrichment and biological process features. Furthermore, we identified that 53 candidate genes are associated with more than one disorder (P<0.000001), suggesting a possibly shared genetic etiology underlying these disorders. Particularly, DNMs of the SCN2A gene are frequently occurred across all four disorders. Finally, we constructed a freely available NPdenovo database, which provides a comprehensive catalog of the DNMs identified in neuropsychiatric disorders.Molecular Psychiatry advance online publication, 7 April 2015; doi:10.1038/mp.2015.40.

PMID: 25849321 [PubMed - as supplied by publisher]

Brain derived neurotrophic factor (BDNF) and autism spectrum disorders (ASD) in childhood.

April 8, 2015 - 11:47am

Brain derived neurotrophic factor (BDNF) and autism spectrum disorders (ASD) in childhood.

Eur J Paediatr Neurol. 2015 Mar 18;

Authors: Bryn V, Halvorsen B, Ueland T, Isaksen J, Kolkova K, Ravn K, Skjeldal OH

Abstract
BACKGROUND: Neurotrophic factors are essential regulators of neuronal maturation including synaptic synthesis. Among those, Brain derived neurotrophic factor (BDNF) has been in particular focus in the understanding of autism spectrum disorders (ASD).
PURPOSE: The aim of our study was to investigate whether BNDF could be used as diagnostic/biological marker for ASD. For this purpose we examined the plasma levels of BDNF and the precursors pro- BDNF in patients with ASD and compared it with non-autistic controls; determined whether there was a correlation between the BDNF and proBDNF levels and clinical severity. We also investigated the coding region of BDNF identify for well-variations which could be associated to ASD.
METHODS: The 65 ASD patients (51 boys) were enrolled from a recent completed epidemiological survey covering two counties (Oppland and Hedmark) in Norway. The mean age of the total number of children who participated in this study was 11,7 years. 30 non-autistic children were included as controls, 14 boys and 16 girls. The mean age was 11.3 years. Exclusion criteria for control group were individuals suffering from either neurological, endocrine, or immune insuffiency.
RESULTS AND CONCLUSIONS: Patients with ASD were characterized by moderately but significantly elevated plasma levels of BDNF compared to matched controls. No differences were observed in the proBDNF level between patients and controls. Within the ASD group, children with intellectual disability demonstrated increased BDNF, but not proBDNF levels, while the presence of ADHD had no impact on circulating proBDNF or BDNF. No further associations between plasma proBDNF or BDNF and other clinical demographics were observed.

PMID: 25847750 [PubMed - as supplied by publisher]

Characterization of a 520 kb deletion on chromosome 15q26.1 including ST8SIA2 in a patient with behavioral disturbance, autism spectrum disorder, and epilepsy: Additional information.

April 8, 2015 - 11:47am

Characterization of a 520 kb deletion on chromosome 15q26.1 including ST8SIA2 in a patient with behavioral disturbance, autism spectrum disorder, and epilepsy: Additional information.

Am J Med Genet A. 2015 Apr 2;

Authors: Kamien B, Harraway J, Lundie B, Smallhorne L, Gibbs V, Heath A, Fullerton JM

PMID: 25846131 [PubMed - as supplied by publisher]

The over-pruning hypothesis of autism.

April 8, 2015 - 11:47am

The over-pruning hypothesis of autism.

Dev Sci. 2015 Apr 6;

Authors: Thomas MS, Davis R, Karmiloff-Smith A, Knowland VC, Charman T

Abstract
This article outlines the over-pruning hypothesis of autism. The hypothesis originates in a neurocomputational model of the regressive sub-type (Thomas, Knowland & Karmiloff-Smith, 2011a, 2011b). Here we develop a more general version of the over-pruning hypothesis to address heterogeneity in the timing of manifestation of ASD, including new computer simulations which reconcile the different observed developmental trajectories (early onset, late onset, regression) via a single underlying atypical mechanism; and which show how unaffected siblings of individuals with ASD may differ from controls either by inheriting a milder version of the pathological mechanism or by co-inheriting the risk factors without the pathological mechanism. The proposed atypical mechanism involves overly aggressive synaptic pruning in infancy and early childhood, an exaggeration of a normal phase of brain development. We show how the hypothesis generates novel predictions that differ from existing theories of ASD including that (1) the first few months of development in ASD will be indistinguishable from typical, and (2) the earliest atypicalities in ASD will be sensory and motor rather than social. Both predictions gain cautious support from emerging longitudinal studies of infants at-risk of ASD. We review evidence consistent with the over-pruning hypothesis, its relation to other current theories (including C. Frith's under-pruning proposal; C. Frith, 2003, 2004), as well as inconsistent data and current limitations. The hypothesis situates causal accounts of ASD within a framework of protective and risk factors (Newschaffer et al., 2012); clarifies different versions of the broader autism phenotype (i.e. the implication of observed similarities between individuals with autism and their family members); and integrates data from multiple disciplines, including behavioural studies, neuroscience studies, genetics, and intervention studies.

PMID: 25845529 [PubMed - as supplied by publisher]

Dysregulated brain immunity and neurotrophin signaling in Rett syndrome and autism spectrum disorders.

April 8, 2015 - 11:47am
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Dysregulated brain immunity and neurotrophin signaling in Rett syndrome and autism spectrum disorders.

J Neuroimmunol. 2015 Feb 15;279:33-8

Authors: Theoharides TC, Athanassiou M, Panagiotidou S, Doyle R

Abstract
Rett syndrome is a neurodevelopmental disorder, which occurs in about 1:15,000 females and presents with neurologic and communication defects. It is transmitted as an X-linked dominant linked to mutations of the methyl-CpG-binding protein (MeCP2), a gene transcription suppressor, but its definitive pathogenesis is unknown thus hindering development of effective treatments. Almost half of children with Rett syndrome also have behavioral symptoms consistent with those of autism spectrum disorders (ASDs). PubMed was searched (2005-2014) using the terms: allergy, atopy, brain, brain-derived neurotrophic factor (BDNF), corticotropin-releasing hormone (CRH), cytokines, gene mutations, inflammation, mast cells (MCs), microglia, mitochondria, neurotensin (NT), neurotrophins, seizures, stress, and treatment. There are a number of intriguing differences and similarities between Rett syndrome and ASDs. Rett syndrome occurs in females, while ASDs more often in males, and the former has neurologic disabilities unlike ASDs. There is evidence of dysregulated immune system early in life in both conditions. Lack of microglial phagocytosis and decreased levels of BDNF appear to distinguish Rett syndrome from ASDs, in which there is instead microglia activation and/or proliferation and possibly defective BDNF signaling. Moreover, brain mast cell (MC) activation and focal inflammation may be more prominent in ASDs than Rett syndrome. The flavonoid luteolin blocks microglia and MC activation, provides BDNF-like activity, reverses Rett phenotype in mouse models, and has a significant benefit in children with ASDs. Appropriate formulations of luteolin or other natural molecules may be useful in the treatment of Rett syndrome.

PMID: 25669997 [PubMed - indexed for MEDLINE]

ADHD severity is associated with white matter microstructure in the subgenual cingulum.

April 7, 2015 - 8:04am

ADHD severity is associated with white matter microstructure in the subgenual cingulum.

Neuroimage Clin. 2015;7:653-60

Authors: Cooper M, Thapar A, Jones DK

Abstract
AIMS: This analysis examined hypothesised associations between microstructural attributes in specific white matter (WM) tracts selected a priori and measures of clinical variability in adolescents with a diagnosis of attention deficit hyperactivity disorder (ADHD). Firstly, associations were explored between WM microstructure and ADHD severity in the subgenual cingulum. Secondly, to ensure that tract-specific approaches afforded enhanced rather than differential sensitivity, associations were measured between WM microstructure and autistic traits in the right corticospinal tract based on results of a previously-published voxelwise analysis.
METHODS: 40 right-handed males aged 14-18 years (19 with DSM-IV combined type ADHD and 21 healthy controls) underwent a 60 direction diffusion MRI scan. Clinical ADHD and autism variation were assessed by validated questionnaires. Deterministic tractography based on spherical deconvolution methods was used to map the subgenual cingulum and corticospinal tract.
RESULTS: Fractional anisotropy was positively correlated and radial diffusivity was negatively correlated with a) ADHD severity in the left subgenual cingulum and b) autistic traits in the inferior segment of the right corticospinal tract. No case-control differences were found.
CONCLUSIONS: Results shed light on possible anatomical correlates of ADHD severity and autistic symptoms in pathways which may be involved in the ADHD phenotype. They provide further evidence that tract-specific approaches may a) reveal associations between microstructural metrics and indices of phenotypic variability which would not be detected using voxelwise approaches, and b) provide improved rather than differential sensitivity compared to voxelwise approaches.

PMID: 25844319 [PubMed - in process]

Complex nature of apparently balanced chromosomal rearrangements in patients with autism spectrum disorder.

April 7, 2015 - 8:04am

Complex nature of apparently balanced chromosomal rearrangements in patients with autism spectrum disorder.

Mol Autism. 2015;6:19

Authors: Tabet AC, Verloes A, Pilorge M, Delaby E, Delorme R, Nygren G, Devillard F, Gérard M, Passemard S, Héron D, Siffroi JP, Jacquette A, Delahaye A, Perrin L, Dupont C, Aboura A, Bitoun P, Coleman M, Leboyer M, Gillberg C, Benzacken B, Betancur C

Abstract
BACKGROUND: Apparently balanced chromosomal rearrangements can be associated with an abnormal phenotype, including intellectual disability and autism spectrum disorder (ASD). Genome-wide microarrays reveal cryptic genomic imbalances, related or not to the breakpoints, in 25% to 50% of patients with an abnormal phenotype carrying a microscopically balanced chromosomal rearrangement. Here we performed microarray analysis of 18 patients with ASD carrying balanced chromosomal abnormalities to identify submicroscopic imbalances implicated in abnormal neurodevelopment.
METHODS: Eighteen patients with ASD carrying apparently balanced chromosomal abnormalities were screened using single nucleotide polymorphism (SNP) arrays. Nine rearrangements were de novo, seven inherited, and two of unknown inheritance. Genomic imbalances were confirmed by fluorescence in situ hybridization and quantitative PCR.
RESULTS: We detected clinically significant de novo copy number variants in four patients (22%), including three with de novo rearrangements and one with an inherited abnormality. The sizes ranged from 3.3 to 4.9 Mb; three were related to the breakpoint regions and one occurred elsewhere. We report a patient with a duplication of the Wolf-Hirschhorn syndrome critical region, contributing to the delineation of this rare genomic disorder. The patient has a chromosome 4p inverted duplication deletion, with a 0.5 Mb deletion of terminal 4p and a 4.2 Mb duplication of 4p16.2p16.3. The other cases included an apparently balanced de novo translocation t(5;18)(q12;p11.2) with a 4.2 Mb deletion at the 18p breakpoint, a subject with de novo pericentric inversion inv(11)(p14q23.2) in whom the array revealed a de novo 4.9 Mb deletion in 7q21.3q22.1, and a patient with a maternal inv(2)(q14.2q37.3) with a de novo 3.3 Mb terminal 2q deletion and a 4.2 Mb duplication at the proximal breakpoint. In addition, we identified a rare de novo deletion of unknown significance on a chromosome unrelated to the initial rearrangement, disrupting a single gene, RFX3.
CONCLUSIONS: These findings underscore the utility of SNP arrays for investigating apparently balanced chromosomal abnormalities in subjects with ASD or related neurodevelopmental disorders in both clinical and research settings.

PMID: 25844147 [PubMed]

DSM-5 and Psychiatric Genetics - Round Hole, Meet Square Peg.

April 7, 2015 - 8:04am

DSM-5 and Psychiatric Genetics - Round Hole, Meet Square Peg.

Biol Psychiatry. 2015 May 1;77(9):766-8

Authors: Buxbaum JD

PMID: 25843333 [PubMed - in process]

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