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High resolution magnetic resonance imaging for characterization of the neuroligin-3 knock-in mouse model associated with autism spectrum disorder.

December 29, 2015 - 7:41am
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High resolution magnetic resonance imaging for characterization of the neuroligin-3 knock-in mouse model associated with autism spectrum disorder.

PLoS One. 2014;9(10):e109872

Authors: Kumar M, Duda JT, Hwang WT, Kenworthy C, Ittyerah R, Pickup S, Brodkin ES, Gee JC, Abel T, Poptani H

Abstract
Autism spectrum disorders (ASD) comprise an etiologically heterogeneous set of neurodevelopmental disorders. Neuroligin-3 (NL-3) is a cell adhesion protein that mediates synapse development and has been implicated in ASD. We performed ex-vivo high resolution magnetic resonance imaging (MRI), including diffusion tensor imaging (DTI) and behavioral (social approach and zero maze) tests at 3 different time points (30, 50 and 70 days-of-age) on NL-3 and wild-type littermates to assess developmental brain abnormalities in NL-3 mice. MRI data were segmented in 39 different gray and white matter regions. Volumetric measurements, along with DTI indices from these segmented regions were also performed. After controlling for age and gender, the NL-3 knock-in animals demonstrated significantly reduced sociability and lower anxiety-related behavior in comparison to their wild type littermates. Significantly reduced volume of several white and gray matter regions in the NL-3 knock-in mice were also observed after considering age, gender and time point as covariates. These findings suggest that structural changes in the brain of NL-3 mice are induced by the mutation in the NL-3 gene. No significant differences in DTI indices were observed, which suggests that the NL-3 mutation may not have a profound effect on water diffusion as detected by DTI. The volumetric and DTI studies aid in understanding the biology of disrupting function on an ASD risk model and may assist in the development of imaging biomarkers for ASD.

PMID: 25299583 [PubMed - indexed for MEDLINE]

Genotype/Phenotype Correlations in Tuberous Sclerosis Complex.

December 27, 2015 - 7:38am

Genotype/Phenotype Correlations in Tuberous Sclerosis Complex.

Semin Pediatr Neurol. 2015 Dec;22(4):259-73

Authors: Curatolo P, Moavero R, Roberto D, Graziola F

Abstract
Tuberous sclerosis complex (TSC) is an autosomal dominant disorder characterized by the development of widespread hamartomatous lesions in various organs, including brain, skin, kidneys, heart, and eyes. Central nervous system is almost invariably involved, with up to 85% of patients presenting with epilepsy, and at least half of patients having intellectual disability or other neuropsychiatric disorders including autism spectrum disorder. TSC is caused by the mutation in one of the 2 genes TSC1, at 9q34, and TSC2, at 16p13.3. They respectively encode for hamartin and tuberin, which form an intracellular complex inhibiting the mammalian target of rapamycin. Mammalian target of rapamycin overactivation following the genetic defect determines the cell growth and proliferation responsible for TSC-related lesions, as well as the alterations in neuronal excitability and synaptogenesis leading to epilepsy and neuropsychiatric disorders. A causative mutation for the disorder is identified in about 85% of patients with a clinical diagnosis of TSC. Mosaicism and technology limits likely explain most of the no mutation identified cases. This review confirms that patients with TSC2 mutations considered as a group usually present a more severe phenotype, characterized by higher number of tubers, earlier age at seizure onset and higher prevalence of intellectual disability. However, the clinical phenotype of the disease presents a high variability, thus making the prediction of the phenotype on an individual basis still challenging. The increasing application of new molecular techniques to subjects with TSC has the potential to significantly reduce the rate of patients with no mutation demonstrated and to identify an increasing higher number of mutations. This would hopefully allow a better characterization of higher risk mutations, which might help clinicians to plan individualized surveillance plans. Furthermore, the increasing availability of disease registries to collect clinical and genetics data of patients help to define more valid and clinically oriented genotype or phenotype correlations.

PMID: 26706013 [PubMed - in process]

Mouse Social Interaction Test (MoST): a quantitative computer automated analysis of behavior.

December 26, 2015 - 7:37am

Mouse Social Interaction Test (MoST): a quantitative computer automated analysis of behavior.

J Neural Transm (Vienna). 2015 Dec 24;

Authors: Thanos PK, Restif C, O'Rourke JR, Lam CY, Metaxas D

Abstract
Rodents are the most commonly used preclinical model of human disease assessing the mechanism(s) involved as well as the role of genetics, epigenetics, and pharmacotherapy on this disease as well as identifying vulnerability factors and risk assessment for disease critical in the development of improved treatment strategies. Unfortunately, the majority of rodent preclinical studies utilize single housed approaches where animals are either entirely housed and tested in solitary environments or group housed but tested in solitary environments. This approach, however, ignores the important contribution of social interaction and social behavior. Social interaction in rodents is found to be a major criterion for the ethological validity of rodent species-specific behavioral characteristics (Zurn et al. 2007; Analysis 2011). It is also well established that there is significant and growing number of reports, which illustrates the important role of social environment and social interaction in all diseases, with particularly significance in all neuropsychiatric diseases. Thus, it is imperative that research studies be able to add large-scale evaluations of social interaction and behavior in mice and benefit from automated tracking of behaviors and measurements by removing user bias and by quantifying aspects of behaviors that cannot be assessed by a human observer. Single mouse setups have been used routinely, but cannot be easily extended to multiple-animal studies where social behavior is key, e.g., autism, depression, anxiety, substance and non-substance addictive disorders, aggression, sexual behavior, or parenting. While recent efforts are focusing on multiple-animal tracking alone, a significant limitation remains the lack of insightful measures of social interactions. We present a novel, non-invasive single camera-based automated tracking method described as Mouse Social Test (MoST) and set of measures designed for estimating the interactions of multiple mice at the same time in the same environment interacting freely. Our results show measurement of social interactions and designed to be adaptable and applicable to most existing home cage systems used in research, and provide a greater level of detailed analysis of social behavior than previously possible. The present study describes social behaviors assessed in a home cage environment setup containing six mice that interact freely over long periods of time, and we illustrate how these measures can be interpreted and combined to classify rodent social behaviors. In addition, we illustrate how these measures can be interpreted and combined to classify and analyze comprehensively rodent behaviors involved in several neuropsychiatric diseases as well as provide opportunity for the basic research of rodent behavior previously not possible.

PMID: 26704381 [PubMed - as supplied by publisher]

Gastrointestinal problems in 15q duplication syndrome.

December 25, 2015 - 7:35am
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Gastrointestinal problems in 15q duplication syndrome.

Eur J Med Genet. 2015 Mar;58(3):191-3

Authors: Shaaya EA, Pollack SF, Boronat S, Davis-Cooper S, Zella GC, Thibert RL

Abstract
Chromosome 15q duplication syndrome (Dup15q syndrome) is a neurodevelopmental disorder involving copy number gains of the maternal chromosome 15q11.2-q13 region, characterized by intellectual disability, developmental delay, autism spectrum disorder (ASD), and epilepsy. Gastrointestinal (GI) problems in Dup15q syndrome have been reported only rarely, mostly focused on neonatal feeding difficulties. A retrospective review of the medical records of 46 patients with Dup15q syndrome was conducted to assess GI issues and their treatments in this population. GI symptoms were present in 76.7% of subjects with an isodicentric duplication and 87.5% with an interstitial duplication. There was no clear association between GI issues and ASD, with symptoms occurring in 78.9% of all subjects and 78.2% of ASD subjects. The most commonly reported symptoms were gastroesophageal reflux (56.7%) and constipation (60%), with 30% of subjects reporting both. The most common treatments were polyethylene glycol for constipation and proton pump inhibitors for reflux. Behaviors such as irritability and aggressiveness improved with treatment of GI symptoms in several subjects. The results indicate that GI symptoms are common in Dup15q syndrome and may have an atypical presentation. Diagnosis may be difficult, especially in individuals who are nonverbal or minimally verbal, so increased awareness is critical for early diagnosis and treatment.

PMID: 25573720 [PubMed - indexed for MEDLINE]

Chromodomain helicase DNA-binding proteins in stem cells and human developmental diseases.

December 25, 2015 - 7:35am
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Chromodomain helicase DNA-binding proteins in stem cells and human developmental diseases.

Stem Cells Dev. 2015 Apr 15;24(8):917-26

Authors: Micucci JA, Sperry ED, Martin DM

Abstract
Dynamic regulation of gene expression is vital for proper cellular development and maintenance of differentiated states. Over the past 20 years, chromatin remodeling and epigenetic modifications of histones have emerged as key controllers of rapid reversible changes in gene expression. Mutations in genes encoding enzymes that modify chromatin have also been identified in a variety of human neurodevelopmental disorders, ranging from isolated intellectual disability and autism spectrum disorder to multiple congenital anomaly conditions that affect major organ systems and cause severe morbidity and mortality. In this study, we review recent evidence that chromodomain helicase DNA-binding (CHD) proteins regulate stem cell proliferation, fate, and differentiation in a wide variety of tissues and organs. We also highlight known roles of CHD proteins in human developmental diseases and present current unanswered questions about the pleiotropic effects of CHD protein complexes, their genetic targets, nucleosome sliding functions, and enzymatic effects in cells and tissues.

PMID: 25567374 [PubMed - indexed for MEDLINE]

Novel interactive partners of neuroligin 3: new aspects for pathogenesis of autism.

December 25, 2015 - 7:35am
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Novel interactive partners of neuroligin 3: new aspects for pathogenesis of autism.

J Mol Neurosci. 2015 May;56(1):89-101

Authors: Shen C, Huo LR, Zhao XL, Wang PR, Zhong N

Abstract
Autism is a neurodevelopmental disorder with a strong genetic predisposition. Neurolign 3 (NLGN3) as a postsynaptic transmembrane protein, functions in both neuron synaptogenesis and glia-neuron communications. Previously, a gain of function mutation (R451C) in NLGN3 was identified in autistic patients, which illustrates the involvement of NLGN3 in autism pathogenesis. As proper synaptic targeting and functioning are controlled by intracellular protein interactions, in the current study, we tried to discover the intracellular regulation network in which NLGN3 might be involved by a yeast two-hybrid-based interactor identification. Fifty-one protein candidate partners were identified after screening a human fetal complementary DNA (cDNA) library with an intracellular fragment of NLGN3. The interactions of NLGN3 with a subset of candidates, including EEF1A1, FLNA, ITPRIP, CYP11A1, MT-CO2, GPR175, ACOT2, and QPRT, were further validated in human neuroblastoma cells or brain tissues. Furthermore, our study suggested that NLGN3 was functioning in cytosolic calcium balance and participating in calcium-regulated cellular processes. Our findings of novel NLGN3 binding partners provide evidences of involvement of NLGN3 in multiple biological pathways, especially calcium regulating and mitochondrial function, thus suggesting further significance. This new data not only leads to a better understanding of the physiological functions of NLGN3, but also provide new aspects for pathogenesis of autism.

PMID: 25464930 [PubMed - indexed for MEDLINE]

Gene expression analysis in Fmr1KO mice identifies an immunological signature in brain tissue and mGluR5-related signaling in primary neuronal cultures.

December 24, 2015 - 7:34am

Gene expression analysis in Fmr1KO mice identifies an immunological signature in brain tissue and mGluR5-related signaling in primary neuronal cultures.

Mol Autism. 2015;6:66

Authors: Prilutsky D, Kho AT, Palmer NP, Bhakar AL, Smedemark-Margulies N, Kong SW, Margulies DM, Bear MF, Kohane IS

Abstract
BACKGROUND: Fragile X syndrome (FXS) is a neurodevelopmental disorder whose biochemical manifestations involve dysregulation of mGluR5-dependent pathways, which are widely modeled using cultured neurons. In vitro phenotypes in cultured neurons using standard morphological, functional, and chemical approaches have demonstrated considerable variability. Here, we study transcriptomes obtained in situ in the intact brain tissues of a murine model of FXS to see how they reflect the in vitro state.
METHODS: We used genome-wide mRNA expression profiling as a robust characterization tool for studying differentially expressed pathways in fragile X mental retardation 1 (Fmr1) knockout (KO) and wild-type (WT) murine primary neuronal cultures and in embryonic hippocampal and cortical murine tissue. To study the developmental trajectory and to relate mouse model data to human data, we used an expression map of human development to plot murine differentially expressed genes in KO/WT cultures and brain.
RESULTS: We found that transcriptomes from cell cultures showed a stronger signature of Fmr1KO than whole tissue transcriptomes. We observed an over-representation of immunological signaling pathways in embryonic Fmr1KO cortical and hippocampal tissues and over-represented mGluR5-downstream signaling pathways in Fmr1KO cortical and hippocampal primary cultures. Genes whose expression was up-regulated in Fmr1KO murine cultures tended to peak early in human development, whereas differentially expressed genes in embryonic cortical and hippocampal tissues clustered with genes expressed later in human development.
CONCLUSIONS: The transcriptional profile in brain tissues primarily centered on immunological mechanisms, whereas the profiles from cell cultures showed defects in neuronal activity. We speculate that the isolation and culturing of neurons caused a shift in neurological transcriptome towards a "juvenile" or "de-differentiated" state. Moreover, cultured neurons lack the close coupling with glia that might be responsible for the immunological phenotype in the intact brain. Our results suggest that cultured cells may recapitulate an early phase of the disease, which is also less obscured with a consequent "immunological" phenotype and in vivo compensatory mechanisms observed in the embryonic brain. Together, these results suggest that the transcriptome of cultured primary neuronal cells, in comparison to whole brain tissue, more robustly demonstrated the difference between Fmr1KO and WT mice and might reveal a molecular phenotype, which is typically hidden by compensatory mechanisms present in vivo. Moreover, cultures might be useful for investigating the perturbed pathways in early human brain development and genes previously implicated in autism.

PMID: 26697163 [PubMed]

Decreased aggression and increased repetitive behavior in Pten haploinsufficient mice.

December 24, 2015 - 7:34am
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Decreased aggression and increased repetitive behavior in Pten haploinsufficient mice.

Genes Brain Behav. 2015 Feb;14(2):145-57

Authors: Clipperton-Allen AE, Page DT

Abstract
Aggression is an aspect of social behavior that can be elevated in some individuals with autism spectrum disorder (ASD) and a concern for peers and caregivers. Mutations in Phosphatase and tensin homolog (PTEN), one of several ASD risk factors encoding negative regulators of the PI3K-Akt-mTOR pathway, have been reported in individuals with ASD and comorbid macrocephaly. We previously showed that a mouse model of Pten germline haploinsufficiency (Pten(+/-) ) has selective deficits, primarily in social behavior, along with broad overgrowth of the brain. Here, we further examine the social behavior of Pten(+/-) male mice in the resident-intruder test of aggression, using a comprehensive behavioral analysis to obtain an overall picture of the agonistic, non-agonistic and non-social behavior patterns of Pten(+/-) mice during a free interaction with a novel conspecific. Pten(+/-) male mice were involved in less aggression than their wild-type littermates. Pten(+/-) mice also performed less social investigation, including anogenital investigation and approaching and/or attending to the intruder, which is consistent with our previous finding of decreased sociability in the social approach test. In contrast to these decreases in social behaviors, Pten(+/-) mice showed increased digging. In summary, we report decreased aggression and increased repetitive behavior in Pten(+/-) mice, thus extending our characterization of this model of an ASD risk factor that features brain overgrowth and social deficits.

PMID: 25561290 [PubMed - indexed for MEDLINE]

Behavioral phenotypes in males with XYY and possible role of increased NLGN4Y expression in autism features.

December 24, 2015 - 7:34am
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Behavioral phenotypes in males with XYY and possible role of increased NLGN4Y expression in autism features.

Genes Brain Behav. 2015 Feb;14(2):137-44

Authors: Ross JL, Tartaglia N, Merry DE, Dalva M, Zinn AR

Abstract
The male sex chromosome disorder, 47,XYY syndrome (XYY), is associated with increased risk for social-emotional difficulties, attention-deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD). We hypothesize that increased Y chromosome gene copy number in XYY leads to overexpression of Y-linked genes related to brain development and function, thereby increasing risk for these phenotypes. We measured expression in blood of two Y genes NLGN4Y and RPS4Y in 26 boys with XYY and 11 male controls and evaluated whether NLGN4Y expression correlates with anxiety, ADHD, depression and autistic behaviors (from questionnaires) in boys with XYY. The XYY cohort had increased risk of ASD behaviors on the social responsiveness scale (SRS) and increased attention deficits on the Conners' DSM-IV inattention and hyperactive scales. In contrast, there was no increase in reported symptoms of anxiety or depression by the XYY group. Peripheral expression of two Y genes in boys with XYY vs. typically developing controls was increased twofold in the XYY group. Results from the SRS total and autistic mannerisms scales, but not from the attention, anxiety or depression measures, correlated with peripheral expression of NLGN4Y in boys with XYY. Males with XYY have social phenotypes that include increased risk for autism-related behaviors and ADHD. Expression of NLGN4Y, a gene that may be involved in synaptic function, is increased in boys with XYY, and the level of expression correlates with overall social responsiveness and autism symptoms. Thus, further investigation of NLGN4Y as a plausible ASD risk gene in XYY is warranted.

PMID: 25558953 [PubMed - indexed for MEDLINE]

Distinctive findings in a boy with Simpson-Golabi-Behmel syndrome.

December 23, 2015 - 7:32am

Distinctive findings in a boy with Simpson-Golabi-Behmel syndrome.

Am J Med Genet A. 2015 Dec 22;

Authors: Halayem S, Hamza M, Maazoul F, Ben Turkia H, Touati M, Tebib N, Mrad R, Bouden A

Abstract
Simpson-Golabi-Behmel syndrome (SGBS) is an X-linked condition characterized by pre and post natal overgrowth, facial malformations, and visceral, skeletal, and neurological anomalies. The physical characteristics of SGBS have been well documented; however there is a lack of description regarding the behavioral phenotype. We report the case of a 6-year-old boy, with confirmed deletion of 6-8 exons of the glypican-3 gene (GPC3) who presents three distinctive findings: the persistence of the craniopharyngeal canal, an immune-allergic specificity, and a scarcely behavioral phenotype consisting in the association of Austim Spectrum Disorder with accompanying mild intellectual disability and language impairments. He also fulfilled the criteria of Attention Deficit Hyperactivity Disorder and Oppositional Defiant Disorder according to DSM 5 criteria. The specificities of the case are discussed in the light of recent pathophysiological data. © 2015 Wiley Periodicals, Inc.

PMID: 26692054 [PubMed - as supplied by publisher]

Influence of candidate polymorphisms on the dipeptidyl peptidase IV and μ-opioid receptor genes expression in aspect of the β-casomorphin-7 modulation functions in autism.

December 23, 2015 - 7:32am
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Influence of candidate polymorphisms on the dipeptidyl peptidase IV and μ-opioid receptor genes expression in aspect of the β-casomorphin-7 modulation functions in autism.

Peptides. 2015 Mar;65:6-11

Authors: Cieślińska A, Sienkiewicz-Szłapka E, Wasilewska J, Fiedorowicz E, Chwała B, Moszyńska-Dumara M, Cieśliński T, Bukało M, Kostyra E

Abstract
Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder with population prevalence of approximately 60-70 per 10,000. Data shows that both opioid system function enhancement and opiate administration can result in autistic-like symptoms. Cow milk opioid peptides, including β-casomorphin-7 (BCM7, Tyr-Pro-Phe-Pro-Gly-Pro-Ile), affect the μ-opioid receptor (MOR) and are subjected to degradation resulting from the proline dipeptidyl peptidase IV (DPPIV, EC 3.4.14.5) enzyme activity. The presence of MOR and DPPIV activity are crucial factors determining biological activity of BCM7 in the human body. Our study examined the effect of β-casomorphin-7 on the MOR and DPPIV genes expression according to specific point mutations in these genes. In addition, we investigated frequency of A118G SNP in the MOR gene and rs7608798 of the DPPIV (A/G) gene in healthy and autistic children. Our research indicated correlation in DPPIV gene expression under the influence of BCM7 and hydrolyzed milk between healthy and ASD-affected children with genotype GG (P<0.0001). We also observed increased MOR gene expression in healthy children with genotype AG at polymorphic site A118G under influence of BCM7 and hydrolyzed milk. The G allele frequency was 0.09 in MOR gene and 0.68 in the DPPIV gene. But our results suggest no association between presence of the alleles G and A at position rs7608798 in DPPIV gene nor alleles A and G at position A118G of the MOR and increased incidence of ASD. Our studies emphasize the compulsion for genetic analysis in correlation with genetic factors affecting development and enhancement of autism symptoms.

PMID: 25625371 [PubMed - indexed for MEDLINE]

Cytoplasmic Rbfox1 Regulates the Expression of Synaptic and Autism-Related Genes.

December 22, 2015 - 7:31am

Cytoplasmic Rbfox1 Regulates the Expression of Synaptic and Autism-Related Genes.

Neuron. 2015 Dec 10;

Authors: Lee JA, Damianov A, Lin CH, Fontes M, Parikshak NN, Anderson ES, Geschwind DH, Black DL, Martin KC

Abstract
Human genetic studies have identified the neuronal RNA binding protein, Rbfox1, as a candidate gene for autism spectrum disorders. While Rbfox1 functions as a splicing regulator in the nucleus, it is also alternatively spliced to produce cytoplasmic isoforms. To investigate the function of cytoplasmic Rbfox1, we knocked down Rbfox proteins in mouse neurons and rescued with cytoplasmic or nuclear Rbfox1. Transcriptome profiling showed that nuclear Rbfox1 rescued splicing changes, whereas cytoplasmic Rbfox1 rescued changes in mRNA levels. iCLIP-seq of subcellular fractions revealed that Rbfox1 bound predominantly to introns in nascent RNA, while cytoplasmic Rbox1 bound to 3' UTRs. Cytoplasmic Rbfox1 binding increased target mRNA stability and translation, and Rbfox1 and miRNA binding sites overlapped significantly. Cytoplasmic Rbfox1 target mRNAs were enriched in genes involved in cortical development and autism. Our results uncover a new Rbfox1 regulatory network and highlight the importance of cytoplasmic RNA metabolism to cortical development and disease.

PMID: 26687839 [PubMed - as supplied by publisher]

Anaplerotic triheptanoin diet enhances mitochondrial substrate use to remodel the metabolome and improve lifespan, motor function, and sociability in MeCP2-null mice.

December 22, 2015 - 7:31am
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Anaplerotic triheptanoin diet enhances mitochondrial substrate use to remodel the metabolome and improve lifespan, motor function, and sociability in MeCP2-null mice.

PLoS One. 2014;9(10):e109527

Authors: Park MJ, Aja S, Li Q, Degano AL, Penati J, Zhuo J, Roe CR, Ronnett GV

Abstract
Rett syndrome (RTT) is an autism spectrum disorder (ASD) caused by mutations in the X-linked MECP2 gene that encodes methyl-CpG binding protein 2 (MeCP2). Symptoms range in severity and include psychomotor disabilities, seizures, ataxia, and intellectual disability. Symptom onset is between 6-18 months of age, a critical period of brain development that is highly energy-dependent. Notably, patients with RTT have evidence of mitochondrial dysfunction, as well as abnormal levels of the adipokines leptin and adiponectin, suggesting overall metabolic imbalance. We hypothesized that one contributor to RTT symptoms is energy deficiency due to defective nutrient substrate utilization by the TCA cycle. This energy deficit would lead to a metabolic imbalance, but would be treatable by providing anaplerotic substrates to the TCA cycle to enhance energy production. We show that dietary therapy with triheptanoin significantly increased longevity and improved motor function and social interaction in male mice hemizygous for Mecp2 knockout. Anaplerotic therapy in Mecp2 knockout mice also improved indicators of impaired substrate utilization, decreased adiposity, increased glucose tolerance and insulin sensitivity, decreased serum leptin and insulin, and improved mitochondrial morphology in skeletal muscle. Untargeted metabolomics of liver and skeletal muscle revealed increases in levels of TCA cycle intermediates with triheptanoin diet, as well as normalizations of glucose and fatty acid biochemical pathways consistent with the improved metabolic phenotype in Mecp2 knockout mice on triheptanoin. These results suggest that an approach using dietary supplementation with anaplerotic substrate is effective in improving symptoms and metabolic health in RTT.

PMID: 25299635 [PubMed - indexed for MEDLINE]

Prevalence of Creatine Deficiency Syndromes in Children With Nonsyndromic Autism.

December 20, 2015 - 7:26am

Prevalence of Creatine Deficiency Syndromes in Children With Nonsyndromic Autism.

Pediatrics. 2015 Dec 18;

Authors: Schulze A, Bauman M, Tsai AC, Reynolds A, Roberts W, Anagnostou E, Cameron J, Nozzolillo AA, Chen S, Kyriakopoulou L, Scherer SW, Loh A

Abstract
BACKGROUND AND OBJECTIVE: Creatine deficiency may play a role in the neurobiology of autism and may represent a treatable cause of autism. The goal of the study was to ascertain the prevalence of creatine deficiency syndromes (CDSs) in children with autism spectrum disorder (ASD).
METHODS: In a prospective multicenter study, 443 children were investigated after a confirmed diagnosis of ASD. Random spot urine screening for creatine metabolites (creatine, guanidinoacetate, creatinine, and arginine) with liquid chromatography-tandem mass spectrometry and second-tier testing with high-performance liquid chromatography methodology was followed by recall testing in 24-hour urines and confirmatory testing by Sanger-based DNA sequencing of GAMT, GATM, and SLC6A8 genes. Additional diagnostic tests included plasma creatine metabolites and in vivo brain proton magnetic resonance spectroscopy. The creatine metabolites in spot urine in the autism group were compared with 128 healthy controls controlled for age.
RESULTS: In 443 subjects with ASD investigated for CDS, we had 0 events (event: 0, 95% confidence interval 0-0.0068), therefore with 95% confidence the prevalence of CDS is <7 in 1000 children with ASD. The autism and control groups did not vary in terms of creatine metabolites (P > .0125) in urine.
CONCLUSION: Our study revealed a very low prevalence of CDS in children with nonsyndromic ASD and no obvious association between creatine metabolites and autism. Unlike our study population, we expect more frequent CDS among children with severe developmental delay, speech impairment, seizures, and movement disorders in addition to impairments in social communication, restricted interests, and repetitive behaviors.

PMID: 26684475 [PubMed - as supplied by publisher]

Common mechanisms of excitatory and inhibitory imbalance in schizophrenia and autism spectrum disorders.

December 19, 2015 - 7:25am
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Common mechanisms of excitatory and inhibitory imbalance in schizophrenia and autism spectrum disorders.

Curr Mol Med. 2015;15(2):146-67

Authors: Gao R, Penzes P

Abstract
Autism Spectrum Disorders (ASD) and Schizophrenia (SCZ) are cognitive disorders with complex genetic architectures but overlapping behavioral phenotypes, which suggests common pathway perturbations. Multiple lines of evidence implicate imbalances in excitatory and inhibitory activity (E/I imbalance) as a shared pathophysiological mechanism. Thus, understanding the molecular underpinnings of E/I imbalance may provide essential insight into the etiology of these disorders and may uncover novel targets for future drug discovery. Here, we review key genetic, physiological, neuropathological, functional, and pathway studies that suggest alterations to excitatory/inhibitory circuits are keys to ASD and SCZ pathogenesis.

PMID: 25732149 [PubMed - indexed for MEDLINE]

Analysis of CHRNA7 rare variants in autism spectrum disorder susceptibility.

December 19, 2015 - 7:25am
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Analysis of CHRNA7 rare variants in autism spectrum disorder susceptibility.

Am J Med Genet A. 2015 Apr;167A(4):715-23

Authors: Bacchelli E, Battaglia A, Cameli C, Lomartire S, Tancredi R, Thomson S, Sutcliffe JS, Maestrini E

Abstract
Chromosome 15q13.3 recurrent microdeletions are causally associated with a wide range of phenotypes, including autism spectrum disorder (ASD), seizures, intellectual disability, and other psychiatric conditions. Whether the reciprocal microduplication is pathogenic is less certain. CHRNA7, encoding for the alpha7 subunit of the neuronal nicotinic acetylcholine receptor, is considered the likely culprit gene in mediating neurological phenotypes in 15q13.3 deletion cases. To assess if CHRNA7 rare variants confer risk to ASD, we performed copy number variant analysis and Sanger sequencing of the CHRNA7 coding sequence in a sample of 135 ASD cases. Sequence variation in this gene remains largely unexplored, given the existence of a fusion gene, CHRFAM7A, which includes a nearly identical partial duplication of CHRNA7. Hence, attempts to sequence coding exons must distinguish between CHRNA7 and CHRFAM7A, making next-generation sequencing approaches unreliable for this purpose. A CHRNA7 microduplication was detected in a patient with autism and moderate cognitive impairment; while no rare damaging variants were identified in the coding region, we detected rare variants in the promoter region, previously described to functionally reduce transcription. This study represents the first sequence variant analysis of CHRNA7 in a sample of idiopathic autism.

PMID: 25655306 [PubMed - indexed for MEDLINE]

An inherited small microdeletion at 15q13.3 in a patient with early-onset obsessive-compulsive disorder.

December 19, 2015 - 7:25am
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An inherited small microdeletion at 15q13.3 in a patient with early-onset obsessive-compulsive disorder.

PLoS One. 2014;9(10):e110198

Authors: Cappi C, Hounie AG, Mariani DB, Diniz JB, Silva AR, Reis VN, Busso AF, Silva AG, Fidalgo F, Rogatto SR, Miguel EC, Krepischi AC, Brentani H

Abstract
Copy number variations (CNVs) have been previously associated with several different neurodevelopmental psychiatric disorders, such as autism, schizophrenia, and attention deficit hyperactivity disorder (ADHD). The present study consisted of a pilot genome-wide screen for CNVs in a cohort of 16 patients with early-onset obsessive-compulsive disorder (OCD) and 12 mentally healthy individuals, using array-based comparative genomic hybridization (aCGH) on 44K arrays. A small rare paternal inherited microdeletion (∼64 kb) was identified in chromosome 15q13.3 of one male patient with very early onset OCD. The father did not have OCD. The deletion encompassed part of the FMN1 gene, which is involved with the glutamatergic system. This finding supports the hypothesis of a complex network of several genes expressed in the brain contributing for the genetic risk of OCD, and also supports the glutamatergic involvement in OCD, which has been previously reported in the literature.

PMID: 25303678 [PubMed - indexed for MEDLINE]

De novo TBR1 mutations in sporadic autism disrupt protein functions.

December 19, 2015 - 7:25am
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De novo TBR1 mutations in sporadic autism disrupt protein functions.

Nat Commun. 2014;5:4954

Authors: Deriziotis P, O'Roak BJ, Graham SA, Estruch SB, Dimitropoulou D, Bernier RA, Gerdts J, Shendure J, Eichler EE, Fisher SE

Abstract
Next-generation sequencing recently revealed that recurrent disruptive mutations in a few genes may account for 1% of sporadic autism cases. Coupling these novel genetic data to empirical assays of protein function can illuminate crucial molecular networks. Here we demonstrate the power of the approach, performing the first functional analyses of TBR1 variants identified in sporadic autism. De novo truncating and missense mutations disrupt multiple aspects of TBR1 function, including subcellular localization, interactions with co-regulators and transcriptional repression. Missense mutations inherited from unaffected parents did not disturb function in our assays. We show that TBR1 homodimerizes, that it interacts with FOXP2, a transcription factor implicated in speech/language disorders, and that this interaction is disrupted by pathogenic mutations affecting either protein. These findings support the hypothesis that de novo mutations in sporadic autism have severe functional consequences. Moreover, they uncover neurogenetic mechanisms that bridge different neurodevelopmental disorders involving language deficits.

PMID: 25232744 [PubMed - indexed for MEDLINE]

Massively parallel sequencing of patients with intellectual disability, congenital anomalies and/or autism spectrum disorders with a targeted gene panel.

December 19, 2015 - 7:25am
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Massively parallel sequencing of patients with intellectual disability, congenital anomalies and/or autism spectrum disorders with a targeted gene panel.

PLoS One. 2014;9(4):e93409

Authors: Brett M, McPherson J, Zang ZJ, Lai A, Tan ES, Ng I, Ong LC, Cham B, Tan P, Rozen S, Tan EC

Abstract
Developmental delay and/or intellectual disability (DD/ID) affects 1-3% of all children. At least half of these are thought to have a genetic etiology. Recent studies have shown that massively parallel sequencing (MPS) using a targeted gene panel is particularly suited for diagnostic testing for genetically heterogeneous conditions. We report on our experiences with using massively parallel sequencing of a targeted gene panel of 355 genes for investigating the genetic etiology of eight patients with a wide range of phenotypes including DD/ID, congenital anomalies and/or autism spectrum disorder. Targeted sequence enrichment was performed using the Agilent SureSelect Target Enrichment Kit and sequenced on the Illumina HiSeq2000 using paired-end reads. For all eight patients, 81-84% of the targeted regions achieved read depths of at least 20×, with average read depths overlapping targets ranging from 322× to 798×. Causative variants were successfully identified in two of the eight patients: a nonsense mutation in the ATRX gene and a canonical splice site mutation in the L1CAM gene. In a third patient, a canonical splice site variant in the USP9X gene could likely explain all or some of her clinical phenotypes. These results confirm the value of targeted MPS for investigating DD/ID in children for diagnostic purposes. However, targeted gene MPS was less likely to provide a genetic diagnosis for children whose phenotype includes autism.

PMID: 24690944 [PubMed - indexed for MEDLINE]

DUF1220 copy number is associated with schizophrenia risk and severity: implications for understanding autism and schizophrenia as related diseases.

December 17, 2015 - 7:21am

DUF1220 copy number is associated with schizophrenia risk and severity: implications for understanding autism and schizophrenia as related diseases.

Transl Psychiatry. 2015;5:e697

Authors: Searles Quick VB, Davis JM, Olincy A, Sikela JM

Abstract
The copy number of DUF1220, a protein domain implicated in human brain evolution, has been linearly associated with autism severity. Given the possibility that autism and schizophrenia are related disorders, the present study examined DUF1220 copy number variation in schizophrenia severity. There are notable similarities between autism symptoms and schizophrenia negative symptoms, and divergence between autism symptoms and schizophrenia positive symptoms. We therefore also examined DUF1220 copy number in schizophrenia subgroups defined by negative and positive symptom features, versus autistic individuals and controls. In the schizophrenic population (N=609), decreased DUF1220 copy number was linearly associated with increasing positive symptom severity (CON1 P=0.013, HLS1 P=0.0227), an association greatest in adult-onset schizophrenia (CON1 P=0.00155, HLS1 P=0.00361). In schizophrenic males, DUF1220 CON1 subtype copy number increase was associated with increased negative symptom severity (P=0.0327), a finding similar to that seen in autistic populations. Subgroup analyses demonstrated that schizophrenic individuals with predominantly positive symptoms exhibited reduced CON1 copy number compared with both controls (P=0.0237) and schizophrenic individuals with predominantly negative symptoms (P=0.0068). These findings support the view that (1) autism and schizophrenia exhibit both opposing and partially overlapping phenotypes and may represent a disease continuum, (2) variation in DUF1220 copy number contributes to schizophrenia disease risk and to the severity of both disorders, and (3) schizophrenia and autism may be, in part, a harmful by-product of the rapid and extreme evolutionary increase in DUF1220 copy number in the human species.

PMID: 26670282 [PubMed - as supplied by publisher]

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