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Allelic expression analysis in the brain suggests a role for heterogeneous insults affecting epigenetic processes in autism spectrum disorders.

February 24, 2015 - 7:46am
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Allelic expression analysis in the brain suggests a role for heterogeneous insults affecting epigenetic processes in autism spectrum disorders.

Hum Mol Genet. 2014 Aug 1;23(15):4111-24

Authors: Ben-David E, Shohat S, Shifman S

Abstract
Monoallelic expression, including genomic imprinting, X-chromosome inactivation and random monoallelic expression of autosomal genes are epigenetic phenomena. Genes that are expressed in a monoallelic way may be more vulnerable to genetic or epigenetic mutations. Thus, comprehensive exploration of monoallelic expression in human brains may shed light on complex brain disorders. Autism-related disorders are known to be associated with imprinted genes on chromosome 15. However, it is not clear whether other imprinted regions or other types of monoallelic expression are associated with autism spectrum disorder (ASD). Here, we performed a genome-wide survey of allele expression imbalance (AEI) in the human brain using single-nucleotide polymorphisms (SNPs), in 18 individuals with ASD and 15 controls. Individuals with ASD had the most extreme number of monoallelic expressed SNPs in both the autosomes and the X chromosome. In two cases that were studied in detail, the monoallelic expression was confined to specific brain region or cell type. Using these data, we were also able to define the allelic expression status of known imprinted genes in the human brain and to identify abnormal imprinting in an individual with ASD. Lastly, we developed an analysis of individual-level expression, focusing on the difference of each individual from the mean. We found that individuals with ASD had more genes that were up- or down-regulated in an individual-specific manner. We also identified pathways perturbed in specific individuals. These results underline the heterogeneity in gene regulation in ASD, at the level of both allelic and total expression.

PMID: 24659497 [PubMed - indexed for MEDLINE]

Decreased cerebral spinal fluid neurotransmitter levels in Smith-Lemli-Opitz syndrome.

February 24, 2015 - 7:46am
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Decreased cerebral spinal fluid neurotransmitter levels in Smith-Lemli-Opitz syndrome.

J Inherit Metab Dis. 2014 May;37(3):415-20

Authors: Sparks SE, Wassif CA, Goodwin H, Conley SK, Lanham DC, Kratz LE, Hyland K, Gropman A, Tierney E, Porter FD

Abstract
Smith-Lemli-Opitz syndrome (SLOS) is an autosomal recessive, multiple congenital anomaly syndrome with cognitive impairment and a distinct behavioral phenotype that includes autistic features. SLOS is caused by a defect in 3β-hydroxysterol Δ(7)-reductase which leads to decreased cholesterol levels and elevated cholesterol precursors, specifically 7- and 8-dehydrocholesterol. However, the pathological processes contributing to the neurological abnormalities in SLOS have not been defined. In view of prior data suggesting defects in SLOS in vesicular release and given the association of altered serotonin metabolism with autism, we were interested in measuring neurotransmitter metabolite levels in SLOS to assess their potential to be used as biomarkers in therapeutic trials. We measured cerebral spinal fluid levels of serotonin and dopamine metabolites, 5-hydroxyindoleacetic acid (5HIAA) and homovanillic acid (HVA) respectively, in 21 SLOS subjects. Results were correlated with the SLOS anatomical severity score, Aberrant Behavior Checklist scores and concurrent sterol biochemistry. Cerebral spinal fluid (CSF) levels of both 5HIAA and HVA were significantly reduced in SLOS subjects. In individual patients, the levels of both 5HIAA and HVA were reduced to a similar degree. CSF neurotransmitter metabolite levels did not correlate with either CSF sterols or behavioral measures. This is the first study demonstrating decreased levels of CSF neurotransmitter metabolites in SLOS. We propose that decreased levels of neurotransmitters in SLOS are caused by a sterol-related defect in synaptic vesicle formation and that CSF 5HIAA and HVA will be useful biomarkers in development of future therapeutic trials.

PMID: 24500076 [PubMed - indexed for MEDLINE]

Shared familial transmission of autism spectrum and attention-deficit/hyperactivity disorders.

February 24, 2015 - 7:46am
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Shared familial transmission of autism spectrum and attention-deficit/hyperactivity disorders.

J Child Psychol Psychiatry. 2014 Jul;55(7):819-27

Authors: Musser ED, Hawkey E, Kachan-Liu SS, Lees P, Roullet JB, Goddard K, Steiner RD, Nigg JT

Abstract
BACKGROUND: To determine whether familial transmission is shared between autism spectrum disorders and attention-deficit/hyperactivity disorder, we assessed the prevalence, rates of comorbidity, and familial transmission of both disorders in a large population-based sample of children during a recent 7 year period.
METHODS: Study participants included all children born to parents with the Kaiser Permanente Northwest (KPNW) Health Plan between 1 January 1998 and 31 December 2004 (n = 35,073). Children and mothers with physician-identified autism spectrum disorders (ASD) and/or attention-deficit/hyperactivity disorder (ADHD) were identified via electronic medical records maintained for all KPNW members.
RESULTS: Among children aged 6-12 years, prevalence was 2.0% for ADHD and 0.8% for ASD; within those groups, 0.2% of the full sample (19% of the ASD sample and 9.6% of the ADHD sample) had co-occurring ASD and ADHD, when all children were included. When mothers had a diagnosis of ADHD, first born offspring were at 6-fold risk of ADHD alone (OR = 5.02, p < .0001) and at 2.5-fold risk of ASD alone (OR = 2.52, p < .01). Results were not accounted for by maternal age, child gestational age, child gender, and child race.
CONCLUSIONS: Autism spectrum disorders shares familial transmission with ADHD. ADHD and ASD have a partially overlapping diathesis.

PMID: 24444366 [PubMed - indexed for MEDLINE]

Cortical overgrowth in fetuses with isolated ventriculomegaly.

February 24, 2015 - 7:46am
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Cortical overgrowth in fetuses with isolated ventriculomegaly.

Cereb Cortex. 2014 Aug;24(8):2141-50

Authors: Kyriakopoulou V, Vatansever D, Elkommos S, Dawson S, McGuinness A, Allsop J, Molnár Z, Hajnal J, Rutherford M

Abstract
Mild cerebral ventricular enlargement is associated with schizophrenia, autism, epilepsy, and attention-deficit/hyperactivity disorder. Fetal ventriculomegaly is the most common central nervous system (CNS) abnormality affecting 1% of fetuses and is associated with cognitive, language, and behavioral impairments in childhood. Neurodevelopmental outcome is partially predictable by the 2-dimensional size of the ventricles in the absence of other abnormalities. We hypothesized that isolated fetal ventriculomegaly is a marker of altered brain development characterized by relative overgrowth and aimed to quantify brain growth using volumetric magnetic resonance imaging (MRI) in fetuses with isolated ventriculomegaly. Fetal brain MRI (1.5 T) was performed in 60 normal fetuses and 65 with isolated ventriculomegaly, across a gestational age range of 22-38 weeks. Volumetric analysis of the ventricles and supratentorial brain structures was performed on 3-dimensional reconstructed datasets. Fetuses with isolated ventriculomegaly had increased brain parenchyma volumes when compared with the control cohort (9.6%, P < 0.0001) with enlargement restricted to the cortical gray matter (17.2%, P = 0.002). The extracerebral cerebrospinal fluid and third and fourth ventricles were also enlarged. White matter, basal ganglia, and thalamic volumes were not significantly different between cohorts. The presence of relative cortical overgrowth in fetuses with ventriculomegaly may represent the neurobiological substrate for cognitive, language, and behavioral deficits in these children.

PMID: 23508710 [PubMed - indexed for MEDLINE]

Spatiotemporal 16p11.2 Protein Network Implicates Cortical Late Mid-Fetal Brain Development and KCTD13-Cul3-RhoA Pathway in Psychiatric Diseases.

February 20, 2015 - 7:26am

Spatiotemporal 16p11.2 Protein Network Implicates Cortical Late Mid-Fetal Brain Development and KCTD13-Cul3-RhoA Pathway in Psychiatric Diseases.

Neuron. 2015 Feb 18;85(4):742-754

Authors: Lin GN, Corominas R, Lemmens I, Yang X, Tavernier J, Hill DE, Vidal M, Sebat J, Iakoucheva LM

Abstract
The psychiatric disorders autism and schizophrenia have a strong genetic component, and copy number variants (CNVs) are firmly implicated. Recurrent deletions and duplications of chromosome 16p11.2 confer a high risk for both diseases, but the pathways disrupted by this CNV are poorly defined. Here we investigate the dynamics of the 16p11.2 network by integrating physical interactions of 16p11.2 proteins with spatiotemporal gene expression from the developing human brain. We observe profound changes in protein interaction networks throughout different stages of brain development and/or in different brain regions. We identify the late mid-fetal period of cortical development as most critical for establishing the connectivity of 16p11.2 proteins with their co-expressed partners. Furthermore, our results suggest that the regulation of the KCTD13-Cul3-RhoA pathway in layer 4 of the inner cortical plate is crucial for controlling brain size and connectivity and that its dysregulation by de novo mutations may be a potential determinant of 16p11.2 CNV deletion and duplication phenotypes.

PMID: 25695269 [PubMed - as supplied by publisher]

Gene expression analysis of human induced pluripotent stem cell-derived neurons carrying copy number variants of chromosome 15q11-q13.1.

February 20, 2015 - 7:26am

Gene expression analysis of human induced pluripotent stem cell-derived neurons carrying copy number variants of chromosome 15q11-q13.1.

Mol Autism. 2014;5:44

Authors: Germain ND, Chen PF, Plocik AM, Glatt-Deeley H, Brown J, Fink JJ, Bolduc KA, Robinson TM, Levine ES, Reiter LT, Graveley BR, Lalande M, Chamberlain SJ

Abstract
BACKGROUND: Duplications of the chromosome 15q11-q13.1 region are associated with an estimated 1 to 3% of all autism cases, making this copy number variation (CNV) one of the most frequent chromosome abnormalities associated with autism spectrum disorder (ASD). Several genes located within the 15q11-q13.1 duplication region including ubiquitin protein ligase E3A (UBE3A), the gene disrupted in Angelman syndrome (AS), are involved in neural function and may play important roles in the neurobehavioral phenotypes associated with chromosome 15q11-q13.1 duplication (Dup15q) syndrome.
METHODS: We have generated induced pluripotent stem cell (iPSC) lines from five different individuals containing CNVs of 15q11-q13.1. The iPSC lines were differentiated into mature, functional neurons. Gene expression across the 15q11-q13.1 locus was compared among the five iPSC lines and corresponding iPSC-derived neurons using quantitative reverse transcription PCR (qRT-PCR). Genome-wide gene expression was compared between neurons derived from three iPSC lines using mRNA-Seq.
RESULTS: Analysis of 15q11-q13.1 gene expression in neurons derived from Dup15q iPSCs reveals that gene copy number does not consistently predict expression levels in cells with interstitial duplications of 15q11-q13.1. mRNA-Seq experiments show that there is substantial overlap in the genes differentially expressed between 15q11-q13.1 deletion and duplication neurons, Finally, we demonstrate that UBE3A transcripts can be pharmacologically rescued to normal levels in iPSC-derived neurons with a 15q11-q13.1 duplication.
CONCLUSIONS: Chromatin structure may influence gene expression across the 15q11-q13.1 region in neurons. Genome-wide analyses suggest that common neuronal pathways may be disrupted in both the Angelman and Dup15q syndromes. These data demonstrate that our disease-specific stem cell models provide a new tool to decipher the underlying cellular and genetic disease mechanisms of ASD and may also offer a pathway to novel therapeutic intervention in Dup15q syndrome.

PMID: 25694803 [PubMed]

A case of autism spectrum disorder arising from a de novo missense mutation in POGZ.

February 20, 2015 - 7:26am

A case of autism spectrum disorder arising from a de novo missense mutation in POGZ.

J Hum Genet. 2015 Feb 19;

Authors: Fukai R, Hiraki Y, Yofune H, Tsurusaki Y, Nakashima M, Saitsu H, Tanaka F, Miyake N, Matsumoto N

Abstract
Autism spectrum disorder (ASD) is a clinically heterogeneous psychiatric disorder with various genetic backgrounds. Here, we report a novel mutation in the pogo transposable element-derived protein with zinc finger domain gene (POGZ) identified by trio-based whole exome sequencing. To date, a total of seven de novo POGZ mutations in ASD have been reported. POGZ contains a total of five functional domains, and this study reports the first de novo missense mutation in the centromere protein B-like DNA-binding domain. POGZ is highly expressed in the human fetal brain and is involved in mitosis and the regulation of neuronal proliferation. Therefore its loss-of-function or pathogenic missense mutations are likely to be causative of ASD.Journal of Human Genetics advance online publication, 19 February 2015; doi:10.1038/jhg.2015.13.

PMID: 25694107 [PubMed - as supplied by publisher]

MET receptor tyrosine kinase controls dendritic complexity, spine morphogenesis, and glutamatergic synapse maturation in the hippocampus.

February 20, 2015 - 7:26am
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MET receptor tyrosine kinase controls dendritic complexity, spine morphogenesis, and glutamatergic synapse maturation in the hippocampus.

J Neurosci. 2014 Dec 3;34(49):16166-79

Authors: Qiu S, Lu Z, Levitt P

Abstract
The MET receptor tyrosine kinase (RTK), implicated in risk for autism spectrum disorder (ASD) and in functional and structural circuit integrity in humans, is a temporally and spatially regulated receptor enriched in dorsal pallial-derived structures during mouse forebrain development. Here we report that loss or gain of function of MET in vitro or in vivo leads to changes, opposite in nature, in dendritic complexity, spine morphogenesis, and the timing of glutamatergic synapse maturation onto hippocampus CA1 neurons. Consistent with the morphological and biochemical changes, deletion of Met in mutant mice results in precocious maturation of excitatory synapse, as indicated by a reduction of the proportion of silent synapses, a faster GluN2A subunit switch, and an enhanced acquisition of AMPA receptors at synaptic sites. Thus, MET-mediated signaling appears to serve as a mechanism for controlling the timing of neuronal growth and functional maturation. These studies suggest that mistimed maturation of glutamatergic synapses leads to the aberrant neural circuits that may be associated with ASD risk.

PMID: 25471559 [PubMed - indexed for MEDLINE]

Role of an adaptor protein Lin-7B in brain development: possible involvement in autism spectrum disorders.

February 20, 2015 - 7:26am
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Role of an adaptor protein Lin-7B in brain development: possible involvement in autism spectrum disorders.

J Neurochem. 2015 Jan;132(1):61-9

Authors: Mizuno M, Matsumoto A, Hamada N, Ito H, Miyauchi A, Jimbo EF, Momoi MY, Tabata H, Yamagata T, Nagata K

Abstract
Using comparative genomic hybridization analysis for an autism spectrum disorder (ASD) patient, a 73-Kb duplication at 19q13.33 (nt. 49 562 755-49 635 956) including LIN7B and 5 other genes was detected. We then identified a novel frameshift mutation in LIN7B in another ASD patient. Since LIN7B encodes a scaffold protein essential for neuronal function, we analyzed the role of Lin-7B in the development of cerebral cortex. Acute knockdown of Lin-7B with in utero electroporation caused a delay in neuronal migration during corticogenesis. When Lin-7B was knocked down in cortical neurons in one hemisphere, their axons failed to extend efficiently into the contralateral hemisphere after leaving the corpus callosum. Meanwhile, enhanced expression of Lin-7B had no effects on both cortical neuron migration and axon growth. Notably, silencing of Lin-7B did not affect the proliferation of neuronal progenitors and stem cells. Taken together, Lin-7B was found to play a pivotal role in corticogenesis through the regulation of excitatory neuron migration and interhemispheric axon growth, while further analyses are required to directly link functional defects of Lin-7B to ASD pathophysiology. Lin-7 plays a pivotal role as a scaffold protein in synaptic development and plasticity. Based on genetic analyses we identified mutations in LIN-7B gene in some ASD (autism-spectrum disorder) patients. Functional defects in Lin-7B caused abnormal neuronal migration and interhemispheric axon growth during mouse brain development. Thus, functional deficiency in Lin-7B could be implicated in clinical phenotypes in some ASD patients through bringing about abnormal cortical architecture.

PMID: 25196215 [PubMed - indexed for MEDLINE]

Cognitive styles in depressed children with and without comorbid conduct disorder.

February 20, 2015 - 7:26am
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Cognitive styles in depressed children with and without comorbid conduct disorder.

J Adolesc. 2014 Jul;37(5):622-31

Authors: Schepman K, Fombonne E, Collishaw S, Taylor E

Abstract
Little is known about patterns of cognitive impairment in depression comorbid with conduct disorder. The study included clinically depressed children with (N = 23) or without conduct disorder (N = 29), and controls without psychiatric disorder (N = 37). Cognitive biases typical of depression and patterns of social information processing were assessed. Both depressed groups had substantially higher rates of negative cognitive distortions, attributional biases and ruminative responses than non-depressed children. Children in the comorbid group made more hostile attributions and suggested more aggressive responses for dealing with threatening social situations, whilst children with depression only were more likely to be unassertive. Depression has a number of similar depressotypic cognitive biases whether or not complicated by conduct disorder, and may be potentially susceptible to similar interventions. The results also highlight the importance of recognising social information processing deficits when they occur and targeting those too, especially in comorbid presentations.

PMID: 24931565 [PubMed - indexed for MEDLINE]

Duplication Xp11.22-p14 in females: Does X-inactivation help in assessing their significance?

February 19, 2015 - 7:06am

Duplication Xp11.22-p14 in females: Does X-inactivation help in assessing their significance?

Am J Med Genet A. 2015 Mar;167(3):553-62

Authors: Evers C, Mitter D, Strobl-Wildemann G, Haug U, Hackmann K, Maas B, Janssen JW, Jauch A, Hinderhofer K, Moog U

Abstract
In females, large duplications in Xp often lead to preferential inactivation of the aberrant X chromosome and a normal phenotype. Recently, a recurrent ∼4.5 Mb microduplication of Xp11.22-p11.23 was found in females with developmental delay/intellectual disability and other neurodevelopmental disorders (speech development disorder, epilepsy or EEG anomalies, autism spectrum disorder, or behavioral disorder). Unexpectedly, most of them showed preferential inactivation of the normal X chromosome. We describe five female patients carrying de novo Xp duplications encompassing p11.23. Patient 1 carried the recurrent microduplication Xp11.22-p11.23, her phenotype and X-chromosome inactivation (XI) pattern was consistent with previous reports. The other four patients had novel Xp duplications. Two were monozygotic twins with a similar phenotype to Patient 1 and unfavorable XI skewing carrying an overlapping ∼5 Mb duplication of Xp11.23-p11.3. Patient 4 showed a duplication of ∼5.5 Mb comparable to the twins but had a more severe phenotype and unskewed XI. Patient 5 had a ∼8.5 Mb duplication Xp11.23-p11.4 and presented with mild ID, epilepsy, behavioral problems, and inconsistent results of XI analysis. A comparison of phenotype, size and location of the duplications and XI patterns in Patients 1-5 and previously reported females with overlapping duplications provides further evidence that microduplications encompassing Xp11.23 are associated with ID and other neurodevelopmental disorders in females. To further assess the implication of XI for female carriers, we recommend systematic analysis of XI pattern in any female with X imbalances that are known or suspected to be pathogenic. © 2015 Wiley Periodicals, Inc.

PMID: 25691408 [PubMed - in process]

Fetal DNA Methylation of Autism Spectrum Disorders (ASD) Candidate Genes: Association with Spontaneous Preterm Birth.

February 18, 2015 - 6:14am

Fetal DNA Methylation of Autism Spectrum Disorders (ASD) Candidate Genes: Association with Spontaneous Preterm Birth.

Am J Obstet Gynecol. 2015 Feb 13;

Authors: Behnia F, Parets SE, Kechichian T, Yin H, Dutta EH, Saade GR, Smith AK, Menon R

Abstract
OBJECTIVE: Autism Spectrum Disorder (ASD) is associated with preterm birth (PTB); though the reason underlying this relationship is still unclear. Our objective was to examine DNA methylation patterns of four ASD candidate genes in human fetal membranes from spontaneous PTB and uncomplicated term birth (TB).
STUDY DESIGN: A literature search for genes implicated in ASD yielded 14 candidate genes (OXTR, SHANK3, BCL2, RORA, EN2, RELN, MECP2, AUTS2, NLGN3, NRXN1, SLC6A4, UBE3A, GABA, AFF2) that were epigenetically modified in relation to ASD. DNA methylation in fetal leukocyte DNA in four of these genes (OXTR, SHANK3, BCL2 and RORA) associated with PTB in a previous study. This study evaluated DNA methylation, transcription (qPCR) and translation patterns (immunostaining and western blot) in fetal membrane from term labor (TL; n=14), term not in labor (TNIL; n=29) and spontaneous preterm birth (PTB; n=27). Statistical analysis was performed using ANOVA and a p-value of < 0.05 was significant.
RESULTS: Higher methylation of the OXTR promoter was seen in fetal membranes from PTB compared to TL or TNIL. No other gene showed any methylation differences between groups. Expression of OXTR was not different between groups but the 70 kDa OXTR protein was seen only in PTB, and immunostaining was more intense in PTB amniocytes than TL or TNIL.
CONCLUSION: Among the four genes studied, fetal membranes from PTB demonstrate differences in OXTR methylation and regulation and expression, suggesting that epigenetic alteration of this gene in fetal membrane may likely be indicating an in utero programing of this gene and serve as a surrogate in a subset of PTB. The usefulness of OXTR hypermethylation as a surrogate for link to ASD should be further evaluated in longitudinal and in vitro studies.

PMID: 25687563 [PubMed - as supplied by publisher]

How might epigenetic dysregulation in early embryonic life contribute to autism spectrum disorder?

February 18, 2015 - 6:14am

How might epigenetic dysregulation in early embryonic life contribute to autism spectrum disorder?

Epigenomics. 2015 Feb;7(1):1-4

Authors: Berko ER, Greally JM

PMID: 25687459 [PubMed - in process]

Genetic and Developmental Perspective of Language Abnormality in Autism and Schizophrenia: One Disease Occurring at Different Ages in Humans?

February 18, 2015 - 6:14am

Genetic and Developmental Perspective of Language Abnormality in Autism and Schizophrenia: One Disease Occurring at Different Ages in Humans?

Neuroscientist. 2015 Feb 16;

Authors: Wang HG, Jeffries JJ, Wang TF

Abstract
Language and communication through it are two of the defining features of normally developed human beings. However, both these functions are often impaired in autism and schizophrenia. In the former disorder, the problem usually emerges in early childhood (~2 years old) and typically includes a lack of communication. In the latter condition, the language problems usually occur in adolescence and adulthood and presents as disorganized speech. What are the fundamental mechanisms underlying these two disorders? Is there a shared genetic basis? Are the traditional beliefs about them true? Are there any common strategies for their prevention and management? To answer these questions, we searched PubMed by using autism, schizophrenia, gene, and language abnormality as keywords, and we reconsidered the basic concepts about these two diseases or syndromes. We found many functional genes, for example, FOXP2, COMT, GABRB3, and DISC1, are actually implicated in both of them. After observing the symptoms, genetic correlates, and temporal progression of these two disorders as well as their relationships more carefully, we now infer that the occurrence of these two diseases is likely developmentally regulated via interaction between the genome and the environment. Furthermore, we propose a unified view of autism and schizophrenia: a single age-dependently occurred disease that is newly named as Systemic Integral Disorder: if occurring in children before age 2, it is called autism; if in adolescence or a later age, it is called schizophrenia.

PMID: 25686622 [PubMed - as supplied by publisher]

A pilot controlled trial of insulin-like growth factor-1 in children with Phelan-McDermid syndrome.

February 17, 2015 - 8:16am
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A pilot controlled trial of insulin-like growth factor-1 in children with Phelan-McDermid syndrome.

Mol Autism. 2014;5(1):54

Authors: Kolevzon A, Bush L, Wang AT, Halpern D, Frank Y, Grodberg D, Rapaport R, Tavassoli T, Chaplin W, Soorya L, Buxbaum JD

Abstract
BACKGROUND: Autism spectrum disorder (ASD) is now understood to have multiple genetic risk genes and one example is SHANK3. SHANK3 deletions and mutations disrupt synaptic function and result in Phelan-McDermid syndrome (PMS), which causes a monogenic form of ASD with a frequency of at least 0.5% of ASD cases. Recent evidence from preclinical studies with mouse and human neuronal models of SHANK3 deficiency suggest that insulin-like growth factor-1 (IGF-1) can reverse synaptic plasticity and motor learning deficits. The objective of this study was to pilot IGF-1 treatment in children with PMS to evaluate safety, tolerability, and efficacy for core deficits of ASD, including social impairment and restricted and repetitive behaviors.
METHODS: Nine children with PMS aged 5 to 15 were enrolled in a placebo-controlled, double-blind, crossover design study, with 3 months of treatment with IGF-1 and 3 months of placebo in random order, separated by a 4-week wash-out period.
RESULTS: Compared to the placebo phase, the IGF-1 phase was associated with significant improvement in both social impairment and restrictive behaviors, as measured by the Aberrant Behavior Checklist and the Repetitive Behavior Scale, respectively. IGF-1 was found to be well tolerated and there were no serious adverse events in any participants.
CONCLUSIONS: This study establishes the feasibility of IGF-1 treatment in PMS and contributes pilot data from the first controlled treatment trial in the syndrome. Results also provide proof of concept to advance knowledge about developing targeted treatments for additional causes of ASD associated with impaired synaptic development and function.

PMID: 25685306 [PubMed]

The RNA-binding protein Celf6 is highly expressed in diencephalic nuclei and neuromodulatory cell populations of the mouse brain.

February 16, 2015 - 7:17am

The RNA-binding protein Celf6 is highly expressed in diencephalic nuclei and neuromodulatory cell populations of the mouse brain.

Brain Struct Funct. 2015 Feb 15;

Authors: Maloney SE, Khangura E, Dougherty JD

Abstract
The gene CUG-BP, Elav-like factor 6 (CELF6) appears to be important for proper functioning of neurocircuitry responsible for behavioral output. We previously discovered that polymorphisms in or near CELF6 may be associated with autism spectrum disorder (ASD) in humans and that the deletion of this gene in mice results in a partial ASD-like phenotype. Here, to begin to understand which circuits might mediate these behavioral disruptions, we sought to establish in what structures, with what abundance, and at which ages Celf6 protein is present in the mouse brain. Using both a knockout-validated antibody to Celf6 and a novel transgenic mouse line, we characterized Celf6 expression in the mouse brain across development. Celf6 gene products were present early in neurodevelopment and in adulthood. The greatest protein expression was observed in distinct nuclei of the diencephalon and neuromodulatory cell populations of the midbrain and hindbrain, with clear expression in dopaminergic, noradrenergic, histaminergic, serotonergic and cholinergic populations, and a variety of presumptive peptidergic cells of the hypothalamus. These results suggest that disruption of Celf6 expression in hypothalamic nuclei may impact a variety of behaviors downstream of neuropeptide activity, while disruption in neuromodulatory transmitter expressing areas such as the ventral tegmental area, substantia nigra, raphe nuclei and locus coeruleus may have far-reaching influences on overall brain activity.

PMID: 25682262 [PubMed - as supplied by publisher]

Annual Research Review: The (epi)genetics of neurodevelopmental disorders in the era of whole-genome sequencing - unveiling the dark matter.

February 14, 2015 - 8:52am

Annual Research Review: The (epi)genetics of neurodevelopmental disorders in the era of whole-genome sequencing - unveiling the dark matter.

J Child Psychol Psychiatry. 2015 Feb 11;

Authors: Kiser DP, Rivero O, Lesch KP

Abstract
BACKGROUND AND SCOPE: Neurodevelopmental disorders (NDDs) are defined by a wide variety of behavioural phenotypes, psychopathology and clinically informed categorical classifications. Diagnostic entities include intellectual disability (ID), the autism spectrum (ASD) and attention-deficit/hyperactivity disorder (ADHD). The aetiopathogenesis of these conditions and disorders involves an interaction between both genetic and environmental risk factors on the developmental trajectory. Despite their remarkable genetic heterogeneity and complexity of pathophysiological mechanisms, NDDs display an overlap in their phenotypic features, a considerable degree of comorbidity as well as sharing of genetic and environmental risk factors. This review aims to provide an overview of the genetics and epigenetic of NDDs.
FINDINGS: Recent evidence suggests a critical role of defined and tightly regulated neurodevelopmental programs running out of control in NDDs, most notably neuronal proliferation and migration, synapse formation and remodelling, as well as neural network configuration resulting in compromised systems connectivity and function. Moreover, the machinery of epigenetic programming, interacting with genetic liability, impacts many of those processes and pathways, thus modifying vulnerability of, and resilience to, NDDs. Consequently, the categorically defined entities of ID, ADHD and ASD are increasingly viewed as disorders on a multidimensional continuum of molecular and cellular deficiencies in neurodevelopment. As such, this range of NDDs displays a broad phenotypic diversity, which may be explained by a combination and interplay of underlying loss- and potential gain-of-function traits.
CONCLUSION: In this overview, we discuss a backbone continuum concept of NDDs by summarizing pertinent findings in genetics and epigenetics. We also provide an appraisal of the genetic overlap versus differences, with a focus on genome-wide screening approaches for (epi)genetic variation. Finally, we conclude with insights from evolutionary psychobiology suggesting positive selection for discrete NDD-associated traits.

PMID: 25677560 [PubMed - as supplied by publisher]

A case with a ring chromosome 13 in a cohort of 203 children with non-syndromic autism and review of the cytogenetic literature.

February 14, 2015 - 8:52am
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A case with a ring chromosome 13 in a cohort of 203 children with non-syndromic autism and review of the cytogenetic literature.

Cytogenet Genome Res. 2014;144(1):1-8

Authors: Charalsawadi C, Maisrikhaw W, Praphanphoj V, Wirojanan J, Hansakunachai T, Roongpraiwan R, Sombuntham T, Ruangdaraganon N, Limprasert P

Abstract
Autistic spectrum disorder (ASD) is a group of neurodevelopmental disorders characterized by impairments of social interaction, communication and restricted, repetitive and stereotyped patterns of behavior, interests and activities. Frequencies of chromosomal abnormalities in cohorts of individuals with ASD varying between 1.2 and 28.6% have been reported. In this study, we evaluated 203 Thai children who met the criteria of the Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV), for autistic disorder or pervasive developmental disorder not otherwise specified (PDD-NOS), and who had neither major dysmorphic features nor CGG repeat expansions of the FMR1 gene. A routine G-banding chromosome analysis was performed at a minimum of ISCN 400-550 bands. A chromosomal abnormality was observed in one child (0.5%), a 41-month-old boy with a ring chromosome 13 detected by G-banding analysis and subsequently confirmed by FISH. SNP microarray analysis detected a 2.11-Mb deletion of chromosome 13q34, encompassing 23 genes. The MCF2L and UPF3A genes are among those genes that may explain the autistic features in our case. To the best of our knowledge, only one autistic case with a ring chromosome 13 has been previously reported. In this article, we also systemically reviewed 21 studies that utilized a conventional cytogenetic method to detect chromosomal abnormalities in patients with ASD. When we summed all cases with chromosomal abnormalities, including the case from our study, the frequency of chromosomal abnormalities detected by conventional cytogenetics in patients with ASD was 3.2% (118/3,712).

PMID: 25171325 [PubMed - indexed for MEDLINE]

Variations analysis of NLGN3 and NLGN4X gene in Chinese autism patients.

February 14, 2015 - 8:52am
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Variations analysis of NLGN3 and NLGN4X gene in Chinese autism patients.

Mol Biol Rep. 2014 Jun;41(6):4133-40

Authors: Xu X, Xiong Z, Zhang L, Liu Y, Lu L, Peng Y, Guo H, Zhao J, Xia K, Hu Z

Abstract
Autism is a neurodevelopmental disorder clinically characterized by impairment of social interaction, deficits in verbal communication, as well as stereotypic and repetitive behaviors. Several studies have implicated that abnormal synaptogenesis was involved in the incidence of autism. Neuroligins are postsynaptic cell adhesion molecules and interacted with neurexins to regulate the fine balance between excitation and inhibition of synapses. Recently, mutation analysis, cellular and mice models hinted neuroligin mutations probably affected synapse maturation and function. In this study, four missense variations [p.G426S (NLGN3), p.G84R (NLGN4X), p.Q162 K (NLGN4X) and p.A283T (NLGN4X)] in four different unrelated patients have been identified by PCR and direct sequencing. These four missense variations were absent in the 453 controls and have not been reported in 1000 Genomes Project. Bioinformatic analysis of the four missense variations revealed that p.G84R and p.A283T were "Probably Damaging". The variations may cause abnormal synaptic homeostasis and therefore trigger the patients more predisposed to autism. By case-control analysis, we identified the common SNPs (rs3747333 and rs3747334) in the NLGN4X gene significantly associated with risk for autism [p = 5.09E-005; OR 4.685 (95% CI 2.073-10.592)]. Our data provided a further evidence for the involvement of NLGN3 and NLGN4X gene in the pathogenesis of autism in Chinese population.

PMID: 24570023 [PubMed - indexed for MEDLINE]

Paroxysmal kinesigenic dyskinesia caused by 16p11.2 microdeletion.

February 11, 2015 - 8:56am

Paroxysmal kinesigenic dyskinesia caused by 16p11.2 microdeletion.

Tremor Other Hyperkinet Mov (N Y). 2014;4:274

Authors: Termsarasab P, Yang AC, Reiner J, Mei H, Scott SA, Frucht SJ

Abstract
BACKGROUND: Four cases of paroxysmal kinesigenic dyskinesia (PKD) have been reported in individuals with proximal 16p11.2 microdeletions that include PRRT2.
CASE REPORT: We describe a fifth patient with PKD, features of Asperger's syndrome, and mild language delays. Sanger sequencing of the PRRT2 gene did not identify any mutations implicated in PKD. However, microarray-based comparative genomic hybridization (aCGH) detected a 533.9-kb deletion on chromosome 16, encompassing over 20 genes and transcripts.
DISCUSSION: This case underscores the importance of aCGH testing for individuals with PKD who do not have PRRT2 mutations, particularly when developmental delays, speech problems, intellectual disability, and/or autism spectrum disorder are present.

PMID: 25667815 [PubMed]

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