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Catatonia in an adolescent with velo-cardio-facial syndrome.

May 20, 2016 - 7:34am
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Catatonia in an adolescent with velo-cardio-facial syndrome.

Am J Med Genet A. 2015 Sep;167A(9):2150-3

Authors: Faedda GL, Wachtel LE, Higgins AM, Shprintzen RJ

Abstract
Velo-cardio-facial syndrome (VCFS) is the most common microdeletion syndrome in humans and is probably the most frequent genetic cause of psychosis currently known. Many psychiatric disorders have been reported to occur in people with VCFS including, but not limited to schizophrenia, unipolar and bipolar mood disorders (with or without psychotic features), schizoaffective disorder, psychosis NOS, social phobia, generalized and separation anxiety, obsessive-compulsive disorder, autism spectrum disorder, cognitive impairment, and ADHD. This report describes the psychiatric onset and development of catatonia in an adolescent female with VCFS that was undiagnosed until 15 years of age. Catatonia may be a relatively common presentation in people with VCFS with treatment-refractory psychiatric manifestations.

PMID: 25832449 [PubMed - indexed for MEDLINE]

Hypersexuality, Paraphilic Behaviors, and Gender Dysphoria in Individuals with Klinefelter's Syndrome.

May 19, 2016 - 7:33am
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Hypersexuality, Paraphilic Behaviors, and Gender Dysphoria in Individuals with Klinefelter's Syndrome.

J Sex Med. 2015 Dec;12(12):2413-24

Authors: Fisher AD, Castellini G, Casale H, Fanni E, Bandini E, Campone B, Ferruccio N, Maseroli E, Boddi V, Dèttore D, Pizzocaro A, Balercia G, Oppo A, Ricca V, Maggi M

Abstract
INTRODUCTION: An increased risk of autistic traits in Klinefelter syndrome (KS) has been reported. In addition, some studies have shown an increased incidence of gender dysphoria (GD) and paraphilia in autism spectrum disorder.
AIM: The aim of this study was to evaluate the presence of (i) paraphilic fantasies and behaviors; and (ii) GD symptomatology in KS.
METHODS AND MAIN OUTCOMES MEASURES: A sample of 46 KS individuals and 43 healthy male controls (HC) were evaluated. Subjects were studied by means of several psychometric tests, such as Autism Spectrum Quotient (AQ) and Reading the Mind in the Eyes Revised (RME) to measure autistic traits, Gender Identity/GD questionnaire (GIDYQ-AA), and Sexual Addiction Screening Test (SAST). In addition, body uneasiness psychopathological symptoms were assessed using Symptom Checklist 90 Revised (SCL-90-R). The presence and frequency of any paraphilic fantasy and behavior was assessed by means of a clinical interview based on Diagnostic and Statistical Manual of Mental Disorders, 5th Edition criteria. Finally, all individuals included were assessed by Wechsler Adult Intelligence Scale-Revised to evaluate intelligence quotient (IQ). Data from a subsample of a previous published series of male to female GD individuals, with the battery of psychological measures useful to provide a psychopathological explanation of GD in KS population available, was also considered.
RESULTS: When compared with HC, KS reported significantly lower total, verbal and performance IQ scores and higher SCL-90 obsession-compulsive symptoms (all P < 0.001). In line with previously reported findings, KS showed higher autistic traits according with both RME and AQ tests (P < 0.001). With respect to sexuality, KS showed a significant higher frequency of voyeuristic fantasies during masturbation (52.2% vs. 25.6%) and higher SAST scores (P = 0.012). A mediation role of obsessive symptoms on the relationship between Klinefelter and SAST was confirmed (unstandardized estimate b = 2.75, standard error = 0.43 P < 0.001). Finally, KS individuals showed significantly higher gender dysphoric symptoms than HC (P = 0.004), which were mediated by the presence of autistic traits (Sobel's test; P < 0.05).
CONCLUSIONS: KS is associated with hypersexuality, paraphilic behaviors, and GD, which were mediated by obsessive-compulsive and autistic traits.

PMID: 26612786 [PubMed - indexed for MEDLINE]

Dectin-1 Polymorphism: A Genetic Disease Specifier in Autism Spectrum Disorders?

May 19, 2016 - 7:33am
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Dectin-1 Polymorphism: A Genetic Disease Specifier in Autism Spectrum Disorders?

PLoS One. 2015;10(9):e0137339

Authors: Bennabi M, Delorme R, Oliveira J, Fortier C, Lajnef M, Boukouaci W, Feugeas JP, Marzais F, Gaman A, Charron D, Ghaleh B, Krishnamoorthy R, Leboyer M, Tamouza R

Abstract
INTRODUCTION: In autism spectrum disorders (ASD), complex gene-environment interactions contribute to disease onset and progress. Given that gastro-intestinal dysfunctions are common in ASD, we postulated involvement of microbial dysbiosis in ASD and investigated, under a case-control design, the influence of DNA polymorphisms in the CLEC7A gene that encodes a pivotal fungal sensor, Dectin-1.
MATERIAL AND METHODS: DNAs from 478 ASD patients and 351 healthy controls (HC) were analyzed for the CLEC7A rs16910631G/A and rs2078178 A/G single nucleotide polymorphisms (SNPs). Differences in the distribution of allele, genotype and haplotype by Chi-square testing and nonparametric analysis by Kruskal-Wallis/Mann-Whitney tests, where appropriate, were performed. The free statistical package R.2.13 software was used for the statistical analysis.
RESULTS: We found that the CLEC7A rs2078178 G allele and GG genotype were more prevalent in HC as compared to ASD but failed to reach statistical significance for the latter (pc = 0.01, 0.06 respectively). However, after phenotype-based stratification, the CLEC7A rs2078178 G allele and GG genotype were found to be significantly more frequent in the Asperger group as compared to other ASD subsets (pc = 0.02, 0.01), a finding reinforced by haplotype analysis (rs2078178/rs16910631 G-G/G-G) (pc = 0.002). Further, intellectual quotient (IQ)-based stratification of ASD patients revealed that IQ values increase linearly along the CLEC7A rs2078178 AA, AG and GG genotypes (p = 0.05) and in a recessive manner (GG vs. AA+AG p = 0.02), further confirmed by haplotype distribution (CLEC7A rs2078178-16910631; A-G/A-G, A-G/G-G and G-G/G-G, p = 0.02, G-G/G-G vs. others, p = 0.01).
CONCLUSION: Our data suggest that the genetic diversity of CLEC7A gene influences the ASD phenotype by behaving as a disease specifier and imply that the genetic control of innate immune response could determine the ASD phenotype.

PMID: 26352598 [PubMed - indexed for MEDLINE]

Investigating the effects of copy number variants on reading and language performance.

May 18, 2016 - 4:30pm
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Investigating the effects of copy number variants on reading and language performance.

J Neurodev Disord. 2016;8:17

Authors: Gialluisi A, Visconti A, Willcutt EG, Smith SD, Pennington BF, Falchi M, DeFries JC, Olson RK, Francks C, Fisher SE

Abstract
BACKGROUND: Reading and language skills have overlapping genetic bases, most of which are still unknown. Part of the missing heritability may be caused by copy number variants (CNVs).
METHODS: In a dataset of children recruited for a history of reading disability (RD, also known as dyslexia) or attention deficit hyperactivity disorder (ADHD) and their siblings, we investigated the effects of CNVs on reading and language performance. First, we called CNVs with PennCNV using signal intensity data from Illumina OmniExpress arrays (~723,000 probes). Then, we computed the correlation between measures of CNV genomic burden and the first principal component (PC) score derived from several continuous reading and language traits, both before and after adjustment for performance IQ. Finally, we screened the genome, probe-by-probe, for association with the PC scores, through two complementary analyses: we tested a binary CNV state assigned for the location of each probe (i.e., CNV+ or CNV-), and we analyzed continuous probe intensity data using FamCNV.
RESULTS: No significant correlation was found between measures of CNV burden and PC scores, and no genome-wide significant associations were detected in probe-by-probe screening. Nominally significant associations were detected (p~10(-2)-10(-3)) within CNTN4 (contactin 4) and CTNNA3 (catenin alpha 3). These genes encode cell adhesion molecules with a likely role in neuronal development, and they have been previously implicated in autism and other neurodevelopmental disorders. A further, targeted assessment of candidate CNV regions revealed associations with the PC score (p~0.026-0.045) within CHRNA7 (cholinergic nicotinic receptor alpha 7), which encodes a ligand-gated ion channel and has also been implicated in neurodevelopmental conditions and language impairment. FamCNV analysis detected a region of association (p~10(-2)-10(-4)) within a frequent deletion ~6 kb downstream of ZNF737 (zinc finger protein 737, uncharacterized protein), which was also observed in the association analysis using CNV calls.
CONCLUSIONS: These data suggest that CNVs do not underlie a substantial proportion of variance in reading and language skills. Analysis of additional, larger datasets is warranted to further assess the potential effects that we found and to increase the power to detect CNV effects on reading and language.

PMID: 27186239 [PubMed]

Morphological and behavioral characterization of adult mice deficient for SrGAP3.

May 18, 2016 - 4:30pm
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Morphological and behavioral characterization of adult mice deficient for SrGAP3.

Cell Tissue Res. 2016 May 17;

Authors: Bertram J, Koschützke L, Pfannmöller JP, Esche J, van Diepen L, Kuss AW, Hartmann B, Bartsch D, Lotze M, von Bohlen Und Halbach O

Abstract
SrGAP3 belongs to the family of Rho GTPase proteins. These proteins are thought to play essential roles in development and in the plasticity of the nervous system. SrGAP3-deficient mice have recently been created and approximately 10 % of these mice developed a hydrocephalus and died shortly after birth. The others survived into adulthood, but displayed neuroanatomical alteration, including increased ventricular size. We now show that SrGAP3-deficient mice display increased brain weight together with increased hippocampal volume. This increase was accompanied by an increase of the thickness of the stratum oriens of area CA1 as well as of the thickness of the molecular layer of the dentate gyrus (DG). Concerning hippocampal adult neurogenesis, we observed no significant change in the number of proliferating cells. The density of doublecortin-positive cells also did not vary between SrGAP3-deficient mice and controls. By analyzing Golgi-impregnated material, we found that, in SrGAP3-deficient mice, the morphology and number of dendritic spines was not altered in the DG. Likewise, a Sholl-analysis revealed no significant changes concerning dendritic complexity as compared to controls. Despite the distinct morphological alterations in the hippocampus, SrGAP3-deficient mice were relatively inconspicuous in their behavior, not only in the open-field, nest building but also in the Morris water-maze. However, the SrGAP3-deficient mice showed little to no interest in burying marbles; a behavior that is seen in some animal models related to autism, supporting the view that SrGAP3 plays a role in neurodevelopmental disorders.

PMID: 27184948 [PubMed - as supplied by publisher]

Psychiatric and Behavioural Disorders in Children with Epilepsy (ILAE Task Force Report): Behavioural and psychiatric disorders associated with childhood epilepsy syndromes.

May 18, 2016 - 4:30pm
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Psychiatric and Behavioural Disorders in Children with Epilepsy (ILAE Task Force Report): Behavioural and psychiatric disorders associated with childhood epilepsy syndromes.

Epileptic Disord. 2016 May 16;

Authors: Besag F, Gobbi G, Aldenkamp A, Caplan R, Dunn DW, Sillanpää M

Abstract
The categorisation of the childhood epilepsies into a number of different syndromes has allowed greater insight into the prognosis, not only with regard to seizure control but also in relation to cognitive and behavioural outcome. The role of genetics in determining both the syndrome and the behavioural outcome remains promising, although the promise is still largely unfulfilled. The behavioural/psychiatric outcome of a selection of the large number of childhood epilepsy syndromes is presented. The rate of autism in West syndrome, particularly in children who have tuberous sclerosis with temporal tubers, is high. In Dravet syndrome there is a loss of skills, with an associated increase in behavioural problems. The frequency of both subtle and overt seizures in the Lennox-Gastaut syndrome almost certainly accounts for the apparent poor motivation; however, a marked improvement in seizure control with treatment can also result in behavioural problems, probably as a result of the "release phenomenon". A number of cognitive problems can arise in the so-called "benign" syndrome of epilepsy with centrotemporal spikes (BECTS) and the rate of ADHD is high. Autistic features and ADHD have been described in the Landau-Kleffner syndrome and other syndromes associated with electrical status epilepticus of slow-wave sleep (ESES). Early effective treatment may reverse some of these features. There is clear evidence for a behavioural syndrome in relation to juvenile myoclonic epilepsy (JME), in which both clinical descriptions and functional neuroimaging indicate frontal lobe deficits.

PMID: 27184676 [PubMed - as supplied by publisher]

The role of protein intrinsic disorder in major psychiatric disorders.

May 18, 2016 - 4:30pm
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The role of protein intrinsic disorder in major psychiatric disorders.

Am J Med Genet B Neuropsychiatr Genet. 2016 May 17;

Authors: Tovo-Rodrigues L, Recamonde-Mendoza M, Paixão-Côrtes VR, Bruxel EM, Schuch JB, Friedrich DC, Rohde LA, Hutz MH

Abstract
Although new candidate genes for Autism Spectrum Disorder (ASD), Schizophrenia (SCZ), Attention-Deficit/Hyperactivity Disorder (ADHD), and Bipolar Disorder (BD) emerged from genome-wide association studies (GWAS), their underlying molecular mechanisms remain poorly understood. Evidences of the involvement of intrinsically disordered proteins in diseases have grown in the last decade. These proteins lack tridimensional structure under physiological conditions and are involved in important cellular functions such as signaling, recognition and regulation. The aim of the present study was to identify the role and abundance of intrinsically disordered proteins in a set of psychiatric diseases and to test whether diseases are different regarding protein intrinsic disorder. Our hypothesis is that differences across psychiatric illnesses phenotypes and symptoms may arise from differences in intrinsic protein disorder content and properties of each group. A bioinformatics prediction of intrinsic disorder was performed in proteins retrieved based on top findings from GWAS, Copy Number Variation and candidate gene investigations for each disease. This approach revealed that about 80% of studied proteins presented long stretches of disorder. This amount was significantly higher than that observed in general eukaryotic proteins, and those involved in cardiovascular diseases. These results suggest that proteins with intrinsic disorder are a common feature of neurodevelopment and synaptic transmission processes which are potentially involved in the etiology of psychiatric diseases. Moreover, we identified differences between ADHD and ASD when the binary prediction of structure and putative binding sites were compared. These differences may be related to variation in symptom complexity between both diseases. © 2016 Wiley Periodicals, Inc.

PMID: 27184105 [PubMed - as supplied by publisher]

Ultrasound in the first and second trimester and autism; a prospective randomized study.

May 18, 2016 - 4:30pm
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Ultrasound in the first and second trimester and autism; a prospective randomized study.

Ultrasound Obstet Gynecol. 2016 May 17;

Authors: Höglund Carlsson L, Saltvedt S, Anderlid BM, Westerlund J, Gillberg C, Westgren M, Fernell E

Abstract
OBJECTIVES: To analyze whether the frequency of Autism Spectrum Disorder (ASD) differs in Swedish cohorts of children exposed to ultrasound either in the 12th or 18th week of gestation.
METHODS: The study cohort consisted of approximately 30 000 children with birth-years 1999-2003, born to mothers, who, within the framework of a study of nuchal translucency (NT) screening, had been randomized to prenatal ultrasound in either gestational week 12 or 18. The outcome measure in the present study was the rate of ASD diagnoses in the children. Information on ASD diagnoses was based on data from the Swedish Social Insurance Agency concerning granted childcare allowance because of ASD.
RESULTS: No difference in ASD frequency between the early and later subgroup could be detected. A total of 14 726 children were born after early and 14 596 children after later ultrasound in 1999-2003 and of these, 181 (1.2%) and 176 (1.2%) children, respectively, had been diagnosed with ASD.
CONCLUSIONS: Women, subjected to at least one prenatal ultrasound in either gestational week 12 or 18, had children with similar rates of ASD. However, the result reflects the routine used 10 to 15 years ago in Sweden. Today, many and early, higher intensity ultrasound scans are performed during pregnancy and also for non-medical purposes, implying longer exposure time for the fetus. This changing use of ultrasound necessitates further follow-up studies of the possible effects on the developing brain of high exposure to ultrasound during the gestational period.

PMID: 27184020 [PubMed - as supplied by publisher]

Increased nuchal translucency thickness and the risk of neurodevelopmental disorders.

May 18, 2016 - 4:30pm
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Increased nuchal translucency thickness and the risk of neurodevelopmental disorders.

Ultrasound Obstet Gynecol. 2016 May 17;

Authors: Hellmuth SG, Pedersen LH, Miltoft CB, Petersen OB, Kjaergaard S, Ekelund C, Tabor A

Abstract
OBJECTIVE: To investigate the association between fetal nuchal translucency thickness (NT) and neurodevelopmental disorders in euploid children.
METHOD: This study included 222,505 euploid children, with a routine first trimester screening. They were divided into three groups by NT thickness: NT <95(th) percentile, 217,103 (97.6%), NT 95(th) -99(th) percentile, 4,760 (2.1%), and NT >99(th) percentile 642 (0.3%). All children were followed-up through national patient registries at a mean age of 4.4 years. We obtained information on diagnoses of mental retardation, autism spectrum disorders (ASDs), cerebral palsy, epilepsy and febrile seizures.
RESULTS: There was no excess risk of neurodevelopmental disorders among euploid children with a NT between 95(th) and 99(th) percentile. For children with a NT >99(th) percentile, there were increased risks of mental retardation (OR=6.16, 95% confidence interval (CI): 1.51-25.0, 2 cases) and ASDs (OR=2.48, 95%CI: 1.02-5.99, 5 cases) compared to children with a NT<95(th) percentile (110 and 686 cases of mental retardation and ASDs, respectively). There was no detected increased risk of cerebral palsy (OR= 1.91, 95%CI: 0.61-5.95, 3 cases), epilepsy (OR= 1.51, 95%CI: 0.63-3.66, 5 cases) or febrile seizures (OR=0.72, 95%CI: 0.44-1.16, 17 cases) among children with a NT >99(th) percentile.
CONCLUSION: In a large unselected cohort, euploid fetuses with a NT 95(th) -99(th) percentile had no increased risk of neurodevelopmental disorders. Among euploid fetuses with a NT >99(th) percentile there was an increased risk of mental retardation and ASDs but the absolute risk was low (<1%) and thus reassuring.

PMID: 27183961 [PubMed - as supplied by publisher]

Topoisomerase I in Human Disease Pathogenesis and Treatments.

May 18, 2016 - 4:30pm
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Topoisomerase I in Human Disease Pathogenesis and Treatments.

Genomics Proteomics Bioinformatics. 2016 May 12;

Authors: Li M, Liu Y

Abstract
Mammalian topoisomerase 1 (TOP1) is an essential enzyme for normal development. TOP1 relaxes supercoiled DNA to remove helical constraints that can otherwise hinder DNA replication and transcription and thus block cell growth. Unfortunately, this exact activity can covalently trap TOP1 on the DNA that could lead to cell death or mutagenesis, a precursor for tumorigenesis. It is therefore important for cells to find a proper balance between the utilization of the TOP1 catalytic activity to maintain DNA topology and the risk of accumulating the toxic DNA damages due to TOP1 trapping that prevents normal cell growth. In an apparent contradiction to the negative attribute of the TOP1 activity to genome stability, the detrimental effect of the TOP1-induced DNA lesions on cell survival has made this enzyme a prime target for cancer therapies to kill fast-growing cancer cells. In addition, cumulative evidence supports a direct role of TOP1 in promoting transcriptional progression independent of its topoisomerase activity. The involvement of TOP1 in transcriptional regulation has recently become a focus in developing potential new treatments for a subtype of autism spectrum disorders. Clearly, the impact of TOP1 on human health is multifold. In this review, we will summarize our current understandings on how TOP1 contributes to human diseases and how its activity is targeted for disease treatments.

PMID: 27181710 [PubMed - as supplied by publisher]

Prevalence of Creatine Deficiency Syndromes in Children With Nonsyndromic Autism.

May 18, 2016 - 4:30pm
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Prevalence of Creatine Deficiency Syndromes in Children With Nonsyndromic Autism.

Pediatrics. 2016 Jan;137(1)

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 - indexed for MEDLINE]

Shank synaptic scaffold proteins: keys to understanding the pathogenesis of autism and other synaptic disorders.

May 18, 2016 - 4:30pm
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Shank synaptic scaffold proteins: keys to understanding the pathogenesis of autism and other synaptic disorders.

J Neurochem. 2015 Dec;135(5):849-58

Authors: Sala C, Vicidomini C, Bigi I, Mossa A, Verpelli C

Abstract
Shank/ProSAP proteins are essential to synaptic formation, development, and function. Mutations in the family of SHANK genes are strongly associated with autism spectrum disorders (ASD) and other neurodevelopmental and neuropsychiatric disorders, such as intellectual disability (ID), and schizophrenia. Thus, the term 'Shankopathies' identifies a number of neuronal diseases caused by alteration of Shank protein expression leading to abnormal synaptic development. With this review we want to summarize the major genetic, molecular, behavior and electrophysiological studies that provide new clues into the function of Shanks and pave the way for the discovery of new therapeutic drugs targeted to treat patients with SHANK mutations and also patients affected by other neurodevelopmental and neuropsychiatric disorders. Shank/ProSAP proteins are essential to synaptic formation, development, and function. Mutations in the family of SHANK genes are strongly associated with autism spectrum disorders (ASD) and other neurodevelopmental and neuropsychiatric disorders, such as intellectual disability (ID), and schizophrenia (SCZ). With this review we want to summarize the major genetic, molecular, behavior and electrophysiological studies that provide new clues into the function of Shanks and pave the way for the discovery of new therapeutic drugs targeted to treat patients with SHANK mutations.

PMID: 26338675 [PubMed - indexed for MEDLINE]

Using Sibling Designs to Understand Neurodevelopmental Disorders: From Genes and Environments to Prevention Programming.

May 18, 2016 - 4:30pm
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Using Sibling Designs to Understand Neurodevelopmental Disorders: From Genes and Environments to Prevention Programming.

Biomed Res Int. 2015;2015:672784

Authors: Wade M, Prime H, Madigan S

Abstract
Neurodevelopmental disorders represent a broad class of childhood neurological conditions that have a significant bearing on the wellbeing of children, families, and communities. In this review, we draw on evidence from two common and widely studied neurodevelopmental disorders-autism spectrum disorder (ASD) and attention-deficit hyperactivity disorder (ADHD)-to demonstrate the utility of genetically informed sibling designs in uncovering the nature and pathogenesis of these conditions. Specifically, we examine how twin, recurrence risk, and infant prospective tracking studies have contributed to our understanding of genetic and environmental liabilities towards neurodevelopmental morbidity through their impact on neurocognitive processes and structural/functional neuroanatomy. It is suggested that the siblings of children with ASD and ADHD are at risk not only of clinically elevated problems in these areas, but also of subthreshold symptoms and/or subtle impairments in various neurocognitive skills and other domains of psychosocial health. Finally, we close with a discussion on the practical relevance of sibling designs and how these might be used in the service of early screening, prevention, and intervention efforts that aim to alleviate the negative downstream consequences associated with disorders of neurodevelopment.

PMID: 26258141 [PubMed - indexed for MEDLINE]

Systemic dendrimer-drug treatment of ischemia-induced neonatal white matter injury.

May 18, 2016 - 4:30pm
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Systemic dendrimer-drug treatment of ischemia-induced neonatal white matter injury.

J Control Release. 2015 Sep 28;214:112-20

Authors: Nance E, Porambo M, Zhang F, Mishra MK, Buelow M, Getzenberg R, Johnston M, Kannan RM, Fatemi A, Kannan S

Abstract
Extreme prematurity is a major risk factor for perinatal and neonatal brain injury, and can lead to white matter injury that is a precursor for a number of neurological diseases, including cerebral palsy (CP) and autism. Neuroinflammation, mediated by activated microglia and astrocytes, is implicated in the pathogenesis of neonatal brain injury. Therefore, targeted drug delivery to attenuate neuroinflammation may greatly improve therapeutic outcomes in models of perinatal white matter injury. In this work, we use a mouse model of ischemia-induced neonatal white matter injury to study the biodistribution of generation 4, hydroxyl-functionalized polyamidoamine dendrimers. Following systemic administration of the Cy5-labeled dendrimer (D-Cy5), we demonstrate dendrimer uptake in cells involved in ischemic injury, and in ongoing inflammation, leading to secondary injury. The sub-acute response to injury is driven by astrocytes. Within five days of injury, microglial proliferation and migration occurs, along with limited differentiation of oligodendrocytes and oligodendrocyte death. From one day to five days after injury, a shift in dendrimer co-localization occurred. Initially, dendrimer predominantly co-localized with astrocytes, with a subsequent shift towards microglia. Co-localization with oligodendrocytes reduced over the same time period, demonstrating a region-specific uptake based on the progression of the injury. We further show that systemic administration of a single dose of dendrimer-N-acetyl cysteine conjugate (D-NAC) at either sub-acute or delayed time points after injury results in sustained attenuation of the 'detrimental' pro-inflammatory response up to 9days after injury, while not impacting the 'favorable' anti-inflammatory response. The D-NAC therapy also led to improvement in myelination, suggesting reduced white matter injury. Demonstration of treatment efficacy at later time points in the postnatal period provides a greater understanding of how microglial activation and chronic inflammation can be targeted to treat neonatal brain injury. Importantly, it may also provide a longer therapeutic window.

PMID: 26184052 [PubMed - indexed for MEDLINE]

Spatiotemporal dynamics of the postnatal developing primate brain transcriptome.

May 18, 2016 - 4:30pm
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Spatiotemporal dynamics of the postnatal developing primate brain transcriptome.

Hum Mol Genet. 2015 Aug 1;24(15):4327-39

Authors: Bakken TE, Miller JA, Luo R, Bernard A, Bennett JL, Lee CK, Bertagnolli D, Parikshak NN, Smith KA, Sunkin SM, Amaral DG, Geschwind DH, Lein ES

Abstract
Developmental changes in the temporal and spatial regulation of gene expression drive the emergence of normal mature brain function, while disruptions in these processes underlie many neurodevelopmental abnormalities. To solidify our foundational knowledge of such changes in a primate brain with an extended period of postnatal maturation like in human, we investigated the whole-genome transcriptional profiles of rhesus monkey brains from birth to adulthood. We found that gene expression dynamics are largest from birth through infancy, after which gene expression profiles transition to a relatively stable state by young adulthood. Biological pathway enrichment analysis revealed that genes more highly expressed at birth are associated with cell adhesion and neuron differentiation, while genes more highly expressed in juveniles and adults are associated with cell death. Neocortex showed significantly greater differential expression over time than subcortical structures, and this trend likely reflects the protracted postnatal development of the cortex. Using network analysis, we identified 27 co-expression modules containing genes with highly correlated expression patterns that are associated with specific brain regions, ages or both. In particular, one module with high expression in neonatal cortex and striatum that decreases during infancy and juvenile development was significantly enriched for autism spectrum disorder (ASD)-related genes. This network was enriched for genes associated with axon guidance and interneuron differentiation, consistent with a disruption in the formation of functional cortical circuitry in ASD.

PMID: 25954031 [PubMed - indexed for MEDLINE]

Common genetic variants linked with large percentage of autism risk: study finds spontaneous mutations are less-significant risk factors.

May 18, 2016 - 4:30pm
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Common genetic variants linked with large percentage of autism risk: study finds spontaneous mutations are less-significant risk factors.

Am J Med Genet A. 2014 Nov;164A(11):vii-viii

Authors: Levenson D

PMID: 25327469 [PubMed - indexed for MEDLINE]

Diagnostic and clinical characteristics of early-manifesting females with Duchenne or Becker muscular dystrophy.

May 18, 2016 - 4:30pm
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Diagnostic and clinical characteristics of early-manifesting females with Duchenne or Becker muscular dystrophy.

Am J Med Genet A. 2014 Nov;164A(11):2769-74

Authors: Imbornoni L, Price ET, Andrews J, Meaney FJ, Ciafaloni E, Cunniff C

Abstract
Manifestations of Duchenne and Becker muscular dystrophy (DBMD) are present in up to 40% of heterozygous females, but there are few reports of females who exhibit skeletal muscle symptoms in childhood. From the Muscular Dystrophy Surveillance Tracking and Research Network, a multi-site population-based surveillance network for dystrophinopathy, nine symptomatic female heterozygotes with onset of symptoms prior to age 9 years were identified. The median age at diagnosis was 8.3 years, and the median interval from first symptoms to diagnosis was 1.35 years. Of the nine female heterozygotes, four had a positive family history, seven had intellectual disability and five had at least one mental health disorder. Mental health concerns included attention deficit hyperactivity disorder (ADHD), autism spectrum features, bipolar disorder, and depression. The frequency of intellectual and mental health problems in this group is higher than previously reported for affected males and for symptomatic females. These findings may have implications for diagnosis of early manifesting heterozygotes and for their health supervision.

PMID: 25125379 [PubMed - indexed for MEDLINE]

A terminal 3p26.3 deletion is not associated with dysmorphic features and intellectual disability in a four-generation family.

May 18, 2016 - 4:30pm
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A terminal 3p26.3 deletion is not associated with dysmorphic features and intellectual disability in a four-generation family.

Am J Med Genet A. 2014 Nov;164A(11):2863-8

Authors: Moghadasi S, van Haeringen A, Langendonck L, Gijsbers AC, Ruivenkamp CA

Abstract
Terminal deletions of the distal part of the short arm of chromosome 3 cause a wide range of phenotypes from normal to dysmorphic including microcephaly, developmental delay and intellectual disability. We studied the clinical consequences of a terminal deletion of the short arm of chromosome 3 in four generations of a family. The index patient is a14-month-old boy with microcephaly, corpus callosum dysgenesis, and minor dysmorphic features. Single Nucleotide Polymorphism (SNP) array analysis detected a duplication on the long arm of chromosome 6. His apparently healthy mother carries the same 6q duplication, but as an unexpected finding a terminal deletion of 2.9 Mb of the short arm of chromosome 3 was observed. Further co-segregation analysis in the family for the chromosome 3 deletion showed that with the exception of the sister of the index who has autism, speech delay, and learning problems, family members in four generations of this family are carrier of this 3p deletion and apparently healthy. To our knowledge, this is the first report of a study of this terminal 3p deletion in four generations. In this report, we review the literature on terminal 3p deletions and discuss the importance of molecular testing and reporting of copy number variants to achieve accurate genetic counseling in prenatal and postnatal screening.

PMID: 25123480 [PubMed - indexed for MEDLINE]

Early event-related potentials to emotional faces differ for adults with autism spectrum disorder and by serotonin transporter genotype.

May 15, 2016 - 10:24am

Early event-related potentials to emotional faces differ for adults with autism spectrum disorder and by serotonin transporter genotype.

Clin Neurophysiol. 2016 Jun;127(6):2436-47

Authors: Faja S, Dawson G, Aylward E, Wijsman EM, Webb SJ

Abstract
OBJECTIVE: To test differences in neural sensitivity to facial expressions, including expressions with open versus closed mouths, exhibited by (1) adults with autism spectrum disorder (ASD) compared to neurotypical adults, and by (2) short versus long serotonin transporter allele (SLC6A4) carriers.
METHODS: Event related potentials (ERPs) to happy, fearful, and neutral expressions were collected from neurotypical adults (n=25) and adults with ASD (n=27)-of whom 32 had short and 13 had homozygous long SLC6A4 alleles.
RESULTS: In the neurotypical group, we confirmed that the N170, VPP and EPN, but not the P1, were influenced by emotional expressions, and determined the EPN was the earliest component modulated by open mouth. Compared to the neurotypical group, individuals with ASD exhibited differences in EPN amplitude in response to open versus closed mouths and in hemispheric distribution. Across groups, short serotonin transporter allele carriers had reduced P1 amplitude compared to long allele carriers.
CONCLUSIONS: Individuals with ASD exhibited a different pattern of neural response when encoding and recognizing facial expressions at the EPN component. Across groups, SLC6A4 allele type modulated early sensory attention at the P1.
SIGNIFICANCE: These results provide insight into the nature of early responses to emotional information according to genetic variation and clinical condition.

PMID: 27178863 [PubMed - in process]

Generation of a Tph2 Conditional Knockout Mouse Line for Time- and Tissue-Specific Depletion of Brain Serotonin.

May 14, 2016 - 7:23am
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Generation of a Tph2 Conditional Knockout Mouse Line for Time- and Tissue-Specific Depletion of Brain Serotonin.

PLoS One. 2015;10(8):e0136422

Authors: Pelosi B, Pratelli M, Migliarini S, Pacini G, Pasqualetti M

Abstract
Serotonin has been gaining increasing attention during the last two decades due to the dual function of this monoamine as key regulator during critical developmental events and as neurotransmitter. Importantly, unbalanced serotonergic levels during critical temporal phases might contribute to the onset of neuropsychiatric disorders, such as schizophrenia and autism. Despite increasing evidences from both animal models and human genetic studies have underpinned the importance of serotonin homeostasis maintenance during central nervous system development and adulthood, the precise role of this molecule in time-specific activities is only beginning to be elucidated. Serotonin synthesis is a 2-step process, the first step of which is mediated by the rate-limiting activity of Tph enzymes, belonging to the family of aromatic amino acid hydroxylases and existing in two isoforms, Tph1 and Tph2, responsible for the production of peripheral and brain serotonin, respectively. In the present study, we generated and validated a conditional knockout mouse line, Tph2flox/flox, in which brain serotonin can be effectively ablated with time specificity. We demonstrated that the Cre-mediated excision of the third exon of Tph2 gene results in the production of a Tph2null allele in which we observed the near-complete loss of brain serotonin, as well as the growth defects and perinatal lethality observed in serotonin conventional knockouts. We also revealed that in mice harbouring the Tph2null allele, but not in wild-types, two distinct Tph2 mRNA isoforms are present, namely Tph2Δ3 and Tph2Δ3Δ4, with the latter showing an in-frame deletion of amino acids 84-178 and coding a protein that could potentially retain non-negligible enzymatic activity. As we could not detect Tph1 expression in the raphe, we made the hypothesis that the Tph2Δ3Δ4 isoform can be at the origin of the residual, sub-threshold amount of serotonin detected in the brain of Tph2null/null mice. Finally, we set up a tamoxifen administration protocol that allows an efficient, time-specific inactivation of brain serotonin synthesis. On the whole, we generated a suitable genetic tool to investigate how serotonin depletion impacts on time-specific events during central nervous system development and adulthood life.

PMID: 26291320 [PubMed - indexed for MEDLINE]

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