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Reduced burden of very large and rare CNVs in bipolar affective disorder.

July 24, 2014 - 7:50am
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Reduced burden of very large and rare CNVs in bipolar affective disorder.

Bipolar Disord. 2013 Dec;15(8):893-8

Authors: Grozeva D, Kirov G, Conrad DF, Barnes CP, Hurles M, Owen MJ, O'Donovan MC, Craddock N

Abstract
OBJECTIVES: Large, rare chromosomal copy number variants (CNVs) have been shown to increase the risk for schizophrenia and other neuropsychiatric disorders including autism, attention-deficit hyperactivity disorder, learning difficulties, and epilepsy. Their role in bipolar disorder (BD) is less clear. There are no reports of an increase in large, rare CNVs in BD in general, but some have reported an increase in early-onset cases. We previously found that the rate of such CNVs in individuals with BD was not increased, even in early-onset cases. Our aim here was to examine the rate of large rare CNVs in BD in comparison with a new large independent reference sample from the same country.
METHODS: We studied the CNVs in a case-control sample consisting of 1,650 BD cases (reported previously) and 10,259 reference individuals without a known psychiatric disorder who took part in the original Wellcome Trust Case Control Consortium (WTCCC) study. The 10,259 reference individuals were affected with six non-psychiatric disorders (coronary artery disease, types 1 and 2 diabetes, hypertension, Crohn's disease, and rheumatoid arthritis). Affymetrix 500K array genotyping data were used to call the CNVs.
RESULTS: The rate of CNVs > 100 kb was not statistically different between cases and controls. The rate of very large (defined as > 1 Mb) and rare (< 1%) CNVs was significantly lower in patients with BD compared with the reference group. CNV loci associated with schizophrenia were not enriched in BD and, in fact, cases of BD had the lowest number of such CNVs compared with any of the WTCCC cohorts; this finding held even for the early-onset BD cases.
CONCLUSIONS: Schizophrenia and BD differ with respect to CNV burden and association with specific CNVs. Our findings support the hypothesis that BD is etiologically distinct from schizophrenia with respect to large, rare CNVs and the accompanying associated neurodevelopmental abnormalities.

PMID: 24127788 [PubMed - indexed for MEDLINE]

A CTNNA3 compound heterozygous deletion implicates a role for αT-catenin in susceptibility to autism spectrum disorder.

July 23, 2014 - 7:44am

A CTNNA3 compound heterozygous deletion implicates a role for αT-catenin in susceptibility to autism spectrum disorder.

J Neurodev Disord. 2014;6(1):17

Authors: Bacchelli E, Ceroni F, Pinto D, Lomartire S, Giannandrea M, D'Adamo P, Bonora E, Parchi P, Tancredi R, Battaglia A, Maestrini E

Abstract
BACKGROUND: Autism spectrum disorder (ASD) is a highly heritable, neurodevelopmental condition showing extreme genetic heterogeneity. While it is well established that rare genetic variation, both de novo and inherited, plays an important role in ASD risk, recent studies also support a rare recessive contribution.
METHODS: We identified a compound heterozygous deletion intersecting the CTNNA3 gene, encoding αT-catenin, in a proband with ASD and moderate intellectual disability. The deletion breakpoints were mapped at base-pair resolution, and segregation analysis was performed. We compared the frequency of CTNNA3 exonic deletions in 2,147 ASD cases from the Autism Genome Project (AGP) study versus the frequency in 6,639 controls. Western blot analysis was performed to get a quantitative characterisation of Ctnna3 expression during early brain development in mouse.
RESULTS: The CTNNA3 compound heterozygous deletion includes a coding exon, leading to a putative frameshift and premature stop codon. Segregation analysis in the family showed that the unaffected sister is heterozygote for the deletion, having only inherited the paternal deletion. While the frequency of CTNNA3 exonic deletions is not significantly different between ASD cases and controls, no homozygous or compound heterozygous exonic deletions were found in a sample of over 6,000 controls. Expression analysis of Ctnna3 in the mouse cortex and hippocampus (P0-P90) provided support for its role in the early stage of brain development.
CONCLUSION: The finding of a rare compound heterozygous CTNNA3 exonic deletion segregating with ASD, the absence of CTNNA3 homozygous exonic deletions in controls and the high expression of Ctnna3 in both brain areas analysed implicate CTNNA3 in ASD susceptibility.

PMID: 25050139 [PubMed]

Gene-rich large deletions are overrepresented in POAG patients of Indian and Caucasian origins.

July 23, 2014 - 7:44am
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Gene-rich large deletions are overrepresented in POAG patients of Indian and Caucasian origins.

Invest Ophthalmol Vis Sci. 2014 May;55(5):3258-64

Authors: Kaurani L, Vishal M, Kumar D, Sharma A, Mehani B, Sharma C, Chakraborty S, Jha P, Ray J, Sen A, Dash D, Ray K, Mukhopadhyay A

Abstract
PURPOSE: Large copy number variations (CNV) can contribute to increased burden for neurodegenerative diseases. In this study, we analyzed the genome-wide burden of large CNVs > 100 kb in primary open angle glaucoma (POAG), a neurodegenerative disease of the eye that is the largest cause of irreversible blindness.
METHODS: Genome-wide analysis of CNVs > 100 kb were analyzed in a total of 1720 individuals, including an Indian cohort (347 POAG cases and 345 controls) and a Caucasian cohort (624 cases and 404 controls). All the CNV data were obtained from experiments performed on Illumina 660W-Quad (infinium) arrays.
RESULTS: We observed that for both the populations CNVs > 1 Mb was significantly enriched for gene-rich regions unique to the POAG cases (P < 10(-11)). In the Indian cohort CNVs > 1 Mb (39 calls) in patients influenced 125 genes while in controls 31 such CNVs influenced only 5 genes with no overlap. In both cohorts we observed 1.9-fold gene enrichment in patients for deletions compared to duplications, while such a bias was not observed in controls (0.3-fold). Overall duplications > 1 Mb were more than deletions (Del/Dup = 0.82) confirming that the enrichment of gene-rich deletions in patients was associated with the disease. Of the 39 CNVs > 1 Mb from Indian patients, 28 (72%) also were implicated in other neurodegenerative disorders, like autism, schizophrenia, sensorineural hearing loss, and so forth. We found one large duplication encompassing CNTN4 gene in Indian and Caucasian POAG patients that was absent in the controls.
CONCLUSIONS: To our knowledge, our study is the first report on large CNV bias for gene-rich regions in glaucomatous neurodegeneration, implicating its impact across populations of contrasting ethnicities. We identified CNTN4 as a novel candidate gene for POAG.

PMID: 24764060 [PubMed - indexed for MEDLINE]

Most genetic risk for autism resides with common variation.

July 21, 2014 - 7:12am

Most genetic risk for autism resides with common variation.

Nat Genet. 2014 Jul 20;

Authors: Gaugler T, Klei L, Sanders SJ, Bodea CA, Goldberg AP, Lee AB, Mahajan M, Manaa D, Pawitan Y, Reichert J, Ripke S, Sandin S, Sklar P, Svantesson O, Reichenberg A, Hultman CM, Devlin B, Roeder K, Buxbaum JD

Abstract
A key component of genetic architecture is the allelic spectrum influencing trait variability. For autism spectrum disorder (herein termed autism), the nature of the allelic spectrum is uncertain. Individual risk-associated genes have been identified from rare variation, especially de novo mutations. From this evidence, one might conclude that rare variation dominates the allelic spectrum in autism, yet recent studies show that common variation, individually of small effect, has substantial impact en masse. At issue is how much of an impact relative to rare variation this common variation has. Using a unique epidemiological sample from Sweden, new methods that distinguish total narrow-sense heritability from that due to common variation and synthesis of results from other studies, we reach several conclusions about autism's genetic architecture: its narrow-sense heritability is ∼52.4%, with most due to common variation, and rare de novo mutations contribute substantially to individual liability, yet their contribution to variance in liability, 2.6%, is modest compared to that for heritable variation.

PMID: 25038753 [PubMed - as supplied by publisher]

An Autism Case History to Review the Systematic Analysis of Large-Scale Data to Refine the Diagnosis and Treatment of Neuropsychiatric Disorders.

July 19, 2014 - 6:42am

An Autism Case History to Review the Systematic Analysis of Large-Scale Data to Refine the Diagnosis and Treatment of Neuropsychiatric Disorders.

Biol Psychiatry. 2014 Jun 12;

Authors: Kohane IS

Abstract
Analysis of large-scale systems of biomedical data provides a perspective on neuropsychiatric disease that may be otherwise elusive. Described here is an analysis of three large-scale systems of data from autism spectrum disorder (ASD) and of ASD research as an exemplar of what might be achieved from study of such data. First is the biomedical literature that highlights the fact that there are two very successful but quite separate research communities and findings pertaining to genetics and the molecular biology of ASD. There are those studies positing ASD causes that are related to immunological dysregulation and those related to disorders of synaptic function and neuronal connectivity. Second is the emerging use of electronic health record systems and other large clinical databases that allow the data acquired during the course of care to be used to identify distinct subpopulations, clinical trajectories, and pathophysiological substructures of ASD. These systems reveal subsets of patients with distinct clinical trajectories, some of which are immunologically related and others which follow pathologies conventionally thought of as neurological. The third is genome-wide genomic and transcriptomic analyses which show molecular pathways that overlap neurological and immunological mechanisms. The convergence of these three large-scale data perspectives illustrates the scientific leverage that large-scale data analyses can provide in guiding researchers in an approach to the diagnosis of neuropsychiatric disease that is inclusive and comprehensive.

PMID: 25034947 [PubMed - as supplied by publisher]

Role of the PTEN signaling pathway in autism spectrum disorder.

July 19, 2014 - 6:42am
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Role of the PTEN signaling pathway in autism spectrum disorder.

Neurosci Bull. 2013 Dec;29(6):773-8

Authors: Lv JW, Cheng TL, Qiu ZL, Zhou WH

Abstract
Autism is an etiologically heterogeneous group of neurodevelopmental disorders, diagnosed mostly by the clinical behavioral phenotypes. The concept that the tumor-related gene PTEN plays a critical role in autism spectrum disorder has emerged over the last decade. In this review, we focus on the essential role of the PTEN signaling pathway in neuronal differentiation and the formation of neural circuitry, as well as genetic mouse models with Pten manipulations. Particularly, accumulated data suggest that the effect of PTEN on neural stem-cell development contributes significantly to the pathophysiology of autism spectrum disorders.

PMID: 24136242 [PubMed - indexed for MEDLINE]

Susceptibility genes are enriched in those of the herpes simplex virus 1/host interactome in psychiatric and neurological disorders.

July 19, 2014 - 6:42am
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Susceptibility genes are enriched in those of the herpes simplex virus 1/host interactome in psychiatric and neurological disorders.

Pathog Dis. 2013 Dec;69(3):240-61

Authors: Carter CJ

Abstract
Herpes simplex virus 1 (HSV-1) can promote beta-amyloid deposition and tau phosphorylation, demyelination or cognitive deficits relevant to Alzheimer's disease or multiple sclerosis and to many neuropsychiatric disorders with which it has been implicated. A seroprevalence much higher than disease incidence has called into question any primary causal role. However, as also the case with risk-promoting polymorphisms (also present in control populations), any causal effects are likely to be conditional. During its life cycle, the virus binds to many proteins and modifies the expression of multiple genes creating a host/pathogen interactome involving 1347 host genes. This data set is heavily enriched in the susceptibility genes for multiple sclerosis (P = 1.3E-99) > Alzheimer's disease > schizophrenia > Parkinsonism > depression > bipolar disorder > childhood obesity > chronic fatigue > autism > and anorexia (P = 0.047) but not attention deficit hyperactivity disorder, a relationship maintained for genome-wide association study data sets in multiple sclerosis and Alzheimer's disease. Overlapping susceptibility gene/interactome data sets disrupt signalling networks relevant to each disease, suggesting that disease susceptibility genes may filter the attentions of the pathogen towards particular pathways and pathologies. In this way, the same pathogen could contribute to multiple diseases in a gene-dependent manner and condition the risk-promoting effects of the genes whose function it disrupts.

PMID: 23913659 [PubMed - indexed for MEDLINE]

Seizures and EEG pattern in the 22q13.3 deletion syndrome: Clinical report of six Italian cases.

July 17, 2014 - 6:47am

Seizures and EEG pattern in the 22q13.3 deletion syndrome: Clinical report of six Italian cases.

Seizure. 2014 Jul 1;

Authors: Figura MG, Coppola A, Bottitta M, Calabrese G, Grillo L, Luciano D, Del Gaudio L, Torniero C, Striano S, Elia M

Abstract
PURPOSE: The 22q13.3 deletion syndrome, also known as Phelan-McDermid syndrome, is a rare genetic disorder characterized by hypotonia, severely impaired development of speech and language, autistic-like behaviour, and minor dysmorphic features. Neurologic problems may include seizures of different types, such as febrile, generalized tonic-clonic, focal, and absence seizures. No peculiar EEG features have been associated with 22q13 deletion syndrome to date. In order to verify if a peculiar clinical and EEG pattern is present in 22q13.3 deletion syndrome, we studied six Italian patients with this chromosome abnormality.
METHOD: Array CGH analysis was carried out in the six subjects (1 male, 5 females, age range 11-30 years, median 19.5). They underwent a complete general and neurologic examinations. The EEG study consisted of at least one awake and one nap-sleep video-EEG recordings and evaluation of other EEGs performed elsewhere.
RESULTS: Three subjects suffered from myoclonic or generalized tonic-clonic seizures with a rather benign course; all showed multifocal paroxysmal abnormalities on EEG recording, predominant over the frontal-temporal regions, activated during sleep.
CONCLUSION: 22q13.3 deletion syndrome seems to be associated, at least in a subgroup of patients, with a peculiar clinical and EEG pattern, characterized by a childhood epilepsy with a rather benign evolution and with multifocal paroxysmal EEG abnormalities activated by sleep.

PMID: 25027555 [PubMed - as supplied by publisher]

Role of parental occupation in autism spectrum disorder diagnosis and severity.

July 16, 2014 - 8:37am
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Role of parental occupation in autism spectrum disorder diagnosis and severity.

Res Autism Spectr Disord. 2014 Sep 1;8(9):997-1007

Authors: Dickerson AS, Pearson DA, Loveland KA, Rahbar MH, Filipek PA

PMID: 25024741 [PubMed - as supplied by publisher]

Autism susceptibility genes and the transcriptional landscape of the human brain.

July 16, 2014 - 8:37am
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Autism susceptibility genes and the transcriptional landscape of the human brain.

Int Rev Neurobiol. 2013;113:303-18

Authors: Miyauchi S, Voineagu I

Abstract
Autism is the most severe end of a spectrum of neurodevelopmental conditions, autism spectrum disorders (ASD). ASD are genetically heterogeneous, and hundreds of genes have been implicated in the etiology of the disease. Here, we discuss the contribution of brain transcriptome studies in advancing our understanding of the genetic mechanisms of ASD and review recent work characterizing the spatial and temporal variation of the human brain transcriptome, with a focus on the relevance of these data to autism susceptibility genes.

PMID: 24290390 [PubMed - indexed for MEDLINE]

Orchestration of neurodevelopmental programs by RBFOX1: implications for autism spectrum disorder.

July 16, 2014 - 8:37am
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Orchestration of neurodevelopmental programs by RBFOX1: implications for autism spectrum disorder.

Int Rev Neurobiol. 2013;113:251-67

Authors: Bill BR, Lowe JK, Dybuncio CT, Fogel BL

Abstract
Neurodevelopmental and neuropsychiatric disorders result from complex interactions between critical genetic factors and as-yet-unknown environmental components. To gain clinical insight, it is critical to develop a comprehensive understanding of these genetic components. RBFOX1, an RNA splicing factor, regulates expression of large genetic networks during early neuronal development, and haploinsufficiency causes severe neurodevelopmental phenotypes including autism spectrum disorder (ASD), intellectual disability, and epilepsy. Genomic testing in individuals and large patient cohorts has identified phenotypically similar cases possessing copy number variations in RBFOX1, implicating the gene as an important cause of neurodevelopmental disease. However, a significant proportion of the observed structural variation is inherited from phenotypically normal individuals, raising questions regarding overall pathogenicity of variation at the RBFOX1 locus. In this chapter, we discuss the molecular, cellular, and clinical evidence supporting the role of RBFOX1 in neurodevelopment and present a comprehensive model for the contribution of structural variation in RBFOX1 to ASD.

PMID: 24290388 [PubMed - indexed for MEDLINE]

Transcriptional dysregulation of neocortical circuit assembly in ASD.

July 16, 2014 - 8:37am
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Transcriptional dysregulation of neocortical circuit assembly in ASD.

Int Rev Neurobiol. 2013;113:167-205

Authors: Kwan KY

Abstract
Autism spectrum disorders (ASDs) impair social cognition and communication, key higher-order functions centered in the human neocortex. The assembly of neocortical circuitry is a precisely regulated developmental process susceptible to genetic alterations that can ultimately affect cognitive abilities. Because ASD is an early onset neurodevelopmental disorder that disrupts functions executed by the neocortex, miswiring of neocortical circuits has been hypothesized to be an underlying mechanism of ASD. This possibility is supported by emerging genetic findings and data from imaging studies. Recent research on neocortical development has identified transcription factors as key determinants of neocortical circuit assembly, mediating diverse processes including neuronal specification, migration, and wiring. Many of these TFs (TBR1, SOX5, FEZF2, and SATB2) have been implicated in ASD. Here, I will discuss the functional roles of these transcriptional programs in neocortical circuit development and their neurobiological implications for the emerging etiology of ASD.

PMID: 24290386 [PubMed - indexed for MEDLINE]

MET receptor tyrosine kinase as an autism genetic risk factor.

July 16, 2014 - 8:37am
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MET receptor tyrosine kinase as an autism genetic risk factor.

Int Rev Neurobiol. 2013;113:135-65

Authors: Peng Y, Huentelman M, Smith C, Qiu S

Abstract
In this chapter, we will briefly discuss recent literature on the role of MET receptor tyrosine kinase (RTK) in brain development and how perturbation of MET signaling may alter normal neurodevelopmental outcomes. Recent human genetic studies have established MET as a risk factor for autism, and the molecular and cellular underpinnings of this genetic risk are only beginning to emerge from obscurity. Unlike many autism risk genes that encode synaptic proteins, the spatial and temporal expression pattern of MET RTK indicates this signaling system is ideally situated to regulate neuronal growth, functional maturation, and establishment of functional brain circuits, particularly in those brain structures involved in higher levels of cognition, social skills, and executive functions.

PMID: 24290385 [PubMed - indexed for MEDLINE]

Connecting signaling pathways underlying communication to ASD vulnerability.

July 16, 2014 - 8:37am
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Connecting signaling pathways underlying communication to ASD vulnerability.

Int Rev Neurobiol. 2013;113:97-133

Authors: Lepp S, Anderson A, Konopka G

Abstract
Language is a human-specific trait that likely facilitated the rapid increase in higher cognitive function in our species. A consequence of the selective pressures that have permitted language and cognition to flourish in humans is the unique vulnerability of humans to developing cognitive disorders such as autism. Therefore, progress in understanding the genetic and molecular mechanisms of language evolution should provide insight into such disorders. Here, we discuss the few genes that have been identified in both autism-related pathways and language. We also detail the use of animal models to uncover the function of these genes at a mechanistic and circuit level. Finally, we present the use of comparative genomics to identify novel genes and gene networks involved in autism. Together, all of these approaches will allow for a broader and deeper view of the molecular brain mechanisms involved in the evolution of language and the gene disruptions associated with autism.

PMID: 24290384 [PubMed - indexed for MEDLINE]

Identifying essential cell types and circuits in autism spectrum disorders.

July 16, 2014 - 8:37am
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Identifying essential cell types and circuits in autism spectrum disorders.

Int Rev Neurobiol. 2013;113:61-96

Authors: Maloney SE, Rieger MA, Dougherty JD

Abstract
Autism spectrum disorder (ASD) is highly genetic in its etiology, with potentially hundreds of genes contributing to risk. Despite this heterogeneity, these disparate genetic lesions may result in the disruption of a limited number of key cell types or circuits-information which could be leveraged for the design of therapeutic interventions. While hypotheses for cellular disruptions can be identified by postmortem anatomical analysis and expression studies of ASD risk genes, testing these hypotheses requires the use of animal models. In this review, we explore the existing evidence supporting the contribution of different cell types to ASD, specifically focusing on rodent studies disrupting serotonergic, GABAergic, cerebellar, and striatal cell types, with particular attention to studies of the sufficiency of specific cellular disruptions to generate ASD-related behavioral abnormalities. This evidence suggests multiple cellular routes can create features of the disorder, though it is currently unclear if these cell types converge on a final common circuit. We hope that in the future, systematic studies of cellular sufficiency and genetic interaction will help to classify patients into groups by type of cellular disruptions which suggest tractable therapeutic targets.

PMID: 24290383 [PubMed - indexed for MEDLINE]

Contribution of long noncoding RNAs to autism spectrum disorder risk.

July 16, 2014 - 8:37am
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Contribution of long noncoding RNAs to autism spectrum disorder risk.

Int Rev Neurobiol. 2013;113:35-59

Authors: Wilkinson B, Campbell DB

Abstract
Accumulating evidence indicates that long noncoding RNAs (lncRNAs) contribute to autism spectrum disorder (ASD) risk. Although a few lncRNAs have long been recognized to have important functions, the vast majority of this class of molecules remains uncharacterized. Because lncRNAs are more abundant in human brain than protein-coding RNAs, it is likely that they contribute to brain disorders, including ASD. We review here the known functions of lncRNAs and the potential contributions of lncRNAs to ASD.

PMID: 24290382 [PubMed - indexed for MEDLINE]

Autism spectrum disorder and the cerebellum.

July 16, 2014 - 8:37am
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Autism spectrum disorder and the cerebellum.

Int Rev Neurobiol. 2013;113:1-34

Authors: Becker EB, Stoodley CJ

Abstract
The cerebellum has been long known for its importance in motor learning and coordination. Recently, anatomical, clinical, and neuroimaging studies strongly suggest that the cerebellum supports cognitive functions, including language and executive functions, as well as affective regulation. Furthermore, the cerebellum has emerged as one of the key brain regions affected in autism. Here, we discuss our current understanding of the role of the cerebellum in autism, including evidence from genetic, molecular, clinical, behavioral, and neuroimaging studies. Cerebellar findings in autism suggest developmental differences at multiple levels of neural structure and function, indicating that the cerebellum is an important player in the complex neural underpinnings of autism spectrum disorder, with behavioral implications beyond the motor domain.

PMID: 24290381 [PubMed - indexed for MEDLINE]

[Autism and epigenetics. A model of explanation for the understanding of the genesis in autism spectrum disorders].

July 16, 2014 - 8:37am
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[Autism and epigenetics. A model of explanation for the understanding of the genesis in autism spectrum disorders].

Medicina (B Aires). 2013;73 Suppl 1:20-9

Authors: Arberas C, Ruggieri V

Abstract
Autism spectrum disorders are characterized by impairment of social integration and language development and restricted interests. Autism spectrum disorders manifest during childhood and may have a varying clinical expression over the years related to different therapeutic approaches, behavior-modifying drugs, and environmental factors, among others. So far, the genetic alterations identified are not sufficient to explain the genesis of all these processes, as many of the mutations found are also present in unaffected individuals. Findings on the underlying biological and pathophysiological mechanisms of entities strongly associated with autism spectrum disorders, such as Rett, fragile X, Angelman, and fetal alcohol syndromes, point to the role of epigenetic changes in disorders of neurodevelopment. Epigenetic phenomena are normal biological processes necessary for cell and thus human life, especially related to embryonic development. Different phenomena that affect epigenetic processes (changes that change operation or expression of a gene, without modifying the DNA structure) have also been shown to be important in the genesis of neurodevelopmental disorders. Alterations in the epigenetic mechanism may be reversible, which may explain the variation in the autism phenotype over time. Here we analyze the normal epigenetic mechanisms, autism spectrum disorders, their association with specific entities associated with altered epigenetic mechanisms, and possible therapeutic approaches targeting these alterations.

PMID: 24072048 [PubMed - indexed for MEDLINE]

Mutations in SLC35A3 cause autism spectrum disorder, epilepsy and arthrogryposis.

July 16, 2014 - 8:37am
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Mutations in SLC35A3 cause autism spectrum disorder, epilepsy and arthrogryposis.

J Med Genet. 2013 Nov;50(11):733-9

Authors: Edvardson S, Ashikov A, Jalas C, Sturiale L, Shaag A, Fedick A, Treff NR, Garozzo D, Gerardy-Schahn R, Elpeleg O

Abstract
BACKGROUND: The heritability of autism spectrum disorder is currently estimated at 55%. Identification of the molecular basis of patients with syndromic autism extends our understanding of the pathogenesis of autism in general. The objective of this study was to find the gene mutated in eight patients from a large kindred, who suffered from autism spectrum disorder, arthrogryposis and epilepsy.
METHODS AND RESULTS: By linkage analysis and exome sequencing, we identified deleterious mutations in SLC35A3 in these patients. SLC35A3 encodes the major Golgi uridine diphosphate N-acetylglucosamine (UDP-GlcNAc) transporter. In Golgi vesicles isolated from patient fibroblasts the transport of the respective nucleotide sugar was significantly reduced causing a massive decrease in the content of cell surface expressed highly branched N-glycans and a concomitant sharp increase of lower branched glycoforms.
CONCLUSIONS: Spontaneous mutation in SLC35A3 has been discovered in cattle worldwide, recapitulating the human phenotype with arthrogryposis and additional skeletal defects known as Complex Vertebral Malformation syndrome. The skeletal anomalies in the mutant cattle and in our patients, and perhaps even the neurological symptoms are likely the consequence of the lack of high-branched N-glycans and the concomitant abundance of lower-branched glycoforms at the cell surface. This pattern has previously been associated with growth arrest and induction of differentiation. With this study, we add SLC35A3 to the gene list of autism spectrum disorders, and underscore the crucial importance of UDP-GlcNAc in the regulation of the N-glycan branching pathway in the Golgi apparatus.

PMID: 24031089 [PubMed - indexed for MEDLINE]

ADHD, autism spectrum disorder, temperament, and character: phenotypical associations and etiology in a Swedish childhood twin study.

July 16, 2014 - 8:37am
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ADHD, autism spectrum disorder, temperament, and character: phenotypical associations and etiology in a Swedish childhood twin study.

Compr Psychiatry. 2013 Nov;54(8):1140-7

Authors: Kerekes N, Brändström S, Lundström S, Råstam M, Nilsson T, Anckarsäter H

Abstract
OBJECTIVE: To explore the links between neurodevelopmental disorders - attention deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) - and personality in a population-based, genetically sensitive study of children.
METHOD: A population-based sample of 1886 twins aged 9 and 12, enriched for childhood mental health problems, was recruited from the Child and Adolescent Twin Study in Sweden (CATSS). Parents were interviewed over the telephone using the Autism-Tics, AD/HD and other Comorbidities (A-TAC) inventory, and in a second step they rated their children according to the Junior Temperament and Character Inventory (JTCI).
RESULTS: ADHD was strongly correlated with novelty seeking, while ASD was correlated positively with harm avoidance and negatively with reward dependence. The strongest associations between personality traits and neurodevelopmental disorders were negative correlations between the character dimensions of self-directedness and cooperativeness and ADHD and ASD alike. Cross-twin cross-trait correlations between ADHD, ASD, and personality dimensions in monozygotic twins were more than double those in dizygotic twins, indicating a strong genetic effect behind the phenotypic covariation between neurodevelopmental disorders and personality.
CONCLUSIONS: Neurodevelopmental disorders are linked specifically to particular temperament profiles and generally to hampered development of the self-governing strategies referred to as "character." Poor self-agency and cooperation may be core functional outcomes in the separation of children with handicapping conditions from those with traits only reminiscent of neurodevelopmental disorders. The associations between neurodevelopmental disorders and personality are at least partly due to genetic effects influencing both conditions. As a consequence, personality must be broadly considered in neuropsychiatry, just as neuropsychiatric disorders and their genetic, neurodevelopmental, and cognitive susceptibilities have to be in personality research and clinical treatment.

PMID: 23790516 [PubMed - indexed for MEDLINE]

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