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The Evolving Diagnostic and Genetic Landscapes of Autism Spectrum Disorder.

May 21, 2016 - 7:35am

The Evolving Diagnostic and Genetic Landscapes of Autism Spectrum Disorder.

Front Genet. 2016;7:65

Authors: Ziats MN, Rennert OM

Abstract
The autism spectrum disorders (ASD) are a heterogeneous set of neurodevelopmental syndromes defined by impairments in verbal and non-verbal communication, restricted social interaction, and the presence of stereotyped patterns of behavior. The prevalence of ASD is rising, and the diagnostic criteria and clinical perspectives on the disorder continue to evolve in parallel. Although the majority of individuals with ASD will not have an identifiable genetic cause, almost 25% of cases have identifiable causative DNA variants. The rapidly improving ability to identify genetic mutations because of advances in next generation sequencing, coupled with previous epidemiological studies demonstrating high heritability of ASD, have led to many recent attempts to identify causative genetic mutations underlying the ASD phenotype. However, although hundreds of mutations have been identified to date, they are either rare variants affecting only a handful of ASD patients, or are common variants in the general population conferring only a small risk for ASD. Furthermore, the genes implicated thus far are heterogeneous in their structure and function, hampering attempts to understand shared molecular mechanisms among all ASD patients; an understanding that is crucial for the development of targeted diagnostics and therapies. However, new work is beginning to suggest that the heterogeneous set of genes implicated in ASD may ultimately converge on a few common pathways. In this review, we discuss the parallel evolution of our diagnostic and genetic understanding of autism spectrum disorders, and highlight recent attempts to infer common biology underlying this complicated syndrome.

PMID: 27200076 [PubMed]

CNVs in neurodevelopmental disorders.

May 21, 2016 - 7:35am
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CNVs in neurodevelopmental disorders.

Oncotarget. 2015 Jul 30;6(21):18238-9

Authors: Lee CT, Freed WJ, Mash DC

PMID: 26285833 [PubMed - indexed for MEDLINE]

Concern for Another's Distress in Toddlers at High and Low Genetic Risk for Autism Spectrum Disorder.

May 21, 2016 - 7:35am
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Concern for Another's Distress in Toddlers at High and Low Genetic Risk for Autism Spectrum Disorder.

J Autism Dev Disord. 2015 Nov;45(11):3594-605

Authors: Campbell SB, Leezenbaum NB, Schmidt EN, Day TN, Brownell CA

Abstract
We examined concern for others in 22-month-old toddlers with an older sibling with autism spectrum disorder (ASD) and low risk typically-developing toddlers with older siblings. Responses to a crying infant and an adult social partner who pretended to hurt her finger were coded. Children with a later diagnosis of ASD showed limited empathic concern in either context compared to low risk toddlers. High risk toddlers without a later diagnosis fell between the ASD and low risk groups. During the crying baby probe the low risk and high risk toddlers without a diagnosis engaged their parent more often than the toddlers with ASD. Low levels of empathic concern and engagement with parents may signal emerging ASD in toddlerhood.

PMID: 26093390 [PubMed - indexed for MEDLINE]

Restoration of Normal Cerebral Oxygen Consumption with Rapamycin Treatment in a Rat Model of Autism-Tuberous Sclerosis.

May 21, 2016 - 7:35am
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Restoration of Normal Cerebral Oxygen Consumption with Rapamycin Treatment in a Rat Model of Autism-Tuberous Sclerosis.

Neuromolecular Med. 2015 Sep;17(3):305-13

Authors: Chi OZ, Wu CC, Liu X, Rah KH, Jacinto E, Weiss HR

Abstract
Tuberous sclerosis (TSC) is associated with autism spectrum disorders and has been linked to metabolic dysfunction and unrestrained signaling of the mammalian target of rapamycin (mTOR). Inhibition of mTOR by rapamycin can mitigate some of the phenotypic abnormalities associated with TSC and autism, but whether this is due to the mTOR-related function in energy metabolism remains to be elucidated. In young Eker rats, an animal model of TSC and autism, which harbors a germ line heterozygous Tsc2 mutation, we previously reported that cerebral oxygen consumption was pronouncedly elevated. Young (4 weeks) male control Long-Evans and Eker rats were divided into control and rapamycin-treated (20 mg/kg once daily for 2 days) animals. Cerebral regional blood flow ((14)C-iodoantipyrine) and O2 consumption (cryomicrospectrophotometry) were determined in isoflurane-anesthetized rats. We found significantly increased basal O2 consumption in the cortex (8.7 ± 1.5 ml O2/min/100 g Eker vs. 2.7 ± 0.2 control), hippocampus, pons and cerebellum. Regional cerebral blood flow and cerebral O2 extractions were also elevated in all brain regions. Rapamycin had no significant effect on O2 consumption in any brain region of the control rats, but significantly reduced consumption in the cortex (4.1 ± 0.3) and all other examined regions of the Eker rats. Phosphorylation of mTOR and S6K1 was similar in the two groups and equally reduced by rapamycin. Thus, a rapamycin-sensitive, mTOR-dependent but S6K1-independent, signal led to enhanced oxidative metabolism in the Eker brain. We found decreased Akt phosphorylation in Eker but not Long-Evans rat brains, suggesting that this may be related to the increased cerebral O2 consumption in the Eker rat. Our findings suggest that rapamycin targeting of Akt to restore normal cerebral metabolism could have therapeutic potential in tuberous sclerosis and autism.

PMID: 26048361 [PubMed - indexed for MEDLINE]

Are Molecules Involved in Neuritogenesis and Axon Guidance Related to Autism Pathogenesis?

May 21, 2016 - 7:35am
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Are Molecules Involved in Neuritogenesis and Axon Guidance Related to Autism Pathogenesis?

Neuromolecular Med. 2015 Sep;17(3):297-304

Authors: Bakos J, Bacova Z, Grant SG, Castejon AM, Ostatnikova D

Abstract
Autism spectrum disorder is a heterogeneous disease, and numerous alterations of gene expression come into play to attempt to explain potential molecular and pathophysiological causes. Abnormalities of brain development and connectivity associated with alterations in cytoskeletal rearrangement, neuritogenesis and elongation of axons and dendrites might represent or contribute to the structural basis of autism pathology. Slit/Robo signaling regulates cytoskeletal remodeling related to axonal and dendritic branching. Components of its signaling pathway (ABL and Cdc42) are suspected to be molecular bases of alterations of normal development. The present review describes the most important mechanisms underlying neuritogenesis, axon pathfinding and the role of GTPases in neurite outgrowth, with special emphasis on alterations associated with autism spectrum disorders. On the basis of analysis of publicly available microarray data, potential biomarkers of autism are discussed.

PMID: 25989848 [PubMed - indexed for MEDLINE]

Elevated levels of tissue plasminogen activator and E-selectin in male children with autism spectrum disorder.

May 20, 2016 - 7:34am

Elevated levels of tissue plasminogen activator and E-selectin in male children with autism spectrum disorder.

Autism Res. 2016 May 19;

Authors: Şimşek Ş, Çetin İ, Çim A, Kaya S

Abstract
Although the etiopathology of autism spectrum disorder (ASD) is not clear, immune dysfunction has been proposed as a mechanism for the pathophysiology of ASD. The purpose of this study is to examine serum levels of tissue plasminogen activator (t-PA) and some adhesion molecules in children with ASD that have not been investigated previously in detail. The study group included 35 male children aged from 2 to 9 diagnosed with ASD according to DSM-V criteria. Soluble platelet endothelial adhesion molecule-1 (sPECAM-1), P-selectin, E-selectin, and t-PA in the serum were determined with enzyme-linked immunosorbent assay. Autism behavior check list (ABC) is used for the assessment of ASD severity. The levels of t-PA (P = 0.025) and E-selectin (P = 0.007) was detected significantly higher in children with ASD than control group. Serum levels of sPECAM-1 showed statistically significant negative correlation with sensory, body and object-use, language, social, and self-help and total scores in the patient group (r = -0.349, P = 0.04; r = -0.411, P = 0.01; r = -0.412, P = 0.01; r = -0.417, P = 0.01, and r = -0.531, P < 0.01, respectively). Serum levels of P-selectin levels showed statistically significant negative correlation with ABC total score in the patient group (r = -0.378, P = 0.03). It may be suggested that t-PA, E-selectin, P-selectin, and sPECAM-1 a crucial role in inflammatory conditions in children with ASD. Autism Res 2016. © 2016 International Society for Autism Research, Wiley Periodicals, Inc.

PMID: 27194368 [PubMed - as supplied by publisher]

microRNAs and Fragile X Syndrome.

May 20, 2016 - 7:34am
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microRNAs and Fragile X Syndrome.

Adv Exp Med Biol. 2015;888:107-21

Authors: Lin SL

Abstract
Fragile X syndrome (FXS) is one of the major causes for autism and mental retardation in humans. The etiology of FXS is linked to the expansion of the CGG trinucleotide repeats, r(CGG), suppressing the fragile X mental retardation 1 (FMR1) gene on the X chromosome, resulting in a loss of fragile X mental retardation protein (FMRP) expression, which is required for regulating normal neuronal connectivity and plasticity. Recent studies have further identified that microRNAs are involved in the mechanisms underlying FXS pathogenesis at three different developmental stages. During early embryogenesis before the blastocyst stage, an embryonic stem cell (ESC)-specific microRNA, miR-302, interferes with FMR1 mRNA translation to maintain the stem cell status and inhibit neural development. After blastocyst, the downregulation of miR-302 releases FMRP synthesis and subsequently leads to neuronal development; yet, in FXS, certain r(CGG)-derived microRNAs, such as miR-fmr1s, are expressed and accumulated and then induce DNA hypermethylation on the FMR1 gene promoter regions, resulting in transcriptional inactivation of the FMR1 gene and the loss of FMRP. In normal neuronal development, FMRP is an RNA-binding protein responsible for interacting with miR-125 and miR-132 to regulate the signaling of Group 1 metabotropic glutamate receptor (mGluR1) and N-methyl-D-aspartate receptor (NMDAR), respectively, and consequently affecting synaptic plasticity. As a result, the loss of FMRP impairs these signaling controls and eventually causes FXS-associated disorders, such as autism and mental retardation. Based on these current findings, this chapter will summarize the etiological causes of FXS and further provides significant insights into the molecular mechanisms underlying microRNA-mediated FXS pathogenesis and the related therapy development.

PMID: 26663181 [PubMed - indexed for MEDLINE]

microRNA and Autism.

May 20, 2016 - 7:34am
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microRNA and Autism.

Adv Exp Med Biol. 2015;888:71-83

Authors: Anitha A, Thanseem I

Abstract
Autism is a complex neurodevelopmental disorder characterized by deficiencies in social interaction and communication, and by repetitive and stereotyped behaviors. According to a recent report, the prevalence of this pervasive developmental disorder has risen to 1 in 88. This will have enormous public health implications in the future, and has necessitated the need to discover predictive biomarkers that could index for autism before the onset of symptoms. microRNAs (miRNAs) are small, noncoding RNAs that regulate gene expression at the posttranscriptional level. They have recently emerged as prominent epigenetic regulators of various cellular processes including neurodevelopment. They are abundantly present in the brain, and their dysfunction has been implicated in an array of neuropathological conditions including autism. miRNAs, previously known to be expressed only in cells and tissues, have also been detected in extracellular body fluids such as serum, plasma, saliva, and urine. Altered expression of cellular and circulating miRNAs have been observed in autistic individuals compared to healthy controls. miRNAs are now being considered as potential targets for the development of novel therapeutic strategies for autism.

PMID: 26663179 [PubMed - indexed for MEDLINE]

An assessment of sex bias in neurodevelopmental disorders.

May 20, 2016 - 7:34am
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An assessment of sex bias in neurodevelopmental disorders.

Genome Med. 2015;7:94

Authors: Polyak A, Rosenfeld JA, Girirajan S

Abstract
BACKGROUND: Neurodevelopmental disorders such as autism and intellectual disability have a sex bias skewed towards boys; however, systematic assessment of this bias is complicated by the presence of significant genetic and phenotypic heterogeneity of these disorders.
METHODS: To assess the extent and characteristics of sex bias, we analyzed the frequency of comorbid features, the magnitude of genetic load, and the existence of family history within 32,155 individuals ascertained clinically for autism or intellectual disability/developmental delay (ID/DD), including a subset of 8,373 individuals carrying rare copy-number variants (CNVs).
RESULTS: We find that girls were more likely than boys to show comorbid features within both autism (P = 2.9 × 10(-6), OR = 1.34) and ID/DD (P = 7.2 × 10(-4), OR = 1.08) cohorts. The frequency of comorbid features in ID/DD was higher in boys (1q21.1 deletion, 15q11.2q13.1 duplication) or girls (15q13.3 deletion, 16p11.2 deletion) carrying specific CNVs associated with variable expressivity while such differences were the smallest for syndromic CNVs (Smith-Magenis syndrome, DiGeorge syndrome). The extent of the male sex bias also varied according to the specific comorbid feature, being most extreme for autism with psychiatric comorbidities and least extreme for autism comorbid with epilepsy. The sex ratio was also specific to certain CNVs, from an 8:1 male:female ratio observed among autistic individuals carrying the 22q11.2 duplication to 1.3:1 male:female ratio in those carrying the 16p11.2 deletion. Girls carried a higher burden of large CNVs compared to boys for autism or ID/DD, and this difference diminished when severe comorbidities were considered. Affected boys showed a higher frequency of neuropsychiatric family histories such as autism (P = 0.01) or specific learning disability (P = 0.03), while affected girls showed a higher frequency of developmental family histories such as growth abnormalities (P = 0.02).
CONCLUSIONS: The sex bias within neurodevelopmental disorders is influenced by the presence of specific comorbidities, specific CNVs, mutational burden, and pre-existing family history of neurodevelopmental phenotypes.

PMID: 26307204 [PubMed - indexed for MEDLINE]

Pharmacogenetic Study of Serotonin Transporter and 5HT2A Genotypes in Autism.

May 20, 2016 - 7:34am
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Pharmacogenetic Study of Serotonin Transporter and 5HT2A Genotypes in Autism.

J Child Adolesc Psychopharmacol. 2015 Aug;25(6):467-74

Authors: Najjar F, Owley T, Mosconi MW, Jacob S, Hur K, Guter SJ, Sweeney JA, Gibbons RD, Cook EH, Bishop JR

Abstract
OBJECTIVE: The purpose of this study was to determine whether polymorphisms in the serotonin transporter (SLC6A4) and serotonin-2A receptor (HTR2A) genes are associated with response to escitalopram in patients with autism spectrum disorder (ASD).
METHODS: Forty-four participants with ASD were enrolled in a 6 week, forced titration, open label examination of the selective serotonin reuptake inhibitor (SSRI) escitalopram. Doses increased at weekly intervals starting at 2.5mg daily with a maximum possible dose of 20 mg daily achieved by the end of the study. If adverse events were experienced, participants subsequently received the previously tolerated dose for the duration of study. SLC6A4 (5-HTTLPR) and HTR2A (rs7997012) genotype groups were assessed in relation to treatment outcomes and drug doses.
RESULTS: Insistence on sameness and irritability symptoms significantly improved over the course of the 6 week treatment period (p<0.0001) in this open-label trial. There were no significant differences observed in the rate of symptom improvement over time across genotype groups. Similarly, dosing trajectory was not significantly associated with genotype groups.
CONCLUSIONS: Previous studies have identified SLC6A4 and HTR2A associations with SSRI response in patients with depression and 5-HTTLPR (SLC6A4) associations with escitalopram response in ASD. We did not observe evidence for similar relationships in this ASD study.

PMID: 26262902 [PubMed - indexed for MEDLINE]

Deletion of 15q11.2(BP1-BP2) region: further evidence for lack of phenotypic specificity in a pediatric population.

May 20, 2016 - 7:34am
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Deletion of 15q11.2(BP1-BP2) region: further evidence for lack of phenotypic specificity in a pediatric population.

Am J Med Genet A. 2015 Sep;167A(9):2098-102

Authors: Hashemi B, Bassett A, Chitayat D, Chong K, Feldman M, Flanagan J, Goobie S, Kawamura A, Lowther C, Prasad C, Siu V, So J, Tung S, Speevak M, Stavropoulos DJ, Carter MT

Abstract
Microdeletion of the BP1-BP2 region at 15q11.2 is a recurrent copy number variant (CNV) frequently found in patients undergoing chromosomal microarray (CMA). Genetic counselling regarding this CNV is challenging due to the wide range of phenotypic presentation in reported patients and lack of general population-based data. As one of the most common reasons for CMA is childhood developmental delay, clinicians need to be cognizant of the inherent ascertainment bias in the literature. We performed a detailed medical record review for 55 patients with this 15q11.2 microdeletion and report the clinical features of the 35 patients for whom information was available. We compared our results to the recent report by Cafferkey et al. in this journal. Our conclusion is that the phenotypic spectrum is too broad and non-specific to constitute a bona fide "syndrome" and that further research must be done to delineate the contribution of this CNV to phenotype.

PMID: 25946043 [PubMed - indexed for MEDLINE]

Improvement of regressive autism symptoms in a child with TMLHE deficiency following carnitine supplementation.

May 20, 2016 - 7:34am
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Improvement of regressive autism symptoms in a child with TMLHE deficiency following carnitine supplementation.

Am J Med Genet A. 2015 Sep;167A(9):2162-7

Authors: Ziats MN, Comeaux MS, Yang Y, Scaglia F, Elsea SH, Sun Q, Beaudet AL, Schaaf CP

Abstract
Disorders of carnitine biosynthesis have recently been associated with neurodevelopmental syndromes such as autism spectrum disorder (ASD). A 4-year-old male with autism and two episodes of neurodevelopmental regression was identified to have a mutation in the TMLHE gene, which encodes the first enzyme in the carnitine biosynthesis pathway, and concurrent carnitine deficiency. Following carnitine supplementation, the patient's regression ended, and the boy started gaining developmental milestones. This case report suggests that deficits in carnitine biosynthesis may be responsible for some cases of regression in individuals with ASD, and that testing for the respective biochemical pathway should be considered. Furthermore, this case suggests that carnitine supplementation may be useful in treating (and potentially preventing) regressive episodes in patients with carnitine deficiency. Further work to better define the role of disorders of carnitine biosynthesis in autism spectrum disorder is warranted.

PMID: 25943046 [PubMed - indexed for MEDLINE]

High functioning male with fragile X syndrome and fragile X-associated tremor/ataxia syndrome.

May 20, 2016 - 7:34am
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High functioning male with fragile X syndrome and fragile X-associated tremor/ataxia syndrome.

Am J Med Genet A. 2015 Sep;167A(9):2154-61

Authors: Basuta K, Schneider A, Gane L, Polussa J, Woodruff B, Pretto D, Hagerman R, Tassone F

Abstract
Fragile X syndrome (FXS) affects individuals with more than 200 CGG repeats (full mutation) in the fragile X mental retardation 1 (FMR1) gene. Those born with FXS experience cognitive and social impairments, developmental delays, and some features of autism spectrum disorders. Carriers of a premutation (55-200 CGG repeats) are generally not severely affected early in life; however, are at high risk of developing the late onset neurodegenerative disorder, Fragile X-associated Tremor/Ataxia Syndrome (FXTAS), or Fragile X-associated Primary Ovarian Insufficiency (FXPOI), and may have other medical conditions such as developmental delay, autism spectrum disorders, hypertension, anxiety, and immune-mediated disorders. Here we present a case of a 58-year-old man with a borderline IQ, average memory skills, and executive function deficits. He met criteria for multiple psychiatric diagnoses and presented with tremor and ataxia, meeting criteria for FXTAS. Molecular testing unveiled a completely unmethylated FMR1 full mutation in peripheral blood mononucleated cells with elevated FMR1 mRNA and premutation alleles of different sizes in two other tissues (primary fibroblasts and sperm), indicating the presence of allele instability based on both inter- and intra-tissue mosaicism. The observation of FXTAS in this case of a full mutation mosaic man suggests that the pathogenic mechanism underlying this disorder is not observed exclusively in premutation carriers as it was originally thought. The concomitant presence of features of FXS and late onset neurological deterioration with probable FXTAS likely result from a combined molecular pathology of elevated FMR1 mRNA levels, a molecular hallmark of FXTAS and low FMRP expression that leads to FXS.

PMID: 25920745 [PubMed - indexed for MEDLINE]

Autistic and Rett-like features associated with 2q33.3-q34 interstitial deletion.

May 20, 2016 - 7:34am
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Autistic and Rett-like features associated with 2q33.3-q34 interstitial deletion.

Am J Med Genet A. 2015 Sep;167A(9):2213-8

Authors: Jang DH, Chae H, Kim M

Abstract
We describe the fourth reported case of a de novo 2q33.3-q34 interstitial deletion and review the literature in attempt to identify relevant candidate genes. A 15-month-old female patient presented for evaluation with poor eye contact and developmental delay. She had microcephaly and mild dysmorphic features, such as downslanting palpebral fissures, high forehead, small mouth, high palate, and general hypotonia. At 30 months of age, she was referred to the genetic clinic for an evaluation of persistent developmental delay, autistic traits, and Rett-like features, including bruxism and repetitive movement of the left hand. Chromosome analysis revealed 46,XX at the 550 band level. No abnormalities were found on analysis of MECP2 gene for Rett syndrome and a DNA methylation test for Prader-Willi syndrome. An array comparative genomic hybridization analysis revealed a de novo 2q33.3-q34 heterozygous deletion (206,048,173-211,980,867). The deletion was estimated to be 5.9 Mb in size and contained 34 known genes. Candidate genes were identified as NRP2, ADAM23, KLF7, CREB1, MAP2, UNC80, and LANCL1 for the 2q33.3-q34 interstitial deletion.

PMID: 25899208 [PubMed - indexed for MEDLINE]

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]

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