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Xq11.1-11.2 deletion involving ARHGEF9 in a girl with autism spectrum disorder.

May 31, 2016 - 8:05am

Xq11.1-11.2 deletion involving ARHGEF9 in a girl with autism spectrum disorder.

Eur J Med Genet. 2016 May 26;

Authors: Bhat G, LaGrave D, Millson A, Herriges J, Lamb AN, Matalon R

Abstract
We report an 8-year-old female with autism spectrum disorder (ASD), intellectual disability and speech delay who was found to carry a de novo 82 kb deletion of chromosome Xq11.1-11.2 involving the ARHGEF9 gene on chromosomal microarray. So far, 11 patients with point mutations, disruptions due to chromosomal rearrangements and deletions involving ARHGEF9 have been reported in the literature. ARHGEF9-related disorders comprise a wide phenotypic spectrum, including behavior disorders, autism spectrum disorder, intellectual disability, hyperekplexia and infantile epileptic encephalopathy. ARHGEF9 encodes for collybistin which plays an important role in post synaptic clustering of glycine and inhibitory gamma-aminobutyric acid receptors along with its scaffolding partner, gephyrin. The reduction of inhibitory receptor clusters in brain has been proposed as a plausible underlying pathophysiological mechanism. With this report, we provide further evidence for the role of ARHGEF9 in neurocognitive function, its implication in ASD, and review the clinical features of previously published individuals with ARHGEF9-related intellectual disability.

PMID: 27238888 [PubMed - as supplied by publisher]

Rab3 interacting molecule 3 mutations associated with autism alter regulation of voltage-dependent Ca²⁺ channels.

May 31, 2016 - 8:05am
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Rab3 interacting molecule 3 mutations associated with autism alter regulation of voltage-dependent Ca²⁺ channels.

Cell Calcium. 2015 Sep;58(3):296-306

Authors: Takada Y, Hirano M, Kiyonaka S, Ueda Y, Yamaguchi K, Nakahara K, Mori MX, Mori Y

Abstract
Autism is a neurodevelopmental psychiatric disorder characterized by impaired reciprocal social interaction, disrupted communication, and restricted and stereotyped patterns of interests. Autism is known to have a strong genetic component. Although mutations in several genes account for only a small proportion of individuals with autism, they provide insight into potential biological mechanisms that underlie autism, such as dysfunction in Ca(2+) signaling, synaptic dysfunction, and abnormal brain connectivity. In autism patients, two mutations have been reported in the Rab3 interacting molecule 3 (RIM3) gene. We have previously demonstrated that RIM3 physically and functionally interacts with voltage-dependent Ca(2+) channels (VDCCs) expressed in neurons via the β subunits, and increases neurotransmitter release. Here, by introducing corresponding autism-associated mutations that replace glutamic acid residue 176 with alanine (E176A) and methionine residue 259 with valine (M259V) into the C2B domain of mouse RIM3, we demonstrate that both mutations partly cancel the suppressive RIM3 effect on voltage-dependent inactivation of Ba(2+) currents through P/Q-type CaV2.1 recombinantly expressed in HEK293 cells. In recombinant N-type CaV2.2 VDCCs, the attenuation of the suppressive RIM3 effect on voltage-dependent inactivation is conserved for M259V but not E176A. Slowing of activation speed of P/Q-type CaV2.1 currents by RIM3 is abolished in E176A, while the physical interaction between RIM3 and β subunits is significantly attenuated in M259V. Moreover, increases by RIM3 in depolarization-induced Ca(2+) influx and acetylcholine release are significantly attenuated by E176A in rat pheochromocytoma PC12 cells. Thus, our data raise the interesting possibility that autism phenotypes are elicited by synaptic dysfunction via altered regulation of presynaptic VDCC function and neurotransmitter release.

PMID: 26142343 [PubMed - indexed for MEDLINE]

Brief Report: SETD2 Mutation in a Child with Autism, Intellectual Disabilities and Epilepsy.

May 31, 2016 - 8:05am
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Brief Report: SETD2 Mutation in a Child with Autism, Intellectual Disabilities and Epilepsy.

J Autism Dev Disord. 2015 Nov;45(11):3764-70

Authors: Lumish HS, Wynn J, Devinsky O, Chung WK

Abstract
Whole exome sequencing (WES) has been utilized with increasing frequency to identify mutations underlying rare diseases. Autism spectrum disorders (ASD) and intellectual disability (ID) are genetically heterogeneous, and novel genes for these disorders are rapidly being identified, making these disorders ideal candidates for WES. Here we report a 17-year-old girl with ASD, developmental delay, ID, seizures, Chiari I malformation, macrocephaly, and short stature. She was found by WES to have a de novo c.2028delT (P677LfsX19) mutation in the SET domain-containing protein 2 (SETD2) gene, predicted to be gene-damaging. This case offers evidence for the potential the role of SETD2 in ASD and ID and provides further detail about the phenotypic manifestations of mutations in SETD2.

PMID: 26084711 [PubMed - indexed for MEDLINE]

Chromosome 17q12 microdeletions but not intragenic HNF1B mutations link developmental kidney disease and psychiatric disorder.

May 29, 2016 - 7:56am

Chromosome 17q12 microdeletions but not intragenic HNF1B mutations link developmental kidney disease and psychiatric disorder.

Kidney Int. 2016 May 24;

Authors: Clissold RL, Shaw-Smith C, Turnpenny P, Bunce B, Bockenhauer D, Kerecuk L, Waller S, Bowman P, Ford T, Ellard S, Hattersley AT, Bingham C

Abstract
Heterozygous mutations of the HNF1B gene are the commonest known monogenic cause of developmental kidney disease. Half of patients have a deletion (approximately 1.3 Mb) of chromosome 17q12, encompassing HNF1B plus 14 additional genes. This 17q12 deletion has been linked with an increased risk of neurodevelopmental disorders, such as autism. Here we compared the neurodevelopmental phenotype of 38 patients with HNF1B-associated renal disease due to an intragenic mutation in 18 patients or due to 17q12 deletion in 20 patients to determine whether haploinsufficiency of HNF1B is responsible for the neurodevelopmental phenotype. Significantly, brief behavioral screening in children with the deletion showed high levels of psychopathology and its impact. Eight individuals (40%) with a deletion had a clinical diagnosis of a neurodevelopmental disorder compared to none with an intragenic mutation. The 17q12 deletions were also associated with more autistic traits. Two independent clinical geneticists were able to predict the presence of a deletion with a sensitivity of 83% and specificity of 79% when assessing facial dysmorphic features as a whole. Thus, the 17q12 deletions but not HNF1B intragenic mutations are associated with neurodevelopmental disorders. Hence, the HNF1B gene is not involved in the neurodevelopmental phenotype of these patients. Nephrologists need to be aware of this association to ensure appropriate referral to psychiatric services.

PMID: 27234567 [PubMed - as supplied by publisher]

Angelman Syndrome Protein Ube3a Regulates Synaptic Growth and Endocytosis by Inhibiting BMP Signaling in Drosophila.

May 28, 2016 - 7:55am

Angelman Syndrome Protein Ube3a Regulates Synaptic Growth and Endocytosis by Inhibiting BMP Signaling in Drosophila.

PLoS Genet. 2016 May;12(5):e1006062

Authors: Li W, Yao A, Zhi H, Kaur K, Zhu YC, Jia M, Zhao H, Wang Q, Jin S, Zhao G, Xiong ZQ, Zhang YQ

Abstract
Altered expression of the E3 ubiquitin ligase UBE3A, which is involved in protein degradation through the proteasome-mediated pathway, is associated with neurodevelopmental and behavioral defects observed in Angelman syndrome (AS) and autism. However, little is known about the neuronal function of UBE3A and the pathogenesis of UBE3A-associated disorders. To understand the in vivo function of UBE3A in the nervous system, we generated multiple mutations of ube3a, the Drosophila ortholog of UBE3A. We found a significantly increased number of total boutons and satellite boutons in conjunction with compromised endocytosis in the neuromuscular junctions (NMJs) of ube3a mutants compared to the wild type. Genetic and biochemical analysis showed upregulation of bone morphogenetic protein (BMP) signaling in the nervous system of ube3a mutants. An immunochemical study revealed a specific increase in the protein level of Thickveins (Tkv), a type I BMP receptor, but not other BMP receptors Wishful thinking (Wit) and Saxophone (Sax), in ube3a mutants. Ube3a was associated with and specifically ubiquitinated lysine 227 within the cytoplasmic tail of Tkv, and promoted its proteasomal degradation in Schneider 2 cells. Negative regulation of Tkv by Ube3a was conserved in mammalian cells. These results reveal a critical role for Ube3a in regulating NMJ synapse development by repressing BMP signaling. This study sheds new light onto the neuronal functions of UBE3A and provides novel perspectives for understanding the pathogenesis of UBE3A-associated disorders.

PMID: 27232889 [PubMed - as supplied by publisher]

α5GABAA receptor deficiency causes autism-like behaviors.

May 28, 2016 - 7:55am

α5GABAA receptor deficiency causes autism-like behaviors.

Ann Clin Transl Neurol. 2016 May;3(5):392-8

Authors: Zurek AA, Kemp SW, Aga Z, Walker S, Milenkovic M, Ramsey AJ, Sibille E, Scherer SW, Orser BA

Abstract
The prevalence of autism spectrum disorders (ASDs), which affect over 1% of the population, has increased twofold in recent years. Reduced expression of GABAA receptors has been observed in postmortem brain tissue and neuroimaging of individuals with ASDs. We found that deletion of the gene for the α5 subunit of the GABAA receptor caused robust autism-like behaviors in mice, including reduced social contacts and vocalizations. Screening of human exome sequencing data from 396 ASD subjects revealed potential missense mutations in GABRA5 and in RDX, the gene for the α5GABAA receptor-anchoring protein radixin, further supporting a α5GABAA receptor deficiency in ASDs.

PMID: 27231709 [PubMed]

Significant neuronal soma volume deficit in the limbic system in subjects with 15q11.2-q13 duplications.

May 28, 2016 - 7:55am
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Significant neuronal soma volume deficit in the limbic system in subjects with 15q11.2-q13 duplications.

Acta Neuropathol Commun. 2015;3:63

Authors: Wegiel J, Flory M, Schanen NC, Cook EH, Nowicki K, Kuchna I, Imaki H, Ma SY, Wegiel J, London E, Casanova MF, Wisniewski T, Brown WT

Abstract
INTRODUCTION: Autism is diagnosed in numerous genetic and genomic developmental disorders associated with an overlap in high-risk genes and loci that underlie intellectual disability (ID) and epilepsy. The aim of this stereological study of neuronal soma volume in 25 brain structures and their subdivisions in eight individuals 9 to 26 years of age who were diagnosed with chromosome 15q11.2-13.1 duplication syndrome [dup(15)], autism, ID and epilepsy; eight age-matched subjects diagnosed with autism of unknown etiology (idiopathic autism) and seven control individuals was to establish whether defects of neuronal soma growth are a common denominator of developmental pathology in idiopathic and syndromic autism and how genetic modifications alter the trajectory of neuronal soma growth in dup(15) autism.
RESULTS: Application of the Nucleator software to estimate neuronal size revealed significant neuronal soma volume deficits in 11 of 25 structures and their subregions (44 %) in subjects diagnosed with dup(15) autism, including consistent neuronal soma volume deficits in the limbic system (sectors CA2, 3 and 4 in Ammon's horn, the second and third layers of the entorhinal cortex and in the amygdala), as well as in the thalamus, nucleus accumbens, external globus pallidus, and Ch3 nucleus in the magnocellular basal complex, and in the inferior olive in the brainstem. The second feature distinguishing dup(15) autism was persistent neuronal soma deficits in adolescents and young adults, whereas in idiopathic autism, neuronal volume deficit is most prominent in 4- to 8-year-old children but affects only a few brain regions in older subjects.
CONCLUSIONS: This study demonstrates that alterations in the trajectory of neuronal growth throughout the lifespan are a core pathological features of idiopathic and syndromic autism. However, dup(15) causes persistent neuronal volume deficits in adolescence and adulthood, with prominent neuronal growth deficits in all major compartments of the limbic system. The more severe neuronal nuclear and cytoplasic volume deficits in syndromic autism found in this study and the more severe focal developmental defects in the limbic system in dup(15) previously reported in this cohort may contribute to the high prevalence of early onset intractable epilepsy and sudden unexpected death in epilepsy.

PMID: 26463344 [PubMed - indexed for MEDLINE]

Tuberous sclerosis complex.

May 27, 2016 - 7:53am
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Tuberous sclerosis complex.

Nat Rev Dis Primers. 2016;2:16035

Authors: Henske EP, Jóźwiak S, Kingswood JC, Sampson JR, Thiele EA

Abstract
Tuberous sclerosis complex (TSC) is an autosomal dominant disorder that affects multiple organ systems and is caused by loss-of-function mutations in one of two genes: TSC1 or TSC2. The disorder can affect both adults and children. First described in depth by Bourneville in 1880, it is now estimated that nearly 2 million people are affected by the disease worldwide. The clinical features of TSC are distinctive and can vary widely between individuals, even within one family. Major features of the disease include tumours of the brain, skin, heart, lungs and kidneys, seizures and TSC-associated neuropsychiatric disorders, which can include autism spectrum disorder and cognitive disability. TSC1 (also known as hamartin) and TSC2 (also known as tuberin) form the TSC protein complex that acts as an inhibitor of the mechanistic target of rapamycin (mTOR) signalling pathway, which in turn plays a pivotal part in regulating cell growth, proliferation, autophagy and protein and lipid synthesis. Remarkable progress in basic and translational research, in addition to several randomized controlled trials worldwide, has led to regulatory approval of the use of mTOR inhibitors for the treatment of renal angiomyolipomas, brain subependymal giant cell astrocytomas and pulmonary lymphangioleiomyomatosis, but further research is needed to establish full indications of therapeutic treatment. In this Primer, we review the state-of-the-art knowledge in the TSC field, including the molecular and cellular basis of the disease, medical management, major knowledge gaps and ongoing research towards a cure.

PMID: 27226234 [PubMed - in process]

Association of oligodendrocytes differentiation regulator gene DUSP15 with autism.

May 26, 2016 - 7:49am

Association of oligodendrocytes differentiation regulator gene DUSP15 with autism.

World J Biol Psychiatry. 2016 May 25;:1-8

Authors: Tian Y, Wang L, Jia M, Lu T, Ruan Y, Wu Z, Wang L, Liu J, Zhang D

Abstract
OBJECTIVES: Autism is a pervasive neurodevelopmental disorder with high heritability. Genetic factors play crucial roles in the aetiology of autism. Dual specificity phosphatase 15 (DUSP15) has been recognised as a key regulator gene for oligodendrocytes differentiation. A previous study detected one de novo missense variant (p.Thr107Met) with probable deleterious function in exon 6 of DUSP15 among patients with autism. Therefore, we sequenced this mutation in autistic children and performed an association analysis between DUSP15 polymorphisms and autism.
METHODS: We performed a case-control study between 255 children affected with autism and 427 healthy controls. Four tag-single nucleotide polymorphisms (SNPs) were selected. These SNPs and the previously reported mutation in exon 6 of DUSP15 were genotyped via Sanger sequencing.
RESULTS: Our results showed that rs3746599 was significantly associated with autism under allelic, additive and dominant models, respectively (χ(2 )=( )9.699, P = 0.0018; χ(2 )=( )16.224, P = 0.001; χ(2 )=( )7.198, P = 0.007). The association remained significant after Bonferroni correction and permutation tests (n = 10,000). We did not detect the missense variant p.Thr107Met reported in previous studies. However, a de novo missense variant of DUSP15 (p.Ala56Thr) with a probable disease-causing effect was detected in one autistic child while absent in healthy controls.
CONCLUSIONS: Our findings initially suggest that DUSP15 might be a susceptibility gene for autism in Chinese Han population.

PMID: 27223645 [PubMed - as supplied by publisher]

The Psychological Impact of Prenatal Diagnosis and Disclosure of Susceptibility Loci: First Impressions of Parents' Experiences.

May 26, 2016 - 7:49am

The Psychological Impact of Prenatal Diagnosis and Disclosure of Susceptibility Loci: First Impressions of Parents' Experiences.

J Genet Couns. 2016 May 25;

Authors: van der Steen SL, Riedijk SR, Verhagen-Visser J, Govaerts LC, Srebniak MI, Van Opstal D, Joosten M, Knapen MF, Tibben A, Diderich KE, Galjaard RJ

Abstract
Genomic microarray may detect susceptibility loci (SL) for neurodevelopmental disorders such as autism and epilepsy, with a yet unquantifiable risk for the fetus. The prenatal disclosure of susceptibility loci is a topic of much debate. Many health care professionals fear that reporting susceptibility loci may put a psychological burden on pregnant couples. It is our policy to disclose prenatal susceptibility loci as we recognize them as actionable for prospective parents. The aim of this report was to evaluate the psychological impact of disclosing a prenatal diagnosis of susceptibility loci. The psychological impact of disclosing susceptibility loci was evaluated in the first patients who received such results. Eight out of 15 women who had a susceptibility locus disclosed and four of their partners consented to share their experiences through a telephonic evaluation (n = 12). Follow-up time ranged from 3 to 15 months after their prenatal test result. The reporting of susceptibility loci was initially 'shocking' for five parents while the other seven felt 'worried'. Ten out of 12 participants indicated they would like to be informed about the susceptibility locus again, two were unsure. Most had no enduring worries. Participants unanimously indicated that pregnant couples should have an individualized pre-test choice about susceptibility loci (non)disclosure. We observed no negative psychological impact with the prenatal diagnosis and disclosure of SL on participants. A key factor in mitigating parental anxiety with SL disclosure appears to be post-test genetic counseling. Our report confirms that pregnant women and their partners prefer an individualized choice regarding the scope of prenatal testing.

PMID: 27220741 [PubMed - as supplied by publisher]

Mice with Shank3 Mutations Associated with ASD and Schizophrenia Display Both Shared and Distinct Defects.

May 26, 2016 - 7:49am
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Mice with Shank3 Mutations Associated with ASD and Schizophrenia Display Both Shared and Distinct Defects.

Neuron. 2016 Jan 6;89(1):147-62

Authors: Zhou Y, Kaiser T, Monteiro P, Zhang X, Van der Goes MS, Wang D, Barak B, Zeng M, Li C, Lu C, Wells M, Amaya A, Nguyen S, Lewis M, Sanjana N, Zhou Y, Zhang M, Zhang F, Fu Z, Feng G

Abstract
Genetic studies have revealed significant overlaps of risk genes among psychiatric disorders. However, it is not clear how different mutations of the same gene contribute to different disorders. We characterized two lines of mutant mice with Shank3 mutations linked to ASD and schizophrenia. We found both shared and distinct synaptic and behavioral phenotypes. Mice with the ASD-linked InsG3680 mutation manifest striatal synaptic transmission defects before weaning age and impaired juvenile social interaction, coinciding with the early onset of ASD symptoms. On the other hand, adult mice carrying the schizophrenia-linked R1117X mutation show profound synaptic defects in prefrontal cortex and social dominance behavior. Furthermore, we found differential Shank3 mRNA stability and SHANK1/2 upregulation in these two lines. These data demonstrate that different alleles of the same gene may have distinct phenotypes at molecular, synaptic, and circuit levels in mice, which may inform exploration of these relationships in human patients.

PMID: 26687841 [PubMed - indexed for MEDLINE]

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

May 26, 2016 - 7:49am
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Cytoplasmic Rbfox1 Regulates the Expression of Synaptic and Autism-Related Genes.

Neuron. 2016 Jan 6;89(1):113-28

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

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

PMID: 26687839 [PubMed - indexed for MEDLINE]

Examining the Genetic and Environmental Associations between Autistic Social and Communication Deficits and Psychopathic Callous-Unemotional Traits.

May 26, 2016 - 7:49am
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Examining the Genetic and Environmental Associations between Autistic Social and Communication Deficits and Psychopathic Callous-Unemotional Traits.

PLoS One. 2015;10(9):e0134331

Authors: O'Nions E, Tick B, Rijsdijk F, Happé F, Plomin R, Ronald A, Viding E

Abstract
BACKGROUND: Difficulties in appropriate social interaction are characteristic of both children with autism spectrum disorders and children with callous-unemotional traits (who are at risk of developing psychopathy). Extant experimental studies suggest that the nature of atypical social cognition that characterises these two profiles is not identical. However, 'empathizing' difficulties have been hypothesised for both groups, raising questions about the degree of aetiological separation between social impairments that characterize each disorder. This study explored the relative contribution of independent vs. shared aetiological influences to social and communication impairments associated with autistic traits and callous-unemotional traits, indexed by parent-report in a population-based cohort of twins.
METHODS: Participants were over 5,000 twin pairs from a UK cohort (the Twins Early Development Study; TEDS), assessed for callous-unemotional traits at 7 years and autistic social and communication impairments at 8 years. Multivariate model-fitting was used to explore the relative contribution of independent vs. overlapping genetic/environmental influences on these traits.
RESULTS: Both social and communication impairments and callous-unemotional traits were highly heritable, although the genetic and environmental influences accounting for individual differences on each domain were predominantly independent.
CONCLUSIONS: Extant evidence from experimental and neuro-imaging studies has suggested that, despite some superficially overlapping behaviours, the social difficulties seen in children with autism spectrum disorders and callous-unemotional traits are largely distinct. The current study is the first to demonstrate considerable aetiological independence of the social interaction difficulties seen in children with autism spectrum disorders and those with callous-unemotional traits.

PMID: 26325039 [PubMed - indexed for MEDLINE]

Heterozygous L1-deficient mice express an autism-like phenotype.

May 26, 2016 - 7:49am
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Heterozygous L1-deficient mice express an autism-like phenotype.

Behav Brain Res. 2015 Oct 1;292:432-42

Authors: Sauce B, Wass C, Netrakanti M, Saylor J, Schachner M, Matzel LD

Abstract
The L1CAM (L1) gene encodes a cell adhesion molecule that contributes to several important processes in the developing and adult nervous system, including neuronal migration, survival, and plasticity. In humans and mice, mutations in the X chromosome-linked gene L1 cause severe neurological defects in males. L1 heterozygous female mice with one functional copy of the L1 gene show complex morphological features that are different from L1 fully-deficient and wild-type littermate mice. However, almost no information is available on the behavior of L1 heterozygous mice and humans. Here, we investigated the behavior of heterozygous female mice in which the L1 gene is constitutively inactivated. These mice were compared to wild-type littermate females. Animals were assessed in five categories of behavioral tests: five tests for anxiety/stress/exploration, four tests for motor abilities, two tests for spatial learning, three tests for social behavior, and three tests for repetitive behavior. We found that L1 heterozygous mice express an autism-like phenotype, comprised of reduced social behaviors and excessive self-grooming (a repetitive behavior also typical in animal models of autism). L1 heterozygous mice also exhibited an increase in sensitivity to light, assessed by a reluctance to enter the lighted areas of novel environments. However, levels of anxiety, stress, motor abilities, and spatial learning in L1 heterozygous mice were similar to those of wild-type mice. These observations raise the possibility that using molecules known to trigger L1 functions may become valuable in the treatment of autism in humans.

PMID: 26079769 [PubMed - indexed for MEDLINE]

Association of rare variation in the glutamate receptor gene SLC1A2 with susceptibility to bipolar disorder and schizophrenia.

May 25, 2016 - 7:44am
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Association of rare variation in the glutamate receptor gene SLC1A2 with susceptibility to bipolar disorder and schizophrenia.

Eur J Hum Genet. 2015 Sep;23(9):1200-6

Authors: Fiorentino A, Sharp SI, McQuillin A

Abstract
The SLC1A2 gene encodes the excitatory amino acid transporter 2 (EAAT2). Glutamate is the major mediator of excitatory neurotransmission and EAAT2 is responsible for clearing the neurotransmitter from the synaptic cleft. Genetic variation in SLC1A2 has been implicated in a range of neurological and neuropsychiatric conditions including schizophrenia (SZ), autism and in core phenotypes of bipolar disorder (BD). The coding and putative regulatory regions of SLC1A2 gene were screened for variants using high resolution melting or sequenced in 1099 or in 32 BD subjects. Thirty-two variants were detected in the SLC1A2 gene. Fifteen potentially etiological variants were selected for genotyping in 1099 BD and 1095 control samples. Five amino acid changing variants were also genotyped in 630 participants suffering from SZ. None of the variants were found to be associated with BD or SZ or with the two diseases combined. However, two recurrent missense variants (rs145827578:G>A, p.(G6S); rs199599866:G>A, p.(R31Q)) and one recurrent 5'-untranslated region (UTR) variant (ss825678885:G>T) were detected in cases only. Combined analysis of the recurrent-case-only missense variants and of the case-only missense and 5'-UTR variants showed nominal evidence for association with the combined diseases (Fisher's P=0.019 and 0.0076). These findings are exploratory in nature and await replication in larger cohorts, however, they provide intriguing evidence that potentially functional rare variants in the SLC1A2 gene may confer susceptibility to psychotic disorders.

PMID: 25406999 [PubMed - indexed for MEDLINE]

Finding novel distinctions between the sAPPα-mediated anabolic biochemical pathways in Autism Spectrum Disorder and Fragile X Syndrome plasma and brain tissue.

May 24, 2016 - 7:41am

Finding novel distinctions between the sAPPα-mediated anabolic biochemical pathways in Autism Spectrum Disorder and Fragile X Syndrome plasma and brain tissue.

Sci Rep. 2016;6:26052

Authors: Ray B, Sokol DK, Maloney B, Lahiri DK

Abstract
UNLABELLED: Autism spectrum disorder (ASD) and Fragile X syndrome (FXS) are developmental disorders. No validated blood-based biomarkers exist for either, which impedes bench-to-bedside approaches. Amyloid-β (Aβ) precursor protein (APP) and metabolites are usually associated with Alzheimer's disease (AD). APP cleavage by α-secretase produces potentially neurotrophic secreted APPα (sAPPα) and the P3 peptide fragment. β-site APP cleaving enzyme (BACE1) cleavage produces secreted APPβ (sAPPβ) and intact Aβ. Excess Aβ is potentially neurotoxic and can lead to atrophy of brain regions such as amygdala in AD. By contrast, amygdala is enlarged in ASD but not FXS. We previously reported elevated levels of sAPPα in ASD and FXS vs.
CONTROLS: We now report elevated plasma Aβ and total APP levels in FXS compared to both ASD and typically developing controls, and elevated levels of sAPPα in ASD and FXS vs.
CONTROLS: By contrast, plasma and brain sAPPβ and Aβ were lower in ASD vs. controls but elevated in FXS plasma vs.
CONTROLS: We also detected age-dependent increase in an α-secretase in ASD brains. We report a novel mechanistic difference in APP pathways between ASD (processing) and FXS (expression) leading to distinct APP metabolite profiles in these two disorders. These novel, distinctive biochemical differences between ASD and FXS pave the way for blood-based biomarkers for ASD and FXS.

PMID: 27212113 [PubMed - in process]

[Behavioral phenotypes of autism spectrum disorder patients and their parents].

May 24, 2016 - 7:41am
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[Behavioral phenotypes of autism spectrum disorder patients and their parents].

Zhonghua Yi Xue Yi Chuan Xue Za Zhi. 2015 Dec;32(6):797-800

Authors: Situ M, Hu X, Cai J, Guo K, Huang Y

Abstract
OBJECTIVE: To explore the relationship between the behavior phenotypes of patients with autism spectrum disorder (ASD) and their parents through family study.
METHODS: Forty-five core families with ASD and 30 control families from Chengdu area were examined using Autism Spectrum Quotient (AQ). Descriptive statistical analysis, correlation analysis, and Logistic regression analysis were used to investigate the effect of various factors, especially genetic factors that may affect the pathogenesis of ASD.
RESULTS: The social skills factor and communication factor of the father's AQ scale, as well as the mother's age of childbearing and AQ social skills factor are related to whether children with ASD (R were 0.46, 0.39, 0.39 and 0.36, P<0.05). The communication factor of the parents' AQ and mother's attention to detail factor are related to whether children will show developmental anomaly before the age of 36 months (R were 0.55, 0.51 and 0.54, P<0.05). The social skill problems of parents and father's communication problems are risk factors for children with autism.
CONCLUSION: ASD may be influenced by both genetic and environmental factors. The autistic behavior phenotype of parents is a risk factor for ASD and is associated with developmental anomalies of early childhood.

PMID: 26663051 [PubMed - indexed for MEDLINE]

A de-novo interstitial microduplication involving 2p16.1-p15 and mirroring 2p16.1-p15 microdeletion syndrome: Clinical and molecular analysis.

May 24, 2016 - 7:41am
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A de-novo interstitial microduplication involving 2p16.1-p15 and mirroring 2p16.1-p15 microdeletion syndrome: Clinical and molecular analysis.

Eur J Paediatr Neurol. 2015 Nov;19(6):711-5

Authors: Mimouni-Bloch A, Yeshaya J, Kahana S, Maya I, Basel-Vanagaite L

Abstract
BACKGROUND: Microdeletions of various sizes in the 2p16.1-p15 chromosomal region have been grouped together under the 2p16.1-p15 microdeletion syndrome. Children with this syndrome generally share certain features including microcephaly, developmental delay, facial dysmorphism, urogenital and skeletal abnormalities. We present a child with a de-novo interstitial 1665 kb duplication of 2p16.1-p15.
METHODS AND RESULTS: Clinical features of this child are distinct from those of children with the 2p16.1-p15 microdeletion syndrome, specifically the head circumference which is within the normal range and mild intellectual disability with absence of autistic behaviors. Microduplications many times bear milder clinical phenotypes in comparison with corresponding microdeletion syndromes. Indeed, as compared to the microdeletion syndrome patients, the 2p16.1-p15 microduplication seems to have a milder cognitive effect and no effect on other body systems. Limited information available in genetic databases about cases with overlapping duplications indicates that they all have abnormal developmental phenotypes.
CONCLUSION: The involvement of genes in this location including BCL11A, USP34 and PEX13, affecting fundamental developmental processes both within and outside the nervous system may explain the clinical features of the individual described in this report.

PMID: 26278498 [PubMed - indexed for MEDLINE]

Is it possible to diagnose Rett syndrome before classical symptoms become obvious? Review of 24 Danish cases born between 2003 and 2012.

May 24, 2016 - 7:41am
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Is it possible to diagnose Rett syndrome before classical symptoms become obvious? Review of 24 Danish cases born between 2003 and 2012.

Eur J Paediatr Neurol. 2015 Nov;19(6):679-87

Authors: Bisgaard AM, Schönewolf-Greulich B, Ravn K, Rønde G

Abstract
BACKGROUND/PURPOSE: Rett syndrome (RTT) is a neurodevelopmental disorder that affects mainly females; it results in multiple disabilities and carries a risk of medical comorbidities. Early diagnosis is important to help establish the best treatment opportunities and preventive care in order to slow down the progression of symptoms. We wanted to test our hypothesis that it is possible to diagnose RTT before the classical symptoms become obvious.
METHODS: We analysed development and symptoms before and at the time of the RTT diagnosis, as well as the symptoms that triggered MECP2 mutation analysis, in a cohort of girls with RTT born in Denmark between 2003 and 2012.
RESULTS: Twenty-four girls were included, and 87.5% of these girls were diagnosed when the classical RTT symptoms were recognized. However, parents were concerned about their daughters between 3 and 58 months prior to the RTT diagnosis, and they felt that the professionals did not share their concern in the beginning. When reviewing medical files and questionnaires, we noted that the majority of girls did have combinations of concerning symptoms such as developmental delay and a collection of subtle signs such as autistic traits, placidity, floppiness with suspicion of muscular or mitochondrial diseases, hair pulling, teeth grinding, development of incontinence and problems with initiating movements.
CONCLUSION: We conclude that many individuals with MECP2 mutation exhibit characteristics that should raise suspicion for RTT, prior to evolution of the core clinical criteria. As RTT is a rare disease, it is of importance to constantly educate clinicians for heightened awareness of RTT.

PMID: 26228846 [PubMed - indexed for MEDLINE]

Autism Spectrum Disorder, Developmental and Psychiatric Features in 16p11.2 Duplication.

May 22, 2016 - 7:37am

Autism Spectrum Disorder, Developmental and Psychiatric Features in 16p11.2 Duplication.

J Autism Dev Disord. 2016 May 21;

Authors: Green Snyder L, D'Angelo D, Chen Q, Bernier R, Goin-Kochel RP, Wallace AS, Gerdts J, Kanne S, Berry L, Blaskey L, Kuschner E, Roberts T, Sherr E, Martin CL, Ledbetter DH, Spiro JE, Chung WK, Hanson E, Simons VIP consortium

Abstract
The 16p11.2 duplication (BP4-BP5) is associated with Autism Spectrum Disorder (ASD), although significant heterogeneity exists. Quantitative ASD, behavioral and neuropsychological measures and DSM-IV diagnoses in child and adult carriers were compared with familial non-carrier controls, and to published results from deletion carriers. The 16p11.2 duplication phenotype ranges widely from asymptomatic presentation to significant disability. The most common diagnoses were intellectual disability, motor delays and Attention Deficit Hyperactivity Disorder in children, and anxiety in adults. ASD occurred in nearly 20 % of child cases, but a majority of carriers did not show the unique social features of ASD. The 16p11.2 duplication phenotype is characterized by wider variability than the reciprocal deletion, likely reflecting contributions from additional risk factors.

PMID: 27207092 [PubMed - as supplied by publisher]

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