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Prenatal stress-induced increases in placental inflammation and offspring hyperactivity are male-specific and ameliorated by maternal antiinflammatory treatment.

August 26, 2014 - 7:39am
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Prenatal stress-induced increases in placental inflammation and offspring hyperactivity are male-specific and ameliorated by maternal antiinflammatory treatment.

Endocrinology. 2014 Jul;155(7):2635-46

Authors: Bronson SL, Bale TL

Abstract
Adverse experiences during gestation such as maternal stress and infection are known risk factors for neurodevelopmental disorders, including schizophrenia, autism, and attention deficit/hyperactivity disorder. The mechanisms by which these distinct exposures may confer similar psychiatric vulnerability remain unclear, although likely involve pathways common to both stress and immune responses at the maternal-fetal interface. We hypothesized that maternal stress-induced activation of immune pathways within the placenta, the sex-specific maternal-fetal intermediary, may contribute to prenatal stress programming effects on the offspring. Therefore, we assessed for markers indicative of stress-induced placental inflammation, and examined the ability of maternal nonsteroidal antiinflammatory drug (NSAID) treatment to ameliorate placental effects and thereby rescue the stress-dysregulation phenotype observed in our established mouse model of early prenatal stress (EPS). As expected, placental gene expression analyses revealed increased levels of immune response genes, including the proinflammatory cytokines IL-6 and IL-1β, specifically in male placentas. NSAID treatment partially ameliorated these EPS effects. Similarly, in adult offspring, males displayed stress-induced locomotor hyperactivity, a hallmark of dopaminergic dysregulation, which was ameliorated by maternal NSAID treatment. Fitting with these outcomes and supportive of dopamine pathway involvement, expression of dopamine D1 and D2 receptors was altered by EPS in males. These studies support an important interaction between maternal stress and a proinflammatory state in the long-term programming effects of maternal stress.

PMID: 24797632 [PubMed - indexed for MEDLINE]

Epigenetic programing of depression during gestation.

August 26, 2014 - 7:39am
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Epigenetic programing of depression during gestation.

Bioessays. 2014 Apr;36(4):353-8

Authors: Dulawa SC

Abstract
Gestational factors play a role in the development of several neuropsychiatric disorders including schizophrenia and autism. In utero conditions influence future mental health through epigenetic mechanisms, which alter gene expression without affecting DNA coding sequence. Environmental factors account for at least 60% of the risk for developing major depression, and earlier onset of depressive illness has been observed over the past decades. I speculate that gestational factors may play a greater role in programing depression than previously recognized. Here, I examine recent evidence for a role for gestational factors in programing mood disorders, and how epigenetic mechanisms mediate this effect.

PMID: 24446085 [PubMed - indexed for MEDLINE]

[Influence of acupuncture of "Changqiang" (GV 1) on learning-memory ability and gap junction-related protein expression in the prefrontal cortex in autism rats].

August 22, 2014 - 8:05am
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[Influence of acupuncture of "Changqiang" (GV 1) on learning-memory ability and gap junction-related protein expression in the prefrontal cortex in autism rats].

Zhen Ci Yan Jiu. 2014 Jun;39(3):173-9

Authors: Hong YZ, Zhang XJ, Hong L, Huang QR, Wu Q

Abstract
OBJECTIVE: To observe the effect of acupuncture stimulation of "Changqiang" (GV 1) on learning-memory ability and gap junction-related protein expression in the prefrontal cortex in autism rats.
METHODS: Forty Wistar rats were equally randomized into control, model, GV 1 and non-acupoint groups. For establishing autism model, Valproate acid (VPA) sodium (600 mg/kg) was given (i. p.) to pregnancy rats whose intimate filial generation was confirmed to be successful autism by eye-open tests, swimming test and Morris water maze swimming tasks. GV 1 or non-acupoint (the spot below the costal region, i.e., 2 cm superior to the posterior superior iliac spine and about 3 cm lateral to the spine) was punctured and stimulated for about 1 min by using a filiform needle, once daily for 30 days except the weekends. The rats' learning-memory ability was detected by Morris water maze tasks. The expression of gap junction-related proteins connexin 43 (CX 43), CX 32 and CX 36 in the frontal cortex tissue was detected by immunohistochemistry.
RESULTS: After modeling, the postnatal rats' eye-open time on day 14, 15 and 16 was significantly later (P < 0.05); and the swimming ability on postnatal day 13 and 15 was obviously lower in comparison with that of the control group (P < 0.05). After acupuncture treatment, the increased escape latency and the decreased swimming velocity of the autism rats were obviously suppressed in the GV 1 group, rather than in the non-acupoint group (P < 0.05). It suggests an improvement of learning-memory ability after acupuncture stimulation of GV 1. In comparison with the control group, the expression levels of cerebral CX 43, CX 32 and CX 36 proteins (mean grey values) were considerably down-regulated in the model group (P < 0.05). While compared to the model group, their expression levels were apparently up-regulated in the GV 1 group (P < 0.05) but not in the non-acupoint group.
CONCLUSION: Acupuncture intervention of GV 1 can improve the learning- memory ability in autism rats, which may be closely related to its effects in up-regulating expression levels of CX 43, CX 32 and CX 36 in the frontal cortex.

PMID: 25069191 [PubMed - indexed for MEDLINE]

Traits of autism spectrum disorders in adults with gender dysphoria.

August 22, 2014 - 8:05am
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Traits of autism spectrum disorders in adults with gender dysphoria.

Arch Sex Behav. 2014 Feb;43(2):387-93

Authors: Pasterski V, Gilligan L, Curtis R

Abstract
The literature examining the co-occurrence of gender dysphoria (GD) and autistic traits has so far been limited to a series of small case studies and two systematic studies, one looking at autistic traits in gender dysphoric children and the other set within the context of the extreme male brain hypothesis and looking at adults. The current study examined this co-occurrence of GD and autistic traits in an adult population, to see whether this heightened prevalence persisted from childhood as well as to provide further comparison of MtF versus FtM transsexuals and homosexual versus nonhomosexual individuals. Using the Autistic Spectrum Quotient (AQ), 91 GD adults (63 male-to-female [MtF] and 28 female-to-male [FtM]) undertaking treatment at a gender clinic completed the AQ. The prevalence of autistic traits consistent with a clinical diagnosis for an autism spectrum disorder (ASD) was 5.5 % (n = 3 MtF and n = 2 FtM) compared to reports of clinical diagnoses of 0.5-2.0 % in the general population. In contrast to the single previous report in adults, there was no significant difference between MtF and FtM on AQ scores; however, all of those who scored above the clinical cut-off were classified as nonhomosexual with respect to natal sex. Results were considered in the context of emerging theories for the observed co-occurrence of GD and autistic traits.

PMID: 23864402 [PubMed - indexed for MEDLINE]

Ube3a, the E3 ubiquitin ligase causing Angelman syndrome and linked to autism, regulates protein homeostasis through the proteasomal shuttle Rpn10.

August 21, 2014 - 7:52am
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Ube3a, the E3 ubiquitin ligase causing Angelman syndrome and linked to autism, regulates protein homeostasis through the proteasomal shuttle Rpn10.

Cell Mol Life Sci. 2014 Jul;71(14):2747-58

Authors: Lee SY, Ramirez J, Franco M, Lectez B, Gonzalez M, Barrio R, Mayor U

Abstract
Ubiquitination, the covalent attachment of ubiquitin to a target protein, regulates most cellular processes and is involved in several neurological disorders. In particular, Angelman syndrome and one of the most common genomic forms of autism, dup15q, are caused respectively by lack of or excess of UBE3A, a ubiquitin E3 ligase. Its Drosophila orthologue, Ube3a, is also active during brain development. We have now devised a protocol to screen for substrates of this particular ubiquitin ligase. In a neuronal cell system, we find direct ubiquitination by Ube3a of three proteasome-related proteins Rpn10, Uch-L5, and CG8209, as well as of the ribosomal protein Rps10b. Only one of these, Rpn10, is targeted for degradation upon ubiquitination by Ube3a, indicating that degradation might not be the only effect of Ube3a on its substrates. Furthermore, we report the genetic interaction in vivo between Ube3a and the C-terminal part of Rpn10. Overexpression of these proteins leads to an enhanced accumulation of ubiquitinated proteins, further supporting the biochemical evidence of interaction obtained in neuronal cells.

PMID: 24292889 [PubMed - indexed for MEDLINE]

The cognitive neuropsychological phenotype of carriers of the FMR1 premutation.

August 20, 2014 - 7:05am

The cognitive neuropsychological phenotype of carriers of the FMR1 premutation.

J Neurodev Disord. 2014;6(1):28

Authors: Grigsby J, Cornish K, Hocking D, Kraan C, Olichney JM, Rivera SM, Schneider A, Sherman S, Wang JY, Yang JC

Abstract
The fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset neurodegenerative disorder affecting a subset of carriers of the FMR1 (fragile X mental retardation 1) premutation. Penetrance and expression appear to be significantly higher in males than females. Although the most obvious aspect of the phenotype is the movement disorder that gives FXTAS its name, the disorder is also accompanied by progressive cognitive impairment. In this review, we address the cognitive neuropsychological and neurophysiological phenotype for males and females with FXTAS, and for male and female unaffected carriers. Despite differences in penetrance and expression, the cognitive features of the disorder appear similar for both genders, with impairment of executive functioning, working memory, and information processing the most prominent. Deficits in these functional systems may be largely responsible for impairment on other measures, including tests of general intelligence and declarative learning. FXTAS is to a large extent a white matter disease, and the cognitive phenotypes observed are consistent with what some have described as white matter dementia, in contrast to the impaired cortical functioning more characteristic of Alzheimer's disease and related disorders. Although some degree of impaired executive functioning appears to be ubiquitous among persons with FXTAS, the data suggest that only a subset of unaffected carriers of the premutation - both female and male - demonstrate such deficits, which typically are mild. The best-studied phenotype is that of males with FXTAS. The manifestations of cognitive impairment among asymptomatic male carriers, and among women with and without FXTAS, are less well understood, but have come under increased scrutiny.

PMID: 25136377 [PubMed]

Gene × Environment interactions in autism spectrum disorders: role of epigenetic mechanisms.

August 20, 2014 - 7:05am

Gene × Environment interactions in autism spectrum disorders: role of epigenetic mechanisms.

Front Psychiatry. 2014;5:53

Authors: Tordjman S, Somogyi E, Coulon N, Kermarrec S, Cohen D, Bronsard G, Bonnot O, Weismann-Arcache C, Botbol M, Lauth B, Ginchat V, Roubertoux P, Barburoth M, Kovess V, Geoffray MM, Xavier J

Abstract
Several studies support currently the hypothesis that autism etiology is based on a polygenic and epistatic model. However, despite advances in epidemiological, molecular and clinical genetics, the genetic risk factors remain difficult to identify, with the exception of a few chromosomal disorders and several single gene disorders associated with an increased risk for autism. Furthermore, several studies suggest a role of environmental factors in autism spectrum disorders (ASD). First, arguments for a genetic contribution to autism, based on updated family and twin studies, are examined. Second, a review of possible prenatal, perinatal, and postnatal environmental risk factors for ASD are presented. Then, the hypotheses are discussed concerning the underlying mechanisms related to a role of environmental factors in the development of ASD in association with genetic factors. In particular, epigenetics as a candidate biological mechanism for gene × environment interactions is considered and the possible role of epigenetic mechanisms reported in genetic disorders associated with ASD is discussed. Furthermore, the example of in utero exposure to valproate provides a good illustration of epigenetic mechanisms involved in ASD and innovative therapeutic strategies. Epigenetic remodeling by environmental factors opens new perspectives for a better understanding, prevention, and early therapeutic intervention of ASD.

PMID: 25136320 [PubMed]

MAOA/B deletion syndrome in male siblings with severe developmental delay and sudden loss of muscle tonus.

August 19, 2014 - 6:52am
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MAOA/B deletion syndrome in male siblings with severe developmental delay and sudden loss of muscle tonus.

Brain Dev. 2014 Jan;36(1):64-9

Authors: Saito M, Yamagata T, Matsumoto A, Shiba Y, Nagashima M, Taniguchi S, Jimbo E, Momoi MY

Abstract
Deletion of the monoamine oxidase (MAO)-A and MAO-B was detected in two male siblings and in their mother. The approximately 800-kb deletion, extending from about 43.0MB to 43.8MB, was detected by array comparative genomic hybridization analysis. The MAOA and MAOB genes were included in the deletion, but the adjacent Norrie disease gene, NDP, was not deleted. The boys had short stature, hypotonia, severe developmental delays, episodes of sudden loss of muscle tone, exiting behavior, lip-smacking and autistic features. The serotonin levels in their cerebrospinal fluid were extremely elevated. Another set of siblings with this deletion was reported previously. We propose recognition of MAOA/B deletion syndrome as a distinct disorder.

PMID: 23414621 [PubMed - indexed for MEDLINE]

Duplication of the NPHP1 gene in patients with autism spectrum disorder and normal intellectual ability: a case series.

August 16, 2014 - 8:24am

Duplication of the NPHP1 gene in patients with autism spectrum disorder and normal intellectual ability: a case series.

Ann Gen Psychiatry. 2014;13:22

Authors: Yasuda Y, Hashimoto R, Fukai R, Okamoto N, Hiraki Y, Yamamori H, Fujimoto M, Ohi K, Taniike M, Mohri I, Nakashima M, Tsurusaki Y, Saitsu H, Matsumoto N, Miyake N, Takeda M

Abstract
Autism spectrum disorder is a neurodevelopmental disorder characterized by impairments in social interactions, reduced verbal communication abilities, stereotyped repetitive behaviors, and restricted interests. It is a complex condition caused by genetic and environmental factors; the high heritability of this disorder supports the presence of a significant genetic contribution. Many studies have suggested that copy-number variants contribute to the etiology of autism spectrum disorder. Recently, copy-number variants of the nephronophthisis 1 gene have been reported in patients with autism spectrum disorder. To the best of our knowledge, only six autism spectrum disorder cases with duplications of the nephronophthisis 1 gene have been reported. These patients exhibited intellectual dysfunction, including verbal dysfunction in one patient, below-average verbal intellectual ability in one patient, and intellectual disability in four patients. In this study, we identified nephronophthisis 1 duplications in two unrelated Japanese patients with autism spectrum disorder using a high-resolution single-nucleotide polymorphism array. This report is the first to describe a nephronophthisis 1 duplication in an autism spectrum disorder patient with an average verbal intelligence quotient and an average performance intelligence quotient. However, the second autism spectrum disorder patient with a nephronophthisis 1 duplication had a below-average performance intelligence quotient. Neither patient exhibited physical dysfunction, motor developmental delay, or neurological abnormalities. This study supports the clinical observation of nephronophthisis 1 duplication in autism spectrum disorder cases and might contribute to our understanding of the clinical phenotype that arises from this duplication.

PMID: 25126106 [PubMed]

A novel variant in GABRB2 associated with intellectual disability and epilepsy.

August 16, 2014 - 8:24am

A novel variant in GABRB2 associated with intellectual disability and epilepsy.

Am J Med Genet A. 2014 Aug 13;

Authors: Srivastava S, Cohen J, Pevsner J, Aradhya S, McKnight D, Butler E, Johnston M, Fatemi A

Abstract
The γ-aminobutyric acid type A (GABAA ) receptor is one of the three main classes of receptors activated by GABA, the principal inhibitory neurotransmitter in the central nervous system. Mutations in genes encoding various subunits of this receptor (GABRA1, GABRA2, GABRA4, GABRA5, GABRA6, GABRB1, GABRB3, GABRG1, GABRG2, GABRG3, and GABRD) are implicated in a number of neurological and developmental disorders, including epilepsy and autism. To date, no human genetics studies have implicated mutations in GABRB2, encoding the β2 subunit of the GABAA receptor, with neurodevelopmental disorders. Here we present a 12-year-old girl with intellectual disability and epilepsy, who was discovered by whole exome sequencing to have a de novo heterozygous missense variant in exon 4 of GABRB2 (c.236T > C; p.M79T). This variant is likely pathogenic, based on in silico analyses, as well as the fact that it results in the non-conservative substitution of a non-polar amino acid with a polar amino acid at a position that is evolutionarily conserved across multiple species. Our findings underscore the need for further investigation into the mechanisms by which mutations in GABRB2 contribute to neurological and developmental dysfunction. © 2014 Wiley Periodicals, Inc.

PMID: 25124326 [PubMed - as supplied by publisher]

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

August 16, 2014 - 8:24am

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

Am J Med Genet A. 2014 Aug 13;

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

Abstract
Terminal deletions of the distal part of the short arm of chromosome 3 cause a wide range of phenotypes from normal to dysmorphic including microcephaly, developmental delay and intellectual disability. We studied the clinical consequences of a terminal deletion of the short arm of chromosome 3 in four generations of a family. The index patient is a14-month-old boy with microcephaly, corpus callosum dysgenesis, and minor dysmorphic features. Single Nucleotide Polymorphism (SNP) array analysis detected a duplication on the long arm of chromosome 6. His apparently healthy mother carries the same 6q duplication, but as an unexpected finding a terminal deletion of 2.9 Mb of the short arm of chromosome 3 was observed. Further co-segregation analysis in the family for the chromosome 3 deletion showed that with the exception of the sister of the index who has autism, speech delay, and learning problems, family members in four generations of this family are carrier of this 3p deletion and apparently healthy. To our knowledge, this is the first report of a study of this terminal 3p deletion in four generations. In this report, we review the literature on terminal 3p deletions and discuss the importance of molecular testing and reporting of copy number variants to achieve accurate genetic counseling in prenatal and postnatal screening. © 2014 Wiley Periodicals, Inc.

PMID: 25123480 [PubMed - as supplied by publisher]

Valproic acid downregulates Cdk5 activity via the transcription of the p35 mRNA.

August 15, 2014 - 7:43am
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Valproic acid downregulates Cdk5 activity via the transcription of the p35 mRNA.

Biochem Biophys Res Commun. 2014 May 16;447(4):678-82

Authors: Takahashi M, Ishida M, Saito T, Ohshima T, Hisanaga S

Abstract
The cyclin-dependent kinase 5 (Cdk5) is a neuron-specific Ser/Thr kinase that is activated by the regulatory subunit p35. Overactivation of Cdk5, which is induced by the cleavage of p35 by calpain, is implicated in neuronal death in various neurodegenerative diseases. In contrast, depletion of the Cdk5 activity renders neurons vulnerable to stresses. Recent reports suggest the involvement of Cdk5 in mental disorders. We hypothesized that perturbation of Cdk5 activity is related to mental conditions. To verify this hypothesis, we investigated the effect of valproic acid (VPA), which is a drug of choice for psychiatric disorders, on Cdk5 activity. VPA decreased the expression of p35 at both the protein and mRNA levels in cultured neurons, resulting in a decrease of Cdk5 activity. VPA decreased the p35 mRNA via histone deacetylase inhibition. The chronic administration of VPA also downregulated p35 in mouse brains. These results indicate that VPA regulates Cdk5 activity in neurons via p35 transcription mediated by HDAC inhibition.

PMID: 24755075 [PubMed - indexed for MEDLINE]

Uncovering the etiology of autism spectrum disorders: genomics, bioinformatics, environment, data collection and exploration, and future possibilities.

August 15, 2014 - 7:43am
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Uncovering the etiology of autism spectrum disorders: genomics, bioinformatics, environment, data collection and exploration, and future possibilities.

Pac Symp Biocomput. 2014;:422-6

Authors: Pendergrass S, Girirajan S, Selleck S

Abstract
A clear and predictive understanding of the etiology of autism spectrum disorders (ASD), a group of neurodevelopmental disorders characterized by varying deficits in social interaction and communication as well as repetitive behaviors, has not yet been achieved. There remains active debate about the origins of autism, and the degree to which genetic and environmental factors, and their interplay, produce the range and heterogeneity of cognitive, developmental, and behavioral features seen in children carrying a diagnosis of ASD. Unlocking the causes of these complex developmental disorders will require a collaboration of experts in many disciplines, including clinicians, environmental exposure experts, bioinformaticists, geneticists, and computer scientists. For this workshop we invited prominent researchers in the field of autism, covering a range of topics from genetic and environmental research to ethical considerations. The goal of this workshop: provide an introduction to the current state of autism research, highlighting the potential for multi-disciplinary collaborations that rigorously evaluate the many potential contributors to ASD. It is further anticipated that approaches that successfully advance the understanding of ASD can be applied to the study of other common, complex disorders. Herein we provide a short review of ASD and the work of the invited speakers.

PMID: 24297568 [PubMed - indexed for MEDLINE]

The glial perspective of autism spectrum disorders.

August 13, 2014 - 6:43am
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The glial perspective of autism spectrum disorders.

Neurosci Biobehav Rev. 2014 Jan;38:160-72

Authors: Zeidán-Chuliá F, Salmina AB, Malinovskaya NA, Noda M, Verkhratsky A, Moreira JC

Abstract
The aetiology of autism spectrum disorders remains unclear although a growing number of associated genetic abnormalities and environmental factors have been discovered in recent decades. These advancements coincided with a remarkable increase in the comprehension of physiological functions and pathological potential of neuroglia in the central nervous system that led to a notion of fundamental contribution of glial cells into multiple neuropathologies, including neuropsychiatric and developmental disorders. Growing evidence indicates a role for deregulation of astroglial control over homeostasis and plastic potential of neural networks as well as microglial malfunction and neuroinflammatory response in the brains of autistic patients. In this review, we shall summarize the status and pathological potential of neuroglia and argue for neuroglial roots of autistic disorders.

PMID: 24300694 [PubMed - in process]

Parental influence on a child's autistic traits.

August 13, 2014 - 6:43am
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Parental influence on a child's autistic traits.

J Dev Behav Pediatr. 2013 Nov-Dec;34(9):730-2

Authors: Phelps R, Nickel R, Eisert D, Stein MT

Abstract
CASE: Robbie is a 4-year-old boy whose parents are concerned about his speech, social skills, and repetitive behaviors. He has poor articulation; at time, he is difficult to understand. On the other hand, he has a fair vocabulary, and he has good intent to communicate. He is generally able to communicate his needs and wants. He likes to tell his parents about his day. When he begins the day at preschool, Robbie initially stands by himself and watches. He slowly warms up and eventually participates in activities. He engages in parallel play or follows other children. He knows names of children at preschool, and he is well liked. He is affectionate with his parents. When Robbie is excited, he wiggles his fingers, flaps his arms, and grimaces. He can be quite rigid; for example, he gets very distressed when his mother sets his cup down on his right side instead of his left. However, in general, Robbie has a sunny personality. He likes to watch children's television shows. He pretends plays with action figures. Robbie is an only child who lives with both parents. His mother works full-time, and his father is in home with Robbie during the day. When examined in the office, Robbie had a bright affect, good eye contact, and social referencing. He demonstrated good communicative intent, but poor articulation and some jargoning. He frequently wiggled his fingers and flapped his hands with excitement. Robbie had a borderline score on the Autism Diagnostic Observation Schedule. During the visit, the pediatrician noted that Robbie's father was rather quiet and rarely responded to questions. When he did respond, he had a monotone quality to his voice. He maintained either a flat or nervous affect throughout the visit. He made limited eye contact, and occasionally he stared excessively.

PMID: 24217028 [PubMed - in process]

Different neurodevelopmental symptoms have a common genetic etiology.

August 13, 2014 - 6:43am
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Different neurodevelopmental symptoms have a common genetic etiology.

J Child Psychol Psychiatry. 2013 Dec;54(12):1356-65

Authors: Pettersson E, Anckarsäter H, Gillberg C, Lichtenstein P

Abstract
BACKGROUND: Although neurodevelopmental disorders are demarcated as discrete entities in the Diagnostic Statistical Manual of mental disorders, empirical evidence indicates that there is a high degree of overlap among them. The first aim of this investigation was to explore if a single general factor could account for the large degree of observed overlap among neurodevelopmental problems, and explore whether this potential factor was primarily genetic or environmental in origin. The second aim was to explore whether there was systematic covariation, either genetic or environmental, over and above that contributed by the potential general factor, unique to each syndrome.
METHOD: Parents of all Swedish 9- and 12-year-old twin pairs born between 1992 and 2002 were targeted for interview regarding problems typical of autism spectrum disorders, ADHD and other neurodevelopmental conditions (response rate: 80 percent). Structural equation modeling was conducted on 6,595 pairs to examine the genetic and environmental structure of 53 neurodevelopmental problems.
RESULTS: One general genetic factor accounted for a large proportion of the phenotypic covariation among the 53 symptoms. Three specific genetic subfactors identified 'impulsivity,' 'learning problems,' and 'tics and autism,' respectively. Three unique environment factors identified 'autism,' 'hyperactivity and impulsivity,' and 'inattention and learning problems,' respectively.
CONCLUSION: One general genetic factor was responsible for the wide-spread phenotypic overlap among all neurodevelopmental symptoms, highlighting the importance of addressing broad patient needs rather than specific diagnoses. The unique genetic factors may help guide diagnostic nomenclature, whereas the unique environmental factors may highlight that neurodevelopmental symptoms are responsive to change at the individual level and may provide clues into different mechanisms and treatments. Future research would benefit from assessing the general factor separately from specific factors to better understand observed overlap among neurodevelopmental problems.

PMID: 24127638 [PubMed - in process]

Autism traits in the RASopathies.

August 13, 2014 - 6:43am
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Autism traits in the RASopathies.

J Med Genet. 2014 Jan;51(1):10-20

Authors: Adviento B, Corbin IL, Widjaja F, Desachy G, Enrique N, Rosser T, Risi S, Marco EJ, Hendren RL, Bearden CE, Rauen KA, Weiss LA

Abstract
BACKGROUND: Mutations in Ras/mitogen-activated protein kinase (Ras/MAPK) pathway genes lead to a class of disorders known as RASopathies, including neurofibromatosis type 1 (NF1), Noonan syndrome (NS), Costello syndrome (CS), and cardio-facio-cutaneous syndrome (CFC). Previous work has suggested potential genetic and phenotypic overlap between dysregulation of Ras/MAPK signalling and autism spectrum disorders (ASD). Although the literature offers conflicting evidence for association of NF1 and autism, there has been no systematic evaluation of autism traits in the RASopathies as a class to support a role for germline Ras/MAPK activation in ASDs.
METHODS: We examined the association of autism traits with NF1, NS, CS and CFC, comparing affected probands with unaffected sibling controls and subjects with idiopathic ASDs using the qualitative Social Communication Questionnaire (SCQ) and the quantitative Social Responsiveness Scale (SRS).
RESULTS: Each of the four major RASopathies showed evidence for increased qualitative and quantitative autism traits compared with sibling controls. Further, each RASopathy exhibited a distinct distribution of quantitative social impairment. Levels of social responsiveness show some evidence of correlation between sibling pairs, and autism-like impairment showed a male bias similar to idiopathic ASDs.
CONCLUSIONS: Higher prevalence and severity of autism traits in RASopathies compared to unaffected siblings suggests that dysregulation of Ras/MAPK signalling during development may be implicated in ASD risk. Evidence for sex bias and potential sibling correlation suggests that autism traits in the RASopathies share characteristics with autism traits in the general population and clinical ASD population and can shed light on idiopathic ASDs.

PMID: 24101678 [PubMed - in process]

Candidate gene associations with withdrawn behavior.

August 13, 2014 - 6:43am
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Candidate gene associations with withdrawn behavior.

J Child Psychol Psychiatry. 2013 Dec;54(12):1337-45

Authors: Rubin DH, Althoff RR, Ehli EA, Davies GE, Rettew DC, Crehan ET, Walkup JT, Hudziak JJ

Abstract
BACKGROUND: Social withdrawal is a core neuropsychiatric phenomenon in developmental psychopathology. Its presence predicts psychopathology across many domains, including depression, psychosis, autism, anxiety, and suicide. Withdrawn behavior is highly heritable, persistent, and characteristically worsens without intervention. To date, few studies have successfully identified genetic associations with withdrawn behavior, despite the abundance of evidence of its heritability. This may be due to reliance of categorical over dimensional measures of the behaviorally inhibited phenotype. The aim of this study is to identify associations between known psychiatric candidate genes and a dimensionally derived measure of withdrawn behavior.
METHODS: Genetic information was collected on 20 single-nucleotide polymorphisms (SNPs) from a custom-designed SNP chip and TAQMAN arrays of 4 variable number of tandem repeat (VNTR) genes for 551 individuals from 187 families. Linear mixed modeling was employed to examine the relationship between genotypes of interest and Child Behavior Checklist (CBCL) Withdrawn Behavior Subscale Score (WBS) while controlling for gender and age through multiple linear regressions.
RESULTS: Withdrawn behavior was highly associated with polymorphism rs6314 of the serotonin receptor 2A (HTR2A) [p = .009, estimate = 0.310 (bootstrap 95% CI 0.155-0.448), bootstrap p = .001] and rs1800544 of the alpha 2-adrenergic (ADRA2A) [p = .001, estimate = -0.310 (bootstrap 95% CI -0.479 to -0.126), bootstrap p = .001] genes after correction for gender and age. The association between withdrawn behavior and ADRA2A was stronger for younger children.
CONCLUSIONS: HTR2A and ADRA2A genes are associated with withdrawn behavior. This reinforces the role of catecholaminergic genes in the heritability of withdrawn behavior.

PMID: 23808549 [PubMed - in process]

Shank mutant mice as an animal model of autism.

August 12, 2014 - 8:46am
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Shank mutant mice as an animal model of autism.

Philos Trans R Soc Lond B Biol Sci. 2014 Jan 5;369(1633):20130143

Authors: Yoo J, Bakes J, Bradley C, Collingridge GL, Kaang BK

Abstract
In this review, we focus on the role of the Shank family of proteins in autism. In recent years, autism research has been flourishing. With genetic, molecular, imaging and electrophysiological studies being supported by behavioural studies using animal models, there is real hope that we may soon understand the fundamental pathology of autism. There is also genuine potential to develop a molecular-level pharmacological treatment that may be able to deal with the most severe symptoms of autism, and clinical trials are already underway. The Shank family of proteins has been strongly implicated as a contributing factor in autism in certain individuals and sits at the core of the alleged autistic pathway. Here, we analyse studies that relate Shank to autism and discuss what light this sheds on the possible causes of autism.

PMID: 24298145 [PubMed - indexed for MEDLINE]

Glycogen synthase kinase-3 inhibitors reverse deficits in long-term potentiation and cognition in fragile X mice.

August 12, 2014 - 8:46am
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Glycogen synthase kinase-3 inhibitors reverse deficits in long-term potentiation and cognition in fragile X mice.

Biol Psychiatry. 2014 Feb 1;75(3):198-206

Authors: Franklin AV, King MK, Palomo V, Martinez A, McMahon LL, Jope RS

Abstract
BACKGROUND: Identifying feasible therapeutic interventions is crucial for ameliorating the intellectual disability and other afflictions of fragile X syndrome (FXS), the most common inherited cause of intellectual disability and autism. Hippocampal glycogen synthase kinase-3 (GSK3) is hyperactive in the mouse model of FXS (FX mice), and hyperactive GSK3 promotes locomotor hyperactivity and audiogenic seizure susceptibility in FX mice, raising the possibility that specific GSK3 inhibitors may improve cognitive processes.
METHODS: We tested if specific GSK3 inhibitors improve deficits in N-methyl-D-aspartate receptor-dependent long-term potentiation at medial perforant path synapses onto dentate granule cells and dentate gyrus-dependent cognitive behavioral tasks.
RESULTS: GSK3 inhibitors completely rescued deficits in long-term potentiation at medial perforant path-dentate granule cells synapses in FX mice. Furthermore, synaptosomes from the dentate gyrus of FX mice displayed decreased inhibitory serine-phosphorylation of GSK3β compared with wild-type littermates. The potential therapeutic utility of GSK3 inhibitors was further tested on dentate gyrus-dependent cognitive behaviors. In vivo administration of GSK3 inhibitors completely reversed impairments in several cognitive tasks in FX mice, including novel object detection, coordinate and categorical spatial processing, and temporal ordering for visual objects.
CONCLUSIONS: These findings establish that synaptic plasticity and cognitive deficits in FX mice can be improved by intervention with inhibitors of GSK3, which may prove therapeutically beneficial in FXS.

PMID: 24041505 [PubMed - indexed for MEDLINE]

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