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Acute behavioral crises in psychiatric inpatients with autism spectrum disorder (ASD): Recognition of concomitant medical or non-ASD psychiatric conditions predicts enhanced improvement.

January 13, 2015 - 7:29am

Acute behavioral crises in psychiatric inpatients with autism spectrum disorder (ASD): Recognition of concomitant medical or non-ASD psychiatric conditions predicts enhanced improvement.

Res Dev Disabil. 2015 Jan 6;38C:242-255

Authors: Guinchat V, Cravero C, Diaz L, Périsse D, Xavier J, Amiet C, Gourfinkel-An I, Bodeau N, Wachtel L, Cohen D, Consoli A

Abstract
During adolescence, some individuals with autism spectrum disorder (ASD) engage in severe challenging behaviors, such as aggression, self-injury, disruption, agitation and tantrums. We aimed to assess risk factors associated with very acute behavioral crises in adolescents with ASD admitted to a dedicated neurobehavioral unit. We included retrospectively in 2008 and 2009 29 adolescents and young adults with ASD hospitalized for severe challenging behaviors and proposed a guideline (Perisse et al., 2010) that we applied prospectively for 29 patients recruited for the same indications between 2010 and 2012. In total, 58 patients were admitted (n=70 hospitalizations, mean age=15.66 (±4.07) years, 76% male). We systematically collected data describing socio-demographic characteristics, clinical variables (severity, presence of language, cognitive level), comorbid organic conditions, etiologic diagnosis of the episode, and treatments. We explored predictors of Global Assessment Functioning Scale (GAFS) score and duration of hospitalization at discharge. All but 2 patients exhibited severe autistic symptoms and intellectual disability (ID), and two-thirds had no functional verbal language. During the inpatient stay (mean=84.3 (±94.9) days), patients doubled on average their GAFS scores (mean=17.66 (±9.05) at admission vs. mean=31.4 (±9.48) at discharge). Most common etiologies for acute behavioral crises were organic causes [n=20 (28%), including epilepsy: n=10 (14%) and painful medical conditions: n=10 (14%)], environmental causes [n=17 (25%) including lack of treatment: n=11 (16%) and adjustment disorder: n=6 (9%)], and non-ASD psychiatric condition [n=33 (48%) including catatonia: n=5 (7%), major depressive episode: n=6 (9%), bipolar disorder: n=4 (6%), schizophrenia: n=6 (9%), other/unknown diagnosis: n=12 (17%)]. We found no influence of age, gender, socio-economic status, migration, level of ID, or history of seizure on improvement of GAFS score at discharge. Severity of autism at admission was the only negative predictor (p<.001). Painful medical conditions (p=.04), non-ASD psychiatric diagnoses (p=.001), prior usage of specialized ASD care programs (p=.004), functional language (p=.007), as well as a higher number of challenging behaviors upon admission (p=.001) were associated with higher GAFS scores at discharge. Clinical severity at admission, based on the number of challenging behaviors (r=.35, p=.003) and GAFS score (r=-.32, p=.008) was correlated with a longer inpatient stay. Longer hospitalization was however correlated (r=.27, p=.03) with higher GAFS score at discharge even after adjustment for confounding factors. Challenging behaviors among adolescents with ASD may stem from diverse risk factors, including environmental problems, comorbid acute psychiatric conditions, or somatic illness such as epilepsy or acute pain. The management of these behavioral challenges requires a unified, multidisciplinary approach.

PMID: 25575287 [PubMed - as supplied by publisher]

Whole exome sequencing in females with autism implicates novel and candidate genes.

January 13, 2015 - 7:29am

Whole exome sequencing in females with autism implicates novel and candidate genes.

Int J Mol Sci. 2015;16(1):1312-35

Authors: Butler MG, Rafi SK, Hossain W, Stephan DA, Manzardo AM

Abstract
Classical autism or autistic disorder belongs to a group of genetically heterogeneous conditions known as Autism Spectrum Disorders (ASD). Heritability is estimated as high as 90% for ASD with a recently reported compilation of 629 clinically relevant candidate and known genes. We chose to undertake a descriptive next generation whole exome sequencing case study of 30 well-characterized Caucasian females with autism (average age, 7.7 ± 2.6 years; age range, 5 to 16 years) from multiplex families. Genomic DNA was used for whole exome sequencing via paired-end next generation sequencing approach and X chromosome inactivation status. The list of putative disease causing genes was developed from primary selection criteria using machine learning-derived classification score and other predictive parameters (GERP2, PolyPhen2, and SIFT). We narrowed the variant list to 10 to 20 genes and screened for biological significance including neural development, function and known neurological disorders. Seventy-eight genes identified met selection criteria ranging from 1 to 9 filtered variants per female. Five females presented with functional variants of X-linked genes (IL1RAPL1, PIR, GABRQ, GPRASP2, SYTL4) with cadherin, protocadherin and ankyrin repeat gene families most commonly altered (e.g., CDH6, FAT2, PCDH8, CTNNA3, ANKRD11). Other genes related to neurogenesis and neuronal migration (e.g., SEMA3F, MIDN), were also identified.

PMID: 25574603 [PubMed - in process]

Social learning and amygdala disruptions in Nf1 mice are rescued by blocking p21-activated kinase.

January 13, 2015 - 7:29am
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Social learning and amygdala disruptions in Nf1 mice are rescued by blocking p21-activated kinase.

Nat Neurosci. 2014 Nov;17(11):1583-90

Authors: Molosh AI, Johnson PL, Spence JP, Arendt D, Federici LM, Bernabe C, Janasik SP, Segu ZM, Khanna R, Goswami C, Zhu W, Park SJ, Li L, Mechref YS, Clapp DW, Shekhar A

Abstract
Children with neurofibromatosis type 1 (NF1) are increasingly recognized as having a high prevalence of social difficulties and autism spectrum disorders (ASDs). We demonstrated a selective social learning deficit in mice with deletion of a single Nf1 allele (Nf1(+/-)), along with greater activation of the mitogen-activated protein kinase pathway in neurons from the amygdala and frontal cortex, structures that are relevant to social behaviors. The Nf1(+/-) mice showed aberrant amygdala glutamate and GABA neurotransmission, deficits in long-term potentiation and specific disruptions in the expression of two proteins that are associated with glutamate and GABA neurotransmission: a disintegrin and metalloprotease domain 22 (Adam22) and heat shock protein 70 (Hsp70), respectively. All of these amygdala disruptions were normalized by the additional deletion of the p21 protein-activated kinase (Pak1) gene. We also rescued the social behavior deficits in Nf1(+/-) mice with pharmacological blockade of Pak1 directly in the amygdala. These findings provide insights and therapeutic targets for patients with NF1 and ASDs.

PMID: 25242307 [PubMed - indexed for MEDLINE]

Most genetic risk for autism resides with common variation.

January 13, 2015 - 7:29am
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Most genetic risk for autism resides with common variation.

Nat Genet. 2014 Aug;46(8):881-5

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

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

PMID: 25038753 [PubMed - indexed for MEDLINE]

The neuroanatomical distribution of oxytocin receptor binding and mRNA in the male rhesus macaque (Macaca mulatta).

January 13, 2015 - 7:29am
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The neuroanatomical distribution of oxytocin receptor binding and mRNA in the male rhesus macaque (Macaca mulatta).

Psychoneuroendocrinology. 2014 Jul;45:128-41

Authors: Freeman SM, Inoue K, Smith AL, Goodman MM, Young LJ

Abstract
The rhesus macaque (Macaca mulatta) is an important primate model for social cognition, and recent studies have begun to explore the impact of oxytocin on social cognition and behavior. Macaques have great potential for elucidating the neural mechanisms by which oxytocin modulates social cognition, which has implications for oxytocin-based pharmacotherapies for psychiatric disorders such as autism and schizophrenia. Previous attempts to localize oxytocin receptors (OXTR) in the rhesus macaque brain have failed due to reduced selectivity of radioligands, which in primates bind to both OXTR and the structurally similar vasopressin 1a receptor (AVPR1A). We have developed a pharmacologically-informed competitive binding autoradiography protocol that selectively reveals OXTR and AVPR1A binding sites in primate brain sections. Using this protocol, we describe the neuroanatomical distribution of OXTR in the macaque. Finally, we use in situ hybridization to localize OXTR mRNA. Our results demonstrate that OXTR expression in the macaque brain is much more restricted than AVPR1A. OXTR is largely limited to the nucleus basalis of Meynert, pedunculopontine tegmental nucleus, the superficial gray layer of the superior colliculus, the trapezoid body, and the ventromedial hypothalamus. These regions are involved in a variety of functions relevant to social cognition, including modulating visual attention, processing auditory and multimodal sensory stimuli, and controlling orienting responses to visual stimuli. These results provide insights into the neural mechanisms by which oxytocin modulates social cognition and behavior in this species, which, like humans, uses vision and audition as the primary modalities for social communication.

PMID: 24845184 [PubMed - indexed for MEDLINE]

A genome wide association study of mathematical ability reveals an association at chromosome 3q29, a locus associated with autism and learning difficulties: a preliminary study.

January 13, 2015 - 7:29am
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A genome wide association study of mathematical ability reveals an association at chromosome 3q29, a locus associated with autism and learning difficulties: a preliminary study.

PLoS One. 2014;9(5):e96374

Authors: Baron-Cohen S, Murphy L, Chakrabarti B, Craig I, Mallya U, Lakatošová S, Rehnstrom K, Peltonen L, Wheelwright S, Allison C, Fisher SE, Warrier V

Abstract
Mathematical ability is heritable, but few studies have directly investigated its molecular genetic basis. Here we aimed to identify specific genetic contributions to variation in mathematical ability. We carried out a genome wide association scan using pooled DNA in two groups of U.K. samples, based on end of secondary/high school national academic exam achievement: high (n = 419) versus low (n = 183) mathematical ability while controlling for their verbal ability. Significant differences in allele frequencies between these groups were searched for in 906,600 SNPs using the Affymetrix GeneChip Human Mapping version 6.0 array. After meeting a threshold of p<1.5×10(-5), 12 SNPs from the pooled association analysis were individually genotyped in 542 of the participants and analyzed to validate the initial associations (lowest p-value 1.14 ×10(-6)). In this analysis, one of the SNPs (rs789859) showed significant association after Bonferroni correction, and four (rs10873824, rs4144887, rs12130910 rs2809115) were nominally significant (lowest p-value 3.278 × 10(-4)). Three of the SNPs of interest are located within, or near to, known genes (FAM43A, SFT2D1, C14orf64). The SNP that showed the strongest association, rs789859, is located in a region on chromosome 3q29 that has been previously linked to learning difficulties and autism. rs789859 lies 1.3 kbp downstream of LSG1, and 700 bp upstream of FAM43A, mapping within the potential promoter/regulatory region of the latter. To our knowledge, this is only the second study to investigate the association of genetic variants with mathematical ability, and it highlights a number of interesting markers for future study.

PMID: 24801482 [PubMed - indexed for MEDLINE]

De novo mutations in schizophrenia implicate chromatin remodeling and support a genetic overlap with autism and intellectual disability.

January 13, 2015 - 7:29am
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De novo mutations in schizophrenia implicate chromatin remodeling and support a genetic overlap with autism and intellectual disability.

Mol Psychiatry. 2014 Jun;19(6):652-8

Authors: McCarthy SE, Gillis J, Kramer M, Lihm J, Yoon S, Berstein Y, Mistry M, Pavlidis P, Solomon R, Ghiban E, Antoniou E, Kelleher E, O'Brien C, Donohoe G, Gill M, Morris DW, McCombie WR, Corvin A

Abstract
Schizophrenia is a serious psychiatric disorder with a broadly undiscovered genetic etiology. Recent studies of de novo mutations (DNMs) in schizophrenia and autism have reinforced the hypothesis that rare genetic variation contributes to risk. We carried out exome sequencing on 57 trios with sporadic or familial schizophrenia. In sporadic trios, we observed a ~3.5-fold increase in the proportion of nonsense DNMs (0.101 vs 0.031, empirical P=0.01, Benjamini-Hochberg-corrected P=0.044). These mutations were significantly more likely to occur in genes with highly ranked probabilities of haploinsufficiency (P=0.0029, corrected P=0.006). DNMs of potential functional consequence were also found to occur in genes predicted to be less tolerant to rare variation (P=2.01 × 10(-)(5), corrected P=2.1 × 10(-)(3)). Genes with DNMs overlapped with genes implicated in autism (for example, AUTS2, CHD8 and MECP2) and intellectual disability (for example, HUWE1 and TRAPPC9), supporting a shared genetic etiology between these disorders. Functionally CHD8, MECP2 and HUWE1 converge on epigenetic regulation of transcription suggesting that this may be an important risk mechanism. Our results were consistent in an analysis of additional exome-based sequencing studies of other neurodevelopmental disorders. These findings suggest that perturbations in genes, which function in the epigenetic regulation of brain development and cognition, could have a central role in the susceptibility to, pathogenesis and treatment of mental disorders.

PMID: 24776741 [PubMed - indexed for MEDLINE]

Autistic children display elevated urine levels of bovine casomorphin-7 immunoreactivity.

January 13, 2015 - 7:29am
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Autistic children display elevated urine levels of bovine casomorphin-7 immunoreactivity.

Peptides. 2014 Jun;56:68-71

Authors: Sokolov O, Kost N, Andreeva O, Korneeva E, Meshavkin V, Tarakanova Y, Dadayan A, Zolotarev Y, Grachev S, Mikheeva I, Varlamov O, Zozulya A

Abstract
Elevated concentrations of circulating casomorphins (CM), the exogenous opioid peptides from milk casein, may contribute to the pathogenesis of autism in children. Because several mass spectrometry studies failed to detect casomorphins in autistic children, it was questioned whether these peptides can be detected in body fluids by mass spec. Here we demonstrated, using a novel high sensitivity ELISA method, that autistic children have significantly higher levels of urine CM-7 than control children. The severity of autistic symptoms correlated with concentrations of CM-7 in the urine. Because CMs interact with opioid and serotonin receptors, the known modulators of synaptogenesis, we suggest that chronic exposure to elevated levels of bovine CMs may impair early child development, setting the stage for autistic disorders.

PMID: 24657283 [PubMed - indexed for MEDLINE]

Absence of strong strain effects in behavioral analyses of Shank3-deficient mice.

January 13, 2015 - 7:29am
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Absence of strong strain effects in behavioral analyses of Shank3-deficient mice.

Dis Model Mech. 2014 Jun;7(6):667-81

Authors: Drapeau E, Dorr NP, Elder GA, Buxbaum JD

Abstract
Haploinsufficiency of SHANK3, caused by chromosomal abnormalities or mutations that disrupt one copy of the gene, leads to a neurodevelopmental syndrome called Phelan-McDermid syndrome, symptoms of which can include absent or delayed speech, intellectual disability, neurological changes and autism spectrum disorders. The SHANK3 protein forms a key structural part of the post-synaptic density. We previously generated and characterized mice with a targeted disruption of Shank3 in which exons coding for the ankyrin-repeat domain were deleted and expression of full-length Shank3 was disrupted. We documented specific deficits in synaptic function and plasticity, along with reduced reciprocal social interactions, in Shank3 heterozygous mice. Changes in phenotype owing to a mutation at a single locus are quite frequently modulated by other loci, most dramatically when the entire genetic background is changed. In mice, each strain of laboratory mouse represents a distinct genetic background and alterations in phenotype owing to gene knockout or transgenesis are frequently different across strains, which can lead to the identification of important modifier loci. We have investigated the effect of genetic background on phenotypes of Shank3 heterozygous, knockout and wild-type mice, using C57BL/6, 129SVE and FVB/Ntac strain backgrounds. We focused on observable behaviors with the goal of carrying out subsequent analyses to identify modifier loci. Surprisingly, there were very modest strain effects over a large battery of analyses. These results indicate that behavioral phenotypes associated with Shank3 haploinsufficiency are largely strain-independent.

PMID: 24652766 [PubMed - indexed for MEDLINE]

Germline disruption of Pten localization causes enhanced sex-dependent social motivation and increased glial production.

January 13, 2015 - 7:29am
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Germline disruption of Pten localization causes enhanced sex-dependent social motivation and increased glial production.

Hum Mol Genet. 2014 Jun 15;23(12):3212-27

Authors: Tilot AK, Gaugler MK, Yu Q, Romigh T, Yu W, Miller RH, Frazier TW, Eng C

Abstract
PTEN Hamartoma Tumor Syndrome (PHTS) is an autosomal-dominant genetic condition underlying a subset of autism spectrum disorder (ASD) with macrocephaly. Caused by germline mutations in PTEN, PHTS also causes increased risks of multiple cancers via dysregulation of the PI3K and MAPK signaling pathways. Conditional knockout models have shown that neural Pten regulates social behavior, proliferation and cell size. Although much is known about how the intracellular localization of PTEN regulates signaling in cancer cell lines, we know little of how PTEN localization influences normal brain physiology and behavior. To address this, we generated a germline knock-in mouse model of cytoplasm-predominant Pten and characterized its behavioral and cellular phenotypes. The homozygous Pten(m3m4) mice have decreased total Pten levels including a specific drop in nuclear Pten and exhibit region-specific increases in brain weight. The Pten(m3m4) model displays sex-specific increases in social motivation, poor balance and normal recognition memory-a profile reminiscent of some individuals with high functioning ASD. The cytoplasm-predominant protein caused cellular hypertrophy limited to the soma and led to increased NG2 cell proliferation and accumulation of glia. The animals also exhibit significant astrogliosis and microglial activation, indicating a neuroinflammatory phenotype. At the signaling level, Pten(m3m4) mice show brain region-specific differences in Akt activation. These results demonstrate that differing alterations to the same autism-linked gene can cause distinct behavioral profiles. The Pten(m3m4) model is the first murine model of inappropriately elevated social motivation in the context of normal cognition and may expand the range of autism-related behaviors replicated in animal models.

PMID: 24470394 [PubMed - indexed for MEDLINE]

CNS expression of murine fragile X protein (FMRP) as a function of CGG-repeat size.

January 13, 2015 - 7:29am
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CNS expression of murine fragile X protein (FMRP) as a function of CGG-repeat size.

Hum Mol Genet. 2014 Jun 15;23(12):3228-38

Authors: Ludwig AL, Espinal GM, Pretto DI, Jamal AL, Arque G, Tassone F, Berman RF, Hagerman PJ

Abstract
Large expansions of a CGG-repeat element (>200 repeats; full mutation) in the fragile X mental retardation 1 (FMR1) gene cause fragile X syndrome (FXS), the leading single-gene form of intellectual disability and of autism spectrum disorder. Smaller expansions (55-200 CGG repeats; premutation) result in the neurodegenerative disorder, fragile X-associated tremor/ataxia syndrome (FXTAS). Whereas FXS is caused by gene silencing and insufficient FMR1 protein (FMRP), FXTAS is thought to be caused by 'toxicity' of expanded-CGG-repeat mRNA. However, as FMRP expression levels decrease with increasing CGG-repeat length, lowered protein may contribute to premutation-associated clinical involvement. To address this issue, we measured brain Fmr1 mRNA and FMRP levels as a function of CGG-repeat length in a congenic (CGG-repeat knock-in) mouse model using 57 wild-type and 97 expanded-CGG-repeat mice carrying up to ~250 CGG repeats. While Fmr1 message levels increased with repeat length, FMRP levels trended downward over the same range, subject to significant inter-subject variation. Human comparisons of protein levels in the frontal cortex of 7 normal and 17 FXTAS individuals revealed that the mild FMRP decrease in mice mirrored the more limited data for FMRP expression in the human samples. In addition, FMRP expression levels varied in a subset of mice across the cerebellum, frontal cortex, and hippocampus, as well as at different ages. These results provide a foundation for understanding both the CGG-repeat-dependence of FMRP expression and for interpreting clinical phenotypes in premutation carriers in terms of the balance between elevated mRNA and lowered FMRP expression levels.

PMID: 24463622 [PubMed - indexed for MEDLINE]

Possible association between the oxytocin receptor gene and N-acetylaspartate of the right medial temporal lobe in autism spectrum disorders.

January 13, 2015 - 7:29am
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Possible association between the oxytocin receptor gene and N-acetylaspartate of the right medial temporal lobe in autism spectrum disorders.

Psychiatry Clin Neurosci. 2014 Jan;68(1):83

Authors: Egawa J, Watanabe Y, Endo T, Kitamura H, Someya T

PMID: 24393355 [PubMed - indexed for MEDLINE]

Characterization of depression in children with autism spectrum disorders.

January 13, 2015 - 7:29am
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Characterization of depression in children with autism spectrum disorders.

J Dev Behav Pediatr. 2011 May;32(4):332-40

Authors: Magnuson KM, Constantino JN

Abstract
Depressive syndromes represent a disabling comorbidity for many children with autism spectrum disorders (ASD); however, the ascertainment of depression can be complicated by phenotypic overlap between the 2 conditions, by ways in which autistic symptomatology can mask cardinal features of depression and by atypical manifestations of depression in children with ASD. These issues have contributed to wide variation in the estimation of prevalence rates of depression in individuals with ASD and invoke the need for new approaches to the specific detection of depression and other neuropsychiatric comorbidities that aggregate in children affected by ASD. The authors review the scientific literature relevant to the occurrence of depression in ASD and consider important parameters of risk, including psychosocial factors such as insight into affectation status, as well as biological factors such as the aggregation of depressive syndromes in certain families affected by autism, which has suggested possible overlap in genetic influences underlying the 2 conditions. Variability in the manifestations of depression across environmental contexts provides important clues to intervention and underscores the potential importance of involving multiple informants in ascertaining depression in children and adolescents with ASD. A practical strategy for evaluating the presence of depression in youth with ASD is synthesized from the available data and discussed.

PMID: 21502871 [PubMed - indexed for MEDLINE]

Dihydropyrimidine Dehydrogenase Deficiency in Two Malaysian Siblings with Abnormal MRI Findings.

January 8, 2015 - 7:25am

Dihydropyrimidine Dehydrogenase Deficiency in Two Malaysian Siblings with Abnormal MRI Findings.

Mol Syndromol. 2014 Dec;5(6):299-303

Authors: Chen BC, Mohd Rawi R, Meinsma R, Meijer J, Hennekam RC, van Kuilenburg AB

Abstract
Dihydropyrimidine dehydrogenase (DPD) deficiency is an autosomal recessive disorder of the pyrimidine metabolism. Deficiency of this enzyme leads to an accumulation of thymine and uracil and a deficiency of metabolites distal to the catabolic enzyme. The disorder presents with a wide clinical spectrum, ranging from asymptomatic to severe neurological manifestations, including intellectual disability, seizures, microcephaly, autistic behavior, and eye abnormalities. Here, we report on an 11-year-old Malaysian girl and her 6-year-old brother with DPD deficiency who presented with intellectual disability, microcephaly, and hypotonia. Brain MRI scans showed generalized cerebral and cerebellar atrophy and callosal body dysgenesis in the boy. Urine analysis showed strongly elevated levels of uracil in the girl and boy (571 and 578 mmol/mol creatinine, respectively) and thymine (425 and 427 mmol/mol creatinine, respectively). Sequence analysis of the DPYD gene showed that both siblings were homozygous for the mutation c.1651G>A (pAla551Thr).

PMID: 25565930 [PubMed - as supplied by publisher]

Association of dopamine gene variants, emotion dysregulation and ADHD in autism spectrum disorder.

January 8, 2015 - 7:25am
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Association of dopamine gene variants, emotion dysregulation and ADHD in autism spectrum disorder.

Res Dev Disabil. 2014 Jul;35(7):1658-65

Authors: Gadow KD, Pinsonneault JK, Perlman G, Sadee W

Abstract
The aim of the present study was to evaluate the association of dopaminergic gene variants with emotion dysregulation (EMD) and attention-deficit/hyperactivity disorder (ADHD) symptoms in children with autism spectrum disorder (ASD). Three dopamine transporter gene (SLC6A3/DAT1) polymorphisms (intron8 5/6 VNTR, 3'-UTR 9/10 VNTR, rs27072 in the 3'-UTR) and one dopamine D2 receptor gene (DRD2) variant (rs2283265) were selected for genotyping based on à priori evidence of regulatory activity or, in the case of DAT1 9/10 VNTR, commonly reported associations with ADHD. A sample of 110 children with ASD was assessed with a rigorously validated DSM-IV-referenced rating scale. Global EMD severity (parents' ratings) was associated with DAT1 intron8 (ηp(2)=.063) and rs2283265 (ηp(2)=.044). Findings for DAT1 intron8 were also significant for two EMD subscales, generalized anxiety (ηp(2)=.065) and depression (ηp(2)=.059), and for DRD2 rs2283265, depression (ηp(2)=.053). DRD2 rs2283265 was associated with teachers' global ratings of ADHD (ηp(2)=.052). DAT1 intron8 was associated with parent-rated hyperactivity (ηp(2)=.045) and both DAT1 9/10 VNTR (ηp(2)=.105) and DRD2 rs2283265 (ηp(2)=.069) were associated with teacher-rated inattention. These findings suggest that dopaminergic gene polymorphisms may modulate EMD and ADHD symptoms in children with ASD but require replication with larger independent samples.

PMID: 24780147 [PubMed - indexed for MEDLINE]

Neurodevelopmental outcome in Angelman syndrome: genotype-phenotype correlations.

January 8, 2015 - 7:25am
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Neurodevelopmental outcome in Angelman syndrome: genotype-phenotype correlations.

Res Dev Disabil. 2014 Jul;35(7):1742-7

Authors: Mertz LG, Thaulov P, Trillingsgaard A, Christensen R, Vogel I, Hertz JM, Ostergaard JR

Abstract
Angelman syndrome (AS) is a neurogenetic disorder characterized by intellectual disability, developmental delay, lack of speech, and epileptic seizures. Previous studies have indicated that children with AS due to 15q11.2-q13 deletions have a more severe developmental delay and present more often autistic features than those with AS caused by other genetic etiologies. The present study investigated the neurodevelopmental profiles of the different genetic etiologies of AS, and examined the evolution of mental development and autistic features over a 12-year period in children with a 15q11.2-q13 deletion. This study included 42 children with AS. Twelve had a Class I deletion, 18 had Class II deletions, three showed atypical large deletions, five had paternal uniparental disomy (pUPD) and four had UBE3A mutations. Children with a deletion (Class I and Class II) showed significantly reduced developmental age in terms of visual perception, receptive language, and expressive language when compared to those with a UBE3A mutation and pUPD. Within all subgroups, expressive language performance was significantly reduced when compared to the receptive performance. A follow-up study of seven AS cases with 15q11.2-q13 deletions revealed that over 12 years, the level of autistic features did not change, but both receptive and expressive language skills improved.

PMID: 24656292 [PubMed - indexed for MEDLINE]

Fragile X mice have robust mGluR5-dependent alterations of social behaviour in the Automated Tube Test.

January 7, 2015 - 6:44am

Fragile X mice have robust mGluR5-dependent alterations of social behaviour in the Automated Tube Test.

Neurobiol Dis. 2015 Jan 3;

Authors: Cef E, van den Berg WE, Ram B, Jaafar IA, Nieuwenhuizen-Bakker IM, Gasparini F, Kushner SA, Willemsen R

Abstract
Fragile X syndrome is the most common monogenetic form of intellectual disability and autism. Although the Fmr1 knockout mouse model recapitulates many aspects of the human FXS condition, the establishment of robust social behavioural phenotypes suitable for drug screening has been difficult. Here, we describe a novel social behavioural paradigm, the Automated Tube Test (ATT), for which Fmr1 knockout mice demonstrate a highly reliable and robust phenotype. Fmr1 KO mice show highly dominant behaviour over wild-type littermates in the ATT. Consistent with previous findings, we observed a highly significant, albeit partial, rescue of the altered social behaviour of Fmr1 knockout mice in the ATT, using genetic (mGluR5 deletion) or pharmacological inhibition (mGluR5 antagonist) of mGluR5 signalling independently. Together, our results validate the Automated Tube Test as a robust outcome measure for social behaviour in preclinical research for FXS, and confirm the pathophysiological relevance of mGluR5 signalling. Moreover, our findings highlight the strategy of initiating pharmacological intervention in adulthood as holding significant clinical potential.

PMID: 25562659 [PubMed - as supplied by publisher]

Identification and functional characterization of rare SHANK2 variants in schizophrenia.

January 7, 2015 - 6:44am

Identification and functional characterization of rare SHANK2 variants in schizophrenia.

Mol Psychiatry. 2015 Jan 6;

Authors: Peykov S, Berkel S, Schoen M, Weiss K, Degenhardt F, Strohmaier J, Weiss B, Proepper C, Schratt G, Nöthen MM, Boeckers TM, Rietschel M, Rappold GA

Abstract
Recent genetic data on schizophrenia (SCZ) have suggested that proteins of the postsynaptic density of excitatory synapses have a role in its etiology. Mutations in the three SHANK genes encoding for postsynaptic scaffolding proteins have been shown to represent risk factors for autism spectrum disorders and other neurodevelopmental disorders. To address if SHANK2 variants are associated with SCZ, we sequenced SHANK2 in 481 patients and 659 unaffected individuals. We identified a significant increase in the number of rare (minor allele frequency<1%) SHANK2 missense variants in SCZ individuals (6.9%) compared with controls (3.9%, P=0.039). Four out of fifteen non-synonymous variants identified in the SCZ cohort (S610Y, R958S, P1119T and A1731S) were selected for functional analysis. Overexpression and knockdown-rescue experiments were carried out in cultured primary hippocampal neurons with a major focus on the analysis of morphological changes. Furthermore, the effect on actin polymerization in fibroblast cell lines was investigated. All four variants revealed functional impairment to various degrees, as a consequence of alterations in spine volume and clustering at synapses and an overall loss of presynaptic contacts. The A1731S variant was identified in four unrelated SCZ patients (0.83%) but not in any of the sequenced controls and public databases (P=4.6 × 10(-5)). Patients with the A1731S variant share an early prodromal phase with an insidious onset of psychiatric symptoms. A1731S overexpression strongly decreased the SHANK2-Bassoon-positive synapse number and diminished the F/G-actin ratio. Our results strongly suggest a causative role of rare SHANK2 variants in SCZ and underline the contribution of SHANK2 gene mutations in a variety of neuropsychiatric disorders.Molecular Psychiatry advance online publication, 6 January 2015; doi:10.1038/mp.2014.172.

PMID: 25560758 [PubMed - as supplied by publisher]

[Genes, environment and autism spectrum disorders].

January 7, 2015 - 6:44am
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[Genes, environment and autism spectrum disorders].

Tijdschr Psychiatr. 2014;56(10):668-9

Authors: Staal W

PMID: 25327348 [PubMed - indexed for MEDLINE]

[The influence of genes and environment on the development of autism spectrum disorders].

January 7, 2015 - 6:44am
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[The influence of genes and environment on the development of autism spectrum disorders].

Tijdschr Psychiatr. 2014;56(10):660-7

Authors: Spek AA

Abstract
BACKGROUND: Autism spectrum disorders (asd) occur in 0,6% of the general population. On the basis of research in the 70s, 80s and 90s many experts came to the conclusion that asd were in fact genetically determined and were linked only slightly to environmental factors. Recent research, however, indicates that environmental factors really do play an important role.
AIM: To describe and identify the main trends in current research into the causes of asd.
METHOD: The literature was studied with the help of Medline, Cochrane, Web of Science and ScienceDirect.
RESULTS: Recent studies indicate that there is an underlying genetic cause in 35 to 60% of the cases of asd. Environmental factors play a greater role than previously thought and trigger the development of asd in people with a genetic vulnerability to asd. Not only is there evidence of risk factors for asd, but there is also evidence that certain factors protect against asd, for instance the use of folic acid before and during pregnancy.
CONCLUSION: asd are probably related to a combination of gene mutations and environmental factors and to the interactions between the two. Further research is needed into the genetic and environmental causes of asd.

PMID: 25327347 [PubMed - indexed for MEDLINE]

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