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Genomic and Genetic Aspects of Autism Spectrum Disorder.

September 1, 2014 - 8:01am

Genomic and Genetic Aspects of Autism Spectrum Disorder.

Biochem Biophys Res Commun. 2014 Aug 27;

Authors: Liu X, Takumi T

Abstract
Autism spectrum disorder (ASD) is a neurodevelopmental disorder with a strong genetic component. The past decade has witnessed tremendous progress in the genetic studies of ASD. In this article, we review the accumulating literatures on the monogenic forms of ASD and chromosomal abnormalities associated with ASD, the genome-wide linkage and association studies, the copy number variation (CNV) and the next generation sequencing (NGS) studies. With more than hundreds of mutations being implicated, the convergent biological pathways are emerging and the genetic landscape of ASD becomes clearer. The genetic studies provide a solid basis for future translational study for better diagnoses, intervention and treatment of ASD.

PMID: 25173933 [PubMed - as supplied by publisher]

B vitamin polymorphisms and behavior: Evidence of associations with neurodevelopment, depression, schizophrenia, bipolar disorder and cognitive decline.

September 1, 2014 - 8:01am

B vitamin polymorphisms and behavior: Evidence of associations with neurodevelopment, depression, schizophrenia, bipolar disorder and cognitive decline.

Neurosci Biobehav Rev. 2014 Aug 27;

Authors: Mitchell ES, Conus N, Kaput J

Abstract
The B vitamins folic acid, vitamin B12 and B6 are essential for neuronal function, and severe deficiencies have been linked to increased risk of neurodevelopmental disorders, psychiatric disease and dementia. Polymorphisms of genes involved in B vitamin absorption, metabolism and function, such as methylene tetrahydrofolate reductase (MTHFR), cystathionine β synthase (CβS), transcobalamin 2 receptor (TCN2) and methionine synthase reductase (MTRR), have also been linked to increased incidence of psychiatric and cognitive disorders. However, the effects of these polymorphisms are often quite small and many studies failed to show any meaningful or consistent associations. This review discusses previous findings from clinical studies and highlights gaps in knowledge. Future studies assessing B vitamin-associated polymorphisms must take into account not just traditional demographics, but subjects' overall diet, relevant biomarkers of nutritional status and also analyze related genetic factors that may exacerbate behavioral effects or nutritional status.

PMID: 25173634 [PubMed - as supplied by publisher]

Point mutation frequency in the FMR1 gene as revealed by fragile X syndrome screening.

August 31, 2014 - 7:31am

Point mutation frequency in the FMR1 gene as revealed by fragile X syndrome screening.

Mol Cell Probes. 2014 Aug 26;

Authors: Handt M, Epplen A, Hoffjan S, Mese K, Epplen JT, Dekomien G

Abstract
Fragile X syndrome (FXS) is a common cause of intellectual disability, developmental delay and autism spectrum disorders. This syndrome is due to a functional loss of the FMR1 gene product FMRP, and, in most cases, it is caused by CGG repeat expansion in the FMR1 promoter. Yet, also other FMR1 mutations may cause a FXS-like phenotype. Since standard molecular testing does not include the analysis of the FMR1 coding region, the prevalence of point mutations causing FXS is not well known. Here, high resolution melting (HRM) was used to screen for FMR1 gene mutations in 508 males with clinical signs of mental retardation and developmental delay, but without CGG and GCC repeat expansions in the FMR1 gene and AFF2 genes, respectively. Sequence variations were identified by HRM analysis and verified by direct DNA sequencing. Two novel missense mutations (p.Gly482Ser in one patient and p.Arg534His in two unrelated patients), one intronic and two 3'-untranslated region (UTR) variations were identified in the FMR1 gene. Missense mutations in the FMR1 gene might account for a considerable proportion of cases in male patients with FXS-related symptoms, such as those linked to mental retardation and developmental delay.

PMID: 25171808 [PubMed - as supplied by publisher]

Copy number variation in Han Chinese individuals with autism spectrum disorder.

August 30, 2014 - 6:50am

Copy number variation in Han Chinese individuals with autism spectrum disorder.

J Neurodev Disord. 2014;6(1):34

Authors: Gazzellone MJ, Zhou X, Lionel AC, Uddin M, Thiruvahindrapuram B, Liang S, Sun C, Wang J, Zou M, Tammimies K, Walker S, Selvanayagam T, Wei J, Wang Z, Wu L, Scherer SW

Abstract
BACKGROUND: Autism spectrum disorders (ASDs) are a group of neurodevelopmental conditions with a demonstrated genetic etiology. Rare (<1% frequency) copy number variations (CNVs) account for a proportion of the genetic events involved, but the contribution of these events in non-European ASD populations has not been well studied. Here, we report on rare CNVs detected in a cohort of individuals with ASD of Han Chinese background.
METHODS: DNA samples were obtained from 104 ASD probands and their parents who were recruited from Harbin, China. Samples were genotyped on the Affymetrix CytoScan HD platform. Rare CNVs were identified by comparing data with 873 technology-matched controls from Ontario and 1,235 additional population controls of Han Chinese ethnicity.
RESULTS: Of the probands, 8.6% had at least 1 de novo CNV (overlapping the GIGYF2, SPRY1, 16p13.3, 16p11.2, 17p13.3-17p13.2, DMD, and NAP1L6 genes/loci). Rare inherited CNVs affected other plausible neurodevelopmental candidate genes including GRID2, LINGO2, and SLC39A12. A 24-kb duplication was also identified at YWHAE, a gene previously implicated in ASD and other developmental disorders. This duplication is observed at a similar frequency in cases and in population controls and is likely a benign Asian-specific copy number polymorphism.
CONCLUSIONS: Our findings help define genomic features relevant to ASD in the Han Chinese and emphasize the importance of using ancestry-matched controls in medical genetic interpretations.

PMID: 25170348 [PubMed]

Coffin-Siris syndrome and related disorders involving components of the BAF (mSWI/SNF) complex: Historical review and recent advances using next generation sequencing.

August 30, 2014 - 6:50am

Coffin-Siris syndrome and related disorders involving components of the BAF (mSWI/SNF) complex: Historical review and recent advances using next generation sequencing.

Am J Med Genet C Semin Med Genet. 2014 Aug 28;

Authors: Kosho T, Miyake N, Carey JC

Abstract
This issue of Seminars in Medical Genetics, American Journal of Medical Genetics Part C investigates the human diseases caused by mutations in the BAF complex (also known as the mammalian SWI/SNF complex) genes, particularly focusing on Coffin-Siris syndrome (CSS). CSS is a rare congenital malformation syndrome characterized by developmental delay or intellectual disability (ID), coarse facial appearance, feeding difficulties, frequent infections, and hypoplasia/aplasia of the fifth fingernails and fifth distal phalanges. In 2012, 42 years after the first description of CSS in 1970, five causative genes (SMARCB1, SMARCE1, SMARCA4, ARID1A, ARID1B), all encoding components of the BAF complex, were identified as being responsible for CSS through whole exome sequencing and pathway-based genetic screening. The identification of two additional causative genes (PHF6, SOX11) followed. Mutations in another BAF complex gene (SMARCA2) and (TBC1D24) were found to cause clinically similar conditions with ID, Nicolaides-Baraitser syndrome and DOORS syndrome, respectively. Also, ADNP was found to be mutated in an autism/ID syndrome. Furthermore, there is growing evidences for germline or somatic mutations in the BAF complex genes to be causal for cancer/cancer predisposition syndromes. These discoveries have highlighted the role of the BAF complex in the human development and cancer formation. The biology of BAF is very complicated and much remains unknown. Ongoing research is required to reveal the whole picture of the BAF complex in human development, and will lead to the development of new targeted therapies for related disorders in the future. © 2014 Wiley Periodicals, Inc.

PMID: 25169878 [PubMed - as supplied by publisher]

Autism prevalence and meat consumption - A hypothesis that needs to be tested.

August 30, 2014 - 6:50am

Autism prevalence and meat consumption - A hypothesis that needs to be tested.

Med Hypotheses. 2014 Aug 15;

Authors: Pisula W, Pisula E

Abstract
Prevalence of ASD seems to have increase in recent decades. There have been many attempts to find the responsible agent at various levels, from genetics to environmental factors. In this paper we draw attention to the possibility that one of the hidden agents spurring the rise in autism prevalence is to be identified within the industrial system of food production, particularly meat production with special emphasis on poultry meat. The paper presents some exploratory analyses demonstrating the correlation between particular aspects of meat consumption and autism prevalence. This initial exploration has lead to the hypothesis that industrial meat production - especially of poultry meat - may involve significant risk factors requiring thorough investigation. The main suspects seem to be hormonal and other growth-promoting agents.

PMID: 25169037 [PubMed - as supplied by publisher]

Genome-wide copy number variation analysis in adult attention-deficit and hyperactivity disorder.

August 30, 2014 - 6:50am
Related Articles

Genome-wide copy number variation analysis in adult attention-deficit and hyperactivity disorder.

J Psychiatr Res. 2014 Feb;49:60-7

Authors: Ramos-Quiroga JA, Sánchez-Mora C, Casas M, Garcia-Martínez I, Bosch R, Nogueira M, Corrales M, Palomar G, Vidal R, Coll-Tané M, Bayés M, Cormand B, Ribasés M

Abstract
Attention-deficit and hyperactivity disorder (ADHD) is a common psychiatric disorder with a worldwide prevalence of 5-6% in children and 4.4% in adults. Recently, copy number variations (CNVs) have been implicated in different neurodevelopmental disorders such as ADHD. Based on these previous reports that focused on pediatric cohorts, we hypothesize that structural variants may also contribute to adult ADHD and that such genomic variation may be enriched for CNVs previously identified in children with ADHD. To address this issue, we performed for the first time a whole-genome CNV study on 400 adults with ADHD and 526 screened controls. In agreement with recent reports in children with ADHD or in other psychiatric disorders, we identified a significant excess of insertions in ADHD patients compared to controls. The overall rate of CNVs >100 kb was 1.33 times higher in ADHD subjects than in controls (p = 2.4e-03), an observation mainly driven by a higher proportion of small events (from 100 kb to 500 kb; 1.35-fold; p = 1.3e-03). These differences remained significant when we considered CNVs that overlap genes or when structural variants spanning candidate genes for psychiatric disorders were evaluated, with duplications showing the greatest difference (1.41-fold, p = 0.024 and 2.85-fold, p = 8.5e-03, respectively). However, no significant enrichment was detected in our ADHD cohort for childhood ADHD-associated CNVs, CNVs previously identified in at least one ADHD patient or CNVs previously implicated in autism or schizophrenia. In conclusion, our study provides tentative evidence for a higher rate of CNVs in adults with ADHD compared to controls and contributes to the growing list of structural variants potentially involved in the etiology of the disease.

PMID: 24269040 [PubMed - indexed for MEDLINE]

Sequence analysis of 17 NRXN1 deletions.

August 29, 2014 - 6:18am
Related Articles

Sequence analysis of 17 NRXN1 deletions.

Am J Med Genet B Neuropsychiatr Genet. 2014 Jan;165B(1):52-61

Authors: Enggaard Hoeffding LK, Hansen T, Ingason A, Doung L, Thygesen JH, Møller RS, Tommerup N, Kirov G, Rujescu D, Larsen LA, Werge T

Abstract
BACKGROUND: Genome instability plays fundamental roles in human evolution and phenotypic variation within our population. This instability leads to genomic rearrangements that are involved in a wide variety of human disorders, including congenital and neurodevelopmental disorders, and cancers. Insight into the molecular mechanisms governing such genomic rearrangements may increase our understanding of disease pathology and evolutionary processes. Here we analyse 17 carriers of non-recurrent deletions in the NRXN1 gene, which have been associated with neurodevelopmental disorders, e.g. schizophrenia, autism and epilepsies.
METHODS: 17 non-recurrent NRXN1 deletions identified by GWA were sequenced to map the breakpoints of each. Meme … etc. was used to identify shared patterns between the deletions and compare these were previously studies on non-recurrent deletions.
RESULTS: We discovered two novel sequence motifs shared between all 17 NRXN1 deletions and a significantly higher AT nucleotide content at the breakpoints, compared to the overall nucleotide content on chromosome 2. We found different alteration of sequence at the breakpoint; small insertions and duplications giving rise to short microhomology sequences.
CONCLUSIONS: No single mechanism seems to be implicated in the deletion events, but the results suggest that NHEJ, FoSTeS or MMBIR is implicated. The two novel sequence motifs together with a high AT content in all in NRXN1 deletions may lead to increased instability leading to a increase susceptibility to a single stranded structures. This favours potentially repaired by NHEJ mechanism of double strand breaks or may leading to replication errors. © 2013 Wiley Periodicals, Inc.

PMID: 24339137 [PubMed - indexed for MEDLINE]

Biomarkers in Autism.

August 28, 2014 - 8:51am

Biomarkers in Autism.

Front Psychiatry. 2014;5:100

Authors: Goldani AA, Downs SR, Widjaja F, Lawton B, Hendren RL

Abstract
Autism spectrum disorders (ASDs) are complex, heterogeneous disorders caused by an interaction between genetic vulnerability and environmental factors. In an effort to better target the underlying roots of ASD for diagnosis and treatment, efforts to identify reliable biomarkers in genetics, neuroimaging, gene expression, and measures of the body's metabolism are growing. For this article, we review the published studies of potential biomarkers in autism and conclude that while there is increasing promise of finding biomarkers that can help us target treatment, there are none with enough evidence to support routine clinical use unless medical illness is suspected. Promising biomarkers include those for mitochondrial function, oxidative stress, and immune function. Genetic clusters are also suggesting the potential for useful biomarkers.

PMID: 25161627 [PubMed - as supplied by publisher]

Early Neurodevelopmental Screening in Tuberous Sclerosis Complex: A Potential Window of Opportunity.

August 28, 2014 - 8:51am

Early Neurodevelopmental Screening in Tuberous Sclerosis Complex: A Potential Window of Opportunity.

Pediatr Neurol. 2014 Sep;51(3):398-402

Authors: Gipson TT, Gerner G, Srivastava S, Poretti A, Vaurio R, Hartman A, Johnston MV

Abstract
BACKGROUND: Infants born with tuberous sclerosis complex, a genetic condition resulting from a mutation in TSC1 or TSC2, are at increased risk for intellectual disability and/or autism. Features of epilepsy, neuropathology, genetics, as well as timing and type of mechanism-based medications have been proposed as risk factors. Neurodevelopmental outcomes have been reported among these studies; however, few include data about the individuals' early neurodevelopmental profile, a factor that may contribute significantly to these outcomes. Further, there is no clinical standard for the neurodevelopmental assessment of these infants. The paucity of data regarding the natural history of neurodevelopment in infants with tuberous sclerosis complex and the lack of a gold standard for neurodevelopmental evaluation present a significant challenge for clinicians and researchers.
METHOD: During the first year of life, we tracked the onset of infantile spasms, the type and timing of antiepileptic treatments, and the associated response of two age-matched infants with tuberous sclerosis complex. We also employed Capute Scales as a part of a structured neurodevelopmental evaluation to characterize and compare their neurodevelopmental profiles.
RESULTS: Infant 1 developed infantile spasms with confirmed hypsarrhythmia at 4 months of age. Treatment with vigabatrin was initiated within 24 hours with near immediate cessation of seizures and no further seizures to date. Expressive language delay was detected at 12 months and treated with speech and/or language therapy. Infant 2 developed complex partial seizures at 1 month. Treatment included levetiracetam, oxcarbazepine, and the ketogenic diet. Vigabatrin was initiated on detection of hypsarrhythmia after 4 months. Intractable epilepsy persists to date. Global developmental delay was evident by 8 months and treated with physical, occupational, and speech and/or language therapy.
CONCLUSION: Many risk factors have been associated with intellectual disability and/or autism in individuals with tuberous sclerosis complex; however, few data are available regarding practical clinical tools for early identification. In our case series, inclusion of the Capute Scales as a part of routine medical care led to the identification of developmental delays in the first 12 months of life and selection of targeted neurodevelopmental interventions. Development of a risk-based assessment using this approach will be the focus of future studies as it may provide a potential window of opportunity for both research and clinical purposes. In research, it may serve as an objective outcome measure. Clinically, this type of assessment has potential for informing clinical treatment decisions and serving as a prognostic indicator of long-term cognitive and psychiatric outcomes.

PMID: 25160545 [PubMed - as supplied by publisher]

Prenatal antidepressant exposure is associated with risk for attention-deficit hyperactivity disorder but not autism spectrum disorder in a large health system.

August 27, 2014 - 8:21am

Prenatal antidepressant exposure is associated with risk for attention-deficit hyperactivity disorder but not autism spectrum disorder in a large health system.

Mol Psychiatry. 2014 Aug 26;

Authors: Clements CC, Castro VM, Blumenthal SR, Rosenfield HR, Murphy SN, Fava M, Erb JL, Churchill SE, Kaimal AJ, Doyle AE, Robinson EB, Smoller JW, Kohane IS, Perlis RH

Abstract
Previous studies suggested that risk for Autism Spectrum Disorder (ASD) may be increased in children exposed to antidepressants during the prenatal period. The disease specificity of this risk has not been addressed and the possibility of confounding has not been excluded. Children with ASD or attention-deficit hyperactivity disorder (ADHD) delivered in a large New England health-care system were identified from electronic health records (EHR), and each diagnostic group was matched 1:3 with children without ASD or ADHD. All children were linked with maternal health data using birth certificates and EHRs to determine prenatal medication exposures. Multiple logistic regression was used to examine association between prenatal antidepressant exposures and ASD or ADHD risk. A total of 1377 children diagnosed with ASD and 2243 with ADHD were matched with healthy controls. In models adjusted for sociodemographic features, antidepressant exposure prior to and during pregnancy was associated with ASD risk, but risk associated with exposure during pregnancy was no longer significant after controlling for maternal major depression (odds ratio (OR) 1.10 (0.70-1.70)). Conversely, antidepressant exposure during but not prior to pregnancy was associated with ADHD risk, even after adjustment for maternal depression (OR 1.81 (1.22-2.70)). These results suggest that the risk of autism observed with prenatal antidepressant exposure is likely confounded by severity of maternal illness, but further indicate that such exposure may still be associated with ADHD risk. This risk, modest in absolute terms, may still be a result of residual confounding and must be balanced against the substantial consequences of untreated maternal depression.Molecular Psychiatry advance online publication, 26 August 2014; doi:10.1038/mp.2014.90.

PMID: 25155880 [PubMed - as supplied by publisher]

AMPD1 functional variants associated with autism in Han Chinese population.

August 27, 2014 - 8:21am

AMPD1 functional variants associated with autism in Han Chinese population.

Eur Arch Psychiatry Clin Neurosci. 2014 Aug 26;

Authors: Zhang L, Ou J, Xu X, Peng Y, Guo H, Pan Y, Chen J, Wang T, Peng H, Liu Q, Tian D, Pan Q, Zou X, Zhao J, Hu Z, Xia K

Abstract
Autism is a childhood neurodevelopmental disorder with high heterogeneity. Following our genome-wide associated loci with autism, we performed sequencing analysis of the coding regions, UTR and flanking splice junctions of AMPD1 in 830 Chinese autism individuals as well as 514 unrelated normal controls. Fourteen novel variants in the coding sequence were identified, including 11 missense variants and 3 synonymous mutations. Among these missense variants, 10 variants were absent in 514 control subjects, and conservative and functional prediction was carried out. Mitochondria activity and lactate dehydrogenase assay were performed in 5 patients' lymphoblast cell lines; p.P572S and p.S626C showed decreased mitochondrial complex I activity, and p.S626C increased lactate dehydrogenase release in medium. Conclusively, our data suggested that mutational variants in AMPD1 contribute to autism risk in Han Chinese population, uncovering the contribution of mutant protein to disease development that operates via mitochondria dysfunction and cell necrosis.

PMID: 25155876 [PubMed - as supplied by publisher]

Brain-derived neurotrophic factor and Rett syndrome.

August 27, 2014 - 8:21am
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Brain-derived neurotrophic factor and Rett syndrome.

Handb Exp Pharmacol. 2014;220:481-95

Authors: Katz DM

Abstract
Rett syndrome (RTT) is a devastating neurodevelopmental disorder with autistic features caused by loss-of-function mutations in the gene encoding methyl-CpG-binding protein 2 (MECP2), a transcriptional regulatory protein. RTT has attracted widespread attention not only because of the urgent need for treatments, but also because it has become a window into basic mechanisms underlying epigenetic regulation of neuronal genes, including BDNF. In addition, work in mouse models of the disease has demonstrated the possibility of symptom reversal upon restoration of normal gene function. This latter finding has resulted in a paradigm shift in RTT research and, indeed, in the field of neurodevelopmental disorders as a whole, and spurred the search for potential therapies for RTT and related syndromes. In this context, the discovery that expression of BDNF is dysregulated in RTT and mouse models of the disease has taken on particular importance. This chapter reviews the still evolving story of how MeCP2 might regulate expression of BDNF, the functional consequences of BDNF deficits in Mecp2 mutant mice, and progress in developing BDNF-targeted therapies for the treatment of RTT.

PMID: 24668484 [PubMed - indexed for MEDLINE]

A genome-wide survey of transgenerational genetic effects in autism.

August 27, 2014 - 8:21am
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A genome-wide survey of transgenerational genetic effects in autism.

PLoS One. 2013;8(10):e76978

Authors: Tsang KM, Croen LA, Torres AR, Kharrazi M, Delorenze GN, Windham GC, Yoshida CK, Zerbo O, Weiss LA

Abstract
Effects of parental genotype or parent-offspring genetic interaction are well established in model organisms for a variety of traits. However, these transgenerational genetic models are rarely studied in humans. We have utilized an autism case-control study with 735 mother-child pairs to perform genome-wide screening for maternal genetic effects and maternal-offspring genetic interaction. We used simple models of single locus parent-child interaction and identified suggestive results (P<10(-4)) that cannot be explained by main effects, but no genome-wide significant signals. Some of these maternal and maternal-child associations were in or adjacent to autism candidate genes including: PCDH9, FOXP1, GABRB3, NRXN1, RELN, MACROD2, FHIT, RORA, CNTN4, CNTNAP2, FAM135B, LAMA1, NFIA, NLGN4X, RAPGEF4, and SDK1. We attempted validation of potential autism association under maternal-specific models using maternal-paternal comparison in family-based GWAS datasets. Our results suggest that further study of parental genetic effects and parent-child interaction in autism is warranted.

PMID: 24204716 [PubMed - indexed for MEDLINE]

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]

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