pubmed: autism and genetics

Subscribe to pubmed: autism and genetics feed pubmed: autism and genetics
NCBI: db=pubmed; Term=autism AND genetics
Updated: 1 hour 37 min ago

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
Related Articles

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
Related Articles

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
Related Articles

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
Related Articles

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
Related Articles

[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
Related Articles

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
Related Articles

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
Related Articles

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
Related Articles

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
Related Articles

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
Related Articles

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
Related Articles

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]

Pages