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Prevalence of autism and attention-deficit-hyperactivity disorder in Down syndrome: a population-based study.

August 10, 2016 - 8:29am

Prevalence of autism and attention-deficit-hyperactivity disorder in Down syndrome: a population-based study.

Dev Med Child Neurol. 2016 Aug 9;

Authors: Oxelgren UW, Myrelid Å, Annerén G, Ekstam B, Göransson C, Holmbom A, Isaksson A, Åberg M, Gustafsson J, Fernell E

Abstract
AIM: To investigate the prevalence of autism spectrum disorder (ASD) and attention-deficit-hyperactivity disorder (ADHD) in a population-based group of children and adolescents with Down syndrome, and to relate the findings to level of intellectual disability and to medical conditions.
METHOD: From a population-based cohort of 60 children and adolescents with Down syndrome, 41 individuals (29 males, 12 females; mean age 11y, age range 5-17y) for whom parents gave consent for participation were clinically assessed with regard to ASD and ADHD. The main instruments used were the Autism Diagnostic Interview-Revised, Autism Diagnostic Observation Schedule, Swanson, Nolan, and Pelham-IV Rating Scale, and the Adaptive Behavior Assessment System-II.
RESULTS: High rates of ASD and ADHD were found: 17 (42%) and 14 (34%) of the 41 children met DSM criteria for ASD and ADHD respectively.
INTERPRETATION: Children with Down syndrome and coexisting neurodevelopmental/neuropsychiatric disorders in addition to intellectual disability and medical disorders constitute a severely disabled group. Based on the results, we suggest that screening is implemented for both ASD and ADHD, at the age of 3 to 5 years and early school years respectively, to make adequate interventions possible.

PMID: 27503703 [PubMed - as supplied by publisher]

Neurodevelopmental, emotional, and behavioural problems in Duchenne muscular dystrophy in relation to underlying dystrophin gene mutations.

August 10, 2016 - 8:29am
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Neurodevelopmental, emotional, and behavioural problems in Duchenne muscular dystrophy in relation to underlying dystrophin gene mutations.

Dev Med Child Neurol. 2016 Jan;58(1):77-84

Authors: Ricotti V, Mandy WP, Scoto M, Pane M, Deconinck N, Messina S, Mercuri E, Skuse DH, Muntoni F

Abstract
AIM: Duchenne muscular dystrophy (DMD) is associated with neuropsychiatric disorders. The aim of the study was to characterize the DMD neuropsychiatric profile fully and to explore underlying genotype/phenotype associations.
METHOD: One hundred and thirty males with DMD (mean age 9y 10mo, range 5-17y) in four European centres were included and completed IQ assessment and a neurodevelopmental-screening questionnaire. Of these, 87 underwent comprehensive neuropsychiatric assessment using structured diagnostic interview and parent-reported questionnaires.
RESULTS: The overall mean score on the neurodevelopmental questionnaire was significantly abnormal compared with the general population of children (p<0.001). On average, intelligence was below the population mean, with intellectual disability observed in 34 males (26%). Autistic spectrum disorder was identified in 18 (21%), hyperactivity in 21 (24%), and inattention in 38 (44%). Clinical levels of internalizing and externalizing problems were observed in 21 (24%) and 13 (15%) respectively. Over a third of males scored more than two measures of emotional, behavioural, or neurodevelopmental problems. Males with mutations at the 3' end of the DMD gene affecting all protein isoforms had higher rates of intellectual disability and clusters of symptoms.
INTERPRETATION: Males with DMD are at very high risk of neuropsychiatric disturbance, and this risk appears to increase with mutations at the 3' end of the gene. Patterns of symptom clusters suggest a DMD neuropsychiatric syndrome, which may require prompt evaluation and early intervention.

PMID: 26365034 [PubMed - indexed for MEDLINE]

From estimating activation locality to predicting disorder: A review of pattern recognition for neuroimaging-based psychiatric diagnostics.

August 10, 2016 - 8:29am
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From estimating activation locality to predicting disorder: A review of pattern recognition for neuroimaging-based psychiatric diagnostics.

Neurosci Biobehav Rev. 2015 Oct;57:328-49

Authors: Wolfers T, Buitelaar JK, Beckmann CF, Franke B, Marquand AF

Abstract
Psychiatric disorders are increasingly being recognised as having a biological basis, but their diagnosis is made exclusively behaviourally. A promising approach for 'biomarker' discovery has been based on pattern recognition methods applied to neuroimaging data, which could yield clinical utility in future. In this review we survey the literature on pattern recognition for making diagnostic predictions in psychiatric disorders, and evaluate progress made in translating such findings towards clinical application. We evaluate studies on many criteria, including data modalities used, the types of features extracted and algorithm applied. We identify problems common to many studies, such as a relatively small sample size and a primary focus on estimating generalisability within a single study. Furthermore, we highlight challenges that are not widely acknowledged in the field including the importance of accommodating disease prevalence, the necessity of more extensive validation using large carefully acquired samples, the need for methodological innovations to improve accuracy and to discriminate between multiple disorders simultaneously. Finally, we identify specific clinical contexts in which pattern recognition can add value in the short to medium term.

PMID: 26254595 [PubMed - indexed for MEDLINE]

[Structural variations of the genome in autistic spectrum disorders with intellectual disability].

August 9, 2016 - 8:26am

[Structural variations of the genome in autistic spectrum disorders with intellectual disability].

Zh Nevrol Psikhiatr Im S S Korsakova. 2016;116(7):50-54

Authors: Yurov IY, Vorsanova SG, Korostelev SA, Vasin KS, Zelenova MA, Kurinnaya OS, Yurov YB

Abstract
AIM: To analyze structural variations in the genome in children with autism and intellectual disability.
MATERIAL AND METHODS: Using high-resolution karyotyping (AffymetrixCytoScan HD Array) and original bioinformatic technology, 200 children with autism and intellectual disability were studied.
RESULTS AND CONCLUSION: Data on structural variations in the genome in children with autism and intellectual disability are provided. Causative genomic pathology (chromosome abnormalities and copy number variations - CNV) was determined in 97 cases (48.5%). Based on these RESULTS: 24 candidate genes for autism with intellectual disability were selected. In 16 cases (8%), the chromosome mosaicism manifested as aneuploidy of whole autosomes and sex chromosomes (gonosomes) was identified. In 87 children (43.5%), there were genomic variations, which are characteristic of the so-called «grey zone» of genetic pathology in mental illnesses. Bioinformatic analysis showed that these genomic variations had a pleiotropic effect on the phenotype.

PMID: 27500877 [PubMed - as supplied by publisher]

Insulin-Independent GABAA Receptor-Mediated Response in the Barrel Cortex of Mice with Impaired Met Activity.

August 9, 2016 - 8:26am
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Insulin-Independent GABAA Receptor-Mediated Response in the Barrel Cortex of Mice with Impaired Met Activity.

J Neurosci. 2016 Mar 30;36(13):3691-7

Authors: Lo FS, Erzurumlu RS, Powell EM

Abstract
UNLABELLED: Autism spectrum disorder (ASD) is a neurodevelopmental disorder caused by genetic variants, susceptibility alleles, and environmental perturbations. The autism associated geneMETtyrosine kinase has been implicated in many behavioral domains and endophenotypes of autism, including abnormal neural signaling in human sensory cortex. We investigated somatosensory thalamocortical synaptic communication in mice deficient in Met activity in cortical excitatory neurons to gain insights into aberrant somatosensation characteristic of ASD. The ratio of excitation to inhibition is dramatically increased due to decreased postsynaptic GABAAreceptor-mediated inhibition in the trigeminal thalamocortical pathway of mice lacking active Met in the cerebral cortex. Furthermore, in contrast to wild-type mice, insulin failed to increase GABAAreceptor-mediated response in the barrel cortex of mice with compromised Met signaling. Thus, lacking insulin effects may be a risk factor in ASD pathogenesis.
SIGNIFICANCE STATEMENT: A proposed common cause of neurodevelopmental disorders is an imbalance in excitatory neural transmission, provided by the glutamatergic neurons, and the inhibitory signals from the GABAergic interneurons. Many genes associated with autism spectrum disorders impair synaptic transmission in the expected cell type. Previously, inactivation of the autism-associated Met tyrosine kinase receptor in GABAergic interneurons led to decreased inhibition. In thus report, decreased Met signaling in glutamatergic neurons had no effect on excitation, but decimated inhibition. Further experiments indicate that loss of Met activity downregulates GABAAreceptors on glutamatergic neurons in an insulin independent manner. These data provide a new mechanism for the loss of inhibition and subsequent abnormal excitation/inhibition balance and potential molecular candidates for treatment or prevention.

PMID: 27030755 [PubMed - indexed for MEDLINE]

Prenatal minocycline treatment alters synaptic protein expression, and rescues reduced mother call rate in oxytocin receptor-knockout mice.

August 9, 2016 - 8:26am
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Prenatal minocycline treatment alters synaptic protein expression, and rescues reduced mother call rate in oxytocin receptor-knockout mice.

Biochem Biophys Res Commun. 2016 Apr 1;472(2):319-23

Authors: Miyazaki S, Hiraoka Y, Hidema S, Nishimori K

Abstract
Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by impaired communication, difficulty in companionship, repetitive behaviors and restricted interests. Recent studies have shown amelioration of ASD symptoms by intranasal administration of oxytocin and demonstrated the association of polymorphisms in the oxytocin receptor (Oxtr) gene with ASD patients. Deficient pruning of synapses by microglial cells in the brain has been proposed as potential mechanism of ASD. Other researchers have shown specific activation of microglial cells in brain regions related to sociality in patients with ASD. Although the roles of Oxtr and microglia in ASD are in the spotlight, the relationship between them remains to be elucidated. In this study, we found abnormal activation of microglial cells and a reduction of postsynaptic density protein PSD95 expression in the Oxtr-deficient brain. Moreover, pharmacological inhibition of microglia during development can alter the expression of PSD95 and ameliorate abnormal mother-infant communication in Oxtr-deficient mice. Our results suggest that microglial abnormality is a potential mechanism of the development of Oxt/Oxtr mediated ASD-like phenotypes.

PMID: 26926566 [PubMed - indexed for MEDLINE]

AMPA Receptors as Therapeutic Targets for Neurological Disorders.

August 9, 2016 - 8:26am
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AMPA Receptors as Therapeutic Targets for Neurological Disorders.

Adv Protein Chem Struct Biol. 2016;103:203-61

Authors: Lee K, Goodman L, Fourie C, Schenk S, Leitch B, Montgomery JM

Abstract
Almost every neurological disease directly or indirectly affects synapse function in the brain. However, these diseases alter synapses through different mechanisms, ultimately resulting in altered synaptic transmission and/or plasticity. Glutamate is the major neurotransmitter that mediates excitatory synaptic transmission in the brain through activation of alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionate (AMPA) receptors. These receptors have therefore been identified as a target for the development of therapeutic treatments for neurological disorders including epilepsy, neurodegenerative diseases, autism, and drug addiction. The fact that AMPA receptors play a dominant role throughout the brain raises the significant challenge of selectively targeting only those regions affected by disease, and clinical trials have raised doubt regarding the feasibility of specifically targeting AMPA receptors for new therapeutic options. Benzamide compounds that act as positive allosteric AMPA receptor modulators, known as AMPAkines, can act on specific brain regions and were initially proposed to revolutionize the treatment of cognitive deficits associated with neurological disorders. Their therapeutic potential has since declined due to inconsistent results in clinical trials. However, recent advances in basic biomedical research are significantly increasing our knowledge of AMPA receptor structure, binding sites, and interactions with auxiliary proteins. In particular, the large complex of postsynaptic proteins that interact with AMPA receptor subunits have been shown to control AMPA receptor insertion, location, pharmacology, synaptic transmission, and plasticity. These proteins are now being considered as alternative therapeutic target sites for modulating AMPA receptors in neurological disorders.

PMID: 26920691 [PubMed - indexed for MEDLINE]

Evaluation of the neuroactive steroid ganaxolone on social and repetitive behaviors in the BTBR mouse model of autism.

August 9, 2016 - 8:26am
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Evaluation of the neuroactive steroid ganaxolone on social and repetitive behaviors in the BTBR mouse model of autism.

Psychopharmacology (Berl). 2016 Jan;233(2):309-23

Authors: Kazdoba TM, Hagerman RJ, Zolkowska D, Rogawski MA, Crawley JN

Abstract
RATIONALE: Abnormalities in excitatory/inhibitory neurotransmission are hypothesized to contribute to autism spectrum disorder (ASD) etiology. BTBR T (+) Itpr3 (tf) /J (BTBR), an inbred mouse strain, displays social deficits and repetitive self-grooming, offering face validity to ASD diagnostic symptoms. Reduced GABAergic neurotransmission in BTBR suggests that GABAA receptor positive allosteric modulators (PAMs) could improve ASD-relevant BTBR phenotypes. The neuroactive steroid ganaxolone acts as a PAM, displaying anticonvulsant properties in rodent epilepsy models and an anxiolytic-like profile in the elevated plus-maze.
OBJECTIVES: We evaluated ganaxolone in BTBR and C57BL/6J mice in standardized assays for sociability and repetitive behaviors. Open field and anxiety-related behaviors were tested as internal controls and for comparison with the existing neuroactive steroid literature.
RESULTS: Ganaxolone improved aspects of social approach and reciprocal social interactions in BTBR, with no effect on repetitive self-grooming, and no detrimental effects in C57BL/6J. Ganaxolone increased overall exploratory activity in BTBR and C57BL/6J in the open field, social approach, and elevated plus-maze, introducing a confound for the interpretation of social improvements. Allopregnanolone and diazepam similarly increased total entries in the elevated plus-maze, indicating that behavioral activation may be a general property of GABAA receptor PAMs in these strains.
CONCLUSIONS: Ganaxolone shows promise for improving sociability. In addition, ganaxolone, as well as other GABAA receptor PAMs, enhanced overall BTBR activity. The translational implications of specific sociability improvements and nonspecific behavioral activation by ganaxolone in the BTBR model remain to be determined. Future studies to explore whether PAMs provide a novel profile with unique benefits for ASD treatment will be worthwhile.

PMID: 26525567 [PubMed - indexed for MEDLINE]

Genetic architecture, epigenetic influence and environment exposure in the pathogenesis of Autism.

August 9, 2016 - 8:26am
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Genetic architecture, epigenetic influence and environment exposure in the pathogenesis of Autism.

Sci China Life Sci. 2015 Oct;58(10):958-67

Authors: Yu L, Wu Y, Wu BL

Abstract
Autism spectrum disorder (ASD) is a spectral neurodevelopment disorder affecting approximately 1% of the population. ASD is characterized by impairments in reciprocal social interaction, communication deficits and restricted patterns of behavior. Multiple factors, including genetic/genomic, epigenetic/epigenomic and environmental, are thought to be necessary for autism development. Recent reviews have provided further insight into the genetic/genomic basis of ASD. It has long been suspected that epigenetic mechanisms, including DNA methylation, chromatin structures and long non-coding RNAs may play important roles in the pathology of ASD. In addition to genetic/genomic alterations and epigenetic/epigenomic influences, environmental exposures have been widely accepted as an important role in autism etiology, among which immune dysregulation and gastrointestinal microbiota are two prominent ones.

PMID: 26490976 [PubMed - indexed for MEDLINE]

Autism spectrum disorder model mice: Focus on copy number variation and epigenetics.

August 9, 2016 - 8:26am
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Autism spectrum disorder model mice: Focus on copy number variation and epigenetics.

Sci China Life Sci. 2015 Oct;58(10):976-84

Authors: Nakai N, Otsuka S, Myung J, Takumi T

Abstract
Autism spectrum disorder (ASD) is gathering concerns in socially developed countries. ASD is a neuropsychiatric disorder of genetic origin with high prevalence of 1%-2%. The patients with ASD characteristically show impaired social skills. Today, many genetic studies identify numerous susceptible genes and genetic loci associated with ASD. Although some genetic factors can lead to abnormal brain function linked to ASD phenotypes, the pathogenic mechanism of ASD is still unclear. Here, we discuss a new mouse model for ASD as an advanced tool to understand the mechanism of ASD.

PMID: 26335737 [PubMed - indexed for MEDLINE]

CACNB2: An Emerging Pharmacological Target for Hypertension, Heart Failure, Arrhythmia and Mental Disorders.

August 9, 2016 - 8:26am
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CACNB2: An Emerging Pharmacological Target for Hypertension, Heart Failure, Arrhythmia and Mental Disorders.

Curr Mol Pharmacol. 2015;8(1):32-42

Authors: Soldatov NM

Abstract
The voltage-gated Cav1.2 calcium channels respond to membrane depolarization by increasing the membrane permeability to Ca(2+), a major signal for cardiac muscle contraction, regulation of vascular tone and CREB-dependent transcriptional activation. CACNB2 is one of the four homologous genes coding for the auxiliary Cavβ subunits, which are important modulators of the Ca(2+) channel activity. Five serious mental disorders - autism spectrum disorder, attention deficit-hyperactivity disorder, bipolar disorder, major depressive disorder, and schizophrenia, - and three major cardiovascular diseases - hypertension, heart failure and sudden cardiac death, - have recently been linked to the CACNB2 gene coding for the Cavβ2 subunits. Here I will focus on the Cavβ2-specific molecular determinant β2-CED as an emerging pharmacological target.

PMID: 25966706 [PubMed - indexed for MEDLINE]

Regulation of neuronal migration, an emerging topic in autism spectrum disorders.

August 7, 2016 - 11:22am
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Regulation of neuronal migration, an emerging topic in autism spectrum disorders.

J Neurochem. 2016 Feb;136(3):440-56

Authors: Reiner O, Karzbrun E, Kshirsagar A, Kaibuchi K

Abstract
Autism spectrum disorders (ASD) encompass a group of neurodevelopmental diseases that demonstrate strong heritability, however, the inheritance is not simple and many genes have been associated with these disorders. ASD is regarded as a neurodevelopmental disorder, and abnormalities at different developmental stages are part of the disease etiology. This review provides a general background on neuronal migration during brain development and discusses recent advancements in the field connecting ASD and aberrant neuronal migration. We propose that neuronal migration impairment may be an important common pathophysiology in autism spectrum disorders (ASD). This review provides a general background on neuronal migration during brain development and discusses recent advancements in the field connecting ASD and aberrant neuronal migration.

PMID: 26485324 [PubMed - indexed for MEDLINE]

Schizophrenia genetics complements its mechanistic understanding.

August 5, 2016 - 8:19am
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Schizophrenia genetics complements its mechanistic understanding.

Nat Neurosci. 2016 Apr;19(4):523-5

Authors: Ruzzo EK, Geschwind DH

PMID: 26998600 [PubMed - indexed for MEDLINE]

Perturbed Hippocampal Synaptic Inhibition and γ-Oscillations in a Neuroligin-4 Knockout Mouse Model of Autism.

August 5, 2016 - 8:19am
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Perturbed Hippocampal Synaptic Inhibition and γ-Oscillations in a Neuroligin-4 Knockout Mouse Model of Autism.

Cell Rep. 2015 Oct 20;13(3):516-23

Authors: Hammer M, Krueger-Burg D, Tuffy LP, Cooper BH, Taschenberger H, Goswami SP, Ehrenreich H, Jonas P, Varoqueaux F, Rhee JS, Brose N

Abstract
Loss-of-function mutations in the synaptic adhesion protein Neuroligin-4 are among the most common genetic abnormalities associated with autism spectrum disorders, but little is known about the function of Neuroligin-4 and the consequences of its loss. We assessed synaptic and network characteristics in Neuroligin-4 knockout mice, focusing on the hippocampus as a model brain region with a critical role in cognition and memory, and found that Neuroligin-4 deletion causes subtle defects of the protein composition and function of GABAergic synapses in the hippocampal CA3 region. Interestingly, these subtle synaptic changes are accompanied by pronounced perturbations of γ-oscillatory network activity, which has been implicated in cognitive function and is altered in multiple psychiatric and neurodevelopmental disorders. Our data provide important insights into the mechanisms by which Neuroligin-4-dependent GABAergic synapses may contribute to autism phenotypes and indicate new strategies for therapeutic approaches.

PMID: 26456829 [PubMed - indexed for MEDLINE]

mTORC1 and mTORC2 have largely distinct functions in Purkinje cells.

August 4, 2016 - 8:17am
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mTORC1 and mTORC2 have largely distinct functions in Purkinje cells.

Eur J Neurosci. 2015 Oct;42(8):2595-612

Authors: Angliker N, Burri M, Zaichuk M, Fritschy JM, Rüegg MA

Abstract
The mammalian target of rapamycin (mTOR) is a key regulator of cellular growth which associates with other proteins to form two multi-protein complexes called mTORC1 and mTORC2. Dysregulation of mTORC1 signalling in brain is implicated in neuropathological conditions such as autism spectrum or neurodegenerative disorders. Accordingly, allosteric mTOR inhibitors are currently in clinical trials for the treatment of such disorders. Here, we ablated either mTORC1 or mTORC2 conditionally in Purkinje cells of the mouse cerebellum to dissect their role in the development, function and survival of these neurons. We find that the two mouse models largely differ from each other by phenotype and cellular responses. Inactivation of mTORC2, but not of mTORC1, led to motor coordination deficits at an early age. This phenotype correlated with developmental deficits in climbing fibre elimination and impaired dendritic self-avoidance in mTORC2-deficient Purkinje cells. In contrast, inactivation of mTORC1, but not of mTORC2, affected social interest of the mice and caused a progressive loss of Purkinje cells due to apoptosis. This cell loss was paralleled by age-dependent motor deficits. Comparison of mTORC1-deficient Purkinje cells with those deficient for the mTORC1 inhibitor TSC1 revealed a striking overlap in Purkinje cell degeneration and death, which included neurofilamentopathy and reactive gliosis. Altogether, our study reveals distinct roles of mTORC1 and mTORC2 in Purkinje cells for mouse behaviour and the survival of neurons. Our study also highlights a convergence between the phenotypes of Purkinje cells lacking mTORC1 activity and those expressing constitutively active mTORC1 due to TSC1 deficiency.

PMID: 26296489 [PubMed - indexed for MEDLINE]

The GABAA receptor is an FMRP target with therapeutic potential in fragile X syndrome.

August 4, 2016 - 8:17am
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The GABAA receptor is an FMRP target with therapeutic potential in fragile X syndrome.

Cell Cycle. 2015;14(18):2985-95

Authors: Braat S, D'Hulst C, Heulens I, De Rubeis S, Mientjes E, Nelson DL, Willemsen R, Bagni C, Van Dam D, De Deyn PP, Kooy RF

Abstract
Previous research indicates that the GABAAergic system is involved in the pathophysiology of the fragile X syndrome, a frequent form of inherited intellectual disability and associated with autism spectrum disorder. However, the molecular mechanism underlying GABAAergic deficits has remained largely unknown. Here, we demonstrate reduced mRNA expression of GABAA receptor subunits in the cortex and cerebellum of young Fmr1 knockout mice. In addition, we show that the previously reported underexpression of specific subunits of the GABAA receptor can be corrected in YAC transgenic rescue mice, containing the full-length human FMR1 gene in an Fmr1 knockout background. Moreover, we demonstrate that FMRP directly binds several GABAA receptor mRNAs. Finally, positive allosteric modulation of GABAA receptors with the neurosteroid ganaxolone can modulate specific behaviors in Fmr1 knockout mice, emphasizing the therapeutic potential of the receptor.

PMID: 25790165 [PubMed - indexed for MEDLINE]

Peripheral Attentional Targets under Covert Attention Lead to Paradoxically Enhanced Alpha Desynchronization in Neurofibromatosis Type 1.

August 2, 2016 - 11:14am
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Peripheral Attentional Targets under Covert Attention Lead to Paradoxically Enhanced Alpha Desynchronization in Neurofibromatosis Type 1.

PLoS One. 2016;11(2):e0148600

Authors: Silva G, Ribeiro MJ, Costa GN, Violante I, Ramos F, Saraiva J, Castelo-Branco M

Abstract
The limited capacity of the human brain to process the full extent of visual information reaching the visual cortex requires the recruitment of mechanisms of information selection through attention. Neurofibromatosis type-1 (NF1) is a neurodevelopmental disease often exhibiting attentional deficits and learning disabilities, and is considered to model similar impairments common in other neurodevelopmental disorders such as autism. In a previous study, we found that patients with NF1 are more prone to miss targets under overt attention conditions. This finding was interpreted as a result of increased occipito-parietal alpha oscillations. In the present study, we used electroencephalography (EEG) to study alpha power modulations and the performance of patients with NF1 in a covert attention task. Covert attention was required in order to perceive changes (target offset) of a peripherally presented stimulus. Interestingly, alpha oscillations were found to undergo greater desynchronization under this task in the NF1 group compared with control subjects. A similar pattern of desynchronization was found for beta frequencies while no changes in gamma oscillations could be identified. These results are consistent with the notion that different attentional states and task demands generate different patterns of abnormal modulation of alpha oscillatory processes in NF1. Under covert attention conditions and while target offset was reported with relatively high accuracy (over 90% correct responses), excessive desynchronization was found. These findings suggest an abnormal modulation of oscillatory activity and attentional processes in NF1. Given the known role of alpha in modulating attention, we suggest that alpha patterns can show both abnormal increases and decreases that are task and performance dependent, in a way that enhanced alpha desynchronization may reflect a compensatory mechanism to keep performance at normal levels. These results suggest that dysregulation of alpha oscillations may occur in NF1 both in terms of excessive or diminished activation patterns.

PMID: 26881921 [PubMed - indexed for MEDLINE]

Cortical interneuron dysfunction in epilepsy associated with autism spectrum disorders.

August 2, 2016 - 11:14am
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Cortical interneuron dysfunction in epilepsy associated with autism spectrum disorders.

Epilepsia. 2016 Feb;57(2):182-93

Authors: Jacob J

Abstract
Autism and epilepsy are two associated disorders that are highly prevalent, share common developmental origins, and demonstrate substantial heritability. In this review, cross-disciplinary data in a rapidly evolving field that bridges neurology and psychiatry are synthesized to identify shared biologic mechanisms. The relationship between these debilitating, lifelong conditions is examined at the clinical, genetic, and neurophysiologic levels in humans and in animal models. Scopus and PubMed searches were used to identify relevant literature. Clinical observations have prompted speculation about the interdependence of autism and epilepsy, but causal relationships have proved difficult to determine. Despite their heritability, the genetic basis of autism spectrum disorder (ASD) and epilepsy has remained largely elusive until the advent of next-generation sequencing. This approach has revealed that mutations that are either causal or confer an increased disease risk are found in numerous different genes, any one of which accounts for only a small percentage of cases. Conversely, even cases with identical clinical phenotypes can be genetically heterogeneous. Candidate gene identification has facilitated the development of mouse genetic models, which in parallel with human studies have implicated shared brain regions and circuits that mediate disease expression. Diverse genetic causes of ASD and epilepsy converge on cortical interneuron circuits as one important mediator of both disorders. Cortical interneurons are among the most diverse cell types in the brain and their unique chemical and electrical coupling exert a powerful inhibitory influence on excitatory neurons via the release of the neurotransmitter, γ-aminobutyric acid (GABA). These multifaceted approaches have validated theories derived from the field of developmental neurobiology, which propose that the neurologic and neuropsychiatric manifestations are caused by an altered ratio of excitation to inhibition in the cortex.

PMID: 26682992 [PubMed - indexed for MEDLINE]

Epigenetics in Clinical Practice: Characterizing Patient and Provider Experiences with MTHFR Polymorphisms and Methylfolate.

August 2, 2016 - 11:14am
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Epigenetics in Clinical Practice: Characterizing Patient and Provider Experiences with MTHFR Polymorphisms and Methylfolate.

J Nutrigenet Nutrigenomics. 2015;8(3):137-50

Authors: Oberg E, Givant C, Fisk B, Parikh C, Bradley R

Abstract
BACKGROUND: Observational research associating 5,10-methylenetetrahydrofolate reductase (MTHFR) polymorphisms with risk of autism, depression, cancer, and cardiovascular disease has led to increased diagnoses of MTHFR; however, doctors lack knowledge about safety, effectiveness, and clinical implications of MTHFR treatment. Treatment strategies are hypothetical and mechanistically based, including methylfolate with or without other B vitamins.
AIMS: This study was designed to formally describe patient and health care provider experiences with the diagnosis and clinical management of MTHFR.
METHODS: Guided by a structured interview guide, a qualitative study queried patients' and providers' observations regarding: testing indications, reaction to results, treatment protocols, and clinical response including adverse effects.
RESULTS: Thirty patients and 8 doctors participated. Patient themes included emotionality associated with diagnosis, classification of signs and symptoms, and challenges with treatment. They expressed confusion over their diagnosis, and frustration with the state of knowledge their providers had regarding MTHFR. Testing indications included: fatigue (21%), hormone imbalances (13%), and neurological symptoms (13%) including brain fog (8%). Patients reported improvements in physical (60%) and mental/behavioral symptoms (36%) following treatment. A minority of participants reported side effects, but they occurred in almost every body system and ranged in severity. Doctors relied on trial and error to determine treatment doses, frequency and components.
CONCLUSIONS: MTHFR testing results in variable clinical processes in domains related to delivery of diagnosis and prognosis, and therapeutic options. However, patients report largely positive experiences. Clinicians and patients would benefit from therapeutic algorithms based on rigorous research.

PMID: 26484755 [PubMed - indexed for MEDLINE]

Bone marrow failure and developmental delay caused by mutations in poly(A)-specific ribonuclease (PARN).

August 2, 2016 - 11:14am
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Bone marrow failure and developmental delay caused by mutations in poly(A)-specific ribonuclease (PARN).

J Med Genet. 2015 Nov;52(11):738-48

Authors: Dhanraj S, Gunja SM, Deveau AP, Nissbeck M, Boonyawat B, Coombs AJ, Renieri A, Mucciolo M, Marozza A, Buoni S, Turner L, Li H, Jarrar A, Sabanayagam M, Kirby M, Shago M, Pinto D, Berman JN, Scherer SW, Virtanen A, Dror Y

Abstract
BACKGROUND: Deadenylation regulates RNA function and fate. Poly(A)-specific ribonuclease (PARN) is a deadenylase that processes mRNAs and non-coding RNA. Little is known about the biological significance of germline mutations in PARN.
METHODS: We identified mutations in PARN in patients with haematological and neurological manifestations. Genomic, biochemical and knockdown experiments in human marrow cells and in zebrafish have been performed to clarify the role of PARN in the human disease.
RESULTS: We identified large monoallelic deletions in PARN in four patients with developmental delay or mental illness. One patient in particular had a severe neurological phenotype, central hypomyelination and bone marrow failure. This patient had an additional missense mutation on the non-deleted allele and severely reduced PARN protein and deadenylation activity. Cells from this patient had impaired oligoadenylation of specific H/ACA box small nucleolar RNAs. Importantly, PARN-deficient patient cells manifested short telomeres and an aberrant ribosome profile similar to those described in some variants of dyskeratosis congenita. Knocking down PARN in human marrow cells and zebrafish impaired haematopoiesis, providing further evidence for a causal link with the human disease.
CONCLUSIONS: Large monoallelic mutations of PARN can cause developmental/mental illness. Biallelic PARN mutations cause severe bone marrow failure and central hypomyelination.

PMID: 26342108 [PubMed - indexed for MEDLINE]

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