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Clinical presentation of PTEN mutations in childhood in the absence of family history of Cowden syndrome.

April 2, 2016 - 6:21am
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Clinical presentation of PTEN mutations in childhood in the absence of family history of Cowden syndrome.

Eur J Paediatr Neurol. 2015 Mar;19(2):188-92

Authors: Busa T, Milh M, Degardin N, Girard N, Sigaudy S, Longy M, Olshchwang S, Sobol H, Chabrol B, Philip N

Abstract
BACKGROUND: PTEN gene (MIM 601628) is a tumor suppressor gene implicated in PTEN hamartoma tumor syndromes (PHTS) including Cowden syndrome, Bannayan-Riley-Ruvalcaba syndrome, and Proteus-like syndrome. Bannayan-Riley-Ruvalcaba syndrome is considered as the pediatric form of PHTS. More recently, children presenting autism spectrum disorders with macrocephaly (ASD-M) have been reported.
METHODS: We report clinical data from seven patients diagnosed in childhood with a PTEN germline mutation, excluding cases of familial Cowden syndrome.
RESULTS: This study underlines the variability of phenotype associated with PTEN mutations diagnosed at pediatric age. Most of the patients did not fulfill usual criteria of Bannayan-Riley-Ruvalcaba syndrome or ASD-M.
CONCLUSION: PTEN testing should be considered in any child presenting with severe macrocephaly (>+4SD) and another feature of PHTS.

PMID: 25549896 [PubMed - indexed for MEDLINE]

PlexinA polymorphisms mediate the developmental trajectory of human corpus callosum microstructure.

April 2, 2016 - 6:21am
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PlexinA polymorphisms mediate the developmental trajectory of human corpus callosum microstructure.

J Hum Genet. 2015 Mar;60(3):147-50

Authors: Belyk M, Kraft SJ, Brown S, Pediatric Imaging, Neurocognition and Genetics Study

Abstract
PlexinA is a neuronal receptor protein that facilitates axon guidance during embryogenesis. This gene is associated with several neurological disorders including Alzheimer's disease, Parkinson's disease and autism. However, the effect of variants of PlexinA on brain structure remains unclear. We demonstrate that single-nucleotide polymorphisms within the intron and 3'-untranslated region segments of several human PlexinA genes alter the post-natal developmental trajectory of corpus callosum microstructure. This is the first demonstration that PLXNA mediation of neuroanatomical traits can be detected in humans using in vivo neuroimaging techniques. This result should encourage future research that targets specific disease-related polymorphisms and their relevant neural pathways.

PMID: 25518740 [PubMed - indexed for MEDLINE]

Extending the use of stiripentol to other epileptic syndromes: a case of PCDH19-related epilepsy.

April 2, 2016 - 6:21am
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Extending the use of stiripentol to other epileptic syndromes: a case of PCDH19-related epilepsy.

Eur J Paediatr Neurol. 2015 Mar;19(2):248-50

Authors: Trivisano M, Specchio N, Vigevano F

Abstract
Stiripentol is an antiepileptic drug (AED) approved by the European Medicines Agency for the treatment of Dravet Syndrome (DS) as adjunct treatment with valproate and clobazam. PCDH19-related epilepsy is an emerging epileptic syndrome characterized by the occurrence of epilepsy in female patients associated with mental retardation and autistic features in most cases. It shares many features with DS: age of onset, normal development before the onset, fever sensitivity, cognitive impairment during the time, drug-resistance. Basing on the numerous similarities between DS and PCDH19-related epilepsy, we tried stiripentol in a nine and half year old female patient with PCDH19-related resistant epilepsy, as add-on treatment to valproate and clobazam. It had a surprising efficacy as the patient had a two years and ten months seizure free period, as never in her epilepsy history. Up to date, clinical trials of stiripentol have been always focused on DS. The delineation of new epileptic syndromes, as PCDH19-related epilepsy, opens new scenarios to the utilization of this AED. This case report is suggestive of a good response of PCDH19-related Epilepsy to stiripentol. However further cases and above all clinical trials are necessary to confirm this result.

PMID: 25510386 [PubMed - indexed for MEDLINE]

Neurodevelopmental and neurobehavioral characteristics in males and females with CDKL5 duplications.

April 2, 2016 - 6:21am
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Neurodevelopmental and neurobehavioral characteristics in males and females with CDKL5 duplications.

Eur J Hum Genet. 2015 Jul;23(7):915-21

Authors: Szafranski P, Golla S, Jin W, Fang P, Hixson P, Matalon R, Kinney D, Bock HG, Craigen W, Smith JL, Bi W, Patel A, Wai Cheung S, Bacino CA, Stankiewicz P

Abstract
Point mutations and genomic deletions of the CDKL5 (STK9) gene on chromosome Xp22 have been reported in patients with severe neurodevelopmental abnormalities, including Rett-like disorders. To date, only larger-sized (8-21 Mb) duplications harboring CDKL5 have been described. We report seven females and four males from seven unrelated families with CDKL5 duplications 540-935 kb in size. Three families of different ethnicities had identical 667kb duplications containing only the shorter CDKL5 isoform. Four affected boys, 8-14 years of age, and three affected girls, 6-8 years of age, manifested autistic behavior, developmental delay, language impairment, and hyperactivity. Of note, two boys and one girl had macrocephaly. Two carrier mothers of the affected boys reported a history of problems with learning and mathematics while at school. None of the patients had epilepsy. Similarly to CDKL5 mutations and deletions, the X-inactivation pattern in all six studied females was random. We hypothesize that the increased dosage of CDKL5 might have affected interactions of this kinase with its substrates, leading to perturbation of synaptic plasticity and learning, and resulting in autistic behavior, developmental and speech delay, hyperactivity, and macrocephaly.

PMID: 25315662 [PubMed - indexed for MEDLINE]

CLK2 inhibition ameliorates autistic features associated with SHANK3 deficiency.

April 1, 2016 - 6:10am
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CLK2 inhibition ameliorates autistic features associated with SHANK3 deficiency.

Science. 2016 Mar 11;351(6278):1199-203

Authors: Bidinosti M, Botta P, Krüttner S, Proenca CC, Stoehr N, Bernhard M, Fruh I, Mueller M, Bonenfant D, Voshol H, Carbone W, Neal SJ, McTighe SM, Roma G, Dolmetsch RE, Porter JA, Caroni P, Bouwmeester T, Lüthi A, Galimberti I

Abstract
SH3 and multiple ankyrin repeat domains 3 (SHANK3) haploinsufficiency is causative for the neurological features of Phelan-McDermid syndrome (PMDS), including a high risk of autism spectrum disorder (ASD). We used unbiased, quantitative proteomics to identify changes in the phosphoproteome of Shank3-deficient neurons. Down-regulation of protein kinase B (PKB/Akt)-mammalian target of rapamycin complex 1 (mTORC1) signaling resulted from enhanced phosphorylation and activation of serine/threonine protein phosphatase 2A (PP2A) regulatory subunit, B56β, due to increased steady-state levels of its kinase, Cdc2-like kinase 2 (CLK2). Pharmacological and genetic activation of Akt or inhibition of CLK2 relieved synaptic deficits in Shank3-deficient and PMDS patient-derived neurons. CLK2 inhibition also restored normal sociability in a Shank3-deficient mouse model. Our study thereby provides a novel mechanistic and potentially therapeutic understanding of deregulated signaling downstream of Shank3 deficiency.

PMID: 26847545 [PubMed - indexed for MEDLINE]

Molecular Genetic Evidence for Shared Etiology of Autism and Prodigy.

March 31, 2016 - 6:05am
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Molecular Genetic Evidence for Shared Etiology of Autism and Prodigy.

Hum Hered. 2015;79(2):53-9

Authors: Ruthsatz J, Petrill SA, Li N, Wolock SL, Bartlett CW

Abstract
Child prodigies are rare individuals with an exceptional working memory and unique attentional skills that may facilitate the attainment of professional skill levels at an age well before what is observed in the general population. Some characteristics of prodigy have been observed to be quantitatively similar to those observed in autism spectrum disorder (ASD), suggesting possible shared etiology, though objectively validated prodigies are so rare that evidence has been sparse. We performed a family-based genome-wide linkage analysis on 5 nuclear and extended families to search for genetic loci that influence the presence of both prodigy and ASD, assuming that the two traits have the same genetic etiology in the analysis model in order to find shared loci. A shared locus on chromosome 1p31-q21 reached genome-wide significance with two extended family-based linkage methods consisting of the Bayesian PPL method and the LOD score maximized over the trait parameters (i.e., MOD), yielding a simulation-based empirical significance of p = 0.000742 and p = 0.000133, respectively. Within linkage regions, we performed association analysis and assessed if copy number variants could account for the linkage signal. No evidence of specificity for either the prodigy or the ASD trait was observed. This finding suggests that a locus on chromosome 1 increases the likelihood of both prodigy and autism in these families.

PMID: 25791271 [PubMed - indexed for MEDLINE]

Theta frequency prefrontal-hippocampal driving relationship during free exploration in mice.

March 30, 2016 - 9:00am
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Theta frequency prefrontal-hippocampal driving relationship during free exploration in mice.

Neuroscience. 2015 Aug 6;300:554-65

Authors: Zhan Y

Abstract
Inter-connected brain areas coordinate to process information and synchronized neural activities engage in learning and memory processes. Recent electrophysiological studies in rodents have implicated hippocampal-prefrontal connectivity in anxiety, spatial learning and memory-related tasks. In human patients with schizophrenia and autism, robust reduced connectivity between the hippocampus (HPC) and prefrontal cortex (PFC) has been reported. However little is known about the directionality of these oscillations and their roles during active behaviors remain unclear. Here the directional information processing in mice was measured by Granger causality, a mathematical tool that has been used in neuroscience to quantify the oscillatory driving relationship between the ventral HPC (vHPC) and the PFC in two anxiety tests and between the dorsal HPC (dHPC) and the PFC in social interaction test. In the open field test, stronger vHPC driving to the PFC was found in the center compartment than in the wall area. In the light-dark box test, PFC to vHPC causality was higher than vHPC to PFC causality although no difference was found between the light and dark areas for the causality in both directions. In the social interaction test using Cx3cr1 knockout mice which model for deficient microglia-dependent synaptic pruning, higher PFC driving to the dHPC was found than driving from the dHPC to the PFC in both knockout mice and wild-type mice. Cx3cr1 knockout mice showed reduced baseline PFC driving to the dHPC compared to their wild-type littermates. PFC to dHPC causality could predict the actual time spent interacting with the social stimuli. The current findings indicate that directed oscillatory activities between the PFC and the HPC have task-dependent roles during exploration in the anxiety test and in the social interaction test.

PMID: 26037805 [PubMed - indexed for MEDLINE]

Transient Blockade of ERK Phosphorylation in the Critical Period Causes Autistic Phenotypes as an Adult in Mice.

March 30, 2016 - 9:00am
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Transient Blockade of ERK Phosphorylation in the Critical Period Causes Autistic Phenotypes as an Adult in Mice.

Sci Rep. 2015;5:10252

Authors: Yufune S, Satoh Y, Takamatsu I, Ohta H, Kobayashi Y, Takaenoki Y, Pagès G, Pouysségur J, Endo S, Kazama T

Abstract
The critical period is a distinct time-window during the neonatal stage when animals display elevated sensitivity to certain environmental stimuli, and particular experiences can have profound and long-lasting effects on behaviors. Increasing evidence suggests that disruption of neuronal activity during the critical period contributes to autistic phenotype, although the pathogenic mechanism is largely unknown. Herein we show that extracellular signal-regulated protein kinases (ERKs) play important roles in proper formation of neural circuits during the critical period. Transient blockade of ERKs phosphorylation at postnatal day 6 (P6) by intraperitoneal injection of blood-brain barrier-penetrating MEK inhibitor, α-[amino[(4-aminophenyl)thio]methylene]-2-(trifluoromethyl)benzeneacetonitrile (SL327) caused significant increase of apoptosis in the forebrain. Furthermore, this induced long-term deleterious effects on brain functioning later in adulthood, resulting in social deficits, impaired memory and reduced long-term potentiation (LTP). Conversely, blockade of ERK phosphorylation at P14 no longer induced apoptosis, nor behavioral deficits, nor the reduced LTP. Thus, surprisingly, these effects of ERKs are strongly age-dependent, indicating that phosphorylation of ERKs during the critical period is absolutely required for proper development of brain functioning. This study provides novel insight into the mechanistic basis for neurodevelopment disorders: various neurodevelopment disorders might be generally linked to defects in ERKs signaling during the critical period.

PMID: 25993696 [PubMed - indexed for MEDLINE]

Dissociable deficits of executive function caused by gestational adversity are linked to specific transcriptional changes in the prefrontal cortex.

March 30, 2016 - 9:00am
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Dissociable deficits of executive function caused by gestational adversity are linked to specific transcriptional changes in the prefrontal cortex.

Neuropsychopharmacology. 2015 May;40(6):1353-63

Authors: Grissom NM, Herdt CT, Desilets J, Lidsky-Everson J, Reyes TM

Abstract
Poor-quality maternal diet during pregnancy, and subsequent gestational growth disturbances in the offspring, have been implicated in the etiology of multiple neurodevelopmental disorders, including ADHD, schizophrenia, and autism. These disorders are characterized, in part, by abnormalities in responses to reward and errors of executive function. Here, we demonstrate dissociable deficits in reward processing and executive function in male and female mice, solely due to maternal malnutrition via high-fat or low-protein diets. Gestational exposure to a high-fat diet delayed acquisition of a fixed ratio response, and decreased motivation as assessed by progressive ratio. In contrast, offspring of a low-protein diet displayed no deficits in operant learning, but were more prone to assign salience to a cue that predicts reward (sign-tracking) in a Pavlovian-conditioned approach task. In the 5-choice serial reaction time task (5-CSRTT), gestational exposure to a high-fat diet promoted impulsivity, whereas exposure to a low-protein diet led to marked inattention. These dissociable executive function deficits are known to be mediated by the medial prefrontal cortex (PFC), which displays markers of epigenetic dysregulation in neurodevelopmental disorders. Following behavioral characterization, we assayed PFC gene expression using a targeted PCR array and found that both maternal diets increased overall transcription in PFC. Cluster analysis of the relationships between individual transcripts and behavioral outcomes revealed a cluster of primarily epigenetic modulators, whose overexpression was linked to executive function deficits. The overexpression of four genes, DNA methyltransferase 1 (DNMT1), δ-opioid receptor (OPRD1), cannabinoid receptor 1 (CNR1), and catechol-o-methyltransferase (COMT), was strongly associated with overall poor performance. All 5-CSRTT deficits were associated with DNMT1 upregulation, whereas impulsive behavior could be dissociated from inattention by overexpression of OPRD1 or COMT, respectively, as well as a distinct cluster of epigenetic regulators. These data provide molecular support for dissociable domains of executive function.

PMID: 25418810 [PubMed - indexed for MEDLINE]

Endocannabinoid-mediated improvement on a test of aversive memory in a mouse model of fragile X syndrome.

March 29, 2016 - 8:55am
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Endocannabinoid-mediated improvement on a test of aversive memory in a mouse model of fragile X syndrome.

Behav Brain Res. 2015 Sep 15;291:164-71

Authors: Qin M, Zeidler Z, Moulton K, Krych L, Xia Z, Smith CB

Abstract
Silencing the gene FMR1 in fragile X syndrome (FXS) with consequent loss of its protein product, FMRP, results in intellectual disability, hyperactivity, anxiety, seizure disorders, and autism-like behavior. In a mouse model (Fmr1 knockout (KO)) of FXS, a deficit in performance on the passive avoidance test of learning and memory is a robust phenotype. We report that drugs acting on the endocannabinoid (eCB) system can improve performance on this test. We present three lines of evidence: (1) Propofol (reported to inhibit fatty acid amide hydrolase (FAAH) activity) administered 30 min after training on the passive avoidance test improved performance in Fmr1 KO mice but had no effect on wild type (WT). FAAH catalyzes the metabolism of the eCB, anandamide, so its inhibition should result in increased anandamide levels. (2) The effect of propofol was blocked by prior administration of the cannabinoid receptor 1 antagonist AM-251. (3) Treatment with the FAAH inhibitor, URB-597, administered 30 min after training on the passive avoidance test also improved performance in Fmr1 KO mice but had no effect on WT. Our results indicate that the eCB system is involved in FXS and suggest that the eCB system is a promising target for treatment of FXS.

PMID: 25979787 [PubMed - indexed for MEDLINE]

MicroRNA-181 promotes synaptogenesis and attenuates axonal outgrowth in cortical neurons.

March 28, 2016 - 8:45am
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MicroRNA-181 promotes synaptogenesis and attenuates axonal outgrowth in cortical neurons.

Cell Mol Life Sci. 2016 Mar 26;

Authors: Kos A, Olde Loohuis N, Meinhardt J, van Bokhoven H, Kaplan BB, Martens GJ, Aschrafi A

Abstract
MicroRNAs (miRs) are non-coding gene transcripts abundantly expressed in both the developing and adult mammalian brain. They act as important modulators of complex gene regulatory networks during neuronal development and plasticity. miR-181c is highly abundant in cerebellar cortex and its expression is increased in autism patients as well as in an animal model of autism. To systematically identify putative targets of miR-181c, we repressed this miR in growing cortical neurons and found over 70 differentially expressed target genes using transcriptome profiling. Pathway analysis showed that the miR-181c-modulated genes converge on signaling cascades relevant to neurite and synapse developmental processes. To experimentally examine the significance of these data, we inhibited miR-181c during rat cortical neuronal maturation in vitro; this loss-of miR-181c function resulted in enhanced neurite sprouting and reduced synaptogenesis. Collectively, our findings suggest that miR-181c is a modulator of gene networks associated with cortical neuronal maturation.

PMID: 27017280 [PubMed - as supplied by publisher]

Quantitative profiling of brain lipid raft proteome in a mouse model of fragile X syndrome.

March 28, 2016 - 8:45am
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Quantitative profiling of brain lipid raft proteome in a mouse model of fragile X syndrome.

PLoS One. 2015;10(4):e0121464

Authors: Kalinowska M, Castillo C, Francesconi A

Abstract
Fragile X Syndrome, a leading cause of inherited intellectual disability and autism, arises from transcriptional silencing of the FMR1 gene encoding an RNA-binding protein, Fragile X Mental Retardation Protein (FMRP). FMRP can regulate the expression of approximately 4% of brain transcripts through its role in regulation of mRNA transport, stability and translation, thus providing a molecular rationale for its potential pleiotropic effects on neuronal and brain circuitry function. Several intracellular signaling pathways are dysregulated in the absence of FMRP suggesting that cellular deficits may be broad and could result in homeostatic changes. Lipid rafts are specialized regions of the plasma membrane, enriched in cholesterol and glycosphingolipids, involved in regulation of intracellular signaling. Among transcripts targeted by FMRP, a subset encodes proteins involved in lipid biosynthesis and homeostasis, dysregulation of which could affect the integrity and function of lipid rafts. Using a quantitative mass spectrometry-based approach we analyzed the lipid raft proteome of Fmr1 knockout mice, an animal model of Fragile X syndrome, and identified candidate proteins that are differentially represented in Fmr1 knockout mice lipid rafts. Furthermore, network analysis of these candidate proteins reveals connectivity between them and predicts functional connectivity with genes encoding components of myelin sheath, axonal processes and growth cones. Our findings provide insight to aid identification of molecular and cellular dysfunctions arising from Fmr1 silencing and for uncovering shared pathologies between Fragile X syndrome and other autism spectrum disorders.

PMID: 25849048 [PubMed - indexed for MEDLINE]

Cerebellar contribution to higher- and lower-order rule learning and cognitive flexibility in mice.

March 26, 2016 - 8:40am

Cerebellar contribution to higher- and lower-order rule learning and cognitive flexibility in mice.

Neuroscience. 2016 Mar 21;

Authors: Dickson PE, Cairns J, Goldowitz D, Mittleman G

Abstract
Cognitive flexibility has traditionally been considered a frontal lobe function. However, converging evidence suggests involvement of a larger brain circuit which includes the cerebellum. Reciprocal pathways connecting the cerebellum to the prefrontal cortex provide a biological substrate through which the cerebellum may modulate higher cognitive functions, and it has been observed that cognitive inflexibility and cerebellar pathology co-occur in psychiatric disorders (e.g., autism, schizophrenia, addiction). However, the degree to which the cerebellum contributes to distinct forms of cognitive flexibility and rule learning is unknown. We tested lurcher↔wildtype aggregation chimeras which lose 0%-100% of cerebellar Purkinje cells during development on a touchscreen-mediated attentional set-shifting task to assess the contribution of the cerebellum to higher- and lower-order rule learning and cognitive flexibility. Purkinje cells, the sole output of the cerebellar cortex, ranged from 0 to 108,390 in tested mice. Reversal learning and extradimensional set-shifting were impaired in mice with ⩾ 95% Purkinje cell loss. Cognitive deficits were unrelated to motor deficits in ataxic mice. Acquisition of a simple visual discrimination and an attentional-set were unrelated to Purkinje cells. A positive relationship was observed between Purkinje cells and errors when exemplars from a novel, non-relevant dimension were introduced. Collectively, these data suggest that the cerebellum contributes to higher-order cognitive flexibility, lower-order cognitive flexibility, and attention to novel stimuli, but not the acquisition of higher- and lower-order rules. These data indicate that the cerebellar pathology observed in psychiatric disorders may underlie deficits involving cognitive flexibility and attention to novel stimuli.

PMID: 27012612 [PubMed - as supplied by publisher]

Autism and chromosome abnormalities - A Review.

March 26, 2016 - 8:40am

Autism and chromosome abnormalities - A Review.

Clin Anat. 2016 Mar 25;

Authors: Bergbaum A, Mackie-Ogilvie C

Abstract
The neuro-behavioral disorder of autism was first described in the 1940s and was predicted to have a biological basis. Since that time, with the growth of genetic investigations particularly in the area of pediatric development, an increasing number of children with autism and related disorders (autistic spectrum disorders, ASD) have been the subject of genetic studies both in the clinical setting and in the wider research environment. However, a full understanding of the biological basis of ASDs has yet to be achieved. Early observations of children with chromosomal abnormalities detected by G-banded chromosome analysis (karyotyping) and in situ hybridization revealed, in some cases, ASD associated with other features arising from such an abnormality. The introduction of higher resolution techniques for whole genome screening, such as array comparative genome hybridization (aCGH), allowed smaller imbalances to be detected, some of which are now considered to represent autism susceptibility loci. In this review, we describe some of the work underpinning the conclusion that ASDs have a genetic basis; a brief history of the developments in genetic analysis tools over the last fifty years; and the most common chromosomal abnormalities found in association with ASDs. Introduction of next generation sequencing (NGS) into the clinical diagnostic setting is likely to provide further insights into this complex field but it will not be covered in this review. This article is protected by copyright. All rights reserved.

PMID: 27012322 [PubMed - as supplied by publisher]

In Pursuit of New Imprinting Syndromes by Epimutation Screening in Idiopathic Neurodevelopmental Disorder Patients.

March 26, 2016 - 8:40am
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In Pursuit of New Imprinting Syndromes by Epimutation Screening in Idiopathic Neurodevelopmental Disorder Patients.

Biomed Res Int. 2015;2015:341986

Authors: Mayo S, Monfort S, Roselló M, Oltra S, Orellana C, Martínez F

Abstract
Alterations of epigenetic mechanisms, and more specifically imprinting modifications, could be responsible of neurodevelopmental disorders such as intellectual disability (ID) or autism together with other associated clinical features in many cases. Currently only eight imprinting syndromes are defined in spite of the fact that more than 200 genes are known or predicted to be imprinted. Recent publications point out that some epimutations which cause imprinting disorders may affect simultaneously different imprinted loci, suggesting that DNA-methylation may have been altered more globally. Therefore, we hypothesised that the detection of altered methylation patterns in known imprinting loci will indirectly allow identifying new syndromes due to epimutations among patients with unexplained ID. In a screening for imprinting alterations in 412 patients with syndromic ID/autism we found five patients with altered methylation in the four genes studied: MEG3, H19, KCNQ1OT1, and SNRPN. Remarkably, the cases with partial loss of methylation in KCNQ1OT1 and SNRPN present clinical features different to those associated with the corresponding imprinting syndromes, suggesting a multilocus methylation defect in accordance with our initial hypothesis. Consequently, our results are a proof of concept that the identification of epimutations in known loci in patients with clinical features different from those associated with known syndromes will eventually lead to the definition of new imprinting disorders.

PMID: 26106604 [PubMed - indexed for MEDLINE]

IQSEC2 and X-linked syndromal intellectual disability.

March 25, 2016 - 8:38am

IQSEC2 and X-linked syndromal intellectual disability.

Psychiatr Genet. 2016 Mar 23;

Authors: Alexander-Bloch AF, McDougle CJ, Ullman Z, Sweetser DA

Abstract
Despite the recent acceleration in the discovery of genetic risk factors for intellectual disability (ID), the genetic etiology of ID is unknown in approximately half of cases and remains a major frontier of genetics in medicine and psychiatry. The distinction between syndromal and nonsyndromal forms of ID is of great clinical importance, but the boundary between these clinical entities is difficult to ascertain for many genes of interest. ID is more common in men than in women, but the genetic explanation of this sex asymmetry is incompletely understood. This Review systematically examines the reported cases of X-linked ID caused by de novo loss-of-function mutations in the gene IQSEC2. This gene is largely known as a cause of X-linked nonsyndromal ID in male patients. However, depending on the severity of the mutation, the phenotypic spectrum of IQSEC2-related ID can range from the classic X-linked nonsyndromal form of the disease to a severe syndrome that has been reported in the context of de novo mutations only, in both male and female patients. Bioinformatics analysis suggests that truncation of the longer of the two protein isoforms of the gene can be sufficient to lead to the syndrome, which may be caused by the disruption of cell signaling and signal transduction pathways. The clinical features of the syndrome converge on a pattern of global developmental delay, deficits in social communication, stereotypical hand movements, and hypotonia. In addition, many if not all of these patients have seizures, microcephaly, and language regression in addition to delay. We argue that it is clinically appropriate to test for IQSEC2 mutations in male and female patients with this symptom profile but without a known genetic mutation.

PMID: 27010919 [PubMed - as supplied by publisher]

Mutations in C8ORF37 cause Bardet Biedl syndrome (BBS21).

March 25, 2016 - 8:38am

Mutations in C8ORF37 cause Bardet Biedl syndrome (BBS21).

Hum Mol Genet. 2016 Mar 22;

Authors: Heon E, Kim G, Qin S, Garrison JE, Tavares E, Vincent A, Nuangchamnong N, Scott CA, Slusarski DC, Sheffield VC

Abstract
Bardet Biedl syndrome (BBS) is a multisystem genetically heterogeneous ciliopathy that most commonly leads to obesity, photoreceptor degeneration, digit anomalies, genito-urinary abnormalities, as well as cognitive impairment with autism, among other features. Sequencing of a DNA sample from a 17 year old female affected with BBS did not identify any mutation in the known BBS genes. Whole genome sequencing identified a novel loss-of-function disease-causing homozygous mutation (K102*) inC8ORF37, a gene coding for a cilia protein. The proband was overweight (BMI 29.1) with a slowly progressive rod-cone dystrophy, a mild learning difficulty, high myopia, 3 limb post-axial polydactyly, horseshoe kidney, abnormally positioned uterus, and elevated liver enzymes. Mutations inC8ORF37were previously associated with severe autosomal recessive retinal dystrophies (retinitis pigmentosa RP64 and cone-rod dystrophy CORD16) but not BBS. To elucidate the functional role ofC8ORF37in a vertebrate system, we performed gene knockdown inDanio rerioand assessed the cardinal features of BBS and visual function. Knockdown ofc8orf37resulted in impaired visual behavior and BBS-related phenotypes, specifically, defects in the formation of Kupffer's vesicle and delays in retrograde transport. Specificity of these phenotypes to BBS knockdown was shown with rescue experiments. Over-expression of human missense mutations in zebrafish also resulted in impaired visual behavior and BBS-related phenotypes. This is the first functional validation and association ofC8ORF37mutations with the BBS phenotype, which identifies BBS21. The zebrafish studies hereby show thatC8ORF37variants underlie clinically diagnosed BBS-related phenotypes as well as isolated retinal degeneration.

PMID: 27008867 [PubMed - as supplied by publisher]

Discovery of Rare Mutations in Autism: Elucidating Neurodevelopmental Mechanisms.

March 25, 2016 - 8:38am
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Discovery of Rare Mutations in Autism: Elucidating Neurodevelopmental Mechanisms.

Neurotherapeutics. 2015 Jul;12(3):553-71

Authors: Gamsiz ED, Sciarra LN, Maguire AM, Pescosolido MF, van Dyck LI, Morrow EM

Abstract
Autism spectrum disorder (ASD) is a group of highly genetic neurodevelopmental disorders characterized by language, social, cognitive, and behavioral abnormalities. ASD is a complex disorder with a heterogeneous etiology. The genetic architecture of autism is such that a variety of different rare mutations have been discovered, including rare monogenic conditions that involve autistic symptoms. Also, de novo copy number variants and single nucleotide variants contribute to disease susceptibility. Finally, autosomal recessive loci are contributing to our understanding of inherited factors. We will review the progress that the field has made in the discovery of these rare genetic variants in autism. We argue that mutation discovery of this sort offers an important opportunity to identify neurodevelopmental mechanisms in disease. The hope is that these mechanisms will show some degree of convergence that may be amenable to treatment intervention.

PMID: 26105128 [PubMed - indexed for MEDLINE]

Therapeutic Advances in Autism and Other Neurodevelopmental Disorders.

March 25, 2016 - 8:38am
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Therapeutic Advances in Autism and Other Neurodevelopmental Disorders.

Neurotherapeutics. 2015 Jul;12(3):519-20

Authors: Neul JL, Sahin M

PMID: 26076992 [PubMed - indexed for MEDLINE]

Angelman Syndrome.

March 25, 2016 - 8:38am
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Angelman Syndrome.

Neurotherapeutics. 2015 Jul;12(3):641-50

Authors: Margolis SS, Sell GL, Zbinden MA, Bird LM

Abstract
In this review we summarize the clinical and genetic aspects of Angelman syndrome (AS), its molecular and cellular underpinnings, and current treatment strategies. AS is a neurodevelopmental disorder characterized by severe cognitive disability, motor dysfunction, speech impairment, hyperactivity, and frequent seizures. AS is caused by disruption of the maternally expressed and paternally imprinted UBE3A, which encodes an E3 ubiquitin ligase. Four mechanisms that render the maternally inherited UBE3A nonfunctional are recognized, the most common of which is deletion of the maternal chromosomal region 15q11-q13. Remarkably, duplication of the same chromosomal region is one of the few characterized persistent genetic abnormalities associated with autistic spectrum disorder, occurring in >1-2% of all cases of autism spectrum disorder. While the overall morphology of the brain and connectivity of neural projections appear largely normal in AS mouse models, major functional defects are detected at the level of context-dependent learning, as well as impaired maturation of hippocampal and neocortical circuits. While these findings demonstrate a crucial role for ubiquitin protein ligase E3A in synaptic development, the mechanisms by which deficiency of ubiquitin protein ligase E3A leads to AS pathophysiology in humans remain poorly understood. However, recent efforts have shown promise in restoring functions disrupted in AS mice, renewing hope that an effective treatment strategy can be found.

PMID: 26040994 [PubMed - indexed for MEDLINE]

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