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Intragenic ILRAPL1 deletion in a male patient with intellectual disability, mild dysmorphic signs, deafness, and behavioral problems.

April 16, 2016 - 6:41am
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Intragenic ILRAPL1 deletion in a male patient with intellectual disability, mild dysmorphic signs, deafness, and behavioral problems.

Am J Med Genet A. 2013 Jun;161A(6):1381-5

Authors: Barone C, Bianca S, Luciano D, Di Benedetto D, Vinci M, Fichera M

Abstract
Intellectual disability affects approximately 2% of the population, with affected males outnumbering affected female, partly due to disturbances involving X-linked genes. To date >90 genes associated with X-linked intellectual disability have been identified and, among these, IL1RAPL1 (interleukin 1 receptor accessory protein-like 1), was first described and mapped to Xp21.3-22.1 in 1999. Intragenic deletions of IL1RAPL1, only rarely identified, have mostly been associated with nonspecific intellectual disability (IDX) and autism spectrum disorder. Array-CGH analysis performed in our patient with intellectual disability, mild dysmorphic signs and changes in behavior identified a 285 Kb deletion in chromosome Xp21.3-21.2, with breakpoints lying in IL1RAPL1 gene intron 2 and intron 3. This is the first patient reported in literature with deletion of only exon 3 of IL1RAPL1 gene. Our patient also exhibits bilateral progressive neurosensorial deafness, which has not been previously associated with IL1RAPL1 mutations.

PMID: 23613341 [PubMed - indexed for MEDLINE]

Additional evidence to support the role of the 20q13.33 region in susceptibility to autism.

April 16, 2016 - 6:41am
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Additional evidence to support the role of the 20q13.33 region in susceptibility to autism.

Am J Med Genet A. 2013 Jun;161A(6):1505-7

Authors: Mosca-Boidron AL, Valduga M, Thauvin-Robinet C, Lagarde N, Marle N, Henry C, Pinoit JM, Huet F, Béri-Deixheimer M, Ragon C, Gueneau L, Payet M, Callier P, Mugneret F, Jonveaux P, Faivre L

PMID: 23613186 [PubMed - indexed for MEDLINE]

Monitoring host responses to the gut microbiota.

April 15, 2016 - 9:07am
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Monitoring host responses to the gut microbiota.

ISME J. 2015 Sep;9(9):1908-15

Authors: Lichtman JS, Sonnenburg JL, Elias JE

Abstract
The gastrointestinal (GI) ecosystem is increasingly understood to be a fundamental component of health, and has been identified as a new focal point for diagnosing, correcting and preventing countless disorders. Shotgun DNA sequencing has emerged as the dominant technology for determining the genetic and microbial composition of the gut microbiota. This technology has linked microbiota dysbioses to numerous GI diseases including inflammatory bowel disease, obesity and allergy, and to non-GI diseases like autism and depression. The importance of establishing causality in the deterioration of the host-microbiota relationship is well appreciated; however, discovery of candidate molecules and pathways that underlie mechanisms remains a major challenge. Targeted approaches, transcriptional assays, cytokine panels and imaging analyses, applied to animals, have yielded important insight into host responses to the microbiota. However, non-invasive, hypothesis-independent means of measuring host responses in humans are necessary to keep pace with similarly unbiased sequencing efforts that monitor microbes. Mass spectrometry-based proteomics has served this purpose in many other fields, but stool proteins exist in such diversity and dynamic range as to overwhelm conventional proteomics technologies. Focused analysis of host protein secretion into the gut lumen and monitoring proteome-level dynamics in stool provides a tractable route toward non-invasively evaluating dietary, microbial, surgical or pharmacological intervention efficacies. This review is intended to guide GI biologists and clinicians through the methods currently used to elucidate host responses in the gut, with a specific focus on mass spectrometry-based shotgun proteomics applied to the study of host protein dynamics within the GI ecosystem.

PMID: 26057846 [PubMed - indexed for MEDLINE]

New insights in the interpretation of array-CGH: autism spectrum disorder and positive family history for intellectual disability predict the detection of pathogenic variants.

April 14, 2016 - 8:39am
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New insights in the interpretation of array-CGH: autism spectrum disorder and positive family history for intellectual disability predict the detection of pathogenic variants.

Ital J Pediatr. 2016;42(1):39

Authors: Cappuccio G, Vitiello F, Casertano A, Fontana P, Genesio R, Bruzzese D, Ginocchio VM, Mormile A, Nitsch L, Andria G, Melis D

Abstract
BACKGROUND: Array-CGH (aCGH) is presently used into routine clinical practice for diagnosis of patients with intellectual disability (ID), multiple congenital anomalies (MCA), and autism spectrum disorder (ASD). ACGH could detect small chromosomal imbalances, copy number variations (CNVs), and closely define their size and gene content. ACGH detects pathogenic imbalances in 14-20 % of patients with ID. The aims of this study were: to establish clinical clues potentially associated with pathogenic CNVs and to identify cytogenetic indicators to predict the pathogenicity of the variants of uncertain significance (VOUS) in a large cohort of paediatric patients.
METHODS: We enrolled 214 patients referred for either: ID, and/or ASD and/or MCA to genetic services at the Federico II University of Naples, Department of Translational Medicine. For each patient we collected clinical and imaging data. All the patients were tested with aCGH or as first-tier test or as part of a wider diagnostic work-up.
RESULTS: Pathologic data were detected in 65 individuals (30 %) and 46 CNVs revealed a known syndrome. The pathological CNVs were usually deletions showing the highest gene-dosage content. The positive family history for ID/ASD/MCA and ASD were good indicators for detecting pathological chromosomal rearrangements. Other clinical features as eyes anomalies, hearing loss, neurological signs, cutaneous dyscromia and endocrinological problems seem to be potential predictors of pathological CNVs. Among patients carrying VOUS we analyzed genetic features including CNVs size, presence of deletion or duplication, genic density, multiple CNVs, to clinical features. Higher gene density was found in patients affected by ID. This result suggest that higher gene content has more chances to include pathogenic gene involved and causing ID in these patients.
CONCLUSION: Our study suggest the use of aCGH as first-tier test in patients with neurdevelopmental phenotypes. The inferred results have been used for building a flow-chart to be applied for children with ID.

PMID: 27072107 [PubMed - in process]

Copy number variants in patients with intellectual disability affect the regulation of ARX transcription factor gene.

April 14, 2016 - 8:39am
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Copy number variants in patients with intellectual disability affect the regulation of ARX transcription factor gene.

Hum Genet. 2015 Nov;134(11-12):1163-82

Authors: Ishibashi M, Manning E, Shoubridge C, Krecsmarik M, Hawkins TA, Giacomotto J, Zhao T, Mueller T, Bader PI, Cheung SW, Stankiewicz P, Bain NL, Hackett A, Reddy CC, Mechaly AS, Peers B, Wilson SW, Lenhard B, Bally-Cuif L, Gecz J, Becker TS, Rinkwitz S

Abstract
Protein-coding mutations in the transcription factor-encoding gene ARX cause various forms of intellectual disability (ID) and epilepsy. In contrast, variations in surrounding non-coding sequences are correlated with milder forms of non-syndromic ID and autism and had suggested the importance of ARX gene regulation in the etiology of these disorders. We compile data on several novel and some already identified patients with or without ID that carry duplications of ARX genomic region and consider likely genetic mechanisms underlying the neurodevelopmental defects. We establish the long-range regulatory domain of ARX and identify its brain region-specific autoregulation. We conclude that neurodevelopmental disturbances in the patients may not simply arise from increased dosage due to ARX duplication. This is further exemplified by a small duplication involving a non-functional ARX copy, but with duplicated enhancers. ARX enhancers are located within a 504-kb region and regulate expression specifically in the forebrain in developing and adult zebrafish. Transgenic enhancer-reporter lines were used as in vivo tools to delineate a brain region-specific negative and positive autoregulation of ARX. We find autorepression of ARX in the telencephalon and autoactivation in the ventral thalamus. Fluorescently labeled brain regions in the transgenic lines facilitated the identification of neuronal outgrowth and pathfinding disturbances in the ventral thalamus and telencephalon that occur when arxa dosage is diminished. In summary, we have established a model for how breakpoints in long-range gene regulation alter the expression levels of a target gene brain region-specifically, and how this can cause subtle neuronal phenotypes relating to the etiology of associated neuropsychiatric disease.

PMID: 26337422 [PubMed - indexed for MEDLINE]

SUMOylation of synapsin Ia maintains synaptic vesicle availability and is reduced in an autism mutation.

April 14, 2016 - 8:39am
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SUMOylation of synapsin Ia maintains synaptic vesicle availability and is reduced in an autism mutation.

Nat Commun. 2015;6:7728

Authors: Tang LT, Craig TJ, Henley JM

Abstract
Synapsins are key components of the presynaptic neurotransmitter release machinery. Their main role is to cluster synaptic vesicles (SVs) to each other and anchor them to the actin cytoskeleton to establish the reserve vesicle pool, and then release them in response to appropriate membrane depolarization. Here we demonstrate that SUMOylation of synapsin Ia (SynIa) at K687 is necessary for SynIa function. Replacement of endogenous SynIa with a non-SUMOylatable mutant decreases the size of the releasable vesicle pool and impairs stimulated SV exocytosis. SUMOylation enhances SynIa association with SVs to promote the efficient reclustering of SynIa following neuronal stimulation and maintain its presynaptic localization. The A548T mutation in SynIa is strongly associated with autism and epilepsy and we show that it leads to defective SynIa SUMOylation. These results identify SUMOylation as a fundamental regulator of SynIa function and reveal a novel link between reduced SUMOylation of SynIa and neurological disorders.

PMID: 26173895 [PubMed - indexed for MEDLINE]

Autism-like Deficits in Shank3-Deficient Mice Are Rescued by Targeting Actin Regulators.

April 14, 2016 - 8:39am
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Autism-like Deficits in Shank3-Deficient Mice Are Rescued by Targeting Actin Regulators.

Cell Rep. 2015 Jun 9;11(9):1400-13

Authors: Duffney LJ, Zhong P, Wei J, Matas E, Cheng J, Qin L, Ma K, Dietz DM, Kajiwara Y, Buxbaum JD, Yan Z

Abstract
Haploinsufficiency of the Shank3 gene, which encodes a scaffolding protein at glutamatergic synapses, is a highly prevalent and penetrant risk factor for autism. Using combined behavioral, electrophysiological, biochemical, imaging, and molecular approaches, we find that Shank3-deficient mice exhibit autism-like social deficits and repetitive behaviors, as well as the significantly diminished NMDA receptor (NMDAR) synaptic function and synaptic distribution in prefrontal cortex. Concomitantly, Shank3-deficient mice have a marked loss of cortical actin filaments, which is associated with the reduced Rac1/PAK activity and increased activity of cofilin, the major actin depolymerizing factor. The social deficits and NMDAR hypofunction are rescued by inhibiting cofilin or activating Rac1 in Shank3-deficient mice and are induced by inhibiting PAK or Rac1 in wild-type mice. These results indicate that the aberrant regulation of synaptic actin filaments and loss of synaptic NMDARs contribute to the manifestation of autism-like phenotypes. Thus, targeting actin regulators provides a strategy for autism treatment.

PMID: 26027926 [PubMed - indexed for MEDLINE]

The Autism Related Protein Contactin-Associated Protein-Like 2 (CNTNAP2) Stabilizes New Spines: An In Vivo Mouse Study.

April 14, 2016 - 8:39am
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The Autism Related Protein Contactin-Associated Protein-Like 2 (CNTNAP2) Stabilizes New Spines: An In Vivo Mouse Study.

PLoS One. 2015;10(5):e0125633

Authors: Gdalyahu A, Lazaro M, Penagarikano O, Golshani P, Trachtenberg JT, Geschwind DH, Gescwind DH

Abstract
The establishment and maintenance of neuronal circuits depends on tight regulation of synaptic contacts. We hypothesized that CNTNAP2, a protein associated with autism, would play a key role in this process. Indeed, we found that new dendritic spines in mice lacking CNTNAP2 were formed at normal rates, but failed to stabilize. Notably, rates of spine elimination were unaltered, suggesting a specific role for CNTNAP2 in stabilizing new synaptic circuitry.

PMID: 25951243 [PubMed - indexed for MEDLINE]

Autism and Intellectual Disability-Associated KIRREL3 Interacts with Neuronal Proteins MAP1B and MYO16 with Potential Roles in Neurodevelopment.

April 14, 2016 - 8:39am
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Autism and Intellectual Disability-Associated KIRREL3 Interacts with Neuronal Proteins MAP1B and MYO16 with Potential Roles in Neurodevelopment.

PLoS One. 2015;10(4):e0123106

Authors: Liu YF, Sowell SM, Luo Y, Chaubey A, Cameron RS, Kim HG, Srivastava AK

Abstract
Cell-adhesion molecules of the immunoglobulin superfamily play critical roles in brain development, as well as in maintaining synaptic plasticity, the dysfunction of which is known to cause cognitive impairment. Recently dysfunction of KIRREL3, a synaptic molecule of the immunoglobulin superfamily, has been implicated in several neurodevelopmental conditions including intellectual disability, autism spectrum disorder, and in the neurocognitive delay associated with Jacobsen syndrome. However, the molecular mechanisms of its physiological actions remain largely unknown. Using a yeast two-hybrid screen, we found that the KIRREL3 extracellular domain interacts with brain expressed proteins MAP1B and MYO16 and its intracellular domain can potentially interact with ATP1B1, UFC1, and SHMT2. The interactions were confirmed by co-immunoprecipitation and colocalization analyses of proteins expressed in human embryonic kidney cells, mouse neuronal cells, and rat primary neuronal cells. Furthermore, we show KIRREL3 colocalization with the marker for the Golgi apparatus and synaptic vesicles. Previously, we have shown that KIRREL3 interacts with the X-linked intellectual disability associated synaptic scaffolding protein CASK through its cytoplasmic domain. In addition, we found a genomic deletion encompassing MAP1B in one patient with intellectual disability, microcephaly and seizures and deletions encompassing MYO16 in two unrelated patients with intellectual disability, autism and microcephaly. MAP1B has been previously implicated in synaptogenesis and is involved in the development of the actin-based membrane skeleton. MYO16 is expressed in hippocampal neurons and also indirectly affects actin cytoskeleton through its interaction with WAVE1 complex. We speculate KIRREL3 interacting proteins are potential candidates for intellectual disability and autism spectrum disorder. Moreover, our findings provide further insight into understanding the molecular mechanisms underlying the physiological action of KIRREL3 and its role in neurodevelopment.

PMID: 25902260 [PubMed - indexed for MEDLINE]

Relationships among parvalbumin-immunoreactive neuron density, phase-locked gamma oscillations, and autistic/schizophrenic symptoms in PDGFR-β knock-out and control mice.

April 14, 2016 - 8:39am
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Relationships among parvalbumin-immunoreactive neuron density, phase-locked gamma oscillations, and autistic/schizophrenic symptoms in PDGFR-β knock-out and control mice.

PLoS One. 2015;10(3):e0119258

Authors: Nakamura T, Matsumoto J, Takamura Y, Ishii Y, Sasahara M, Ono T, Nishijo H

Abstract
Cognitive deficits and negative symptoms are important therapeutic targets for schizophrenia and autism disorders. Although reduction of phase-locked gamma oscillation has been suggested to be a result of reduced parvalbumin-immunoreactive (putatively, GABAergic) neurons, no direct correlations between these have been established in these disorders. In the present study, we investigated such relationships during pharmacological treatment with a newly synthesized drug, T-817MA, which displays neuroprotective and neurotrophic effects. In this study, we used platelet-derived growth factor receptor-β gene knockout (PDGFR-β KO) mice as an animal model of schizophrenia and autism. These mutant mice display a reduction in social behaviors; deficits in prepulse inhibition (PPI); reduced levels of parvalbumin-immunoreactive neurons in the medical prefrontal cortex, hippocampus, amygdala, and superior colliculus; and a deficit in of auditory phase-locked gamma oscillations. We found that oral administration of T-817MA ameliorated all these symptoms in the PDGFR-β KO mice. Furthermore, phase-locked gamma oscillations were significantly correlated with the density of parvalbumin-immunoreactive neurons, which was, in turn, correlated with PPI and behavioral parameters. These findings suggest that recovery of parvalbumin-immunoreactive neurons by pharmacological intervention relieved the reduction of phase-locked gamma oscillations and, consequently, ameliorated PPI and social behavioral deficits. Thus, our findings suggest that phase-locked gamma oscillations could be a useful physiological biomarker for abnormality of parvalbumin-immunoreactive neurons that may induce cognitive deficits and negative symptoms of schizophrenia and autism, as well as of effective pharmacological interventions in both humans and experimental animals.

PMID: 25803852 [PubMed - indexed for MEDLINE]

DNA repair gene XPD Asp312Asn and XRCC4 G-1394T polymorphisms and the risk of autism spectrum disorder.

April 12, 2016 - 8:05am

DNA repair gene XPD Asp312Asn and XRCC4 G-1394T polymorphisms and the risk of autism spectrum disorder.

Cell Mol Biol (Noisy-le-grand). 2016;62(3):46-50

Authors: Dasdemir S, Guven M, Pekkoc KC, Ulucan H, Dogangun B, Kirtas E, Kadak MT, Kucur M, Seven M

Abstract
Autism spectrum disorder (ASD) is a complex disorder, and its extreme heterogeneity further complicates our understanding of its biology. Epidemiological evidence from family and twin studies supports a strong genetic component in ASD etiology. Oxidative stress and abnormal DNA methylation have been implicated in the pathophysiology of ASD. Brain tissues from ASD cases showed higher levels of oxidative stress biomarkers than healthy controls in postmortem analysis. Association between oxidative stress and DNA damage has been well-known. Thus, we sought to investigate a potential link between DNA repair genes and ASD and analyze the role of XPD Asp312Asn and XRCC4 G-1394T gene polymorphisms for ASD in the Turkish population. Genotyping was conducted by PCR-RFLP based on 100 patients and 96 unrelated healthy controls. We, for the first time, demonstrated a positive association between XRCC4 gene variants and ASD risk. Frequencies of XRCC4-1394 T/G+G/G genotypes were higher in patients (%34) than the controls (%18.7). The statistical analysis revealed that the individuals who had XRCC4-1394 T/G+G/G genotype had an increased risk for ASD (OR = 2.23, 95% CI = 1.10-4.55). However, no significant association was found for XPD Asp312Asn polymorphism with the risk of ASD. Our findings suggest that XRCC4 G-1394T polymorphism might be associated with ASD pathogenesis.

PMID: 27064873 [PubMed - as supplied by publisher]

Novel de novo mutations in ZBTB20 in Primrose syndrome with congenital hypothyroidism.

April 12, 2016 - 8:05am

Novel de novo mutations in ZBTB20 in Primrose syndrome with congenital hypothyroidism.

Am J Med Genet A. 2016 Apr 7;

Authors: Mattioli F, Piton A, Gérard B, Superti-Furga A, Mandel JL, Unger S

Abstract
The cardinal features of Primrose syndrome (MIM 259050) are dysmorphic facial features, macrocephaly, and intellectual disability, as well as large body size, height and weight, and calcified pinnae. A variety of neurological signs and symptoms have been reported including hearing loss, autism, behavioral abormalities, hypotonia, cerebral calcifications, and hypoplasia of the corpus callosum. Recently, heterozygous de novo missense mutations in ZBTB20, coding for a zing finger protein, have been identified in Primrose syndrome patients. We report a boy with intellectual disability carrying two de novo missense mutations in the last exon of ZBTB20 (Ser616Phe and Gly741Arg; both previously unreported). One of them, Ser616Phe, affects an amino acid located in one of the C2H2 zing-fingers involved in DNA-binding and close to other missense mutations already described. Reverse phenotyping showed that this patient presents with classic features of Primrose syndrome (dysmorphic facies, macrocephaly, hearing loss, hypotonia, hypoplasia of the corpus callosum) and, in addition, congenital hypothyroidism. Review of the literature reveals another Primrose syndrome patient with hypothyroidism and thus, this may represent an under recognized component that should be investigated in other patients. © 2016 Wiley Periodicals, Inc.

PMID: 27061120 [PubMed - as supplied by publisher]

Presence of an epigenetic signature of prenatal cigarette smoke exposure in childhood.

April 12, 2016 - 8:05am
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Presence of an epigenetic signature of prenatal cigarette smoke exposure in childhood.

Environ Res. 2016 Jan;144(Pt A):139-48

Authors: Ladd-Acosta C, Shu C, Lee BK, Gidaya N, Singer A, Schieve LA, Schendel DE, Jones N, Daniels JL, Windham GC, Newschaffer CJ, Croen LA, Feinberg AP, Daniele Fallin M

Abstract
Prenatal exposure to tobacco smoke has lifelong health consequences. Epigenetic signatures such as differences in DNA methylation (DNAm) may be a biomarker of exposure and, further, might have functional significance for how in utero tobacco exposure may influence disease risk. Differences in infant DNAm associated with maternal smoking during pregnancy have been identified. Here we assessed whether these infant DNAm patterns are detectible in early childhood, whether they are specific to smoking, and whether childhood DNAm can classify prenatal smoke exposure status. Using the Infinium 450K array, we measured methylation at 26 CpG loci that were previously associated with prenatal smoking in infant cord blood from 572 children, aged 3-5, with differing prenatal exposure to cigarette smoke in the Study to Explore Early Development (SEED). Striking concordance was found between the pattern of prenatal smoking associated DNAm among preschool aged children in SEED and those observed at birth in other studies. These DNAm changes appear to be tobacco-specific. Support vector machine classification models and 10-fold cross-validation were applied to show classification accuracy for childhood DNAm at these 26 sites as a biomarker of prenatal smoking exposure. Classification models showed prenatal exposure to smoking can be assigned with 81% accuracy using childhood DNAm patterns at these 26 loci. These findings support the potential for blood-derived DNAm measurements to serve as biomarkers for prenatal exposure.

PMID: 26610292 [PubMed - indexed for MEDLINE]

Whole-exome sequencing in a family with a monozygotic twin pair concordant for autism spectrum disorder and a follow-up study.

April 9, 2016 - 7:30am
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Whole-exome sequencing in a family with a monozygotic twin pair concordant for autism spectrum disorder and a follow-up study.

Psychiatry Res. 2015 Sep 30;229(1-2):599-601

Authors: Egawa J, Watanabe Y, Sugimoto A, Nunokawa A, Shibuya M, Igeta H, Inoue E, Hoya S, Orime N, Hayashi T, Sugiyama T, Someya T

Abstract
Two truncating variations (WDR90 V1125fs and EFCAB5 L1210fs), identified by whole-exome sequencing in a family with a monozygotic twin pair concordant for autism spectrum disorder (ASD), were not detected in 257 ASD patients, 677 schizophrenia patients or 667 controls in a follow-up study. Thus, these variations were exclusively identified in the family, suggesting that rare truncating variations may have a role in the genetic etiology of ASD, at least in a subset of ASD patients.

PMID: 26189338 [PubMed - indexed for MEDLINE]

SYNGAP1 Mutation in Focal and Generalized Epilepsy: A Literature Overview and A Case Report with Special Aspects of the EEG.

April 9, 2016 - 7:30am
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SYNGAP1 Mutation in Focal and Generalized Epilepsy: A Literature Overview and A Case Report with Special Aspects of the EEG.

Neuropediatrics. 2015 Aug;46(4):287-91

Authors: von Stülpnagel C, Funke C, Haberl C, Hörtnagel K, Jüngling J, Weber YG, Staudt M, Kluger G

Abstract
BACKGROUND: SYNGAP1, which encodes a RAS-GTPase-activating protein, is located on the short arm of chromosome 6. Heterozygous SYNGAP1 gene mutations have been associated with autism spectrum disorders, delay of psychomotor development, acquired microcephaly, and several forms of idiopathic generalized epilepsy. Here, we report a patient with a new SYNGAP1 stop mutation, and compare the phenotype with published cases with SYNGAP1 mutations and epilepsy.
PATIENT: This 15-year-old nondysmorphic girl with intellectual disability developed drop attacks at the age of 2 years, later clonic and clonic-tonic as well as myoclonic seizures predominantly during sleep. The epilepsy was well-controlled by valproic acid (VPA) and later on with levetiracetam. Electroencephalogram (EEG) showed a complete EEG-normalization with eye opening as well as photosensitivity. Magnetic resonance imaging was normal. Genetic analysis revealed a de novo heterozygous stop mutation (c.348C>A, p.Y116*) in exon 4 of the SYNGAP1 gene.
DISCUSSION: The main clinical features of our patient (i.e., intellectual disability and idiopathic epilepsy) are compatible with previous reports on patients with SYNGAP1 mutations. The unusual feature of complete EEG normalization with eye opening has not been reported yet for this genetic abnormality. Furthermore, our case provides further support for efficacy of VPA in patients with SYNGAP1 mutation-related epilepsy.

PMID: 26110312 [PubMed - indexed for MEDLINE]

Down Syndrome Disintegrative Disorder: New-Onset Autistic Regression, Dementia, and Insomnia in Older Children and Adolescents With Down Syndrome.

April 9, 2016 - 7:30am
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Down Syndrome Disintegrative Disorder: New-Onset Autistic Regression, Dementia, and Insomnia in Older Children and Adolescents With Down Syndrome.

J Child Neurol. 2015 Aug;30(9):1147-52

Authors: Worley G, Crissman BG, Cadogan E, Milleson C, Adkins DW, Kishnani PS

Abstract
Over a 10-year period in a Down syndrome Clinic, 11 children and adolescents were encountered with a history of new-onset (8) or worsening (3) autistic characteristics. Ten of the 11 (91%) had cognitive decline to a dementia-like state and 9 of the 11 (82%) new-onset insomnia. The mean age at which symptoms developed was 11.4 years (standard deviation = 3.6 years; range 5-14 years), an older age than usual for autistic regression in Down syndrome. Ten of 11 cases (91%) had elevated ("positive") thyroperoxidase antibody titers compared to only 5 of 21 (23%) age-matched control subjects with Down syndrome (P < .001). At follow-up at a mean age of 20.7 years (standard deviation = 3.9 years), 8 of the 11 (73%) were at least somewhat better. Down syndrome disintegrative disorder seems an appropriate name for this newly recognized clinical association, which may be due to autoimmunity.

PMID: 25367918 [PubMed - indexed for MEDLINE]

Novel function of PIWIL1 in neuronal polarization and migration via regulation of microtubule-associated proteins.

April 8, 2016 - 7:21am
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Novel function of PIWIL1 in neuronal polarization and migration via regulation of microtubule-associated proteins.

Mol Brain. 2015;8:39

Authors: Zhao PP, Yao MJ, Chang SY, Gou LT, Liu MF, Qiu ZL, Yuan XB

Abstract
BACKGROUND: Young neurons in the developing brain establish a polarized morphology for proper migration. The PIWI family of piRNA processing proteins are considered to be restrictively expressed in germline tissues and several types of cancer cells. They play important roles in spermatogenesis, stem cell maintenance, piRNA biogenesis, and transposon silencing. Interestingly a recent study showed that de novo mutations of PIWI family members are strongly associated with autism.
RESULTS: Here, we report that PIWI-like 1 (PIWIL1), a PIWI family member known to be essential for the transition of round spermatid into elongated spermatid, plays a role in the polarization and radial migration of newborn neurons in the developing cerebral cortex. Knocking down PIWIL1 in newborn cortical neurons by in utero electroporation of specific siRNAs resulted in retardation of the transition of neurons from the multipolar stage to the bipolar stage followed by a defect in their radial migration to the proper destination. Domain analysis showed that both the RNA binding PAZ domain and the RNA processing PIWI domain in PIWIL1 were indispensable for its function in neuronal migration. Furthermore, we found that PIWIL1 unexpectedly regulates the expression of microtubule-associated proteins in cortical neurons.
CONCLUSIONS: PIWIL1 regulates neuronal polarization and radial migration partly via modulating the expression of microtubule-associated proteins (MAPs). Our finding of PIWIL1's function in neuronal development implies conserved functions of molecules participating in morphogenesis of brain and germline tissue and provides a mechanism as to how mutations of PIWI may be associated with autism.

PMID: 26104391 [PubMed - indexed for MEDLINE]

Brain derived neurotrophic factor (BDNF) and autism spectrum disorders (ASD) in childhood.

April 8, 2016 - 7:21am
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Brain derived neurotrophic factor (BDNF) and autism spectrum disorders (ASD) in childhood.

Eur J Paediatr Neurol. 2015 Jul;19(4):411-4

Authors: Bryn V, Halvorsen B, Ueland T, Isaksen J, Kolkova K, Ravn K, Skjeldal OH

Abstract
BACKGROUND: Neurotrophic factors are essential regulators of neuronal maturation including synaptic synthesis. Among those, Brain derived neurotrophic factor (BDNF) has been in particular focus in the understanding of autism spectrum disorders (ASD).
PURPOSE: The aim of our study was to investigate whether BNDF could be used as diagnostic/biological marker for ASD. For this purpose we examined the plasma levels of BDNF and the precursors pro- BDNF in patients with ASD and compared it with non-autistic controls; determined whether there was a correlation between the BDNF and proBDNF levels and clinical severity. We also investigated the coding region of BDNF identify for well-variations which could be associated to ASD.
METHODS: The 65 ASD patients (51 boys) were enrolled from a recent completed epidemiological survey covering two counties (Oppland and Hedmark) in Norway. The mean age of the total number of children who participated in this study was 11,7 years. 30 non-autistic children were included as controls, 14 boys and 16 girls. The mean age was 11.3 years. Exclusion criteria for control group were individuals suffering from either neurological, endocrine, or immune insuffiency.
RESULTS AND CONCLUSIONS: Patients with ASD were characterized by moderately but significantly elevated plasma levels of BDNF compared to matched controls. No differences were observed in the proBDNF level between patients and controls. Within the ASD group, children with intellectual disability demonstrated increased BDNF, but not proBDNF levels, while the presence of ADHD had no impact on circulating proBDNF or BDNF. No further associations between plasma proBDNF or BDNF and other clinical demographics were observed.

PMID: 25847750 [PubMed - indexed for MEDLINE]

Advancing the understanding of autism disease mechanisms through genetics.

April 7, 2016 - 1:13pm

Advancing the understanding of autism disease mechanisms through genetics.

Nat Med. 2016 Apr 6;22(4):345-361

Authors: de la Torre-Ubieta L, Won H, Stein JL, Geschwind DH

Abstract
Progress in understanding the genetic etiology of autism spectrum disorders (ASD) has fueled remarkable advances in our understanding of its potential neurobiological mechanisms. Yet, at the same time, these findings highlight extraordinary causal diversity and complexity at many levels ranging from molecules to circuits and emphasize the gaps in our current knowledge. Here we review current understanding of the genetic architecture of ASD and integrate genetic evidence, neuropathology and studies in model systems with how they inform mechanistic models of ASD pathophysiology. Despite the challenges, these advances provide a solid foundation for the development of rational, targeted molecular therapies.

PMID: 27050589 [PubMed - as supplied by publisher]

Endosomal System Genetics and Autism Spectrum Disorders: A Literature Review.

April 7, 2016 - 1:13pm

Endosomal System Genetics and Autism Spectrum Disorders: A Literature Review.

Neurosci Biobehav Rev. 2016 Apr 2;

Authors: Patak J, Zhang-James Y, Faraone SV

Abstract
Autism spectrum disorders (ASDs) are a group of debilitating neurodevelopmental disorders thought to have genetic etiology, due to their high heritability. The endosomal system has become increasingly implicated in ASD pathophysiology. In an attempt to summarize the association between endosomal system genes and ASDs we performed a systematic review of the literature. We searched PubMed for relevant articles. Simons Foundation Autism Research Initiative (SFARI) gene database was used to exclude articles regarding genes with less than minimal evidence for association with ASDs. Our search retained 55 articles reviewed in two categories: genes that regulate and genes that are regulated by the endosomal system. Our review shows that the endosomal system is a novel pathway implicated in ASDs as well as other neuropsychiatric disorders. It plays a central role in aspects of cellular physiology on which neurons and glial cells are particularly reliant, due to their unique metabolic and functional demands. The system shows potential for biomarkers and pharmacological intervention and thus more research into this pathway is warranted.

PMID: 27048963 [PubMed - as supplied by publisher]

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