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A quantitative framework to evaluate modeling of cortical development by neural stem cells.

July 6, 2014 - 7:37am
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A quantitative framework to evaluate modeling of cortical development by neural stem cells.

Neuron. 2014 Jul 2;83(1):69-86

Authors: Stein JL, de la Torre-Ubieta L, Tian Y, Parikshak NN, Hernández IA, Marchetto MC, Baker DK, Lu D, Hinman CR, Lowe JK, Wexler EM, Muotri AR, Gage FH, Kosik KS, Geschwind DH

Abstract
Neural stem cells have been adopted to model a wide range of neuropsychiatric conditions in vitro. However, how well such models correspond to in vivo brain has not been evaluated in an unbiased, comprehensive manner. We used transcriptomic analyses to compare in vitro systems to developing human fetal brain and observed strong conservation of in vivo gene expression and network architecture in differentiating primary human neural progenitor cells (phNPCs). Conserved modules are enriched in genes associated with ASD, supporting the utility of phNPCs for studying neuropsychiatric disease. We also developed and validated a machine learning approach called CoNTExT that identifies the developmental maturity and regional identity of in vitro models. We observed strong differences between in vitro models, including hiPSC-derived neural progenitors from multiple laboratories. This work provides a systems biology framework for evaluating in vitro systems and supports their value in studying the molecular mechanisms of human neurodevelopmental disease.

PMID: 24991955 [PubMed - in process]

Clinical report of a 17q12 microdeletion with additionally unreported clinical features.

July 6, 2014 - 7:37am
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Clinical report of a 17q12 microdeletion with additionally unreported clinical features.

Case Rep Genet. 2014;2014:264947

Authors: Roberts JL, Gandomi SK, Parra M, Lu I, Gau CL, Dasouki M, Butler MG

Abstract
Copy number variations involving the 17q12 region have been associated with developmental and speech delay, autism, aggression, self-injury, biting and hitting, oppositional defiance, inappropriate language, and auditory hallucinations. We present a tall-appearing 17-year-old boy with marfanoid habitus, hypermobile joints, mild scoliosis, pectus deformity, widely spaced nipples, pes cavus, autism spectrum disorder, intellectual disability, and psychiatric manifestations including physical and verbal aggression, obsessive-compulsive behaviors, and oppositional defiance. An echocardiogram showed borderline increased aortic root size. An abdominal ultrasound revealed a small pancreas, mild splenomegaly with a 1.3 cm accessory splenule, and normal kidneys and liver. A testing panel for Marfan, aneurysm, and related disorders was negative. Subsequently, a 400 K array-based comparative genomic hybridization (aCGH) + SNP analysis was performed which identified a de novo suspected pathogenic deletion on chromosome 17q12 encompassing 28 genes. Despite the limited number of cases described in the literature with 17q12 rearrangements, our proband's phenotypic features both overlap and expand on previously reported cases. Since syndrome-specific DNA sequencing studies failed to provide an explanation for this patient's unusual habitus, we postulate that this case represents an expansion of the 17q12 microdeletion phenotype. Further analysis of the deleted interval is recommended for new genotype-phenotype correlations.

PMID: 24991439 [PubMed]

Prevalence of autism spectrum disorders in China.

July 6, 2014 - 7:37am
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Prevalence of autism spectrum disorders in China.

Shanghai Arch Psychiatry. 2013 Jun;25(3):176-7

Authors: Cubells JF

PMID: 24991154 [PubMed]

Post-transcriptional regulation of the creatine transporter gene: functional relevance of alternative splicing.

July 6, 2014 - 7:37am
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Post-transcriptional regulation of the creatine transporter gene: functional relevance of alternative splicing.

Biochim Biophys Acta. 2014 Jun;1840(6):2070-9

Authors: Ndika JD, Martinez-Munoz C, Anand N, van Dooren SJ, Kanhai W, Smith DE, Jakobs C, Salomons GS

Abstract
BACKGROUND: Aberrations in about 10-15% of X-chromosome genes account for intellectual disability (ID); with a prevalence of 1-3% (Gécz et al., 2009 [1]). The SLC6A8 gene, mapped to Xq28, encodes the creatine transporter (CTR1). Mutations in SLC6A8, and the ensuing decrease in brain creatine, lead to co-occurrence of speech/language delay, autism-like behaviors and epilepsy with ID. A splice variant of SLC6A8-SLC6A8C, containing intron 4 and exons 5-13, was identified. Herein, we report the identification of a novel variant - SLC6A8D, and functional relevance of these isoforms.
METHODS: Via (quantitative) RT-PCR, uptake assays, and confocal microscopy, we investigated their expression and function vis-à-vis creatine transport.
RESULTS: SLC6A8D is homologous to SLC6A8C except for a deletion of exon 9 (without occurrence of a frame shift). Both contain an open reading frame encoding a truncated protein but otherwise identical to CTR1. Like SLC6A8, both variants are predominantly expressed in tissues with high energy requirement. Our experiments reveal that these truncated isoforms do not transport creatine. However, in SLC6A8 (CTR1)-overexpressing cells, a subsequent infection (transduction) with viral constructs encoding either the SLC6A8C (CTR4) or SLC6A8D (CTR5) isoform resulted in a significant increase in creatine accumulation compared to CTR1 cells re-infected with viral constructs containing the empty vector. Moreover, transient transfection of CTR4 or CTR5 into HEK293 cells resulted in significantly higher creatine uptake.
CONCLUSIONS: CTR4 and CTR5 are possible regulators of the creatine transporter since their overexpression results in upregulated CTR1 protein and creatine uptake.
GENERAL SIGNIFICANCE: Provides added insight into the mechanism(s) of creatine transport regulation.

PMID: 24561156 [PubMed - indexed for MEDLINE]

FOXP1 mutations cause intellectual disability and a recognizable phenotype.

July 6, 2014 - 7:37am
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FOXP1 mutations cause intellectual disability and a recognizable phenotype.

Am J Med Genet A. 2013 Dec;161A(12):3166-75

Authors: Le Fevre AK, Taylor S, Malek NH, Horn D, Carr CW, Abdul-Rahman OA, O'Donnell S, Burgess T, Shaw M, Gecz J, Bain N, Fagan K, Hunter MF

Abstract
Mutations in FOXP1, located at 3p13, have been reported in patients with global developmental delay (GDD), intellectual disability (ID), and speech defects. Mutations in FOXP2, located at 7q31, are well known to cause developmental speech and language disorders, particularly developmental verbal dyspraxia (DVD). FOXP2 has been shown to work co-operatively with FOXP1 in mouse development. An overlap in FOXP1 and FOXP2 expression, both in the songbird and human fetal brain, has suggested that FOXP1 may also have a role in speech and language disorders. We report on a male child with a 0.19 MB intragenic deletion that is predicted to result in haploinsufficiency of FOXP1. Review of our patient and others reported in the literature reveals an emerging phenotype of GDD/ID with moderate to severe speech delay where expressive speech is most severely affected. DVD appears not to be a distinct feature in this group. Facial features include a broad forehead, downslanting palpebral fissures, a short nose with broad tip, relative or true macrocephaly, a frontal hair upsweep and prominent digit pads. Autistic traits and other behavioral problems are likely to be associated with haploinsufficiency of FOXP1. Congenital malformations may be associated.

PMID: 24214399 [PubMed - indexed for MEDLINE]

3q29 microdeletion syndrome: Cognitive and behavioral phenotype in four patients.

July 6, 2014 - 7:37am
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3q29 microdeletion syndrome: Cognitive and behavioral phenotype in four patients.

Am J Med Genet A. 2013 Dec;161A(12):3018-22

Authors: Città S, Buono S, Greco D, Barone C, Alfei E, Bulgheroni S, Usilla A, Pantaleoni C, Romano C

Abstract
The 3q29 microdeletion syndrome is a rare, recurrent genomic disorder, associated with a variable phenotype, despite the same deletion size, consisting in neurodevelopmental features, such as intellectual disability (ID), schizophrenia, autism, bipolar disorder, depression and mild facial morphological anomalies/congenital malformations. A thorough neuropsychiatric evaluation has never been reported in patients with such syndrome. We analyzed the clinical phenotype of four individuals with 3q29 microdeletion syndrome, with special emphasis on the cognitive and behavioral assessment, in order to delineate the neuropsychiatric phenotype related to this condition. We assessed these patients with standardized scales or checklists measuring the cognitive (WISC III or LIPS-R), behavioral (CBCL) and adaptive (VABS) performances. An accurate evaluation in our sample highlights different degrees of ID, variable behavioral disorders, and a preservation of communicative skills among remaining adaptive areas, as the neuropsychiatric hallmark of 3q29 microdeletion syndrome.

PMID: 24214349 [PubMed - indexed for MEDLINE]

Mutations of the synapse genes and intellectual disability syndromes.

July 6, 2014 - 7:37am
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Mutations of the synapse genes and intellectual disability syndromes.

Eur J Pharmacol. 2013 Nov 5;719(1-3):112-6

Authors: Verpelli C, Montani C, Vicidomini C, Heise C, Sala C

Abstract
Intellectual disability syndromes have been found associated to numerous mutated genes that code for proteins functionally involved in synapse formation, the regulation of dendritic spine morphology, the regulation of the synaptic cytoskeleton or the synthesis and degradation of specific synapse proteins. These studies have strongly demonstrated that even mild alterations in synapse morphology and function give rise to mild or severe alteration in intellectual abilities. Interestingly, pharmacological agents that are able to counteract these morphological and functional synaptic anomalies can also improve the symptoms of some of these conditions. This review is summarizing recent discoveries on the functions of some of the genes responsible for intellectual disability syndromes connected with synapse dysfunctions.

PMID: 23872408 [PubMed - indexed for MEDLINE]

Contactins in the neurobiology of autism.

July 6, 2014 - 7:37am
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Contactins in the neurobiology of autism.

Eur J Pharmacol. 2013 Nov 5;719(1-3):63-74

Authors: Zuko A, Kleijer KT, Oguro-Ando A, Kas MJ, van Daalen E, van der Zwaag B, Burbach JP

Abstract
Autism is a disease of brain plasticity. Inspiring work of Willem Hendrik Gispen on neuronal plasticity has stimulated us to investigate gene defects in autism and the consequences for brain development. The central process in the pathogenesis of autism is local dendritic mRNA translation which is dependent on axodendritic communication. Hence, most autism-related gene products (i) are part of the protein synthesis machinery itself, (ii) are components of the mTOR signal transduction pathway, or (iii) shape synaptic activity and plasticity. Accordingly, prototype drugs have been recognized that interfere with these pathways. The contactin (CNTN) family of Ig cell adhesion molecules (IgCAMs) harbours at least three members that have genetically been implicated in autism: CNTN4, CNTN5, and CNTN6. In this chapter we review the genetic and neurobiological data underpinning their role in normal and abnormal development of brain systems, and the consequences for behavior. Although data on each of these CNTNs are far from complete, we tentatively conclude that these three contactins play roles in brain development in a critical phase of establishing brain systems and their plasticity. They modulate neuronal activities, such as neurite outgrowth, synaptogenesis, survival, guidance of projections and terminal branching of axons in forming neural circuits. Current research on these CNTNs concentrate on the neurobiological mechanism of their developmental functions. A future task will be to establish if proposed pharmacological strategies to counteract ASD-related symptomes can also be applied to reversal of phenotypes caused by genetic defects in these CNTN genes.

PMID: 23872404 [PubMed - indexed for MEDLINE]

Evidence for gender-specific endophenotypes in high-functioning autism spectrum disorder during empathy.

July 6, 2014 - 7:37am
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Evidence for gender-specific endophenotypes in high-functioning autism spectrum disorder during empathy.

Autism Res. 2013 Dec;6(6):506-21

Authors: Schneider K, Regenbogen C, Pauly KD, Gossen A, Schneider DA, Mevissen L, Michel TM, Gur RC, Habel U, Schneider F

Abstract
Despite remarkable behavioral gender differences in patients with autism spectrum disorder (ASD), and growing evidence for a diminished male : female ratio for the putative "male disorder" ASD, aspects of gender are not addressed accordingly in ASD research. Our study aims at filling this gap by exploring empathy abilities in a group of 28 patients with high-functioning ASD and 28 gender-, age- and education-matched non-autistic subjects, for the first time by means of functional neuroimaging (fMRI). In an event-related fMRI paradigm, emotional ("E") and neutral ("N") video clips presented actors telling self-related short stories. After each clip, participants were asked to indicate their own emotion and its intensity as well as the emotion and intensity perceived for the actor. Behaviorally, we found significantly less empathic responses in the overall ASD group compared with non-autistic subjects, and inadequate emotion recognition for the neutral clips in the female ASD group compared with healthy women. Neurally, increased activation of the bilateral medial frontal gyrus was found in male patients compared with female patients, a pattern which was not present in the non-autistic group. Additionally, autistic women exhibited decreased activation of midbrain and limbic regions compared with non-autistic women, whereas there was no significant difference within the male group. While we did not find a fundamental empathic deficit in autistic patients, our data propose different ways of processing empathy in autistic men and women, suggesting stronger impairments in cognitive aspects of empathy/theory of mind for men, and alterations of social reciprocity for women.

PMID: 23868876 [PubMed - indexed for MEDLINE]

Confirmation of chromosomal microarray as a first-tier clinical diagnostic test for individuals with developmental delay, intellectual disability, autism spectrum disorders and dysmorphic features.

July 6, 2014 - 7:37am
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Confirmation of chromosomal microarray as a first-tier clinical diagnostic test for individuals with developmental delay, intellectual disability, autism spectrum disorders and dysmorphic features.

Eur J Paediatr Neurol. 2013 Nov;17(6):589-99

Authors: Battaglia A, Doccini V, Bernardini L, Novelli A, Loddo S, Capalbo A, Filippi T, Carey JC

Abstract
BACKGROUND AND OBJECTIVES: Submicroscopic chromosomal rearrangements are the most common identifiable causes of intellectual disability and autism spectrum disorders associated with dysmorphic features. Chromosomal microarray (CMA) can detect copy number variants <1 Mb and identifies size and presence of known genes. The aim of this study was to demonstrate the usefulness of CMA, as a first-tier tool in detecting the etiology of unexplained intellectual disability/autism spectrum disorders (ID/ASDs) associated with dysmorphic features in a large cohort of pediatric patients.
PATIENTS AND METHODS: We studied 349 individuals; 223 males, 126 females, aged 5 months-19 years. Blood samples were analyzed with CMA at a resolution ranging from 1 Mb to 40 Kb. The imbalance was confirmed by FISH or qPCR. We considered copy number variants (CNVs) causative if the variant was responsible for a known syndrome, encompassed gene/s of known function, occurred de novo or, if inherited, the parent was variably affected, and/or the involved gene/s had been reported in association with ID/ASDs in dedicated databases.
RESULTS: 91 CNVs were detected in 77 (22.06%) patients: 5 (6.49%) of those presenting with borderline cognitive impairment, 54 (70.13%) with a variable degree of DD/ID, and 18/77 (23.38%) with ID of variable degree and ASDs. 16/77 (20.8%) patients had two different rearrangements. Deletions exceeded duplications (58 versus 33); 45.05% (41/91) of the detected CNVs were de novo, 45.05% (41/91) inherited, and 9.9% (9/91) unknown. The CNVs caused the phenotype in 57/77 (74%) patients; 12/57 (21.05%) had ASDs/ID, and 45/57 (78.95%) had DD/ID.
CONCLUSIONS: Our study provides further evidence of the high diagnostic yield of CMA for genetic testing in children with unexplained ID/ASDs who had dysmorphic features. We confirm the value of CMA as the first-tier tool in the assessment of those conditions in the pediatric setting.

PMID: 23711909 [PubMed - indexed for MEDLINE]

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