pubmed: autism and genetics

Subscribe to pubmed: autism and genetics feed pubmed: autism and genetics
NCBI: db=pubmed; Term=autism AND genetics
Updated: 53 sec ago

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

July 6, 2014 - 7:37am
Related Articles

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
Related Articles

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
Related Articles

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
Related Articles

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
Related Articles

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
Related Articles

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
Related Articles

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
Related Articles

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
Related Articles

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
Related Articles

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]

Transgenerational effects of prenatal bisphenol A on social recognition.

July 2, 2014 - 7:57am
Related Articles

Transgenerational effects of prenatal bisphenol A on social recognition.

Horm Behav. 2013 Nov;64(5):833-9

Authors: Wolstenholme JT, Goldsby JA, Rissman EF

Abstract
Bisphenol A (BPA) is a man-made endocrine disrupting compound used to manufacture polycarbonate plastics. It is found in plastic bottles, canned food linings, thermal receipts and other commonly used items. Over 93% of people have detectable BPA levels in their urine. Epidemiological studies report correlations between BPA levels during pregnancy and activity, anxiety, and depression in children. We fed female mice control or BPA-containing diets that produced plasma BPA concentrations similar to concentrations in humans. Females were mated and at birth, pups were fostered to control dams to limit BPA exposure to gestation in the first generation. Sibling pairs were bred to the third generation with no further BPA exposure. First (F1) and third (F3) generation juveniles were tested for social recognition and in the open field. Adult F3 mice were tested for olfactory discrimination. In both generations, BPA exposed juvenile mice displayed higher levels of investigation than controls in a social recognition task. In F3 BPA exposed mice, dishabituation to a novel female was impaired. In the open field, no differences were noted in F1 mice, while in F3, BPA lineage mice were more active than controls. No impairments were detected in F3 mice, all were able to discriminate different male urine pools and urine from water. No sex differences were found in any task. These results demonstrate that BPA exposure during gestation has long lasting, transgenerational effects on social recognition and activity in mice. These findings show that BPA exposure has transgenerational actions on behavior and have implications for human neurodevelopmental behavioral disorders.

PMID: 24100195 [PubMed - indexed for MEDLINE]

Brain Volumetric Correlates of Autism Spectrum Disorder Symptoms in Attention Deficit/Hyperactivity Disorder.

July 1, 2014 - 7:17am

Brain Volumetric Correlates of Autism Spectrum Disorder Symptoms in Attention Deficit/Hyperactivity Disorder.

PLoS One. 2014;9(6):e101130

Authors: O'Dwyer L, Tanner C, van Dongen EV, Greven CU, Bralten J, Zwiers MP, Franke B, Oosterlaan J, Heslenfeld D, Hoekstra P, Hartman CA, Rommelse N, Buitelaar JK

Abstract
Autism spectrum disorder (ASD) symptoms frequently occur in subjects with attention deficit/hyperactivity disorder (ADHD). While there is evidence that both ADHD and ASD have differential structural correlates, no study to date has investigated these structural correlates within a framework that robustly accounts for the phenotypic overlap between the two disorders. The presence of ASD symptoms was measured by the parent-reported Children's Social and Behavioural Questionnaire (CSBQ) in ADHD subjects (n = 180), their unaffected siblings (n = 118) and healthy controls (n = 146). ADHD symptoms were assessed by a structured interview (K-SADS-PL) and the Conners' ADHD questionnaires. Whole brain T1-weighted MPRAGE images were acquired and the structural MRI correlates of ASD symptom scores were analysed by modelling ASD symptom scores against white matter (WM) and grey matter (GM) volumes using mixed effects models which controlled for ADHD symptom levels. ASD symptoms were significantly elevated in ADHD subjects relative to both controls and unaffected siblings. ASD scores were predicted by the interaction between WM and GM volumes. Increasing ASD score was associated with greater GM volume. Equivocal results from previous structural studies in ADHD and ASD may be due to the fact that comorbidity has not been taken into account in studies to date. The current findings stress the need to account for issues of ASD comorbidity in ADHD.

PMID: 24979066 [PubMed - as supplied by publisher]

Exome sequencing identifies a de novo SCN2A mutation in a patient with intractable seizures, severe intellectual disability, optic atrophy, muscular hypotonia, and brain abnormalities.

July 1, 2014 - 7:17am
Related Articles

Exome sequencing identifies a de novo SCN2A mutation in a patient with intractable seizures, severe intellectual disability, optic atrophy, muscular hypotonia, and brain abnormalities.

Epilepsia. 2014 Apr;55(4):e25-9

Authors: Baasch AL, Hüning I, Gilissen C, Klepper J, Veltman JA, Gillessen-Kaesbach G, Hoischen A, Lohmann K

Abstract
Epilepsy is a phenotypically and genetically highly heterogeneous disorder with >200 genes linked to inherited forms of the disease. To identify the underlying genetic cause in a patient with intractable seizures, optic atrophy, severe intellectual disability (ID), brain abnormalities, and muscular hypotonia, we performed exome sequencing in a 5-year-old girl and her unaffected parents. In the patient, we detected a novel, de novo missense mutation in the SCN2A (c.5645G>T; p.R1882L) gene encoding the αII -subunit of the voltage-gated sodium channel Nav 1.2. A literature review revealed 33 different SCN2A mutations in 14 families with benign forms of epilepsy and in 21 cases with severe phenotypes. Although almost all benign mutations were inherited, the majority of severe mutations occurred de novo. Of interest, de novo SCN2A mutations have also been reported in five patients without seizures but with ID (n = 3) and/or autism (n = 3). In the present study, we successfully used exome sequencing to detect a de novo mutation in a genetically heterogeneous disorder with epilepsy and ID. Using this approach, we expand the phenotypic spectrum of SCN2A mutations. Our own and literature data indicate that SCN2A-linked severe phenotypes are more likely to be caused by de novo mutations. A PowerPoint slide summarizing this article is available for download in the Supporting Information section here.

PMID: 24579881 [PubMed - indexed for MEDLINE]

A case report of two male siblings with autism and duplication of Xq13-q21, a region including three genes predisposing for autism.

July 1, 2014 - 7:17am
Related Articles

A case report of two male siblings with autism and duplication of Xq13-q21, a region including three genes predisposing for autism.

Eur Child Adolesc Psychiatry. 2014 May;23(5):329-36

Authors: Wentz E, Vujic M, Kärrstedt EL, Erlandsson A, Gillberg C

Abstract
Autism spectrum disorder, severe behaviour problems and duplication of the Xq12 to Xq13 region have recently been described in three male relatives. To describe the psychiatric comorbidity and dysmorphic features, including craniosynostosis, of two male siblings with autism and duplication of the Xq13 to Xq21 region, and attempt to narrow down the number of duplicated genes proposed to be leading to global developmental delay and autism. We performed DNA sequencing of certain exons of the TWIST1 gene, the FGFR2 gene and the FGFR3 gene. We also performed microarray analysis of the DNA. In addition to autism, the two male siblings exhibited severe learning disability, self-injurious behaviour, temper tantrums and hyperactivity, and had no communicative language. Chromosomal analyses were normal. Neither of the two siblings showed mutations of the sequenced exons known to produce craniosynostosis. The microarray analysis detected an extra copy of a region on the long arm of chromosome X, chromosome band Xq13.1-q21.1. Comparison of our two cases with previously described patients allowed us to identify three genes predisposing for autism in the duplicated chromosomal region. Sagittal craniosynostosis is also a new finding linked to the duplication.

PMID: 23974867 [PubMed - indexed for MEDLINE]

Recognition of facial emotion and affective prosody in children with ASD (+ADHD) and their unaffected siblings.

July 1, 2014 - 7:17am
Related Articles

Recognition of facial emotion and affective prosody in children with ASD (+ADHD) and their unaffected siblings.

Eur Child Adolesc Psychiatry. 2014 May;23(5):257-71

Authors: Oerlemans AM, van der Meer JM, van Steijn DJ, de Ruiter SW, de Bruijn YG, de Sonneville LM, Buitelaar JK, Rommelse NN

Abstract
Autism is a highly heritable and clinically heterogeneous neuropsychiatric disorder that frequently co-occurs with other psychopathologies, such as attention-deficit/hyperactivity disorder (ADHD). An approach to parse heterogeneity is by forming more homogeneous subgroups of autism spectrum disorder (ASD) patients based on their underlying, heritable cognitive vulnerabilities (endophenotypes). Emotion recognition is a likely endophenotypic candidate for ASD and possibly for ADHD. Therefore, this study aimed to examine whether emotion recognition is a viable endophenotypic candidate for ASD and to assess the impact of comorbid ADHD in this context. A total of 90 children with ASD (43 with and 47 without ADHD), 79 ASD unaffected siblings, and 139 controls aged 6-13 years, were included to test recognition of facial emotion and affective prosody. Our results revealed that the recognition of both facial emotion and affective prosody was impaired in children with ASD and aggravated by the presence of ADHD. The latter could only be partly explained by typical ADHD cognitive deficits, such as inhibitory and attentional problems. The performance of unaffected siblings could overall be considered at an intermediate level, performing somewhat worse than the controls and better than the ASD probands. Our findings suggest that emotion recognition might be a viable endophenotype in ASD and a fruitful target in future family studies of the genetic contribution to ASD and comorbid ADHD. Furthermore, our results suggest that children with comorbid ASD and ADHD are at highest risk for emotion recognition problems.

PMID: 23824472 [PubMed - indexed for MEDLINE]

A circuitry and biochemical basis for tuberous sclerosis symptoms: from epilepsy to neurocognitive deficits.

June 28, 2014 - 8:21am
Related Articles

A circuitry and biochemical basis for tuberous sclerosis symptoms: from epilepsy to neurocognitive deficits.

Int J Dev Neurosci. 2013 Nov;31(7):667-78

Authors: Feliciano DM, Lin TV, Hartman NW, Bartley CM, Kubera C, Hsieh L, Lafourcade C, O'Keefe RA, Bordey A

Abstract
Tuberous sclerosis complex (TSC) is an autosomal dominant monogenetic disorder that is characterized by the formation of benign tumors in several organs as well as brain malformations and neuronal defects. TSC is caused by inactivating mutations in one of two genes, TSC1 and TSC2, resulting in increased activity of the mammalian Target of Rapamycin (mTOR). Here, we explore the cytoarchitectural and functional CNS aberrations that may account for the neurological presentations of TSC, notably seizures, hydrocephalus, and cognitive and psychological impairments. In particular, recent mouse models of brain lesions are presented with an emphasis on using electroporation to allow the generation of discrete lesions resulting from loss of heterozygosity during perinatal development. Cortical lesions are thought to contribute to epileptogenesis and worsening of cognitive defects. However, it has recently been suggested that being born with a mutant allele without loss of heterozygosity and associated cortical lesions is sufficient to generate cognitive and neuropsychiatric problems. We will thus discuss the function of mTOR hyperactivity on neuronal circuit formation and the potential consequences of being born heterozygous on neuronal function and the biochemistry of synaptic plasticity, the cellular substrate of learning and memory. Ultimately, a major goal of TSC research is to identify the cellular and molecular mechanisms downstream of mTOR underlying the neurological manifestations observed in TSC patients and identify novel therapeutic targets to prevent the formation of brain lesions and restore neuronal function.

PMID: 23485365 [PubMed - indexed for MEDLINE]

A Girl with Tuberous Sclerosis Complex Presenting with Severe Epilepsy and Electrical Status Epilepticus During Sleep, and with High-Functioning Autism and Mutism.

June 27, 2014 - 8:12am

A Girl with Tuberous Sclerosis Complex Presenting with Severe Epilepsy and Electrical Status Epilepticus During Sleep, and with High-Functioning Autism and Mutism.

Cogn Behav Neurol. 2014 Jun;27(2):88-95

Authors: Pacheva I, Panov G, Gillberg C, Neville B

Abstract
Most patients with tuberous sclerosis complex (TSC) suffer from epilepsy, and many have cognitive and behavioral problems like severe intellectual disability, autism, and hyperactivity. Only rare patients with TSC and autism have a normal intelligence quotient. We report a 13-year-old girl with definite TSC who had early-onset severe epilepsy, autistic behavior, and moderate developmental delay. By school age, however, she had normal intelligence; her intelligence quotient was at least 70 based on a Stanford-Binet test that she refused to complete. She showed good reading, writing, and language comprehension skills, and the special abilities of hyperlexia, hypermnesia, and hypercalculia. However, she did not speak. Criteria of the Diagnostic and Statistical Manual of Mental Disorders, 4th edition, and her Childhood Autism Rating Scale score of 36 indicated mild to moderate autism. She had severe electroencephalographic abnormalities: hypsarrhythmia, multifocal or generalized epileptiform discharges, and electrical status epilepticus during sleep, with a continuous left temporal focus. Magnetic resonance imaging showed many cortical tubers in all brain lobes, and subependymal nodules. We discuss possible explanations for her lack of speech. Considered as speech apraxia, her mutism could be either a symptom of her TSC or a component of her autism. Another possibility is that long-lasting electrical status epilepticus during sleep led to her autistic behavior and language arrest. Still another possibility is that a disinhibited mammalian target of rapamycin (mTOR) pathway was at the root of all of her neuropsychiatric symptoms.

PMID: 24968009 [PubMed - as supplied by publisher]

Common variants in genes of the postsynaptic FMRP signalling pathway are risk factors for autism spectrum disorders.

June 27, 2014 - 8:12am
Related Articles

Common variants in genes of the postsynaptic FMRP signalling pathway are risk factors for autism spectrum disorders.

Hum Genet. 2014 Jun;133(6):781-92

Authors: Waltes R, Duketis E, Knapp M, Anney RJ, Huguet G, Schlitt S, Jarczok TA, Sachse M, Kämpfer LM, Kleinböck T, Poustka F, Bölte S, Schmötzer G, Voran A, Huy E, Meyer J, Bourgeron T, Klauck SM, Freitag CM, Chiocchetti AG

Abstract
Autism spectrum disorders (ASD) are heterogeneous disorders with a high heritability and complex genetic architecture. Due to the central role of the fragile X mental retardation gene 1 protein (FMRP) pathway in ASD we investigated common functional variants of ASD risk genes regulating FMRP. We genotyped ten SNPs in two German patient sets (N = 192 and N = 254 families, respectively) and report association for rs7170637 (CYFIP1; set 1 and combined sets), rs6923492 (GRM1; combined sets), and rs25925 (CAMK4; combined sets). An additional risk score based on variants with an odds ratio (OR) >1.25 in set 1 and weighted by their respective log transmitted/untransmitted ratio revealed a significant effect (OR 1.30, 95 % CI 1.11-1.53; P = 0.0013) in the combined German sample. A subsequent meta-analysis including the two German samples, the "Strict/European" ASD subsample of the Autism Genome Project (1,466 families) and a French case/control (541/366) cohort showed again association of rs7170637-A (OR 0.85, 95 % CI 0.75-0.96; P = 0.007) and rs25925-G (OR 1.31, 95 % CI 1.04-1.64; P = 0.021) with ASD. Functional analyses revealed that these minor alleles predicted to alter splicing factor binding sites significantly increase levels of an alternative mRNA isoform of the respective gene while keeping the overall expression of the gene constant. These findings underpin the role of ASD candidate genes in postsynaptic FMRP regulation suggesting that an imbalance of specific isoforms of CYFIP1, an FMRP interaction partner, and CAMK4, a transcriptional regulator of the FMRP gene, modulates ASD risk. Both gene products are related to neuronal regulation of synaptic plasticity, a pathomechanism underlying ASD and may thus present future targets for pharmacological therapies in ASD.

PMID: 24442360 [PubMed - indexed for MEDLINE]

The Autism ProSAP1/Shank2 mouse model displays quantitative and structural abnormalities in ultrasonic vocalisations.

June 27, 2014 - 8:12am
Related Articles

The Autism ProSAP1/Shank2 mouse model displays quantitative and structural abnormalities in ultrasonic vocalisations.

Behav Brain Res. 2013 Nov 1;256:677-89

Authors: Ey E, Torquet N, Le Sourd AM, Leblond CS, Boeckers TM, Faure P, Bourgeron T

Abstract
Mouse ultrasonic vocalisations have been often used as a paradigm to extrapolate vocal communication defects observed in patients with autism spectrum disorders (ASD). The role of these vocalisations as well as their development, structure and informational content, however, remain largely unknown. In the present study, we characterised in depth the emission of pup and adult ultrasonic vocalisations of wild-type mice and their ProSAP1/Shank2(-/-) littermates lacking a synaptic scaffold protein mutated in ASD. We hypothesised that the vocal behaviour of ProSAP1/Shank2(-/-) mice not only differs from the vocal behaviour of their wild-type littermates in a quantitative way, but also presents more qualitative abnormalities in temporal organisation and acoustic structure. We first quantified the rate of emission of ultrasonic vocalisations, and analysed the organisation of vocalisations sequences using Markov models. We subsequently measured duration and peak frequency characteristics of each ultrasonic vocalisation, to characterise their acoustic structure. In wild-type mice, we found a high level of organisation in sequences of ultrasonic vocalisations, suggesting a communicative function in this complex system. Very limited significant sex-related variations were detected in their usage and acoustic structure, even in adult mice. In adult ProSAP1/Shank2(-/-) mice, we found abnormalities in the call usage and the structure of ultrasonic vocalisations. Both ProSAP1/Shank2(-/-) male and female mice uttered less vocalisations with a different call distribution and at lower peak frequency in comparison with wild-type littermates. This study provides a comprehensive framework to characterise abnormalities of ultrasonic vocalisations in mice and confirms that ProSAP1/Shank2(-/-) mice represent a relevant model to study communication defects.

PMID: 23994547 [PubMed - indexed for MEDLINE]

Mutational Analyses of the FMR1 Gene in Chinese Pediatric Population of Fragile X Suspects: Low Tolerance for Point Mutation.

June 26, 2014 - 8:03am

Mutational Analyses of the FMR1 Gene in Chinese Pediatric Population of Fragile X Suspects: Low Tolerance for Point Mutation.

J Child Neurol. 2014 Jun 23;

Authors: Luo S, Huang W, Xia Q, Du Q, Wu L, Duan R

Abstract
CGG repeat expansion is the most common cause of fragile X syndrome. Numerous efforts have been made to identify novel mutations in patients with intellectual disability, developmental delay, and/or autism. To evaluate the mutational spectrum in the at-risk Chinese population, 60 pediatric patients presenting fragile X traits but normal-sized CGG repeats were sequenced for all 17 exons and regulatory regions in FMR1. A c.879A>C mutation, reported to alter a neighboring splicing, was detected in a severely retarded male and his normal mother. However, the exon junction appears unaffected. A 237-kb deletion covering the entire FMR1 was identified to cause moderate intellectual disability and marked hyperactivity in an 8-year-old boy. The 5' and 3' breakpoints were buried in the surrounding long interspersed and short interspersed elements, respectively. In general, missense mutations do not commonly cause fragile X syndrome, whereas deletions should be considered with caution in patient referrals presenting with developmental delay and/or ordinary retardation.

PMID: 24963073 [PubMed - as supplied by publisher]

Pages