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Systemic dendrimer-drug treatment of ischemia-induced neonatal white matter injury.

May 18, 2016 - 4:30pm
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Systemic dendrimer-drug treatment of ischemia-induced neonatal white matter injury.

J Control Release. 2015 Sep 28;214:112-20

Authors: Nance E, Porambo M, Zhang F, Mishra MK, Buelow M, Getzenberg R, Johnston M, Kannan RM, Fatemi A, Kannan S

Abstract
Extreme prematurity is a major risk factor for perinatal and neonatal brain injury, and can lead to white matter injury that is a precursor for a number of neurological diseases, including cerebral palsy (CP) and autism. Neuroinflammation, mediated by activated microglia and astrocytes, is implicated in the pathogenesis of neonatal brain injury. Therefore, targeted drug delivery to attenuate neuroinflammation may greatly improve therapeutic outcomes in models of perinatal white matter injury. In this work, we use a mouse model of ischemia-induced neonatal white matter injury to study the biodistribution of generation 4, hydroxyl-functionalized polyamidoamine dendrimers. Following systemic administration of the Cy5-labeled dendrimer (D-Cy5), we demonstrate dendrimer uptake in cells involved in ischemic injury, and in ongoing inflammation, leading to secondary injury. The sub-acute response to injury is driven by astrocytes. Within five days of injury, microglial proliferation and migration occurs, along with limited differentiation of oligodendrocytes and oligodendrocyte death. From one day to five days after injury, a shift in dendrimer co-localization occurred. Initially, dendrimer predominantly co-localized with astrocytes, with a subsequent shift towards microglia. Co-localization with oligodendrocytes reduced over the same time period, demonstrating a region-specific uptake based on the progression of the injury. We further show that systemic administration of a single dose of dendrimer-N-acetyl cysteine conjugate (D-NAC) at either sub-acute or delayed time points after injury results in sustained attenuation of the 'detrimental' pro-inflammatory response up to 9days after injury, while not impacting the 'favorable' anti-inflammatory response. The D-NAC therapy also led to improvement in myelination, suggesting reduced white matter injury. Demonstration of treatment efficacy at later time points in the postnatal period provides a greater understanding of how microglial activation and chronic inflammation can be targeted to treat neonatal brain injury. Importantly, it may also provide a longer therapeutic window.

PMID: 26184052 [PubMed - indexed for MEDLINE]

Spatiotemporal dynamics of the postnatal developing primate brain transcriptome.

May 18, 2016 - 4:30pm
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Spatiotemporal dynamics of the postnatal developing primate brain transcriptome.

Hum Mol Genet. 2015 Aug 1;24(15):4327-39

Authors: Bakken TE, Miller JA, Luo R, Bernard A, Bennett JL, Lee CK, Bertagnolli D, Parikshak NN, Smith KA, Sunkin SM, Amaral DG, Geschwind DH, Lein ES

Abstract
Developmental changes in the temporal and spatial regulation of gene expression drive the emergence of normal mature brain function, while disruptions in these processes underlie many neurodevelopmental abnormalities. To solidify our foundational knowledge of such changes in a primate brain with an extended period of postnatal maturation like in human, we investigated the whole-genome transcriptional profiles of rhesus monkey brains from birth to adulthood. We found that gene expression dynamics are largest from birth through infancy, after which gene expression profiles transition to a relatively stable state by young adulthood. Biological pathway enrichment analysis revealed that genes more highly expressed at birth are associated with cell adhesion and neuron differentiation, while genes more highly expressed in juveniles and adults are associated with cell death. Neocortex showed significantly greater differential expression over time than subcortical structures, and this trend likely reflects the protracted postnatal development of the cortex. Using network analysis, we identified 27 co-expression modules containing genes with highly correlated expression patterns that are associated with specific brain regions, ages or both. In particular, one module with high expression in neonatal cortex and striatum that decreases during infancy and juvenile development was significantly enriched for autism spectrum disorder (ASD)-related genes. This network was enriched for genes associated with axon guidance and interneuron differentiation, consistent with a disruption in the formation of functional cortical circuitry in ASD.

PMID: 25954031 [PubMed - indexed for MEDLINE]

Common genetic variants linked with large percentage of autism risk: study finds spontaneous mutations are less-significant risk factors.

May 18, 2016 - 4:30pm
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Common genetic variants linked with large percentage of autism risk: study finds spontaneous mutations are less-significant risk factors.

Am J Med Genet A. 2014 Nov;164A(11):vii-viii

Authors: Levenson D

PMID: 25327469 [PubMed - indexed for MEDLINE]

Diagnostic and clinical characteristics of early-manifesting females with Duchenne or Becker muscular dystrophy.

May 18, 2016 - 4:30pm
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Diagnostic and clinical characteristics of early-manifesting females with Duchenne or Becker muscular dystrophy.

Am J Med Genet A. 2014 Nov;164A(11):2769-74

Authors: Imbornoni L, Price ET, Andrews J, Meaney FJ, Ciafaloni E, Cunniff C

Abstract
Manifestations of Duchenne and Becker muscular dystrophy (DBMD) are present in up to 40% of heterozygous females, but there are few reports of females who exhibit skeletal muscle symptoms in childhood. From the Muscular Dystrophy Surveillance Tracking and Research Network, a multi-site population-based surveillance network for dystrophinopathy, nine symptomatic female heterozygotes with onset of symptoms prior to age 9 years were identified. The median age at diagnosis was 8.3 years, and the median interval from first symptoms to diagnosis was 1.35 years. Of the nine female heterozygotes, four had a positive family history, seven had intellectual disability and five had at least one mental health disorder. Mental health concerns included attention deficit hyperactivity disorder (ADHD), autism spectrum features, bipolar disorder, and depression. The frequency of intellectual and mental health problems in this group is higher than previously reported for affected males and for symptomatic females. These findings may have implications for diagnosis of early manifesting heterozygotes and for their health supervision.

PMID: 25125379 [PubMed - indexed for MEDLINE]

A terminal 3p26.3 deletion is not associated with dysmorphic features and intellectual disability in a four-generation family.

May 18, 2016 - 4:30pm
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A terminal 3p26.3 deletion is not associated with dysmorphic features and intellectual disability in a four-generation family.

Am J Med Genet A. 2014 Nov;164A(11):2863-8

Authors: Moghadasi S, van Haeringen A, Langendonck L, Gijsbers AC, Ruivenkamp CA

Abstract
Terminal deletions of the distal part of the short arm of chromosome 3 cause a wide range of phenotypes from normal to dysmorphic including microcephaly, developmental delay and intellectual disability. We studied the clinical consequences of a terminal deletion of the short arm of chromosome 3 in four generations of a family. The index patient is a14-month-old boy with microcephaly, corpus callosum dysgenesis, and minor dysmorphic features. Single Nucleotide Polymorphism (SNP) array analysis detected a duplication on the long arm of chromosome 6. His apparently healthy mother carries the same 6q duplication, but as an unexpected finding a terminal deletion of 2.9 Mb of the short arm of chromosome 3 was observed. Further co-segregation analysis in the family for the chromosome 3 deletion showed that with the exception of the sister of the index who has autism, speech delay, and learning problems, family members in four generations of this family are carrier of this 3p deletion and apparently healthy. To our knowledge, this is the first report of a study of this terminal 3p deletion in four generations. In this report, we review the literature on terminal 3p deletions and discuss the importance of molecular testing and reporting of copy number variants to achieve accurate genetic counseling in prenatal and postnatal screening.

PMID: 25123480 [PubMed - indexed for MEDLINE]

Early event-related potentials to emotional faces differ for adults with autism spectrum disorder and by serotonin transporter genotype.

May 15, 2016 - 10:24am

Early event-related potentials to emotional faces differ for adults with autism spectrum disorder and by serotonin transporter genotype.

Clin Neurophysiol. 2016 Jun;127(6):2436-47

Authors: Faja S, Dawson G, Aylward E, Wijsman EM, Webb SJ

Abstract
OBJECTIVE: To test differences in neural sensitivity to facial expressions, including expressions with open versus closed mouths, exhibited by (1) adults with autism spectrum disorder (ASD) compared to neurotypical adults, and by (2) short versus long serotonin transporter allele (SLC6A4) carriers.
METHODS: Event related potentials (ERPs) to happy, fearful, and neutral expressions were collected from neurotypical adults (n=25) and adults with ASD (n=27)-of whom 32 had short and 13 had homozygous long SLC6A4 alleles.
RESULTS: In the neurotypical group, we confirmed that the N170, VPP and EPN, but not the P1, were influenced by emotional expressions, and determined the EPN was the earliest component modulated by open mouth. Compared to the neurotypical group, individuals with ASD exhibited differences in EPN amplitude in response to open versus closed mouths and in hemispheric distribution. Across groups, short serotonin transporter allele carriers had reduced P1 amplitude compared to long allele carriers.
CONCLUSIONS: Individuals with ASD exhibited a different pattern of neural response when encoding and recognizing facial expressions at the EPN component. Across groups, SLC6A4 allele type modulated early sensory attention at the P1.
SIGNIFICANCE: These results provide insight into the nature of early responses to emotional information according to genetic variation and clinical condition.

PMID: 27178863 [PubMed - in process]

Generation of a Tph2 Conditional Knockout Mouse Line for Time- and Tissue-Specific Depletion of Brain Serotonin.

May 14, 2016 - 7:23am
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Generation of a Tph2 Conditional Knockout Mouse Line for Time- and Tissue-Specific Depletion of Brain Serotonin.

PLoS One. 2015;10(8):e0136422

Authors: Pelosi B, Pratelli M, Migliarini S, Pacini G, Pasqualetti M

Abstract
Serotonin has been gaining increasing attention during the last two decades due to the dual function of this monoamine as key regulator during critical developmental events and as neurotransmitter. Importantly, unbalanced serotonergic levels during critical temporal phases might contribute to the onset of neuropsychiatric disorders, such as schizophrenia and autism. Despite increasing evidences from both animal models and human genetic studies have underpinned the importance of serotonin homeostasis maintenance during central nervous system development and adulthood, the precise role of this molecule in time-specific activities is only beginning to be elucidated. Serotonin synthesis is a 2-step process, the first step of which is mediated by the rate-limiting activity of Tph enzymes, belonging to the family of aromatic amino acid hydroxylases and existing in two isoforms, Tph1 and Tph2, responsible for the production of peripheral and brain serotonin, respectively. In the present study, we generated and validated a conditional knockout mouse line, Tph2flox/flox, in which brain serotonin can be effectively ablated with time specificity. We demonstrated that the Cre-mediated excision of the third exon of Tph2 gene results in the production of a Tph2null allele in which we observed the near-complete loss of brain serotonin, as well as the growth defects and perinatal lethality observed in serotonin conventional knockouts. We also revealed that in mice harbouring the Tph2null allele, but not in wild-types, two distinct Tph2 mRNA isoforms are present, namely Tph2Δ3 and Tph2Δ3Δ4, with the latter showing an in-frame deletion of amino acids 84-178 and coding a protein that could potentially retain non-negligible enzymatic activity. As we could not detect Tph1 expression in the raphe, we made the hypothesis that the Tph2Δ3Δ4 isoform can be at the origin of the residual, sub-threshold amount of serotonin detected in the brain of Tph2null/null mice. Finally, we set up a tamoxifen administration protocol that allows an efficient, time-specific inactivation of brain serotonin synthesis. On the whole, we generated a suitable genetic tool to investigate how serotonin depletion impacts on time-specific events during central nervous system development and adulthood life.

PMID: 26291320 [PubMed - indexed for MEDLINE]

Comprehensive Analysis of the 16p11.2 Deletion and Null Cntnap2 Mouse Models of Autism Spectrum Disorder.

May 14, 2016 - 7:23am
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Comprehensive Analysis of the 16p11.2 Deletion and Null Cntnap2 Mouse Models of Autism Spectrum Disorder.

PLoS One. 2015;10(8):e0134572

Authors: Brunner D, Kabitzke P, He D, Cox K, Thiede L, Hanania T, Sabath E, Alexandrov V, Saxe M, Peles E, Mills A, Spooren W, Ghosh A, Feliciano P, Benedetti M, Luo Clayton A, Biemans B

Abstract
Autism spectrum disorder comprises several neurodevelopmental conditions presenting symptoms in social communication and restricted, repetitive behaviors. A major roadblock for drug development for autism is the lack of robust behavioral signatures predictive of clinical efficacy. To address this issue, we further characterized, in a uniform and rigorous way, mouse models of autism that are of interest because of their construct validity and wide availability to the scientific community. We implemented a broad behavioral battery that included but was not restricted to core autism domains, with the goal of identifying robust, reliable phenotypes amenable for further testing. Here we describe comprehensive findings from two known mouse models of autism, obtained at different developmental stages, using a systematic behavioral test battery combining standard tests as well as novel, quantitative, computer-vision based systems. The first mouse model recapitulates a deletion in human chromosome 16p11.2, found in 1% of individuals with autism. The second mouse model harbors homozygous null mutations in Cntnap2, associated with autism and Pitt-Hopkins-like syndrome. Consistent with previous results, 16p11.2 heterozygous null mice, also known as Del(7Slx1b-Sept1)4Aam weighed less than wild type littermates displayed hyperactivity and no social deficits. Cntnap2 homozygous null mice were also hyperactive, froze less during testing, showed a mild gait phenotype and deficits in the three-chamber social preference test, although less robust than previously published. In the open field test with exposure to urine of an estrous female, however, the Cntnap2 null mice showed reduced vocalizations. In addition, Cntnap2 null mice performed slightly better in a cognitive procedural learning test. Although finding and replicating robust behavioral phenotypes in animal models is a challenging task, such functional readouts remain important in the development of therapeutics and we anticipate both our positive and negative findings will be utilized as a resource for the broader scientific community.

PMID: 26273832 [PubMed - indexed for MEDLINE]

A critical role of RBM8a in proliferation and differentiation of embryonic neural progenitors.

May 14, 2016 - 7:23am
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A critical role of RBM8a in proliferation and differentiation of embryonic neural progenitors.

Neural Dev. 2015;10:18

Authors: Zou D, McSweeney C, Sebastian A, Reynolds DJ, Dong F, Zhou Y, Deng D, Wang Y, Liu L, Zhu J, Zou J, Shi Y, Albert I, Mao Y

Abstract
BACKGROUND: Nonsense mediated mRNA decay (NMD) is an RNA surveillance mechanism that controls RNA stability and ensures the speedy degradation of erroneous and unnecessary transcripts. This mechanism depends on several core factors in the exon junction complex (EJC), eIF4A3, RBM8a, Magoh, and BTZ, as well as peripheral factors to distinguish premature stop codons (PTCs) from normal stop codons in transcripts. Recently, emerging evidence has indicated that NMD factors are associated with neurodevelopmental disorders such as autism spectrum disorder (ASD) and intellectual disability (ID). However, the mechanism in which these factors control embryonic brain development is not clear.
RESULT: We found that RBM8a is critical for proliferation and differentiation in cortical neural progenitor cells (NPCs). RBM8a is highly expressed in the subventricular zone (SVZ) of the early embryonic cortex, suggesting that RBM8a may play a role in regulating NPCs. RBM8a overexpression stimulates embryonic NPC proliferation and suppresses neuronal differentiation. Conversely, knockdown of RBM8a in the neocortex reduces NPC proliferation and promotes premature neuronal differentiation. Moreover, overexpression of RBM8a suppresses cell cycle exit and keeps cortical NPCs in a proliferative state. To uncover the underlying mechanisms of this phenotype, genome-wide RNAseq was used to identify potential downstream genes of RBM8a in the brain, which have been implicated in autism and neurodevelopmental disorders. Interestingly, autism and schizophrenia risk genes are highly represented in downstream transcripts of RBM8a. In addition, RBM8a regulates multiple alternative splicing genes and NMD targets that are implicated in ASD. Taken together, this data suggests a novel role of RBM8a in the regulation of neurodevelopment.
CONCLUSIONS: Our studies provide some insight into causes of mental illnesses and will facilitate the development of new therapeutic strategies for neurodevelopmental illnesses.

PMID: 26094033 [PubMed - indexed for MEDLINE]

Biological factors underlying sex differences in neurological disorders.

May 14, 2016 - 7:23am
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Biological factors underlying sex differences in neurological disorders.

Int J Biochem Cell Biol. 2015 Aug;65:139-50

Authors: Loke H, Harley V, Lee J

Abstract
The prevalence, age of onset, pathophysiology, and symptomatology of many neurological and neuropsychiatric conditions differ significantly between males and females. Females suffer more from mood disorders such as depression and anxiety, whereas males are more susceptible to deficits in the dopamine system including Parkinson's disease (PD), attention-deficit hyperactivity disorder (ADHD), schizophrenia, and autism spectrum disorders (ASD). Until recently, these sex differences have been explained solely by the neuroprotective actions of sex hormones in females. Emerging evidence however indicates that the sex chromosome genes (i.e. X- and Y-linked genes) also contribute to brain sex differences. In particular, the Y-chromosome gene, SRY (Sex-determining Region on the Y chromosome) is an interesting candidate as it is expressed in dopamine-abundant brain regions, where it regulates dopamine biosynthesis and dopamine-mediated functions such as voluntary movement in males. Furthermore, SRY expression is dysregulated in a toxin-induced model of PD, suggesting a role for SRY in the pathogenesis of dopamine cells. Taken together, these studies highlight the importance of understanding the interplay between sex-specific hormones and sex-specific genes in healthy and diseased brain. In particular, better understanding of regulation and function of SRY in the male brain could provide entirely novel and important insights into genetic factors involved in the susceptibility of men to neurological disorders, as well as development of novel sex-specific therapies.

PMID: 26028290 [PubMed - indexed for MEDLINE]

LAMB1 polymorphism is associated with autism symptom severity in Korean autism spectrum disorder patients.

May 14, 2016 - 7:23am
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LAMB1 polymorphism is associated with autism symptom severity in Korean autism spectrum disorder patients.

Nord J Psychiatry. 2015;69(8):594-8

Authors: Kim YJ, Park JK, Kang WS, Kim SK, Park HJ, Nam M, Kim JW

Abstract
BACKGROUND: LAMB1 encodes laminin beta-1, which is expressed during early development of the human nervous system, and could be involved in the pathogenesis of neurodevelopmental disorders.
AIMS: In our study, we aimed to investigate whether single nucleotide polymorphisms (SNPs) in LAMB1 were associated with autism spectrum disorder (ASD) and with related clinical severities of ASD.
METHODS: Two coding SNPs (rs20556 and rs25659) and two intronic SNPs (rs2158836 and rs2237659) were compared between 180 patients with ASD and 147 healthy control subjects using direct sequencing. The Korean version of the Childhood Autism Rating Scale (K-CARS) was used to assess clinical severities. Multiple logistic regression models were employed to analyze genetic data, and associations with symptom severity were tested with the Kruskal-Wallis and the Mann-Whitney U tests.
RESULTS: None of the four examined SNPs was associated with ASD risk. However, the GG genotype of rs2158836 was associated with more severe symptoms for the "object use" and "non-verbal communication" measures.
CONCLUSIONS: The results of our study suggest the association between rs2158836 polymorphisms and symptom severity in ASD.

PMID: 25774865 [PubMed - indexed for MEDLINE]

Maternal Modifiers and Parent-of-Origin Bias of the Autism-Associated 16p11.2 CNV.

May 12, 2016 - 7:17am
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Maternal Modifiers and Parent-of-Origin Bias of the Autism-Associated 16p11.2 CNV.

Am J Hum Genet. 2016 Jan 7;98(1):45-57

Authors: Duyzend MH, Nuttle X, Coe BP, Baker C, Nickerson DA, Bernier R, Eichler EE

Abstract
Recurrent deletions and duplications at chromosomal region 16p11.2 are a major genetic contributor to autism but also associate with a wider range of pediatric diagnoses, including intellectual disability, coordination disorder, and language disorder. In order to investigate the potential genetic basis for phenotype variability, we assessed the parent of origin of the 16p11.2 copy-number variant (CNV) and the presence of additional CNVs in 126 families for which detailed phenotype data were available. Among de novo cases, we found a strong maternal bias for the origin of deletions (59/66, 89.4% of cases, p = 2.38 × 10(-11)), the strongest such effect so far observed for a CNV associated with a microdeletion syndrome. In contrast to de novo events, we observed no transmission bias for inherited 16p11.2 CNVs, consistent with a female meiotic hotspot of unequal crossover driving this maternal bias. We analyzed this 16p11.2 CNV cohort for the presence of secondary CNVs and found a significant maternal transmission bias for secondary deletions (32 maternal versus 14 paternal, p = 1.14 × 10(-2)). Of the secondary deletions that disrupted a gene, 82% were either maternally inherited or de novo (p = 4.3 × 10(-3)). Nine probands carry secondary CNVs that disrupt genes associated with autism and/or intellectual disability risk variants. Our findings demonstrate a strong bias toward maternal origin of 16p11.2 de novo deletions as well as a maternal transmission bias for secondary deletions that contribute to the clinical outcome on a background sensitized by the 16p11.2 CNV.

PMID: 26749307 [PubMed - indexed for MEDLINE]

Ack1 is a dopamine transporter endocytic brake that rescues a trafficking-dysregulated ADHD coding variant.

May 10, 2016 - 7:07am
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Ack1 is a dopamine transporter endocytic brake that rescues a trafficking-dysregulated ADHD coding variant.

Proc Natl Acad Sci U S A. 2015 Dec 15;112(50):15480-5

Authors: Wu S, Bellve KD, Fogarty KE, Melikian HE

Abstract
The dopamine (DA) transporter (DAT) facilitates high-affinity presynaptic DA reuptake that temporally and spatially constrains DA neurotransmission. Aberrant DAT function is implicated in attention-deficit/hyperactivity disorder and autism spectrum disorder. DAT is a major psychostimulant target, and psychostimulant reward strictly requires binding to DAT. DAT function is acutely modulated by dynamic membrane trafficking at the presynaptic terminal and a PKC-sensitive negative endocytic mechanism, or "endocytic brake," controls DAT plasma membrane stability. However, the molecular basis for the DAT endocytic brake is unknown, and it is unknown whether this braking mechanism is unique to DAT or common to monoamine transporters. Here, we report that the cdc42-activated, nonreceptor tyrosine kinase, Ack1, is a DAT endocytic brake that stabilizes DAT at the plasma membrane and is released in response to PKC activation. Pharmacologic and shRNA-mediated Ack1 silencing enhanced basal DAT internalization and blocked PKC-stimulated DAT internalization, but had no effects on SERT endocytosis. Both cdc42 activation and PKC stimulation converge on Ack1 to control Ack1 activity and DAT endocytic capacity, and Ack1 inactivation is required for stimulated DAT internalization downstream of PKC activation. Moreover, constitutive Ack1 activation is sufficient to rescue the gain-of-function endocytic phenotype exhibited by the ADHD DAT coding variant, R615C. These findings reveal a unique endocytic control switch that is highly specific for DAT. Moreover, the ability to rescue the DAT(R615C) coding variant suggests that manipulating DAT trafficking mechanisms may be a potential therapeutic approach to correct DAT coding variants that exhibit trafficking dysregulation.

PMID: 26621748 [PubMed - indexed for MEDLINE]

Chromatin remodeling gene EZH2 involved in the genetic etiology of autism in Chinese Han population.

May 10, 2016 - 7:07am
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Chromatin remodeling gene EZH2 involved in the genetic etiology of autism in Chinese Han population.

Neurosci Lett. 2016 Jan 1;610:182-6

Authors: Li J, You Y, Yue W, Yu H, Lu T, Wu Z, Jia M, Ruan Y, Liu J, Zhang D, Wang L

Abstract
Autism spectrum disorder (ASD) is a group of severe neurodevelopmental disorders. Epigenetic factors play a critical role in the etiology of ASD. Enhancer of zest homolog 2 (EZH2), which encodes a histone methyltransferase, plays an important role in the process of chromatin remodeling during neurodevelopment. Further, EZH2 is located in chromosome 7q35-36, which is one of the linkage regions for autism. However, the genetic relationship between autism and EZH2 remains unclear. To investigate the association between EZH2 and autism in Chinese Han population, we performed a family-based association study between autism and three tagged single nucleotide polymorphisms (SNPs) that covered 95.4% of the whole region of EZH2. In the discovery cohort of 239 trios, two SNPs (rs740949 and rs6464926) showed a significant association with autism. To decrease false positive results, we expanded the sample size to 427 trios. A SNP (rs6464926) was significantly associated with autism even after Bonferroni correction (p=0.008). Haplotype G-T (rs740949 and rs6464926) was a risk factor for autism (Z=2.655, p=0.008, Global p=0.024). In silico function prediction for SNPs indicated that these two SNPs might be regulatory SNPs. Expression pattern of EZH2 showed that it is highly expressed in human embryonic brains. In conclusion, our findings demonstrate that EZH2 might contribute to the genetic etiology of autism in Chinese Han population.

PMID: 26552012 [PubMed - indexed for MEDLINE]

Case report: an unexpected link between partial deletion of the SHANK3 gene and Heller's dementia infantilis, a rare subtype of autism spectrum disorder.

May 10, 2016 - 7:07am
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Case report: an unexpected link between partial deletion of the SHANK3 gene and Heller's dementia infantilis, a rare subtype of autism spectrum disorder.

BMC Psychiatry. 2015;15:256

Authors: Philippe A, Craus Y, Rio M, Bahi-Buisson N, Boddaert N, Malan V, Bonnefont JP, Robel L

Abstract
BACKGROUND: Deletions and mutations involving the SHANK3 gene lead to a nonspecific clinical presentation with moderate to profound intellectual disability, severely delayed or absent speech, and autism spectrum disorders (ASD). Better knowledge of the clinical spectrum of SHANK3 haploinsufficiency is useful to facilitate clinical care monitoring and to guide molecular diagnosis, essential for genetic counselling.
CASE PRESENTATION: Here, we report a detailed clinical description of a 10-year-old girl carrying a pathogenic interstitial 22q13.3 deletion encompassing only the first 17 exons of SHANK3. The clinical features displayed by the girl strongly suggested the diagnosis of dementia infantilis, described by Heller in 1908, also known as childhood disintegrative disorder.
CONCLUSION: Our present case confirms several observations according to which regression may be part of the clinical phenotype of SHANK3 haploinsufficiency. Therefore, we think it is crucial to look for mutations in the gene SHANK3 in patients diagnosed for childhood disintegrative disorder or any developmental disorder with a regressive pattern involving social and communicative skills as well as cognitive and instinctual functions, with onset around 3 years.

PMID: 26489495 [PubMed - indexed for MEDLINE]

Association of polymorphisms in the vitamin D receptor gene and serum 25-hydroxyvitamin D levels in children with autism spectrum disorder.

May 8, 2016 - 7:00am

Association of polymorphisms in the vitamin D receptor gene and serum 25-hydroxyvitamin D levels in children with autism spectrum disorder.

Gene. 2016 May 4;

Authors: Coşkun S, Şimşek Ş, Camkurt MA, Çim A, Çelik SB

Abstract
Vitamin D is implicated in several aspects of human physiology, and polymorphisms in the vitamin D receptor gene (VDR) are associated with a variety of neuropsychiatric disorders. The aims of this study are to determine whether VDR polymorphisms are associated with autism spectrum disorder (ASD), to examine serum 25-hydroxyvitamin D (25(OH)D) levels in ASD, and to explore whether VDR polymorphisms influence serum 25(OH)D levels. We investigated 480 subjects (237 children with ASD and 243 healthy controls) for the following VDR polymorphisms: TaqI, BsmI, FokI, ApaI, and Cdx2.Within the same samples, 25(OH)D levels were available only for 85 patients and 82 controls. The Cdx-2 variation was shown to deviate from Hardy-Weinberg equilibrium in the controls and was therefore excluded from the study. We found that the frequency of rare FokI TT, TaqI CC, and BsmI AA genotypes differed significantly between children with ASD and the controls (p=0.042, p=0.016, p=0.038, respectively). After correction for multiple testing, only the TaqI CC genotype remained significant. Further analysis using a recessive model showed that rare genotypes of these polymorphisms were significantly higher in patients compared to controls (p=0.045, p=0.005 and p=0.031, respectively). However, no significant association was found between ApaI and ASD. We found serum 25(OH)D levels to be significantly higher in children with ASD (p<0.001) and that the FokI polymorphism had an effect on serum 25(OH)D levels in children with ASD (p=0.041). Additionally, we found the haplotype GTTT (BsmI/TaqI/FokI/ApaI) conferred an increased risk for developing ASD (p=0.022; odds ratio [95% confidence interval]=2.322 [1.105-4.879]). This is the first clinical study evaluating the association between serum 25(OH)D levels and VDR polymorphisms in children with ASD. Our results demonstrated a significant association between TaqI, BsmI, and FokI polymorphisms and ASD and showed for the first time that FokI polymorphisms and haplotype GTTT (BsmI/TaqI/FokI/ApaI) are associated with an increased risk of ASD. Our findings support the hypothesis that 25(OH)D is involved in the pathophysiology of autism and that serum 25(OH)D levels may be affected by FokI polymorphisms in children with ASD. Our results should be considered as preliminary and needs confirmation by future studies.

PMID: 27155524 [PubMed - as supplied by publisher]

Repetitive Behavioral Assessments for Compound Screening in Mouse Models of Autism Spectrum Disorders.

May 7, 2016 - 9:54am

Repetitive Behavioral Assessments for Compound Screening in Mouse Models of Autism Spectrum Disorders.

Methods Mol Biol. 2016;1438:293-310

Authors: Rizzo SJ

Abstract
Treatments for repetitive behaviors in Autism Spectrum Disorders (ASD) and other neurodevelopmental disorders remain an unmet medical need. Mouse models are highly valuable tools for investigating the underlying pathophysiology, genetics, and neurocircuitry of ASD, and can also be characterized for ASD-related phenotypes including repetitive behaviors and stereotypies. This chapter describes methods that can be employed for the assessment of repetitive behavior phenotypes and the evaluation of the ability of test compounds to attenuate repetitive behaviors in mouse models of ASD.

PMID: 27150097 [PubMed - in process]

Neurodevelopmental disease: A molecular tightrope.

May 7, 2016 - 9:54am
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Neurodevelopmental disease: A molecular tightrope.

Nature. 2015 Oct 1;526(7571):50-1

Authors: Elgersma Y

PMID: 26432241 [PubMed - indexed for MEDLINE]

Ten new cases further delineate the syndromic intellectual disability phenotype caused by mutations in DYRK1A.

May 7, 2016 - 9:54am
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Ten new cases further delineate the syndromic intellectual disability phenotype caused by mutations in DYRK1A.

Eur J Hum Genet. 2015 Nov;23(11):1482-7

Authors: Bronicki LM, Redin C, Drunat S, Piton A, Lyons M, Passemard S, Baumann C, Faivre L, Thevenon J, Rivière JB, Isidor B, Gan G, Francannet C, Willems M, Gunel M, Jones JR, Gleeson JG, Mandel JL, Stevenson RE, Friez MJ, Aylsworth AS

Abstract
The dual-specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A) gene, located on chromosome 21q22.13 within the Down syndrome critical region, has been implicated in syndromic intellectual disability associated with Down syndrome and autism. DYRK1A has a critical role in brain growth and development primarily by regulating cell proliferation, neurogenesis, neuronal plasticity and survival. Several patients have been reported with chromosome 21 aberrations such as partial monosomy, involving multiple genes including DYRK1A. In addition, seven other individuals have been described with chromosomal rearrangements, intragenic deletions or truncating mutations that disrupt specifically DYRK1A. Most of these patients have microcephaly and all have significant intellectual disability. In the present study, we report 10 unrelated individuals with DYRK1A-associated intellectual disability (ID) who display a recurrent pattern of clinical manifestations including primary or acquired microcephaly, ID ranging from mild to severe, speech delay or absence, seizures, autism, motor delay, deep-set eyes, poor feeding and poor weight gain. We identified unique truncating and non-synonymous mutations (three nonsense, four frameshift and two missense) in DYRK1A in nine patients and a large chromosomal deletion that encompassed DYRK1A in one patient. On the basis of increasing identification of mutations in DYRK1A, we suggest that this gene be considered potentially causative in patients presenting with ID, primary or acquired microcephaly, feeding problems and absent or delayed speech with or without seizures.

PMID: 25920557 [PubMed - indexed for MEDLINE]

CACNA1A haploinsufficiency causes cognitive impairment, autism and epileptic encephalopathy with mild cerebellar symptoms.

May 7, 2016 - 9:54am
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CACNA1A haploinsufficiency causes cognitive impairment, autism and epileptic encephalopathy with mild cerebellar symptoms.

Eur J Hum Genet. 2015 Nov;23(11):1505-12

Authors: Damaj L, Lupien-Meilleur A, Lortie A, Riou É, Ospina LH, Gagnon L, Vanasse C, Rossignol E

Abstract
CACNA1A loss-of-function mutations classically present as episodic ataxia type 2 (EA2), with brief episodes of ataxia and nystagmus, or with progressive spinocerebellar ataxia (SCA6). A minority of patients carrying CACNA1A mutations develops epilepsy. Non-motor symptoms associated with these mutations are often overlooked. In this study, we report 16 affected individuals from four unrelated families presenting with a spectrum of cognitive impairment including intellectual deficiency, executive dysfunction, ADHD and/or autism, as well as childhood-onset epileptic encephalopathy with refractory absence epilepsy, febrile seizures, downbeat nystagmus and episodic ataxia. Sequencing revealed one CACNA1A gene deletion, two deleterious CACNA1A point mutations including one known stop-gain and one new frameshift variant and a new splice-site variant. This report illustrates the phenotypic heterogeneity of CACNA1A loss-of-function mutations and stresses the cognitive and epileptic manifestations caused by the loss of CaV2.1 channels function, presumably affecting cerebellar, cortical and limbic networks.

PMID: 25735478 [PubMed - indexed for MEDLINE]

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