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The CD38 genotype (rs1800561 (4693C>T): R140W) is associated with an increased risk of admission to the neonatal intensive care unit.

April 7, 2016 - 1:13pm
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The CD38 genotype (rs1800561 (4693C>T): R140W) is associated with an increased risk of admission to the neonatal intensive care unit.

Early Hum Dev. 2015 Aug;91(8):467-70

Authors: Enami N, Itaya-Hironaka A, Yamauchi A, Sakuramoto-Tsuchida S, Takasawa S, Takahashi Y

Abstract
BACKGROUNDS: Preterm birth (PTB)/admission to the neonatal intensive care unit (NICU) is a complex disorder associated with significant neonatal mortality and morbidity and long-term adverse health consequences. Multiple lines of evidence suggest that genetic factors play an important role in its etiology.
AIM: Given the role of CD38 in term delivery through oxytocin (OXT) release, we hypothesized that OXT signaling may play a role in the etiology of PTB/admission to the NICU. This study was designed to identify genetic variation in the CD38-oxytocin pathway associated with PTB/admission to the NICU.
METHODS: To identify common genetic variants predisposing individuals to PTB/admission to the NICU, we genotyped two single nucleotide polymorphisms (SNPs) in the CD38-oxytocin pathway in 63 case mothers, 55 control mothers, and 188 female volunteers in Nara Medical University Hospital, Japan.
RESULTS: Maternal genetic effect analysis of the SNP genotype data revealed a significant association between an SNP in CD38 (rs1800561 (4693C>T): R140W), which was reported to be correlated with diabetes and autism, and the risk of NICU admission. On the other hand, an SNP in the oxytocin receptor (OXTR) (rs2254298) showed no correlation with the risk of NICU admission.
CONCLUSION: Our study points to an association between maternal common polymorphisms in the CD38 (rs1800561) gene in Japanese women and susceptibility to PTB/admission to the NICU. Future studies with larger sample sizes are needed to confirm the findings of this study.

PMID: 26025338 [PubMed - indexed for MEDLINE]

Mouse Genetic Models of Human Brain Disorders.

April 6, 2016 - 7:00am

Mouse Genetic Models of Human Brain Disorders.

Front Genet. 2016;7:40

Authors: Leung C, Jia Z

Abstract
Over the past three decades, genetic manipulations in mice have been used in neuroscience as a major approach to investigate the in vivo function of genes and their alterations. In particular, gene targeting techniques using embryonic stem cells have revolutionized the field of mammalian genetics and have been at the forefront in the generation of numerous mouse models of human brain disorders. In this review, we will first examine childhood developmental disorders such as autism, intellectual disability, Fragile X syndrome, and Williams-Beuren syndrome. We will then explore psychiatric disorders such as schizophrenia and lastly, neurodegenerative disorders including Alzheimer's disease and Parkinson's disease. We will outline the creation of these mouse models that range from single gene deletions, subtle point mutations to multi-gene manipulations, and discuss the key behavioral phenotypes of these mice. Ultimately, the analysis of the models outlined in this review will enhance our understanding of the in vivo role and underlying mechanisms of disease-related genes in both normal brain function and brain disorders, and provide potential therapeutic targets and strategies to prevent and treat these diseases.

PMID: 27047540 [PubMed - as supplied by publisher]

The Oscillopathic Nature of Language Deficits in Autism: From Genes to Language Evolution.

April 6, 2016 - 7:00am

The Oscillopathic Nature of Language Deficits in Autism: From Genes to Language Evolution.

Front Hum Neurosci. 2016;10:120

Authors: Benítez-Burraco A, Murphy E

Abstract
Autism spectrum disorders (ASD) are pervasive neurodevelopmental disorders involving a number of deficits to linguistic cognition. The gap between genetics and the pathophysiology of ASD remains open, in particular regarding its distinctive linguistic profile. The goal of this article is to attempt to bridge this gap, focusing on how the autistic brain processes language, particularly through the perspective of brain rhythms. Due to the phenomenon of pleiotropy, which may take some decades to overcome, we believe that studies of brain rhythms, which are not faced with problems of this scale, may constitute a more tractable route to interpreting language deficits in ASD and eventually other neurocognitive disorders. Building on recent attempts to link neural oscillations to certain computational primitives of language, we show that interpreting language deficits in ASD as oscillopathic traits is a potentially fruitful way to construct successful endophenotypes of this condition. Additionally, we will show that candidate genes for ASD are overrepresented among the genes that played a role in the evolution of language. These genes include (and are related to) genes involved in brain rhythmicity. We hope that the type of steps taken here will additionally lead to a better understanding of the comorbidity, heterogeneity, and variability of ASD, and may help achieve a better treatment of the affected populations.

PMID: 27047363 [PubMed - as supplied by publisher]

Compromising the phosphodependent regulation of the GABAAR β3 subunit reproduces the core phenotypes of autism spectrum disorders.

April 5, 2016 - 12:38pm
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Compromising the phosphodependent regulation of the GABAAR β3 subunit reproduces the core phenotypes of autism spectrum disorders.

Proc Natl Acad Sci U S A. 2015 Dec 1;112(48):14805-10

Authors: Vien TN, Modgil A, Abramian AM, Jurd R, Walker J, Brandon NJ, Terunuma M, Rudolph U, Maguire J, Davies PA, Moss SJ

Abstract
Alterations in the efficacy of neuronal inhibition mediated by GABAA receptors (GABAARs) containing β3 subunits are continually implicated in autism spectrum disorders (ASDs). In vitro, the plasma membrane stability of GABAARs is potentiated via phosphorylation of serine residues 408 and 409 (S408/9) in the β3 subunit, an effect that is mimicked by their mutation to alanines. To assess if modifications in β3 subunit expression contribute to ASDs, we have created a mouse in which S408/9 have been mutated to alanines (S408/9A). S408/9A homozygotes exhibited increased phasic, but decreased tonic, inhibition, events that correlated with alterations in the membrane stability and synaptic accumulation of the receptor subtypes that mediate these distinct forms of inhibition. S408/9A mice exhibited alterations in dendritic spine structure, increased repetitive behavior, and decreased social interaction, hallmarks of ASDs. ASDs are frequently comorbid with epilepsy, and consistent with this comorbidity, S408/9A mice exhibited a marked increase in sensitivity to seizures induced by the convulsant kainic acid. To assess the relevance of our studies using S408/9A mice for the pathophysiology of ASDs, we measured S408/9 phosphorylation in Fmr1 KO mice, a model of fragile X syndrome, the most common monogenetic cause of ASDs. Phosphorylation of S408/9 was selectively and significantly enhanced in Fmr1 KO mice. Collectively, our results suggest that alterations in phosphorylation and/or activity of β3-containing GABAARs may directly contribute to the pathophysiology of ASDs.

PMID: 26627235 [PubMed - indexed for MEDLINE]

A de novo microdeletion in NRXN1 in a Dutch patient with mild intellectual disability, microcephaly and gonadal dysgenesis.

April 5, 2016 - 12:38pm
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A de novo microdeletion in NRXN1 in a Dutch patient with mild intellectual disability, microcephaly and gonadal dysgenesis.

Genet Res (Camb). 2015;97:e19

Authors: Agha Z, Iqbal Z, Kleefstra T, Zweier C, Pfundt R, Qamar R, VAN Bokhoven H, Willemsen MH

Abstract
This report is regarding a Dutch female with microcephaly, mild intellectual disability (ID), gonadal dysgenesis and dysmorphic facial features with synophrys. Upon genotyping, an ~455 kb de novo deletion encompassing the first exon of NRXN1 was found. Bidirectional sequencing of the coding exons of the NRXN1 alpha isoform was subsequently performed to investigate the possibility of a pathogenic mutation on the other allele, but we could not find any other mutation. Previously, many heterozygous mutations as well as microdeletions in NRXN1 were shown to be associated with ID, autism, schizophrenia, and other psychiatric and psychotic disorders. Our results are in agreement with other reports that show that NRXN1 deletions can lead to ID, microcephaly and mild dysmorphic features. However, this is the first report of gonadal dysgenesis being associated with such deletions. It is not clear whether there is a causal relationship between the NRXN1 deletion and gonadal dysgenesis, but it is of interest that the FSHR gene, which encodes the follicle-stimulating hormone receptor causative correlation that is mutated in ovarian dysgenesis, is located proximal to the NRXN1 gene. Given that most of the females carrying NRXN1 deletions have been diagnosed at a prepubertal age, gynecologic screening of female carriers of a NRXN1 deletion is warranted.

PMID: 26438105 [PubMed - indexed for MEDLINE]

Family history of autoimmune diseases is associated with an increased risk of autism in children: A systematic review and meta-analysis.

April 5, 2016 - 12:38pm
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Family history of autoimmune diseases is associated with an increased risk of autism in children: A systematic review and meta-analysis.

Neurosci Biobehav Rev. 2015 Aug;55:322-32

Authors: Wu S, Ding Y, Wu F, Li R, Xie G, Hou J, Mao P

Abstract
BACKGROUND: We conducted a systematic review and meta-analysis to summarize the current evidence on the relationship between family history of autoimmune diseases (ADs) and risk of autism in children, as current evidence suggests inconsistent results.
METHODS: We identified relevant studies by searching PubMed, EmBase, and Web of Science databases up to Dec 2014. Risk estimates from individual studies were pooled using random-effects models. Sub-groups analyses were conducted by some study-level factors. Publication bias was assessed by funnel plots, Egger's regression test and Begg-Mazumdar test.
RESULTS: A total of 11 articles were included in the meta-analysis, including 3 cohort studies, 6 case-control studies, and 2 cross-sectional studies. The meta-analysis showed that family history of all ADs combined was associated with a 28% (95% CI: 12-48%) higher risk of autism in children. For some specific ADs, evidence synthesis for risk of autism in children showed a statistically significant association with family history of hypothyroidism (OR=1.64, 95% CI: 1.07-2.50), type 1 diabetes (OR=1.49, 95% CI: 1.23-1.81), rheumatoid arthritis (OR=1.51, 95% CI: 1.19-1.91), and psoriasis (OR=1.59, 95% CI: 1.28-1.97). The results varied in some subgroups.
CONCLUSION: An overall increased risk of autism in children with family history of ADs was identified. More mechanistic studies are needed to further explain the association between family history of ADs and increased risk of autism in children.

PMID: 25981892 [PubMed - indexed for MEDLINE]

The human β-amyloid precursor protein: biomolecular and epigenetic aspects.

April 5, 2016 - 12:38pm
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The human β-amyloid precursor protein: biomolecular and epigenetic aspects.

Biomol Concepts. 2015 Mar;6(1):11-32

Authors: Nguyen KV

Abstract
Beta-amyloid precursor protein (APP) is a membrane-spanning protein with a large extracellular domain and a much smaller intracellular domain. APP plays a central role in Alzheimer's disease (AD) pathogenesis: APP processing generates β-amyloid (Aβ) peptides, which are deposited as amyloid plaques in the brains of AD individuals; point mutations and duplications of APP are causal for a subset of early-onset familial AD (FAD) (onset age <65 years old). However, these mutations in FAD represent a very small percentage of cases (∼1%). Approximately 99% of AD cases are nonfamilial and late-onset, i.e., sporadic AD (SAD) (onset age >65 years old), and the pathophysiology of this disorder is not yet fully understood. APP is an extremely complex molecule that may be functionally important in its full-length configuration, as well as the source of numerous fragments with varying effects on neural function, yet the normal function of APP remains largely unknown. This article provides an overview of our current understanding of APP, including its structure, expression patterns, proteolytic processing and putative functions. Importantly, and for the first time, my recent data concerning its epigenetic regulation, especially in alternative APP pre-mRNA splicing and in the control of genomic rearrangements of the APP gene, are also reported. These findings may provide new directions for investigating the role of APP in neuropathology associated with a deficiency in the enzyme hypoxanthine-guanine phosphoribosyltransferase (HGprt) found in patients with Lesch-Nyhan syndrome (LNS) and its attenuated variants (LNVs). Also, these findings may be of significance for research in neurodevelopmental and neurodegenerative disorders in which the APP gene is involved in the pathogenesis of diseases such as autism, fragile X syndrome (FXS) and AD, with its diversity and complexity, SAD in particular. Accurate quantification of various APP-mRNA isoforms in brain tissues is needed, and antisense drugs are potential treatments.

PMID: 25719338 [PubMed - indexed for MEDLINE]

MicroRNA and Posttranscriptional Dysregulation in Psychiatry.

April 5, 2016 - 12:38pm
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MicroRNA and Posttranscriptional Dysregulation in Psychiatry.

Biol Psychiatry. 2015 Aug 15;78(4):231-9

Authors: Geaghan M, Cairns MJ

Abstract
Psychiatric syndromes, including schizophrenia, mood disorders, and autism spectrum disorders, are characterized by a complex range of symptoms, including psychosis, depression, mania, and cognitive deficits. Although the mechanisms driving pathophysiology are complex and remain largely unknown, advances in the understanding of gene association and gene networks are providing significant clues to their etiology. In recent years, small noncoding RNA molecules known as microRNA (miRNA) have emerged as potential players in the pathophysiology of mental illness. These small RNAs regulate hundreds of target transcripts by modifying their stability and translation on a broad scale, influencing entire gene networks in the process. There is evidence to suggest that numerous miRNAs are dysregulated in postmortem neuropathology of neuropsychiatric disorders, and there is strong genetic support for association of miRNA genes and their targets with these conditions. This review presents the accumulated evidence linking miRNA dysregulation and dysfunction with schizophrenia, bipolar disorder, major depressive disorder, and autism spectrum disorders and the potential of miRNAs as biomarkers or therapeutics for these disorders. We further assess the functional roles of some outstanding miRNAs associated with these conditions and how they may be influencing the development of psychiatric symptoms.

PMID: 25636176 [PubMed - indexed for MEDLINE]

The Sex Ratio of the Sibs of Probands Diagnosed With Autism.

April 4, 2016 - 6:26am

The Sex Ratio of the Sibs of Probands Diagnosed With Autism.

J Theor Biol. 2016 Mar 30;

Authors: James WH

PMID: 27038667 [PubMed - as supplied by publisher]

Inborn error metabolic screening in individuals with nonsyndromic autism spectrum disorders.

April 3, 2016 - 6:23am

Inborn error metabolic screening in individuals with nonsyndromic autism spectrum disorders.

Dev Med Child Neurol. 2016 Mar 31;

Authors: Campistol J, Díez-Juan M, Callejón L, Fernandez-De Miguel A, Casado M, Garcia Cazorla A, Lozano R, Artuch R

Abstract
AIM: To perform metabolic testing on 406 patients (age range 3-22y [mean 6.71, SD 4.15], 343 males and 63 females) with nonsyndromic autism spectrum disorders (ASD) to assess the diagnostic yield. In addition, we reviewed our hospital's clinical database of 8500 patients who had undergone metabolic testing to be identified for inborn errors of metabolism (IEM), and described the characteristics of those with IEM and nonsyndromic ASD.
METHOD: Neuropsychological evaluation included the Social Communication Questionnaire and Child Behavior Checklist. For metabolic testing/screening, urine samples were analyzed for the diagnosis of cerebral creatine deficiency syndromes, purine and pyrimidine disorders, amino acid metabolism defects, mucopolysaccharidoses, and organic acidurias.
RESULTS: The 406 recruited participants fulfilled the Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV) criteria of ASD. No biochemical evidence of a metabolic disorder was detected in any of the 406 patients studied. Concerning the retrospective evaluation from the 8500 who had metabolic testing, 464 individuals had a diagnosis of an IEM (394 without the diagnosis of ASD and 70 with ASD diagnosis). Only one individual with IEM had a diagnosis of nonsyndromic ASD at the time of the metabolic study; the metabolic testing had revealed diagnosis of urea-cycle disorder.
INTERPRETATION: Metabolic testing should be considered in the work-up of individuals with syndromic ASD, but metabolic testing is not cost-effective for individuals with nonsyndromic ASD.

PMID: 27038397 [PubMed - as supplied by publisher]

Overview of Clinical Cytogenetics.

April 3, 2016 - 6:23am

Overview of Clinical Cytogenetics.

Curr Protoc Hum Genet. 2016;89:8.1.1-8.1.13

Authors: Gonzales PR, Carroll AJ, Korf BR

Abstract
Chromosome analysis is one of the first approaches to genetic testing and remains a key component of genetic analysis of constitutional and somatic genetic disorders. Numerical or unbalanced structural chromosome abnormalities usually lead to multiple congenital anomalies. Sometimes these are compatible with live birth, usually resulting in severe cognitive and physical handicaps; other times they result in miscarriage or stillbirth. Chromosome rearrangements also occur as somatic changes in malignancies. Identification of constitutional chromosomal anomalies (anomalies present in most or all cells of the body and/or the germline) can provide important information for genetic counseling. In this unit, we introduce chromosomal microarray analysis (CMA), which is a relatively recent addition to cytogenetic technologies, and has become the recommended first-tier testing method for patients with developmental delay, intellectual disability, autism, and/or multiple congenital anomalies. We also discuss non-invasive prenatal testing/screening (NIPTS), which uses circulating cell-free fetal DNA (cfDNA) from maternal plasma to rapidly screen for autosomal and sex-chromosome aneuploidies. Cytogenetic analysis of tumors is helpful in diagnosis and in monitoring the effects of treatment. The protocols in this chapter cover the clinical study of chromosomes in nonmalignant tissues. © 2016 by John Wiley & Sons, Inc.

PMID: 27037488 [PubMed - as supplied by publisher]

Role of p53, Mitochondrial DNA Deletions, and Paternal Age in Autism: A Case-Control Study.

April 2, 2016 - 6:21am

Role of p53, Mitochondrial DNA Deletions, and Paternal Age in Autism: A Case-Control Study.

Pediatrics. 2016 Mar 31;

Authors: Wong S, Napoli E, Krakowiak P, Tassone F, Hertz-Picciotto I, Giulivi C

Abstract
BACKGROUND: The tumor suppressor p53 responds to a variety of environmental stressors by regulating cell cycle arrest, apoptosis, senescence, DNA repair, bioenergetics and mitochondrial DNA (mtDNA) copy number maintenance. Developmental abnormalities have been reported in p53-deficient mice, and altered p53 and p53-associated pathways in autism (AU). Furthermore, via the Pten-p53 crosstalk, Pten haploinsufficient-mice have autisticlike behavior accompanied by brain mitochondrial dysfunction with accumulation of mtDNA deletions.
METHODS: mtDNA copy number and deletions, and p53 gene copy ratios were evaluated in peripheral blood monocytic cells from children aged 2-5 years with AU (n = 66), race-, gender-, and age-matched typically neurodeveloping children (n = 46), and both parents from each diagnostic group, recruited by the Childhood Autism Risk from Genes and Environment study at the University of California, Davis.
RESULTS: mtDNA deletions and higher p53 gene copy ratios were more common in children with AU and their fathers. The incidence of mtDNA deletions in fathers of children with AU was increased 1.9-fold over fathers of typically neurodeveloping children, suggesting a role for deficient DNA repair capacity not driven by paternal age. Deletions in mtDNA and altered p53 gene copy ratios seem to result from genetics (children with severity scores ≥8) and/or act in concert with environmental factors (children with 6-7 severity scores).
CONCLUSIONS: Given pro- and antioxidant activities of p53, and associations of genomic instability with disorders other than AU, our study suggests a link between DNA repair capacity, genomic instability in the 17p13.1 region influenced by environmental triggers, and AU diagnosis.

PMID: 27033107 [PubMed - as supplied by publisher]

AUTISM. Unraveling a pathway to autism.

April 2, 2016 - 6:21am
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AUTISM. Unraveling a pathway to autism.

Science. 2016 Mar 11;351(6278):1153-4

Authors: Burbach JP

PMID: 26965613 [PubMed - indexed for MEDLINE]

Potocki-Lupski syndrome in conjunction with bilateral clubfoot.

April 2, 2016 - 6:21am
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Potocki-Lupski syndrome in conjunction with bilateral clubfoot.

J Pediatr Orthop B. 2015 Jul;24(4):373-6

Authors: Dhanaraj D, Chu A, Pappas JG, Moran E, Lehman WB

Abstract
Potocki-Lupski syndrome (PTLS) is a rare chromosomal microduplication syndrome resulting in multiple congenital abnormalities including developmental delays, autistic features, and certain structural anomalies, with cardiovascular being the most common. The phenotype of this contiguous gene duplication syndrome is quite variable and may include musculoskeletal abnormalities. Given the infrequency and novelty of this disorder, full phenotypic characterization of PTLS has not yet been fully elucidated. We present a case of severe bilateral clubfoot in a patient with PTLS. Diagnosis was made by array-based comparative genomic hybridization and confirmed by fluorescence in-situ hybridization. Because clubfoot was also present in an apparently unaffected brother, the presence of PTLS may have acted as a modifier of the phenotype. This report highlights the complex interaction of chromosomal and familial factors that contribute to musculoskeletal birth defects.

PMID: 25768679 [PubMed - indexed for MEDLINE]

Where are the strongest associations between autistic traits and traits of ADHD? evidence from a community-based twin study.

April 2, 2016 - 6:21am
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Where are the strongest associations between autistic traits and traits of ADHD? evidence from a community-based twin study.

Eur Child Adolesc Psychiatry. 2015 Sep;24(9):1129-38

Authors: Taylor MJ, Charman T, Ronald A

Abstract
Autism spectrum conditions (ASC) and attention-deficit/hyperactivity disorder (ADHD) regularly co-occur. Twin studies increasingly indicate that these conditions may have overlapping genetic causes. Less is known about the degree to which specific autistic traits relate to specific behaviours characteristic of ADHD. We hence tested, using the classical twin design, whether specific dimensional autistic traits, including social difficulties, communication atypicalities and repetitive behaviours, would display differential degrees of aetiological overlap with specific traits of ADHD, including hyperactivity/impulsivity and inattention. Parents of approximately 4,000 pairs of 12-year-old twins completed the Childhood Autism Spectrum Test and Conners' Parent Rating Scale. These measures were divided into subscales corresponding to different types of autistic and ADHD behaviours. Twin model fitting suggested that the degree of genetic overlap was particularly strong between communication difficulties and traits of ADHD (genetic correlations = .47-.51), while repetitive behaviours and social difficulties showed moderate (genetic correlations = .12-.33) and modest (.05-.11) genetic overlap respectively. Environmental overlap was low across all subscales (correlations = .01-.23). These patterns were also apparent at the extremes of the general population, with communication difficulties showing the highest genetic overlap with traits of ADHD. These findings indicate that molecular genetic studies seeking to uncover the shared genetic basis of ASC and ADHD would benefit from taking a symptom-specific approach. Furthermore, they could also help to explain why studies of the communication abilities of individuals with ASC and ADHD have produced overlapping findings.

PMID: 25600178 [PubMed - indexed for MEDLINE]

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

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

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

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

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

PMID: 25549896 [PubMed - indexed for MEDLINE]

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

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

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

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

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

PMID: 25518740 [PubMed - indexed for MEDLINE]

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

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

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

Authors: Trivisano M, Specchio N, Vigevano F

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

PMID: 25510386 [PubMed - indexed for MEDLINE]

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

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

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

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

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

PMID: 25315662 [PubMed - indexed for MEDLINE]

CLK2 inhibition ameliorates autistic features associated with SHANK3 deficiency.

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

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

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

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

PMID: 26847545 [PubMed - indexed for MEDLINE]

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