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Dysregulated brain immunity and neurotrophin signaling in Rett syndrome and autism spectrum disorders.

April 8, 2015 - 11:47am
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Dysregulated brain immunity and neurotrophin signaling in Rett syndrome and autism spectrum disorders.

J Neuroimmunol. 2015 Feb 15;279:33-8

Authors: Theoharides TC, Athanassiou M, Panagiotidou S, Doyle R

Abstract
Rett syndrome is a neurodevelopmental disorder, which occurs in about 1:15,000 females and presents with neurologic and communication defects. It is transmitted as an X-linked dominant linked to mutations of the methyl-CpG-binding protein (MeCP2), a gene transcription suppressor, but its definitive pathogenesis is unknown thus hindering development of effective treatments. Almost half of children with Rett syndrome also have behavioral symptoms consistent with those of autism spectrum disorders (ASDs). PubMed was searched (2005-2014) using the terms: allergy, atopy, brain, brain-derived neurotrophic factor (BDNF), corticotropin-releasing hormone (CRH), cytokines, gene mutations, inflammation, mast cells (MCs), microglia, mitochondria, neurotensin (NT), neurotrophins, seizures, stress, and treatment. There are a number of intriguing differences and similarities between Rett syndrome and ASDs. Rett syndrome occurs in females, while ASDs more often in males, and the former has neurologic disabilities unlike ASDs. There is evidence of dysregulated immune system early in life in both conditions. Lack of microglial phagocytosis and decreased levels of BDNF appear to distinguish Rett syndrome from ASDs, in which there is instead microglia activation and/or proliferation and possibly defective BDNF signaling. Moreover, brain mast cell (MC) activation and focal inflammation may be more prominent in ASDs than Rett syndrome. The flavonoid luteolin blocks microglia and MC activation, provides BDNF-like activity, reverses Rett phenotype in mouse models, and has a significant benefit in children with ASDs. Appropriate formulations of luteolin or other natural molecules may be useful in the treatment of Rett syndrome.

PMID: 25669997 [PubMed - indexed for MEDLINE]

ADHD severity is associated with white matter microstructure in the subgenual cingulum.

April 7, 2015 - 8:04am

ADHD severity is associated with white matter microstructure in the subgenual cingulum.

Neuroimage Clin. 2015;7:653-60

Authors: Cooper M, Thapar A, Jones DK

Abstract
AIMS: This analysis examined hypothesised associations between microstructural attributes in specific white matter (WM) tracts selected a priori and measures of clinical variability in adolescents with a diagnosis of attention deficit hyperactivity disorder (ADHD). Firstly, associations were explored between WM microstructure and ADHD severity in the subgenual cingulum. Secondly, to ensure that tract-specific approaches afforded enhanced rather than differential sensitivity, associations were measured between WM microstructure and autistic traits in the right corticospinal tract based on results of a previously-published voxelwise analysis.
METHODS: 40 right-handed males aged 14-18 years (19 with DSM-IV combined type ADHD and 21 healthy controls) underwent a 60 direction diffusion MRI scan. Clinical ADHD and autism variation were assessed by validated questionnaires. Deterministic tractography based on spherical deconvolution methods was used to map the subgenual cingulum and corticospinal tract.
RESULTS: Fractional anisotropy was positively correlated and radial diffusivity was negatively correlated with a) ADHD severity in the left subgenual cingulum and b) autistic traits in the inferior segment of the right corticospinal tract. No case-control differences were found.
CONCLUSIONS: Results shed light on possible anatomical correlates of ADHD severity and autistic symptoms in pathways which may be involved in the ADHD phenotype. They provide further evidence that tract-specific approaches may a) reveal associations between microstructural metrics and indices of phenotypic variability which would not be detected using voxelwise approaches, and b) provide improved rather than differential sensitivity compared to voxelwise approaches.

PMID: 25844319 [PubMed - in process]

Complex nature of apparently balanced chromosomal rearrangements in patients with autism spectrum disorder.

April 7, 2015 - 8:04am

Complex nature of apparently balanced chromosomal rearrangements in patients with autism spectrum disorder.

Mol Autism. 2015;6:19

Authors: Tabet AC, Verloes A, Pilorge M, Delaby E, Delorme R, Nygren G, Devillard F, Gérard M, Passemard S, Héron D, Siffroi JP, Jacquette A, Delahaye A, Perrin L, Dupont C, Aboura A, Bitoun P, Coleman M, Leboyer M, Gillberg C, Benzacken B, Betancur C

Abstract
BACKGROUND: Apparently balanced chromosomal rearrangements can be associated with an abnormal phenotype, including intellectual disability and autism spectrum disorder (ASD). Genome-wide microarrays reveal cryptic genomic imbalances, related or not to the breakpoints, in 25% to 50% of patients with an abnormal phenotype carrying a microscopically balanced chromosomal rearrangement. Here we performed microarray analysis of 18 patients with ASD carrying balanced chromosomal abnormalities to identify submicroscopic imbalances implicated in abnormal neurodevelopment.
METHODS: Eighteen patients with ASD carrying apparently balanced chromosomal abnormalities were screened using single nucleotide polymorphism (SNP) arrays. Nine rearrangements were de novo, seven inherited, and two of unknown inheritance. Genomic imbalances were confirmed by fluorescence in situ hybridization and quantitative PCR.
RESULTS: We detected clinically significant de novo copy number variants in four patients (22%), including three with de novo rearrangements and one with an inherited abnormality. The sizes ranged from 3.3 to 4.9 Mb; three were related to the breakpoint regions and one occurred elsewhere. We report a patient with a duplication of the Wolf-Hirschhorn syndrome critical region, contributing to the delineation of this rare genomic disorder. The patient has a chromosome 4p inverted duplication deletion, with a 0.5 Mb deletion of terminal 4p and a 4.2 Mb duplication of 4p16.2p16.3. The other cases included an apparently balanced de novo translocation t(5;18)(q12;p11.2) with a 4.2 Mb deletion at the 18p breakpoint, a subject with de novo pericentric inversion inv(11)(p14q23.2) in whom the array revealed a de novo 4.9 Mb deletion in 7q21.3q22.1, and a patient with a maternal inv(2)(q14.2q37.3) with a de novo 3.3 Mb terminal 2q deletion and a 4.2 Mb duplication at the proximal breakpoint. In addition, we identified a rare de novo deletion of unknown significance on a chromosome unrelated to the initial rearrangement, disrupting a single gene, RFX3.
CONCLUSIONS: These findings underscore the utility of SNP arrays for investigating apparently balanced chromosomal abnormalities in subjects with ASD or related neurodevelopmental disorders in both clinical and research settings.

PMID: 25844147 [PubMed]

DSM-5 and Psychiatric Genetics - Round Hole, Meet Square Peg.

April 7, 2015 - 8:04am

DSM-5 and Psychiatric Genetics - Round Hole, Meet Square Peg.

Biol Psychiatry. 2015 May 1;77(9):766-8

Authors: Buxbaum JD

PMID: 25843333 [PubMed - in process]

Fragile X syndrome neurobiology translates into rational therapy.

April 7, 2015 - 8:04am
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Fragile X syndrome neurobiology translates into rational therapy.

Drug Discov Today. 2014 Apr;19(4):510-9

Authors: Braat S, Kooy RF

Abstract
Causal genetic defects have been identified for various neurodevelopmental disorders. A key example in this respect is fragile X syndrome, one of the most frequent genetic causes of intellectual disability and autism. Since the discovery of the causal gene, insights into the underlying pathophysiological mechanisms have increased exponentially. Over the past years, defects were discovered in pathways that are potentially amendable by pharmacological treatment. These findings have inspired the initiation of clinical trials in patients. The targeted pathways converge in part with those of related neurodevelopmental disorders raising hopes that the treatments developed for this specific disorder might be more broadly applicable.

PMID: 24508819 [PubMed - indexed for MEDLINE]

De Novo Mutations in SIK1 Cause a Spectrum of Developmental Epilepsies.

April 4, 2015 - 8:30am

De Novo Mutations in SIK1 Cause a Spectrum of Developmental Epilepsies.

Am J Hum Genet. 2015 Apr 2;96(4):682-690

Authors: Hansen J, Snow C, Tuttle E, Ghoneim DH, Yang CS, Spencer A, Gunter SA, Smyser CD, Gurnett CA, Shinawi M, Dobyns WB, Wheless J, Halterman MW, Jansen LA, Paschal BM, Paciorkowski AR

Abstract
Developmental epilepsies are age-dependent seizure disorders for which genetic causes have been increasingly identified. Here we report six unrelated individuals with mutations in salt-inducible kinase 1 (SIK1) in a series of 101 persons with early myoclonic encephalopathy, Ohtahara syndrome, and infantile spasms. Individuals with SIK1 mutations had short survival in cases with neonatal epilepsy onset, and an autism plus developmental syndrome after infantile spasms in others. All six mutations occurred outside the kinase domain of SIK1 and each of the mutants displayed autophosphorylation and kinase activity toward HDAC5. Three mutations generated truncated forms of SIK1 that were resistant to degradation and also showed changes in sub-cellular localization compared to wild-type SIK1. We also report the human neuropathologic examination of SIK1-related developmental epilepsy, with normal neuronal morphology and lamination but abnormal SIK1 protein cellular localization. Therefore, these results expand the genetic etiologies of developmental epilepsies by demonstrating SIK1 mutations as a cause of severe developmental epilepsy.

PMID: 25839329 [PubMed - as supplied by publisher]

Alterations of GABAergic and dopaminergic systems in mutant mice with disruption of exons 2 and 3 of the Disc1 gene.

April 4, 2015 - 8:30am
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Alterations of GABAergic and dopaminergic systems in mutant mice with disruption of exons 2 and 3 of the Disc1 gene.

Neurochem Int. 2014 Jul;74:74-83

Authors: Nakai T, Nagai T, Wang R, Yamada S, Kuroda K, Kaibuchi K, Yamada K

Abstract
Disrupted-in-schizophrenia-1 (DISC1) has been widely associated with several psychiatric disorders, including schizophrenia, mood disorders and autism. We previously reported that a deficiency of DISC1 may induce low anxiety and/or high impulsivity in mice with disruption of exons 2 and 3 of the Disc1 gene (Disc1(Δ2-3/Δ2-3)). It remains unclear, however, if deficiency of DISC1 leads to specific alterations in distinct neuronal systems. In the present study, to understand the role of DISC1 in γ-aminobutyric acid (GABA) interneurons and mesocorticolimbic dopaminergic (DAergic) neurons, we investigated the number of parvalbumin (PV)-positive interneurons, methamphetamine (METH)-induced DA release and the expression levels of GABAA, DA transporter (DAT) and DA receptors in wild-type (Disc1(+/+)) and Disc1(Δ2-3/Δ2-3) mice. Female Disc1(Δ2-3/Δ2-3) mice showed a significant reduction of PV-positive interneurons in the hippocampus, while no apparent changes were observed in mRNA expression levels of GABAA receptor subunits. METH-induced DA release was significantly potentiated in the nucleus accumbens (NAc) of female Disc1(Δ2-3/Δ2-3) mice, although there were no significant differences in the expression levels of DAT. Furthermore, the expression levels of DA receptor mRNA were upregulated in the NAc of female Disc1(Δ2-3/Δ2-3) mice. Male Disc1(Δ2-3/Δ2-3) mice showed no apparent differences in all experiments. DISC1 may play a critical role in gender-specific developmental alteration in GABAergic inhibitory interneurons and DAergic neurons.

PMID: 24973713 [PubMed - indexed for MEDLINE]

Developmental language disorders: challenges and implications of cross-group comparisons.

April 4, 2015 - 8:30am
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Developmental language disorders: challenges and implications of cross-group comparisons.

Folia Phoniatr Logop. 2013;65(2):68-77

Authors: Ellis Weismer S

Abstract
Historically, specific language impairment (SLI) and language deficits associated with autism spectrum disorders (ASD) have been viewed as distinct developmental language disorders. However, over the last decade or so, a considerable amount of research has explored general similarities or specific areas of overlap between children with SLI and ASD based on language and cognitive profiles, neuroimaging findings, and genetic research. The clinical classification schemes that are used to identify the children necessarily influence the extent to which SLI and ASD are viewed as overlapping or distinct conditions. Yet, the criteria used to diagnose these two populations vary across countries and even across investigators within a given country. This necessarily impacts the findings from comparative investigations of these groups. With these challenges in mind, clinical implications of evidence for similarities and distinctions between children with SLI and ASD will be discussed with respect to differential diagnosis and treatment.

PMID: 23942044 [PubMed - indexed for MEDLINE]

Psychobiotics and the gut-brain axis: in the pursuit of happiness.

April 3, 2015 - 7:43am

Psychobiotics and the gut-brain axis: in the pursuit of happiness.

Neuropsychiatr Dis Treat. 2015;11:715-723

Authors: Zhou L, Foster JA

Abstract
The human intestine houses an astounding number and species of microorganisms, estimated at more than 10(14) gut microbiota and composed of over a thousand species. An individual's profile of microbiota is continually influenced by a variety of factors including but not limited to genetics, age, sex, diet, and lifestyle. Although each person's microbial profile is distinct, the relative abundance and distribution of bacterial species is similar among healthy individuals, aiding in the maintenance of one's overall health. Consequently, the ability of gut microbiota to bidirectionally communicate with the brain, known as the gut-brain axis, in the modulation of human health is at the forefront of current research. At a basic level, the gut microbiota interacts with the human host in a mutualistic relationship - the host intestine provides the bacteria with an environment to grow and the bacterium aids in governing homeostasis within the host. Therefore, it is reasonable to think that the lack of healthy gut microbiota may also lead to a deterioration of these relationships and ultimately disease. Indeed, a dysfunction in the gut-brain axis has been elucidated by a multitude of studies linked to neuropsychological, metabolic, and gastrointestinal disorders. For instance, altered microbiota has been linked to neuropsychological disorders including depression and autism spectrum disorder, metabolic disorders such as obesity, and gastrointestinal disorders including inflammatory bowel disease and irritable bowel syndrome. Fortunately, studies have also indicated that gut microbiota may be modulated with the use of probiotics, antibiotics, and fecal microbiota transplants as a prospect for therapy in microbiota-associated diseases. This modulation of gut microbiota is currently a growing area of research as it just might hold the key to treatment.

PMID: 25834446 [PubMed - as supplied by publisher]

Malignant rhabdoid tumor of the bladder and ganglioglioma in a 14 year-old male with a germline 22q11.2 deletion.

April 2, 2015 - 7:07am
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Malignant rhabdoid tumor of the bladder and ganglioglioma in a 14 year-old male with a germline 22q11.2 deletion.

Cancer Genet. 2014 Sep;207(9):415-9

Authors: Bosse KR, Shukla AR, Pawel B, Chikwava KR, Santi M, Tooke L, Castagna K, Biegel JA, Bagatell R

Abstract
Malignant rhabdoid tumors (MRTs) are rare pediatric malignancies characterized by clinically aggressive lesions that typically show loss of SMARCB1 expression. We herein describe a case of a malignant rhabdoid tumor of the bladder in a 14-year-old male with an autism spectrum disorder and a de novo 3 Mb germline deletion in chromosome band 22q11.2 that included the SMARCB1 gene. The malignancy developed in the setting of chronic hematuria (>2 years) following the occurrence of two other lesions: a central nervous system ganglioglioma and an intraoral dermoid cyst. MRTs of the bladder are exceedingly rare, and this patient is the oldest child reported with this tumor to date. This case adds to the growing body of literature regarding the recently described, phenotypically diverse, distal 22q11.2 syndrome. Furthermore, this is the first reported case in which an MRT of the bladder appears to have developed from a pre-existing bladder lesion. Finally, this case further supports a rhabdoid tumorigenesis model in which heterozygous loss of SMARCB1 predisposes to initial tumor formation with intact SMARCB1 expression, with subsequent inactivation of the other SMARCB1 allele, which results in transformation into more malignant lesions.

PMID: 25018128 [PubMed - indexed for MEDLINE]

Role of metabolic genes in blood arsenic concentrations of Jamaican children with and without autism spectrum disorder.

April 1, 2015 - 6:39am
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Role of metabolic genes in blood arsenic concentrations of Jamaican children with and without autism spectrum disorder.

Int J Environ Res Public Health. 2014 Aug;11(8):7874-95

Authors: Rahbar MH, Samms-Vaughan M, Ma J, Bressler J, Loveland KA, Ardjomand-Hessabi M, Dickerson AS, Grove ML, Shakespeare-Pellington S, Beecher C, McLaughlin W, Boerwinkle E

Abstract
Arsenic is a toxic metalloid with known adverse effects on human health. Glutathione-S-transferase (GST) genes, including GSTT1, GSTP1, and GSTM1, play a major role in detoxification and metabolism of xenobiotics. We investigated the association between GST genotypes and whole blood arsenic concentrations (BASC) in Jamaican children with and without autism spectrum disorder (ASD). We used data from 100 ASD cases and their 1:1 age- and sex-matched typically developing (TD) controls (age 2-8 years) from Jamaica. Using log-transformed BASC as the dependent variable in a General Linear Model, we observed a significant interaction between GSTP1 and ASD case status while controlling for several confounding variables. However, for GSTT1 and GSTM1 we did not observe any significant associations with BASC. Our findings indicate that TD children who had the Ile/Ile or Ile/Val genotype for GSTP1 had a significantly higher geometric mean BASC than those with genotype Val/Val (3.67 µg/L vs. 2.69 µg/L, p < 0.01). Although, among the ASD cases, this difference was not statistically significant, the direction of the observed difference was consistent with that of the TD control children. These findings suggest a possible role of GSTP1 in the detoxification of arsenic.

PMID: 25101770 [PubMed - indexed for MEDLINE]

Loss of COMMD1 and copper overload disrupt zinc homeostasis and influence an autism-associated pathway at glutamatergic synapses.

April 1, 2015 - 6:39am
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Loss of COMMD1 and copper overload disrupt zinc homeostasis and influence an autism-associated pathway at glutamatergic synapses.

Biometals. 2014 Aug;27(4):715-30

Authors: Baecker T, Mangus K, Pfaender S, Chhabra R, Boeckers TM, Grabrucker AM

Abstract
Recent studies suggest that synaptic pathology in autism spectrum disorder (ASD) might be caused by the disruption of a signaling pathway at excitatory glutamatergic synapses, which can be influenced by environmental factors. Some factors, such as prenatal zinc deficiency, dysfunction of metallothioneins as well as deletion of COMMD1, all affect brain metal-ion homeostasis and have been associated with ASD. Given that COMMD1 regulates copper levels and that copper and zinc have antagonistic properties, here, we followed the idea that copper overload might induce a local zinc deficiency affecting key players of a putative ASD pathway such as ProSAP/Shank proteins as reported before. Our results show that increased copper levels indeed interfere with intracellular zinc concentrations and affect synaptic ProSAP/Shank levels, which similarly are altered by manipulation of copper and zinc levels through overexpression and knockdown of COMMD1. In line with this, acute and prenatal copper overload lead to local zinc deficiencies in mice. Pups exposed to prenatal copper overload furthermore show a reduction in ProSAP/Shank protein levels in the brain as well as a decreased NMDAR subunit 1 concentration. Thus, it might be likely that brain metal ion status influences a distinct pathway in excitatory synapses associated with genetic forms of ASD.

PMID: 25007851 [PubMed - indexed for MEDLINE]

Brain MRI abnormalities and spectrum of neurological and clinical findings in three patients with proximal 16p11.2 microduplication.

April 1, 2015 - 6:39am
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Brain MRI abnormalities and spectrum of neurological and clinical findings in three patients with proximal 16p11.2 microduplication.

Am J Med Genet A. 2014 Aug;164A(8):2003-12

Authors: Filges I, Sparagana S, Sargent M, Selby K, Schlade-Bartusiak K, Lueder GT, Robichaux-Viehoever A, Schlaggar BL, Shimony JS, Shinawi M

Abstract
The phenotype of recurrent ∼600 kb microdeletion and microduplication on proximal 16p11.2 is characterized by a spectrum of neurodevelopmental impairments including developmental delay and intellectual disability, epilepsy, autism and psychiatric disorders which are all subject to incomplete penetrance and variable expressivity. A variety of brain MRI abnormalities were reported in patients with 16p11.2 rearrangements, but no systematic correlation has been studied among patients with similar brain anomalies, their neurodevelopmental and clinical phenotypes. We present three patients with the proximal 16p11.2 microduplication exhibiting significant developmental delay, anxiety disorder and other variable clinical features. Our patients have abnormal brain MRI findings of cerebral T2 hyperintense foci (3/3) and ventriculomegaly (2/3). The neuroradiological or neurological findings in two cases prompted an extensive diagnostic work-up. One patient has exhibited neurological regression and progressive vision impairment and was diagnosed with juvenile neuronal ceroid-lipofuscinosis. We compare the clinical course and phenotype of these patients in regard to the clinical significance of the cerebral lesions and the need for MRI surveillance. We conclude that in all three patients the lesions were not progressive, did not show any sign of malignant transformation and could not be correlated to specific clinical features. We discuss potential etiologic mechanisms that may include overexpression of genes within the duplicated region involved in control of cell proliferation and complex molecular mechanisms such as the MAPK/ERK pathway. Systematic studies in larger cohorts are needed to confirm our observation and to establish the prevalence and clinical significance of these neuroanatomical abnormalities in patients with 16p11.2 duplications.

PMID: 24891046 [PubMed - indexed for MEDLINE]

New insights into the molecular pathophysiology of fragile X syndrome and therapeutic perspectives from the animal model.

April 1, 2015 - 6:39am
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New insights into the molecular pathophysiology of fragile X syndrome and therapeutic perspectives from the animal model.

Int J Biochem Cell Biol. 2014 Aug;53:121-6

Authors: Busquets-Garcia A, Maldonado R, Ozaita A

Abstract
Fragile X syndrome is the most common monogenetic form of intellectual disability and is a leading cause of autism. This syndrome is produced by the reduced transcription of the fragile X mental retardation (FMR1) gene, and it is characterized by a range of symptoms heterogeneously expressed in patients such as cognitive impairment, seizure susceptibility, altered pain sensitivity and anxiety. The recent advances in the understanding of the pathophysiological mechanisms involved have opened novel potential therapeutic approaches identified in preclinical rodent models as a necessary preliminary step for the subsequent evaluation in patients. Among those possible therapeutic approaches, the modulation of the metabotropic glutamate receptor signaling or the GABA receptor signaling have focused most of the attention. New findings in the animal models open other possible therapeutic approaches such as the mammalian target of rapamycin signaling pathway or the endocannabinoid system. This review summarizes the emerging data recently obtained in preclinical models of fragile X syndrome supporting these new therapeutic perspectives.

PMID: 24831882 [PubMed - indexed for MEDLINE]

Intragenic rearrangements in X-linked intellectual deficiency: results of a-CGH in a series of 54 patients and identification of TRPC5 and KLHL15 as potential XLID genes.

April 1, 2015 - 6:39am
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Intragenic rearrangements in X-linked intellectual deficiency: results of a-CGH in a series of 54 patients and identification of TRPC5 and KLHL15 as potential XLID genes.

Am J Med Genet A. 2014 Aug;164A(8):1991-7

Authors: Mignon-Ravix C, Cacciagli P, Choucair N, Popovici C, Missirian C, Milh M, Mégarbané A, Busa T, Julia S, Girard N, Badens C, Sigaudy S, Philip N, Villard L

Abstract
High-resolution array comparative genomic hybridization (a-CGH) enables the detection of intragenic rearrangements, such as single exon deletion or duplication. This approach can lead to the identification of new disease genes. We report on the analysis of 54 male patients presenting with intellectual deficiency (ID) and a family history suggesting X-linked (XL) inheritance or maternal skewed X-chromosome inactivation (XCI), using a home-made X-chromosome-specific microarray covering the whole human X-chromosome at high resolution. The majority of patients had whole genome array-CGH prior to the selection and we did not include large rearrangements such as MECP2 and FMR1 duplications. We identified four rearrangements considered as causative or potentially pathogenic, corresponding to a detection rate of 8%. Two CNVs affected known XLID genes and were therefore considered as causative (IL1RAPL1 and OPHN1 intragenic deletions). Two new CNVs were considered as potentially pathogenic as they affected interesting candidates for ID. The first CNV is a deletion of the first exon of the TRPC5 gene, encoding a cation channel implicated in dendrite growth and patterning, in a child presenting with ID and an autism spectrum disorder (ASD). The second CNV is a partial deletion of KLHL15, in a patient with severe ID, epilepsy, and anomalies of cortical development. In both cases, in spite of strong arguments for clinical relevance, we were not able at this stage to confirm pathogenicity of the mutations, and the causality of the variants identified in XLID remains to be confirmed.

PMID: 24817631 [PubMed - indexed for MEDLINE]

Phenotypic features in patients with 15q11.2(BP1-BP2) deletion: further delineation of an emerging syndrome.

April 1, 2015 - 6:39am
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Phenotypic features in patients with 15q11.2(BP1-BP2) deletion: further delineation of an emerging syndrome.

Am J Med Genet A. 2014 Aug;164A(8):1916-22

Authors: Cafferkey M, Ahn JW, Flinter F, Ogilvie C

Abstract
15q11.2 deletions flanked by BP1 and BP2 of the Prader-Willi/Angelman syndrome region have recently been linked to a range of neurodevelopment disorders including intellectual disability, speech and language delay, motor delay, autism spectrum disorders, epilepsy, and schizophrenia. Array CGH analysis of 14,605 patients referred for diagnostic cytogenetic testing found that 83 patients (0.57%) carried the 15q11.2(BP1-BP2) deletion. Phenotypic frequencies in the deleted cohort (n = 83) were compared with frequencies in the non-deleted cohort (n = 14,522); developmental delay, motor delay, and speech and language delay were all more prevalent in the deleted cohort. Notably, motor delay was significantly more common (OR = 6.37). These data indicate that developmental delay, motor delay, and speech and language delay are common clinical features associated with this deletion, providing substantial evidence to support this CNV as a susceptibility locus for a spectrum of neurodevelopmental disorders. © 2014 Wiley Periodicals, Inc.

PMID: 24715682 [PubMed - indexed for MEDLINE]

MeCP2: multifaceted roles in gene regulation and neural development.

March 31, 2015 - 6:11am
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MeCP2: multifaceted roles in gene regulation and neural development.

Neurosci Bull. 2014 Aug;30(4):601-9

Authors: Cheng TL, Qiu Z

Abstract
Methyl-CpG-binding protein 2 (MeCP2) is a classic methylated-DNA-binding protein, dysfunctions of which lead to various neurodevelopmental disorders such as Rett syndrome and autism spectrum disorder. Initially recognized as a transcriptional repressor, MeCP2 has been studied extensively and its functions have been expanded dramatically in the past two decades. Recently, it was found to be involved in gene regulation at the post-transcriptional level. MeCP2 represses nuclear microRNA processing by interacting directly with the Drosha/DGCR8 complex. In addition to its multifaceted functions, MeCP2 is remarkably modulated by posttranslational modifications such as phosphorylation, SUMOylation, and acetylation, providing more regulatory dimensions to its functions. The role of MeCP2 in the central nervous system has been studied extensively, from neurons to glia. Future investigations combining molecular, cellular, and physiological methods are necessary for defining the roles of MeCP2 in the brain and developing efficient treatments for MeCP2-related brain disorders.

PMID: 25082535 [PubMed - indexed for MEDLINE]

Rescue of fragile X syndrome phenotypes in Fmr1 KO mice by a BKCa channel opener molecule.

March 31, 2015 - 6:11am
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Rescue of fragile X syndrome phenotypes in Fmr1 KO mice by a BKCa channel opener molecule.

Orphanet J Rare Dis. 2014;9:124

Authors: Hébert B, Pietropaolo S, Même S, Laudier B, Laugeray A, Doisne N, Quartier A, Lefeuvre S, Got L, Cahard D, Laumonnier F, Crusio WE, Pichon J, Menuet A, Perche O, Briault S

Abstract
BACKGROUND: Fragile X Syndrome (FXS) is the most common form of inherited intellectual disability and is also associated with autism spectrum disorders. Previous studies implicated BKCa channels in the neuropathogenesis of FXS, but the main question was whether pharmacological BKCa stimulation would be able to rescue FXS neurobehavioral phenotypes.
METHODS AND RESULTS: We used a selective BKCa channel opener molecule (BMS-204352) to address this issue in Fmr1 KO mice, modeling the FXS pathophysiology. In vitro, acute BMS-204352 treatment (10 μM) restored the abnormal dendritic spine phenotype. In vivo, a single injection of BMS-204352 (2 mg/kg) rescued the hippocampal glutamate homeostasis and the behavioral phenotype. Indeed, disturbances in social recognition and interaction, non-social anxiety, and spatial memory were corrected by BMS-204352 in Fmr1 KO mice.
CONCLUSION: These results demonstrate that the BKCa channel is a new therapeutic target for FXS. We show that BMS-204352 rescues a broad spectrum of behavioral impairments (social, emotional and cognitive) in an animal model of FXS. This pharmacological molecule might open new ways for FXS therapy.

PMID: 25079250 [PubMed - indexed for MEDLINE]

Translational control in synaptic plasticity and cognitive dysfunction.

March 31, 2015 - 6:11am
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Translational control in synaptic plasticity and cognitive dysfunction.

Annu Rev Neurosci. 2014;37:17-38

Authors: Buffington SA, Huang W, Costa-Mattioli M

Abstract
Activity-dependent changes in the strength of synaptic connections are fundamental to the formation and maintenance of memory. The mechanisms underlying persistent changes in synaptic strength in the hippocampus, specifically long-term potentiation and depression, depend on new protein synthesis. Such changes are thought to be orchestrated by engaging the signaling pathways that regulate mRNA translation in neurons. In this review, we discuss the key regulatory pathways that govern translational control in response to synaptic activity and the mRNA populations that are specifically targeted by these pathways. The critical contribution of regulatory control over new protein synthesis to proper cognitive function is underscored by human disorders associated with either silencing or mutation of genes encoding proteins that directly regulate translation. In light of these clinical implications, we also consider the therapeutic potential of targeting dysregulated translational control to treat cognitive disorders of synaptic dysfunction.

PMID: 25032491 [PubMed - indexed for MEDLINE]

The WNK-SPAK/OSR1 pathway: master regulator of cation-chloride cotransporters.

March 31, 2015 - 6:11am
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The WNK-SPAK/OSR1 pathway: master regulator of cation-chloride cotransporters.

Sci Signal. 2014 Jul 15;7(334):re3

Authors: Alessi DR, Zhang J, Khanna A, Hochdörfer T, Shang Y, Kahle KT

Abstract
The WNK-SPAK/OSR1 kinase complex is composed of the kinases WNK (with no lysine) and SPAK (SPS1-related proline/alanine-rich kinase) or the SPAK homolog OSR1 (oxidative stress-responsive kinase 1). The WNK family senses changes in intracellular Cl(-) concentration, extracellular osmolarity, and cell volume and transduces this information to sodium (Na(+)), potassium (K(+)), and chloride (Cl(-)) cotransporters [collectively referred to as CCCs (cation-chloride cotransporters)] and ion channels to maintain cellular and organismal homeostasis and affect cellular morphology and behavior. Several genes encoding proteins in this pathway are mutated in human disease, and the cotransporters are targets of commonly used drugs. WNKs stimulate the kinases SPAK and OSR1, which directly phosphorylate and stimulate Cl(-)-importing, Na(+)-driven CCCs or inhibit the Cl(-)-extruding, K(+)-driven CCCs. These coordinated and reciprocal actions on the CCCs are triggered by an interaction between RFXV/I motifs within the WNKs and CCCs and a conserved carboxyl-terminal docking domain in SPAK and OSR1. This interaction site represents a potentially druggable node that could be more effective than targeting the cotransporters directly. In the kidney, WNK-SPAK/OSR1 inhibition decreases epithelial NaCl reabsorption and K(+) secretion to lower blood pressure while maintaining serum K(+). In neurons, WNK-SPAK/OSR1 inhibition could facilitate Cl(-) extrusion and promote γ-aminobutyric acidergic (GABAergic) inhibition. Such drugs could have efficacy as K(+)-sparing blood pressure-lowering agents in essential hypertension, nonaddictive analgesics in neuropathic pain, and promoters of GABAergic inhibition in diseases associated with neuronal hyperactivity, such as epilepsy, spasticity, neuropathic pain, schizophrenia, and autism.

PMID: 25028718 [PubMed - indexed for MEDLINE]

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