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Heterozygous L1-deficient mice express an autism-like phenotype.

May 26, 2016 - 7:49am
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Heterozygous L1-deficient mice express an autism-like phenotype.

Behav Brain Res. 2015 Oct 1;292:432-42

Authors: Sauce B, Wass C, Netrakanti M, Saylor J, Schachner M, Matzel LD

Abstract
The L1CAM (L1) gene encodes a cell adhesion molecule that contributes to several important processes in the developing and adult nervous system, including neuronal migration, survival, and plasticity. In humans and mice, mutations in the X chromosome-linked gene L1 cause severe neurological defects in males. L1 heterozygous female mice with one functional copy of the L1 gene show complex morphological features that are different from L1 fully-deficient and wild-type littermate mice. However, almost no information is available on the behavior of L1 heterozygous mice and humans. Here, we investigated the behavior of heterozygous female mice in which the L1 gene is constitutively inactivated. These mice were compared to wild-type littermate females. Animals were assessed in five categories of behavioral tests: five tests for anxiety/stress/exploration, four tests for motor abilities, two tests for spatial learning, three tests for social behavior, and three tests for repetitive behavior. We found that L1 heterozygous mice express an autism-like phenotype, comprised of reduced social behaviors and excessive self-grooming (a repetitive behavior also typical in animal models of autism). L1 heterozygous mice also exhibited an increase in sensitivity to light, assessed by a reluctance to enter the lighted areas of novel environments. However, levels of anxiety, stress, motor abilities, and spatial learning in L1 heterozygous mice were similar to those of wild-type mice. These observations raise the possibility that using molecules known to trigger L1 functions may become valuable in the treatment of autism in humans.

PMID: 26079769 [PubMed - indexed for MEDLINE]

Association of rare variation in the glutamate receptor gene SLC1A2 with susceptibility to bipolar disorder and schizophrenia.

May 25, 2016 - 7:44am
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Association of rare variation in the glutamate receptor gene SLC1A2 with susceptibility to bipolar disorder and schizophrenia.

Eur J Hum Genet. 2015 Sep;23(9):1200-6

Authors: Fiorentino A, Sharp SI, McQuillin A

Abstract
The SLC1A2 gene encodes the excitatory amino acid transporter 2 (EAAT2). Glutamate is the major mediator of excitatory neurotransmission and EAAT2 is responsible for clearing the neurotransmitter from the synaptic cleft. Genetic variation in SLC1A2 has been implicated in a range of neurological and neuropsychiatric conditions including schizophrenia (SZ), autism and in core phenotypes of bipolar disorder (BD). The coding and putative regulatory regions of SLC1A2 gene were screened for variants using high resolution melting or sequenced in 1099 or in 32 BD subjects. Thirty-two variants were detected in the SLC1A2 gene. Fifteen potentially etiological variants were selected for genotyping in 1099 BD and 1095 control samples. Five amino acid changing variants were also genotyped in 630 participants suffering from SZ. None of the variants were found to be associated with BD or SZ or with the two diseases combined. However, two recurrent missense variants (rs145827578:G>A, p.(G6S); rs199599866:G>A, p.(R31Q)) and one recurrent 5'-untranslated region (UTR) variant (ss825678885:G>T) were detected in cases only. Combined analysis of the recurrent-case-only missense variants and of the case-only missense and 5'-UTR variants showed nominal evidence for association with the combined diseases (Fisher's P=0.019 and 0.0076). These findings are exploratory in nature and await replication in larger cohorts, however, they provide intriguing evidence that potentially functional rare variants in the SLC1A2 gene may confer susceptibility to psychotic disorders.

PMID: 25406999 [PubMed - indexed for MEDLINE]

Finding novel distinctions between the sAPPα-mediated anabolic biochemical pathways in Autism Spectrum Disorder and Fragile X Syndrome plasma and brain tissue.

May 24, 2016 - 7:41am

Finding novel distinctions between the sAPPα-mediated anabolic biochemical pathways in Autism Spectrum Disorder and Fragile X Syndrome plasma and brain tissue.

Sci Rep. 2016;6:26052

Authors: Ray B, Sokol DK, Maloney B, Lahiri DK

Abstract
UNLABELLED: Autism spectrum disorder (ASD) and Fragile X syndrome (FXS) are developmental disorders. No validated blood-based biomarkers exist for either, which impedes bench-to-bedside approaches. Amyloid-β (Aβ) precursor protein (APP) and metabolites are usually associated with Alzheimer's disease (AD). APP cleavage by α-secretase produces potentially neurotrophic secreted APPα (sAPPα) and the P3 peptide fragment. β-site APP cleaving enzyme (BACE1) cleavage produces secreted APPβ (sAPPβ) and intact Aβ. Excess Aβ is potentially neurotoxic and can lead to atrophy of brain regions such as amygdala in AD. By contrast, amygdala is enlarged in ASD but not FXS. We previously reported elevated levels of sAPPα in ASD and FXS vs.
CONTROLS: We now report elevated plasma Aβ and total APP levels in FXS compared to both ASD and typically developing controls, and elevated levels of sAPPα in ASD and FXS vs.
CONTROLS: By contrast, plasma and brain sAPPβ and Aβ were lower in ASD vs. controls but elevated in FXS plasma vs.
CONTROLS: We also detected age-dependent increase in an α-secretase in ASD brains. We report a novel mechanistic difference in APP pathways between ASD (processing) and FXS (expression) leading to distinct APP metabolite profiles in these two disorders. These novel, distinctive biochemical differences between ASD and FXS pave the way for blood-based biomarkers for ASD and FXS.

PMID: 27212113 [PubMed - in process]

[Behavioral phenotypes of autism spectrum disorder patients and their parents].

May 24, 2016 - 7:41am
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[Behavioral phenotypes of autism spectrum disorder patients and their parents].

Zhonghua Yi Xue Yi Chuan Xue Za Zhi. 2015 Dec;32(6):797-800

Authors: Situ M, Hu X, Cai J, Guo K, Huang Y

Abstract
OBJECTIVE: To explore the relationship between the behavior phenotypes of patients with autism spectrum disorder (ASD) and their parents through family study.
METHODS: Forty-five core families with ASD and 30 control families from Chengdu area were examined using Autism Spectrum Quotient (AQ). Descriptive statistical analysis, correlation analysis, and Logistic regression analysis were used to investigate the effect of various factors, especially genetic factors that may affect the pathogenesis of ASD.
RESULTS: The social skills factor and communication factor of the father's AQ scale, as well as the mother's age of childbearing and AQ social skills factor are related to whether children with ASD (R were 0.46, 0.39, 0.39 and 0.36, P<0.05). The communication factor of the parents' AQ and mother's attention to detail factor are related to whether children will show developmental anomaly before the age of 36 months (R were 0.55, 0.51 and 0.54, P<0.05). The social skill problems of parents and father's communication problems are risk factors for children with autism.
CONCLUSION: ASD may be influenced by both genetic and environmental factors. The autistic behavior phenotype of parents is a risk factor for ASD and is associated with developmental anomalies of early childhood.

PMID: 26663051 [PubMed - indexed for MEDLINE]

A de-novo interstitial microduplication involving 2p16.1-p15 and mirroring 2p16.1-p15 microdeletion syndrome: Clinical and molecular analysis.

May 24, 2016 - 7:41am
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A de-novo interstitial microduplication involving 2p16.1-p15 and mirroring 2p16.1-p15 microdeletion syndrome: Clinical and molecular analysis.

Eur J Paediatr Neurol. 2015 Nov;19(6):711-5

Authors: Mimouni-Bloch A, Yeshaya J, Kahana S, Maya I, Basel-Vanagaite L

Abstract
BACKGROUND: Microdeletions of various sizes in the 2p16.1-p15 chromosomal region have been grouped together under the 2p16.1-p15 microdeletion syndrome. Children with this syndrome generally share certain features including microcephaly, developmental delay, facial dysmorphism, urogenital and skeletal abnormalities. We present a child with a de-novo interstitial 1665 kb duplication of 2p16.1-p15.
METHODS AND RESULTS: Clinical features of this child are distinct from those of children with the 2p16.1-p15 microdeletion syndrome, specifically the head circumference which is within the normal range and mild intellectual disability with absence of autistic behaviors. Microduplications many times bear milder clinical phenotypes in comparison with corresponding microdeletion syndromes. Indeed, as compared to the microdeletion syndrome patients, the 2p16.1-p15 microduplication seems to have a milder cognitive effect and no effect on other body systems. Limited information available in genetic databases about cases with overlapping duplications indicates that they all have abnormal developmental phenotypes.
CONCLUSION: The involvement of genes in this location including BCL11A, USP34 and PEX13, affecting fundamental developmental processes both within and outside the nervous system may explain the clinical features of the individual described in this report.

PMID: 26278498 [PubMed - indexed for MEDLINE]

Is it possible to diagnose Rett syndrome before classical symptoms become obvious? Review of 24 Danish cases born between 2003 and 2012.

May 24, 2016 - 7:41am
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Is it possible to diagnose Rett syndrome before classical symptoms become obvious? Review of 24 Danish cases born between 2003 and 2012.

Eur J Paediatr Neurol. 2015 Nov;19(6):679-87

Authors: Bisgaard AM, Schönewolf-Greulich B, Ravn K, Rønde G

Abstract
BACKGROUND/PURPOSE: Rett syndrome (RTT) is a neurodevelopmental disorder that affects mainly females; it results in multiple disabilities and carries a risk of medical comorbidities. Early diagnosis is important to help establish the best treatment opportunities and preventive care in order to slow down the progression of symptoms. We wanted to test our hypothesis that it is possible to diagnose RTT before the classical symptoms become obvious.
METHODS: We analysed development and symptoms before and at the time of the RTT diagnosis, as well as the symptoms that triggered MECP2 mutation analysis, in a cohort of girls with RTT born in Denmark between 2003 and 2012.
RESULTS: Twenty-four girls were included, and 87.5% of these girls were diagnosed when the classical RTT symptoms were recognized. However, parents were concerned about their daughters between 3 and 58 months prior to the RTT diagnosis, and they felt that the professionals did not share their concern in the beginning. When reviewing medical files and questionnaires, we noted that the majority of girls did have combinations of concerning symptoms such as developmental delay and a collection of subtle signs such as autistic traits, placidity, floppiness with suspicion of muscular or mitochondrial diseases, hair pulling, teeth grinding, development of incontinence and problems with initiating movements.
CONCLUSION: We conclude that many individuals with MECP2 mutation exhibit characteristics that should raise suspicion for RTT, prior to evolution of the core clinical criteria. As RTT is a rare disease, it is of importance to constantly educate clinicians for heightened awareness of RTT.

PMID: 26228846 [PubMed - indexed for MEDLINE]

Autism Spectrum Disorder, Developmental and Psychiatric Features in 16p11.2 Duplication.

May 22, 2016 - 7:37am

Autism Spectrum Disorder, Developmental and Psychiatric Features in 16p11.2 Duplication.

J Autism Dev Disord. 2016 May 21;

Authors: Green Snyder L, D'Angelo D, Chen Q, Bernier R, Goin-Kochel RP, Wallace AS, Gerdts J, Kanne S, Berry L, Blaskey L, Kuschner E, Roberts T, Sherr E, Martin CL, Ledbetter DH, Spiro JE, Chung WK, Hanson E, Simons VIP consortium

Abstract
The 16p11.2 duplication (BP4-BP5) is associated with Autism Spectrum Disorder (ASD), although significant heterogeneity exists. Quantitative ASD, behavioral and neuropsychological measures and DSM-IV diagnoses in child and adult carriers were compared with familial non-carrier controls, and to published results from deletion carriers. The 16p11.2 duplication phenotype ranges widely from asymptomatic presentation to significant disability. The most common diagnoses were intellectual disability, motor delays and Attention Deficit Hyperactivity Disorder in children, and anxiety in adults. ASD occurred in nearly 20 % of child cases, but a majority of carriers did not show the unique social features of ASD. The 16p11.2 duplication phenotype is characterized by wider variability than the reciprocal deletion, likely reflecting contributions from additional risk factors.

PMID: 27207092 [PubMed - as supplied by publisher]

The Evolving Diagnostic and Genetic Landscapes of Autism Spectrum Disorder.

May 21, 2016 - 7:35am

The Evolving Diagnostic and Genetic Landscapes of Autism Spectrum Disorder.

Front Genet. 2016;7:65

Authors: Ziats MN, Rennert OM

Abstract
The autism spectrum disorders (ASD) are a heterogeneous set of neurodevelopmental syndromes defined by impairments in verbal and non-verbal communication, restricted social interaction, and the presence of stereotyped patterns of behavior. The prevalence of ASD is rising, and the diagnostic criteria and clinical perspectives on the disorder continue to evolve in parallel. Although the majority of individuals with ASD will not have an identifiable genetic cause, almost 25% of cases have identifiable causative DNA variants. The rapidly improving ability to identify genetic mutations because of advances in next generation sequencing, coupled with previous epidemiological studies demonstrating high heritability of ASD, have led to many recent attempts to identify causative genetic mutations underlying the ASD phenotype. However, although hundreds of mutations have been identified to date, they are either rare variants affecting only a handful of ASD patients, or are common variants in the general population conferring only a small risk for ASD. Furthermore, the genes implicated thus far are heterogeneous in their structure and function, hampering attempts to understand shared molecular mechanisms among all ASD patients; an understanding that is crucial for the development of targeted diagnostics and therapies. However, new work is beginning to suggest that the heterogeneous set of genes implicated in ASD may ultimately converge on a few common pathways. In this review, we discuss the parallel evolution of our diagnostic and genetic understanding of autism spectrum disorders, and highlight recent attempts to infer common biology underlying this complicated syndrome.

PMID: 27200076 [PubMed]

CNVs in neurodevelopmental disorders.

May 21, 2016 - 7:35am
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CNVs in neurodevelopmental disorders.

Oncotarget. 2015 Jul 30;6(21):18238-9

Authors: Lee CT, Freed WJ, Mash DC

PMID: 26285833 [PubMed - indexed for MEDLINE]

Concern for Another's Distress in Toddlers at High and Low Genetic Risk for Autism Spectrum Disorder.

May 21, 2016 - 7:35am
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Concern for Another's Distress in Toddlers at High and Low Genetic Risk for Autism Spectrum Disorder.

J Autism Dev Disord. 2015 Nov;45(11):3594-605

Authors: Campbell SB, Leezenbaum NB, Schmidt EN, Day TN, Brownell CA

Abstract
We examined concern for others in 22-month-old toddlers with an older sibling with autism spectrum disorder (ASD) and low risk typically-developing toddlers with older siblings. Responses to a crying infant and an adult social partner who pretended to hurt her finger were coded. Children with a later diagnosis of ASD showed limited empathic concern in either context compared to low risk toddlers. High risk toddlers without a later diagnosis fell between the ASD and low risk groups. During the crying baby probe the low risk and high risk toddlers without a diagnosis engaged their parent more often than the toddlers with ASD. Low levels of empathic concern and engagement with parents may signal emerging ASD in toddlerhood.

PMID: 26093390 [PubMed - indexed for MEDLINE]

Restoration of Normal Cerebral Oxygen Consumption with Rapamycin Treatment in a Rat Model of Autism-Tuberous Sclerosis.

May 21, 2016 - 7:35am
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Restoration of Normal Cerebral Oxygen Consumption with Rapamycin Treatment in a Rat Model of Autism-Tuberous Sclerosis.

Neuromolecular Med. 2015 Sep;17(3):305-13

Authors: Chi OZ, Wu CC, Liu X, Rah KH, Jacinto E, Weiss HR

Abstract
Tuberous sclerosis (TSC) is associated with autism spectrum disorders and has been linked to metabolic dysfunction and unrestrained signaling of the mammalian target of rapamycin (mTOR). Inhibition of mTOR by rapamycin can mitigate some of the phenotypic abnormalities associated with TSC and autism, but whether this is due to the mTOR-related function in energy metabolism remains to be elucidated. In young Eker rats, an animal model of TSC and autism, which harbors a germ line heterozygous Tsc2 mutation, we previously reported that cerebral oxygen consumption was pronouncedly elevated. Young (4 weeks) male control Long-Evans and Eker rats were divided into control and rapamycin-treated (20 mg/kg once daily for 2 days) animals. Cerebral regional blood flow ((14)C-iodoantipyrine) and O2 consumption (cryomicrospectrophotometry) were determined in isoflurane-anesthetized rats. We found significantly increased basal O2 consumption in the cortex (8.7 ± 1.5 ml O2/min/100 g Eker vs. 2.7 ± 0.2 control), hippocampus, pons and cerebellum. Regional cerebral blood flow and cerebral O2 extractions were also elevated in all brain regions. Rapamycin had no significant effect on O2 consumption in any brain region of the control rats, but significantly reduced consumption in the cortex (4.1 ± 0.3) and all other examined regions of the Eker rats. Phosphorylation of mTOR and S6K1 was similar in the two groups and equally reduced by rapamycin. Thus, a rapamycin-sensitive, mTOR-dependent but S6K1-independent, signal led to enhanced oxidative metabolism in the Eker brain. We found decreased Akt phosphorylation in Eker but not Long-Evans rat brains, suggesting that this may be related to the increased cerebral O2 consumption in the Eker rat. Our findings suggest that rapamycin targeting of Akt to restore normal cerebral metabolism could have therapeutic potential in tuberous sclerosis and autism.

PMID: 26048361 [PubMed - indexed for MEDLINE]

Are Molecules Involved in Neuritogenesis and Axon Guidance Related to Autism Pathogenesis?

May 21, 2016 - 7:35am
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Are Molecules Involved in Neuritogenesis and Axon Guidance Related to Autism Pathogenesis?

Neuromolecular Med. 2015 Sep;17(3):297-304

Authors: Bakos J, Bacova Z, Grant SG, Castejon AM, Ostatnikova D

Abstract
Autism spectrum disorder is a heterogeneous disease, and numerous alterations of gene expression come into play to attempt to explain potential molecular and pathophysiological causes. Abnormalities of brain development and connectivity associated with alterations in cytoskeletal rearrangement, neuritogenesis and elongation of axons and dendrites might represent or contribute to the structural basis of autism pathology. Slit/Robo signaling regulates cytoskeletal remodeling related to axonal and dendritic branching. Components of its signaling pathway (ABL and Cdc42) are suspected to be molecular bases of alterations of normal development. The present review describes the most important mechanisms underlying neuritogenesis, axon pathfinding and the role of GTPases in neurite outgrowth, with special emphasis on alterations associated with autism spectrum disorders. On the basis of analysis of publicly available microarray data, potential biomarkers of autism are discussed.

PMID: 25989848 [PubMed - indexed for MEDLINE]

Elevated levels of tissue plasminogen activator and E-selectin in male children with autism spectrum disorder.

May 20, 2016 - 7:34am

Elevated levels of tissue plasminogen activator and E-selectin in male children with autism spectrum disorder.

Autism Res. 2016 May 19;

Authors: Şimşek Ş, Çetin İ, Çim A, Kaya S

Abstract
Although the etiopathology of autism spectrum disorder (ASD) is not clear, immune dysfunction has been proposed as a mechanism for the pathophysiology of ASD. The purpose of this study is to examine serum levels of tissue plasminogen activator (t-PA) and some adhesion molecules in children with ASD that have not been investigated previously in detail. The study group included 35 male children aged from 2 to 9 diagnosed with ASD according to DSM-V criteria. Soluble platelet endothelial adhesion molecule-1 (sPECAM-1), P-selectin, E-selectin, and t-PA in the serum were determined with enzyme-linked immunosorbent assay. Autism behavior check list (ABC) is used for the assessment of ASD severity. The levels of t-PA (P = 0.025) and E-selectin (P = 0.007) was detected significantly higher in children with ASD than control group. Serum levels of sPECAM-1 showed statistically significant negative correlation with sensory, body and object-use, language, social, and self-help and total scores in the patient group (r = -0.349, P = 0.04; r = -0.411, P = 0.01; r = -0.412, P = 0.01; r = -0.417, P = 0.01, and r = -0.531, P < 0.01, respectively). Serum levels of P-selectin levels showed statistically significant negative correlation with ABC total score in the patient group (r = -0.378, P = 0.03). It may be suggested that t-PA, E-selectin, P-selectin, and sPECAM-1 a crucial role in inflammatory conditions in children with ASD. Autism Res 2016. © 2016 International Society for Autism Research, Wiley Periodicals, Inc.

PMID: 27194368 [PubMed - as supplied by publisher]

microRNAs and Fragile X Syndrome.

May 20, 2016 - 7:34am
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microRNAs and Fragile X Syndrome.

Adv Exp Med Biol. 2015;888:107-21

Authors: Lin SL

Abstract
Fragile X syndrome (FXS) is one of the major causes for autism and mental retardation in humans. The etiology of FXS is linked to the expansion of the CGG trinucleotide repeats, r(CGG), suppressing the fragile X mental retardation 1 (FMR1) gene on the X chromosome, resulting in a loss of fragile X mental retardation protein (FMRP) expression, which is required for regulating normal neuronal connectivity and plasticity. Recent studies have further identified that microRNAs are involved in the mechanisms underlying FXS pathogenesis at three different developmental stages. During early embryogenesis before the blastocyst stage, an embryonic stem cell (ESC)-specific microRNA, miR-302, interferes with FMR1 mRNA translation to maintain the stem cell status and inhibit neural development. After blastocyst, the downregulation of miR-302 releases FMRP synthesis and subsequently leads to neuronal development; yet, in FXS, certain r(CGG)-derived microRNAs, such as miR-fmr1s, are expressed and accumulated and then induce DNA hypermethylation on the FMR1 gene promoter regions, resulting in transcriptional inactivation of the FMR1 gene and the loss of FMRP. In normal neuronal development, FMRP is an RNA-binding protein responsible for interacting with miR-125 and miR-132 to regulate the signaling of Group 1 metabotropic glutamate receptor (mGluR1) and N-methyl-D-aspartate receptor (NMDAR), respectively, and consequently affecting synaptic plasticity. As a result, the loss of FMRP impairs these signaling controls and eventually causes FXS-associated disorders, such as autism and mental retardation. Based on these current findings, this chapter will summarize the etiological causes of FXS and further provides significant insights into the molecular mechanisms underlying microRNA-mediated FXS pathogenesis and the related therapy development.

PMID: 26663181 [PubMed - indexed for MEDLINE]

microRNA and Autism.

May 20, 2016 - 7:34am
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microRNA and Autism.

Adv Exp Med Biol. 2015;888:71-83

Authors: Anitha A, Thanseem I

Abstract
Autism is a complex neurodevelopmental disorder characterized by deficiencies in social interaction and communication, and by repetitive and stereotyped behaviors. According to a recent report, the prevalence of this pervasive developmental disorder has risen to 1 in 88. This will have enormous public health implications in the future, and has necessitated the need to discover predictive biomarkers that could index for autism before the onset of symptoms. microRNAs (miRNAs) are small, noncoding RNAs that regulate gene expression at the posttranscriptional level. They have recently emerged as prominent epigenetic regulators of various cellular processes including neurodevelopment. They are abundantly present in the brain, and their dysfunction has been implicated in an array of neuropathological conditions including autism. miRNAs, previously known to be expressed only in cells and tissues, have also been detected in extracellular body fluids such as serum, plasma, saliva, and urine. Altered expression of cellular and circulating miRNAs have been observed in autistic individuals compared to healthy controls. miRNAs are now being considered as potential targets for the development of novel therapeutic strategies for autism.

PMID: 26663179 [PubMed - indexed for MEDLINE]

An assessment of sex bias in neurodevelopmental disorders.

May 20, 2016 - 7:34am
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An assessment of sex bias in neurodevelopmental disorders.

Genome Med. 2015;7:94

Authors: Polyak A, Rosenfeld JA, Girirajan S

Abstract
BACKGROUND: Neurodevelopmental disorders such as autism and intellectual disability have a sex bias skewed towards boys; however, systematic assessment of this bias is complicated by the presence of significant genetic and phenotypic heterogeneity of these disorders.
METHODS: To assess the extent and characteristics of sex bias, we analyzed the frequency of comorbid features, the magnitude of genetic load, and the existence of family history within 32,155 individuals ascertained clinically for autism or intellectual disability/developmental delay (ID/DD), including a subset of 8,373 individuals carrying rare copy-number variants (CNVs).
RESULTS: We find that girls were more likely than boys to show comorbid features within both autism (P = 2.9 × 10(-6), OR = 1.34) and ID/DD (P = 7.2 × 10(-4), OR = 1.08) cohorts. The frequency of comorbid features in ID/DD was higher in boys (1q21.1 deletion, 15q11.2q13.1 duplication) or girls (15q13.3 deletion, 16p11.2 deletion) carrying specific CNVs associated with variable expressivity while such differences were the smallest for syndromic CNVs (Smith-Magenis syndrome, DiGeorge syndrome). The extent of the male sex bias also varied according to the specific comorbid feature, being most extreme for autism with psychiatric comorbidities and least extreme for autism comorbid with epilepsy. The sex ratio was also specific to certain CNVs, from an 8:1 male:female ratio observed among autistic individuals carrying the 22q11.2 duplication to 1.3:1 male:female ratio in those carrying the 16p11.2 deletion. Girls carried a higher burden of large CNVs compared to boys for autism or ID/DD, and this difference diminished when severe comorbidities were considered. Affected boys showed a higher frequency of neuropsychiatric family histories such as autism (P = 0.01) or specific learning disability (P = 0.03), while affected girls showed a higher frequency of developmental family histories such as growth abnormalities (P = 0.02).
CONCLUSIONS: The sex bias within neurodevelopmental disorders is influenced by the presence of specific comorbidities, specific CNVs, mutational burden, and pre-existing family history of neurodevelopmental phenotypes.

PMID: 26307204 [PubMed - indexed for MEDLINE]

Pharmacogenetic Study of Serotonin Transporter and 5HT2A Genotypes in Autism.

May 20, 2016 - 7:34am
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Pharmacogenetic Study of Serotonin Transporter and 5HT2A Genotypes in Autism.

J Child Adolesc Psychopharmacol. 2015 Aug;25(6):467-74

Authors: Najjar F, Owley T, Mosconi MW, Jacob S, Hur K, Guter SJ, Sweeney JA, Gibbons RD, Cook EH, Bishop JR

Abstract
OBJECTIVE: The purpose of this study was to determine whether polymorphisms in the serotonin transporter (SLC6A4) and serotonin-2A receptor (HTR2A) genes are associated with response to escitalopram in patients with autism spectrum disorder (ASD).
METHODS: Forty-four participants with ASD were enrolled in a 6 week, forced titration, open label examination of the selective serotonin reuptake inhibitor (SSRI) escitalopram. Doses increased at weekly intervals starting at 2.5mg daily with a maximum possible dose of 20 mg daily achieved by the end of the study. If adverse events were experienced, participants subsequently received the previously tolerated dose for the duration of study. SLC6A4 (5-HTTLPR) and HTR2A (rs7997012) genotype groups were assessed in relation to treatment outcomes and drug doses.
RESULTS: Insistence on sameness and irritability symptoms significantly improved over the course of the 6 week treatment period (p<0.0001) in this open-label trial. There were no significant differences observed in the rate of symptom improvement over time across genotype groups. Similarly, dosing trajectory was not significantly associated with genotype groups.
CONCLUSIONS: Previous studies have identified SLC6A4 and HTR2A associations with SSRI response in patients with depression and 5-HTTLPR (SLC6A4) associations with escitalopram response in ASD. We did not observe evidence for similar relationships in this ASD study.

PMID: 26262902 [PubMed - indexed for MEDLINE]

Deletion of 15q11.2(BP1-BP2) region: further evidence for lack of phenotypic specificity in a pediatric population.

May 20, 2016 - 7:34am
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Deletion of 15q11.2(BP1-BP2) region: further evidence for lack of phenotypic specificity in a pediatric population.

Am J Med Genet A. 2015 Sep;167A(9):2098-102

Authors: Hashemi B, Bassett A, Chitayat D, Chong K, Feldman M, Flanagan J, Goobie S, Kawamura A, Lowther C, Prasad C, Siu V, So J, Tung S, Speevak M, Stavropoulos DJ, Carter MT

Abstract
Microdeletion of the BP1-BP2 region at 15q11.2 is a recurrent copy number variant (CNV) frequently found in patients undergoing chromosomal microarray (CMA). Genetic counselling regarding this CNV is challenging due to the wide range of phenotypic presentation in reported patients and lack of general population-based data. As one of the most common reasons for CMA is childhood developmental delay, clinicians need to be cognizant of the inherent ascertainment bias in the literature. We performed a detailed medical record review for 55 patients with this 15q11.2 microdeletion and report the clinical features of the 35 patients for whom information was available. We compared our results to the recent report by Cafferkey et al. in this journal. Our conclusion is that the phenotypic spectrum is too broad and non-specific to constitute a bona fide "syndrome" and that further research must be done to delineate the contribution of this CNV to phenotype.

PMID: 25946043 [PubMed - indexed for MEDLINE]

Improvement of regressive autism symptoms in a child with TMLHE deficiency following carnitine supplementation.

May 20, 2016 - 7:34am
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Improvement of regressive autism symptoms in a child with TMLHE deficiency following carnitine supplementation.

Am J Med Genet A. 2015 Sep;167A(9):2162-7

Authors: Ziats MN, Comeaux MS, Yang Y, Scaglia F, Elsea SH, Sun Q, Beaudet AL, Schaaf CP

Abstract
Disorders of carnitine biosynthesis have recently been associated with neurodevelopmental syndromes such as autism spectrum disorder (ASD). A 4-year-old male with autism and two episodes of neurodevelopmental regression was identified to have a mutation in the TMLHE gene, which encodes the first enzyme in the carnitine biosynthesis pathway, and concurrent carnitine deficiency. Following carnitine supplementation, the patient's regression ended, and the boy started gaining developmental milestones. This case report suggests that deficits in carnitine biosynthesis may be responsible for some cases of regression in individuals with ASD, and that testing for the respective biochemical pathway should be considered. Furthermore, this case suggests that carnitine supplementation may be useful in treating (and potentially preventing) regressive episodes in patients with carnitine deficiency. Further work to better define the role of disorders of carnitine biosynthesis in autism spectrum disorder is warranted.

PMID: 25943046 [PubMed - indexed for MEDLINE]

High functioning male with fragile X syndrome and fragile X-associated tremor/ataxia syndrome.

May 20, 2016 - 7:34am
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High functioning male with fragile X syndrome and fragile X-associated tremor/ataxia syndrome.

Am J Med Genet A. 2015 Sep;167A(9):2154-61

Authors: Basuta K, Schneider A, Gane L, Polussa J, Woodruff B, Pretto D, Hagerman R, Tassone F

Abstract
Fragile X syndrome (FXS) affects individuals with more than 200 CGG repeats (full mutation) in the fragile X mental retardation 1 (FMR1) gene. Those born with FXS experience cognitive and social impairments, developmental delays, and some features of autism spectrum disorders. Carriers of a premutation (55-200 CGG repeats) are generally not severely affected early in life; however, are at high risk of developing the late onset neurodegenerative disorder, Fragile X-associated Tremor/Ataxia Syndrome (FXTAS), or Fragile X-associated Primary Ovarian Insufficiency (FXPOI), and may have other medical conditions such as developmental delay, autism spectrum disorders, hypertension, anxiety, and immune-mediated disorders. Here we present a case of a 58-year-old man with a borderline IQ, average memory skills, and executive function deficits. He met criteria for multiple psychiatric diagnoses and presented with tremor and ataxia, meeting criteria for FXTAS. Molecular testing unveiled a completely unmethylated FMR1 full mutation in peripheral blood mononucleated cells with elevated FMR1 mRNA and premutation alleles of different sizes in two other tissues (primary fibroblasts and sperm), indicating the presence of allele instability based on both inter- and intra-tissue mosaicism. The observation of FXTAS in this case of a full mutation mosaic man suggests that the pathogenic mechanism underlying this disorder is not observed exclusively in premutation carriers as it was originally thought. The concomitant presence of features of FXS and late onset neurological deterioration with probable FXTAS likely result from a combined molecular pathology of elevated FMR1 mRNA levels, a molecular hallmark of FXTAS and low FMRP expression that leads to FXS.

PMID: 25920745 [PubMed - indexed for MEDLINE]

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