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Microdeletions including FMR1 in three female patients with intellectual disability - further delineation of the phenotype and expression studies.

April 10, 2014 - 6:21am

Microdeletions including FMR1 in three female patients with intellectual disability - further delineation of the phenotype and expression studies.

Mol Syndromol. 2014 Feb;5(2):65-75

Authors: Zink AM, Wohlleber E, Engels H, Rødningen OK, Ravn K, Heilmann S, Rehnitz J, Katzorke N, Kraus C, Blichfeldt S, Hoffmann P, Reutter H, Brockschmidt FF, Kreiß-Nachtsheim M, Vogt PH, Prescott TE, Tümer Z, Lee JA

Abstract
Fragile X syndrome (FXS) is one of the most common causes of intellectual disability/developmental delay (ID/DD), especially in males. It is caused most often by CGG trinucleotide repeat expansions, and less frequently by point mutations and partial or full deletions of the FMR1 gene. The wide clinical spectrum of affected females partly depends on their X-inactivation status. Only few female ID/DD patients with microdeletions including FMR1 have been reported. We describe 3 female patients with 3.5-, 4.2- and 9.2-Mb de novo microdeletions in Xq27.3-q28 containing FMR1. X-inactivation was random in all patients, yet they presented with ID/DD as well as speech delay, macrocephaly and other features attributable to FXS. No signs of autism were present. Here, we further delineate the clinical spectrum of female patients with microdeletions. FMR1 expression studies gave no evidence for an absolute threshold below which signs of FXS present. Since FMR1 expression is known to be highly variable between unrelated females, and since FMR1 mRNA levels have been suggested to be more similar among family members, we further explored the possibility of an intrafamilial effect. Interestingly, FMR1 mRNA levels in all 3 patients were significantly lower than in their respective mothers, which was shown to be specific for patients with microdeletions containing FMR1.

PMID: 24715853 [PubMed]

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

April 10, 2014 - 6:21am

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

Am J Med Genet A. 2014 Apr 8;

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 - as supplied by publisher]

The role of AUTS2 in neurodevelopment and human evolution.

April 10, 2014 - 6:21am
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The role of AUTS2 in neurodevelopment and human evolution.

Trends Genet. 2013 Oct;29(10):600-8

Authors: Oksenberg N, Ahituv N

Abstract
The autism susceptibility candidate 2 (AUTS2) gene is associated with multiple neurological diseases, including autism, and has been implicated as an important gene in human-specific evolution. Recent functional analysis of this gene has revealed a potential role in neuronal development. Here, we review the literature regarding AUTS2, including its discovery, expression, association with autism and other neurological and non-neurological traits, implication in human evolution, function, regulation, and genetic pathways. Through progress in clinical genomic analysis, the medical importance of this gene is becoming more apparent, as highlighted in this review, but more work needs to be done to discover the precise function and the genetic pathways associated with AUTS2.

PMID: 24008202 [PubMed - indexed for MEDLINE]

Human genetics: Autism - clues from brains and protein domains.

April 9, 2014 - 8:52am

Human genetics: Autism - clues from brains and protein domains.

Nat Rev Genet. 2014 Apr 8;

Authors: Jones B

PMID: 24709752 [PubMed - as supplied by publisher]

Neuropsychological phenotype of a patient with a de novo 970 kb interstitial deletion in the distal 16p11.2 region.

April 8, 2014 - 8:15am

Neuropsychological phenotype of a patient with a de novo 970 kb interstitial deletion in the distal 16p11.2 region.

Neuropsychiatr Dis Treat. 2014;10:513-7

Authors: Egger JI, Verhoeven WM, Verbeeck W, de Leeuw N

Abstract
The 16p11.2 microdeletion syndrome is characterized by a wide range of phenotypic expressions and is frequently associated with developmental delay, symptoms from the autism spectrum, epilepsy, congenital anomalies, and obesity. These phenotypes are often related to a proximal 16p11.2 deletion of approximately 600 kb (BP4-BP5) that includes the SH2B1 gene that is reported to be causative for morbid obesity. This more centromeric deletion is most strongly related to autism spectrum susceptibility and is functionally different from the more distal 16p12.2p11.2 region, which includes the so-called atypical 16p11.2 BP2-BP3 deletion (approximately 220 kb) presenting with developmental delay, behavioral problems and mild facial dysmorphisms. Here, an adult male with a long history of maladaptive behaviors is described who was referred for diagnostic assessment of his amotivational features. Extensive neuropsychological examination demonstrated rigid thinking, anxious beliefs, and ideas of reference in the presence of normal intelligence. Microarray analysis demonstrated a de novo 970 kb 16p11.2 BP1-BP4 microdeletion that can be regarded as explanatory for his behavioral profile. It is concluded that microdeletion syndromes are not exclusively related to intellectual disabilities and genetic testing is of putative relevance for the understanding of neuropsychiatric and neuropsychological phenomena.

PMID: 24707176 [PubMed]

Phenotype-Based Genetic Association Studies (PGAS)-Towards Understanding the Contribution of Common Genetic Variants to Schizophrenia Subphenotypes.

April 8, 2014 - 8:15am

Phenotype-Based Genetic Association Studies (PGAS)-Towards Understanding the Contribution of Common Genetic Variants to Schizophrenia Subphenotypes.

Genes (Basel). 2014;5(1):97-105

Authors: Ehrenreich H, Nave KA

Abstract
Neuropsychiatric diseases ranging from schizophrenia to affective disorders and autism are heritable, highly complex and heterogeneous conditions, diagnosed purely clinically, with no supporting biomarkers or neuroimaging criteria. Relying on these "umbrella diagnoses", genetic analyses, including genome-wide association studies (GWAS), were undertaken but failed to provide insight into the biological basis of these disorders. "Risk genotypes" of unknown significance with low odds ratios of mostly <1.2 were extracted and confirmed by including ever increasing numbers of individuals in large multicenter efforts. Facing these results, we have to hypothesize that thousands of genetic constellations in highly variable combinations with environmental co-factors can cause the individual disorder in the sense of a final common pathway. This would explain why the prevalence of mental diseases is so high and why mutations, including copy number variations, with a higher effect size than SNPs, constitute only a small part of variance. Elucidating the contribution of normal genetic variation to (disease) phenotypes, and so re-defining disease entities, will be extremely labor-intense but crucial. We have termed this approach PGAS ("phenotype-based genetic association studies"). Ultimate goal is the definition of biological subgroups of mental diseases. For that purpose, the GRAS (Göttingen Research Association for Schizophrenia) data collection was initiated in 2005. With >3000 phenotypical data points per patient, it comprises the world-wide largest currently available schizophrenia database (N > 1200), combining genome-wide SNP coverage and deep phenotyping under highly standardized conditions. First PGAS results on normal genetic variants, relevant for e.g., cognition or catatonia, demonstrated proof-of-concept. Presently, an autistic subphenotype of schizophrenia is being defined where an unfortunate accumulation of normal genotypes, so-called pro-autistic variants of synaptic genes, explains part of the phenotypical variance. Deep phenotyping and comprehensive clinical data sets, however, are expensive and it may take years before PGAS will complement conventional GWAS approaches in psychiatric genetics.

PMID: 24705289 [PubMed]

KASHing up with the nucleus: novel functional roles of KASH proteins at the cytoplasmic surface of the nucleus.

April 8, 2014 - 8:15am

KASHing up with the nucleus: novel functional roles of KASH proteins at the cytoplasmic surface of the nucleus.

Curr Opin Cell Biol. 2014 Apr 3;28C:69-75

Authors: Luxton GG, Starr DA

Abstract
Nuclear-cytoskeletal connections are central to fundamental cellular processes, including nuclear positioning and chromosome movements in meiosis. The cytoskeleton is coupled to the nucleoskeleton through conserved KASH-SUN bridges, or LINC complexes, that span the nuclear envelope. KASH proteins localize to the outer nuclear membrane where they connect the nucleus to the cytoskeleton. New findings have expanded the functional diversity of KASH proteins, showing that they interact with microtubule motors, actin, intermediate filaments, a nonconventional myosin, RanGAP, and each other. The role of KASH proteins in cellular mechanics is discussed. Genetic mutations in KASH proteins are associated with autism, hearing loss, cancer, muscular dystrophy and other diseases.

PMID: 24704701 [PubMed - as supplied by publisher]

An Update on the Hypothesis that One Cause of Autism is High Intrauterine Levels of Testosterone of Maternal Origin.

April 8, 2014 - 8:15am

An Update on the Hypothesis that One Cause of Autism is High Intrauterine Levels of Testosterone of Maternal Origin.

J Theor Biol. 2014 Apr 1;

Authors: James WH

Abstract
Baron-Cohen's hypothesis that autism is caused by exposure to high intrauterine testosterone levels is considered in the context of (1) my hormonal hypothesis of sex ratio and (2) the notion of multifactorial inheritance. This yields the suggestions that 1. Female cases of autism may be the product of (high genetic loading+moderate environmental exposure) and male cases of (high environmental exposure+moderate genetic loading) and that 2. One environmental agent is intrauterine testosterone and that 3. The mother is the major source of that testosterone. These suggestions may help to explain most of the major established epidemiological risk factors for autism. These include various forms of pathology associated with psychological and/or physical stress. Stress of many sorts promotes the secretion of adrenal androgens in women. The three suggestions above may also explain some recently described features of autism including the psychological, behavioural and neuroanatomical differences between male and female cases.

PMID: 24703983 [PubMed - as supplied by publisher]

The PSD protein ProSAP2/Shank3 displays synapto-nuclear shuttling which is deregulated in a schizophrenia-associated mutation.

April 8, 2014 - 8:15am
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The PSD protein ProSAP2/Shank3 displays synapto-nuclear shuttling which is deregulated in a schizophrenia-associated mutation.

Exp Neurol. 2014 Mar;253:126-37

Authors: Grabrucker S, Proepper C, Mangus K, Eckert M, Chhabra R, Schmeisser MJ, Boeckers TM, Grabrucker AM

Abstract
Recently, mutations in ProSAP2/Shank3 have been discovered as one of the genetic factors for schizophrenia (SCZ). Here, we show that the postsynaptic density protein ProSAP2/Shank3 undergoes activity dependent synapse-to-nucleus shuttling in hippocampal neurons. Our study shows that the de novo mutation (R1117X) in ProSAP2/Shank3 that was identified in a patient with SCZ leads to an accumulation of mutated ProSAP2/Shank3 within the nucleus independent of synaptic activity. Furthermore, we identified novel nuclear ProSAP2/Shank3 interaction partners. Nuclear localization of mutated ProSAP2/Shank3 alters transcription of several genes, among them already identified genetic risk factors for SCZ such as Synaptotagmin 1 and LRRTM1. Comparing the SCZ mutation of ProSAP2/Shank3 to the knockdown of ProSAP2/Shank3 we found some shared features such as reduced synaptic density in neuronal cultures. However, hippocampal neurons expressing the ProSAP2/Shank3 SCZ mutation furthermore show altered E/I ratio and reduced dendritic branching. Thus, we conclude that the uncoupling of ProSAP2/Shank3 nuclear shuttling from synaptic activity may represent a molecular mechanism that contributes to the pathology of SCZ in patients with mutations in ProSAP2/Shank3.

PMID: 24382453 [PubMed - indexed for MEDLINE]

Developmental associations between traits of autism spectrum disorder and attention deficit hyperactivity disorder: a genetically informative, longitudinal twin study.

April 8, 2014 - 8:15am
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Developmental associations between traits of autism spectrum disorder and attention deficit hyperactivity disorder: a genetically informative, longitudinal twin study.

Psychol Med. 2013 Aug;43(8):1735-46

Authors: Taylor MJ, Charman T, Robinson EB, Plomin R, Happé F, Asherson P, Ronald A

Abstract
BACKGROUND: Autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD), and associated subclinical traits, regularly co-occur with one another. However, the aetiology of their co-occurrence remains poorly understood. This paper provides the first genetically informative, longitudinal analysis of the interaction between traits of ASD and ADHD, and explores their genetic and environmental overlap.
METHOD: Parents of approximately 5000 twin pairs completed questionnaires assessing traits of ASD and ADHD when twins were aged 8 and 12 years. Cross-lagged longitudinal modelling explored their developmental association, enabling a consideration of phenotypic-driven processes. Overlapping aetiological influences on traits at age 12 years were explored using bivariate twin modelling.
RESULTS: Traits of ADHD at age 8 years were more strongly predictive of traits of ASD at 12 years than traits of ASD at 8 years were of traits of ADHD at 12 years. Analysis of traits by subscales assessing specific symptom domains suggested that communication difficulties were most strongly associated with traits of ADHD. Bivariate modelling suggested moderate genetic overlap on traits in males (genetic correlation = 0.41), and a modest degree of overlap in females (genetic correlation = 0.23) at age 12 years.
CONCLUSIONS: Traits of ADHD at age 8 years significantly influence traits of ASD at age 12 years, after controlling for their initial relationship at age 8 years. In particular, early ADHD traits influenced later communication difficulties. These findings demonstrate the dynamic nature of co-occurring traits across development. In addition, these findings add to a growing body of literature suggesting that traits of ASD and ADHD may arise via similar aetiological processes.

PMID: 23158218 [PubMed - indexed for MEDLINE]

Clinical, cytogenetic, and molecular characterization of six patients with ring chromosomes 22, including one with concomitant 22q11.2 deletion.

April 5, 2014 - 3:51pm

Clinical, cytogenetic, and molecular characterization of six patients with ring chromosomes 22, including one with concomitant 22q11.2 deletion.

Am J Med Genet A. 2014 Apr 3;

Authors: Guilherme RS, Soares KC, Simioni M, Vieira TP, Gil-da-Silva-Lopes VL, Kim CA, Brunoni D, Spinner NB, Conlin LK, Christofolini DM, Kulikowski LD, Steiner CE, Melaragno MI

Abstract
We report here on six patients with a ring chromosome 22 and the range of cytogenetic and phenotypic features presented by them. Genomic analysis was carried out using classical and molecular cytogenetics, MLPA (Multiplex Ligation-dependent Probe Amplification) and genome-wide SNP-array analysis. The ring was found in all patients, but Patient 6 displayed constitutional mosaicism with a normal cell line. Five patients had deletions in the ring chromosome 22, and in four of them the breakpoints-unique for each patient-could be identified by genome-wide SNP-array analysis. One patient presented with a 22q11.2 deletion concomitant with the deletion caused by the ring formation. Common phenotypic features included autism, speech delay and seizures, as previously reported for individuals with r(22) and/or 22q13.3 deletions. Investigation of the genes within the deletions revealed multiple genes related to development of the central nervous system, psychomotor delay, severe language impairment, hypotonia, and autistic symptoms. There was no clear correlation between the severity of clinical features and the size of the deleted segment. This study underscores the variability in ring structure and clinical presentation of the r(22) and adds information to the limited literature on this rare disorder. © 2014 Wiley Periodicals, Inc.

PMID: 24700634 [PubMed - as supplied by publisher]

The relationship of neuroimaging findings and neuropsychiatric comorbidities in children with tuberous sclerosis complex.

April 5, 2014 - 3:51pm

The relationship of neuroimaging findings and neuropsychiatric comorbidities in children with tuberous sclerosis complex.

J Formos Med Assoc. 2014 Mar 31;

Authors: Huang CH, Peng SS, Weng WC, Su YN, Lee WT, National Taiwan University Hospital Tuberous Sclerosis Complex (NTUH TSC) Study Group

Abstract
BACKGROUND/PURPOSE: To clarify the relationship between neuroimaging findings, neuropsychiatric comorbidities, and epilepsy in patients with tuberous sclerosis complex (TSC) in Taiwan.
METHODS: Medical records from 32 patients with TSC were retrospectively reviewed, including mutational analysis, neuroimaging findings, electroencephalogram findings, and neuropsychiatric comorbidities.
RESULTS: Of these patients, six (18.75%) were diagnosed to have autism spectrum disorders (ASD), and 10 (31.25%) were diagnosed to have attention-deficit-hyperactivity disorder. In the latter patients, there were no differences in the regional distribution of tuber burden. In addition to a high prevalence of cystic-like tubers, tubers in insular and temporal areas were associated with ASD. Nonsense mutations in the TSC2 gene group had a correlation with autistic behavior. In 26 (81.25%) patients with a history of epilepsy, infantile spasms and partial seizures were the predominant type of epilepsy. Most of them developed seizures prior to age 1 year.
CONCLUSION: ASD is a common comorbidity in TSC. Cortical tubers in the temporal lobe and insular area were associated with ASD. The presence of cystic-like tubers on magnetic resonance imaging may also offer a structural marker for ASD in TSC.

PMID: 24698169 [PubMed - as supplied by publisher]

De novo EEF1A2 mutations in patients with characteristic facial features, intellectual disability and, autistic behaviors and epilepsy.

April 5, 2014 - 3:51pm

De novo EEF1A2 mutations in patients with characteristic facial features, intellectual disability and, autistic behaviors and epilepsy.

Clin Genet. 2014 Apr 3;

Authors: Nakajima J, Okamoto N, Tohyama J, Kato M, Arai H, Funahashi O, Tsurusaki Y, Nakashima M, Hisashi K, Saitsu H, Matsumoto N, Miyake N

Abstract
Eukaryotic elongation factor 1, alpha-2 (eEF1A2) protein is involved in protein synthesis, suppression of apoptosis, and regulation of actin function and cytoskeletal structure. EEF1A2 gene is highly expressed in the central nervous system and Eef1a2 knockout mice show the neuronal degeneration. Until now, only one missense mutation (c.208G>A, p.Gly70Ser) in EEF1A2 has been reported in two independent patients with neurological disease. In this report, we described two patients with de novo mutations (c.754G>C, p.Asp252His and c.364G>A, p.Glu122Lys) in EEF1A2 found by whole exome sequencing. Common clinical features are shared by all four individuals: severe intellectual disability, autistic behavior, absent speech, neonatal hypotonia, epilepsy and progressive microcephaly. Furthermore, the two patients share the similar characteristic facial features including a depressed nasal bridge, tented upper lip, everted lower lip and downturned corners of the mouth. These data strongly indicate that a new recognizable disorder is caused by EEF1A2 mutations.

PMID: 24697219 [PubMed - as supplied by publisher]

Association of the catechol-o-methyltransferase gene polymorphisms with Korean autism spectrum disorders.

April 5, 2014 - 3:51pm
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Association of the catechol-o-methyltransferase gene polymorphisms with Korean autism spectrum disorders.

J Korean Med Sci. 2013 Sep;28(9):1403-6

Authors: Yoo HJ, Cho IH, Park M, Yang SY, Kim SA

Abstract
This study evaluated the family-based genetic association between autism spectrum disorders (ASDs) and 5 single-nucleotide polymorphisms (SNPs) in the catechol-o-methyltransferase gene (COMT), which was found among 151 Korean ASDs family trios (dominant model Z = 2.598, P = 0.009, P FDR = 0.045). We found a statistically significant allele transmission or association in terms of the rs6269 SNP in the ASDs trios. Moreover, in the haplotype analysis, the haplotypes with rs6269 demonstrated significant evidence of an association with ASDs (additive model rs6269-rs4818-rs4680-rs769224 haplotype P = 0.004, P FDR = 0.040). Thus, an association may exist between the variants of the COMT gene and the occurrence of ASDs in Koreans.

PMID: 24015051 [PubMed - indexed for MEDLINE]

CNTNAP2 polymorphisms and structural brain connectivity: a diffusion-tensor imaging study.

April 5, 2014 - 3:51pm
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CNTNAP2 polymorphisms and structural brain connectivity: a diffusion-tensor imaging study.

J Psychiatr Res. 2013 Oct;47(10):1349-56

Authors: Clemm von Hohenberg C, Wigand MC, Kubicki M, Leicht G, Giegling I, Karch S, Hartmann AM, Konte B, Friedl M, Ballinger T, Eckbo R, Bouix S, Jäger L, Shenton ME, Rujescu D, Mulert C

Abstract
CNTNAP2 is a gene on chromosome 7 that has shown associations with autism and schizophrenia, and there is evidence that it plays an important role for neuronal synchronization and brain connectivity. In this study, we assessed the relationship between Diffusion Tensor Imaging (DTI), a putative marker of anatomical brain connectivity, and multiple single nucleotide polymorphisms (SNPs) spread out over this large gene. 81 healthy controls and 44 patients with schizophrenia (all Caucasian) underwent DTI and genotyping of 31 SNPs within CNTNAP2. We employed Tract-based Spatial Statistics (TBSS) for inter-subject brain registration and computed average diffusivity values for six major white matter tracts. Analyses of Covariance (ANCOVAs) were computed to test for possible associations with genotypes. The strongest association, which survived rigorous Bonferroni correction, was between rs2710126 genotype and Fractional Anisotropy (FA) in the uncinate fasciculus (p = .00003). This anatomical location is particularly interesting given the enriched fronto-temporal expression of CNTNAP2 in the developing brain. For this SNP, no phenotype association has been reported before. There were several further genotype-DTI associations that were nominally significant but did not survive Bonferroni correction, including an association between axial diffusivity in the dorsal cingulum bundle and a region in intron 13 (represented by rs2710102, rs759178, rs2538991), which has previously been reported to be associated with anterior-posterior functional connectivity. We present new evidence about the effects of CNTNAP2 on brain connectivity, whose disruption has been hypothesized to be central to schizophrenia pathophysiology.

PMID: 23871450 [PubMed - indexed for MEDLINE]

Common polymorphism in the oxytocin receptor gene (OXTR) is associated with human social recognition skills.

April 4, 2014 - 8:59am
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Common polymorphism in the oxytocin receptor gene (OXTR) is associated with human social recognition skills.

Proc Natl Acad Sci U S A. 2014 Feb 4;111(5):1987-92

Authors: Skuse DH, Lori A, Cubells JF, Lee I, Conneely KN, Puura K, Lehtimäki T, Binder EB, Young LJ

Abstract
The neuropeptides oxytocin and vasopressin are evolutionarily conserved regulators of social perception and behavior. Evidence is building that they are critically involved in the development of social recognition skills within rodent species, primates, and humans. We investigated whether common polymorphisms in the genes encoding the oxytocin and vasopressin 1a receptors influence social memory for faces. Our sample comprised 198 families, from the United Kingdom and Finland, in whom a single child had been diagnosed with high-functioning autism. Previous research has shown that impaired social perception, characteristic of autism, extends to the first-degree relatives of autistic individuals, implying heritable risk. Assessments of face recognition memory, discrimination of facial emotions, and direction of gaze detection were standardized for age (7-60 y) and sex. A common SNP in the oxytocin receptor (rs237887) was strongly associated with recognition memory in combined probands, parents, and siblings after correction for multiple comparisons. Homozygotes for the ancestral A allele had impairments in the range -0.6 to -1.15 SD scores, irrespective of their diagnostic status. Our findings imply that a critical role for the oxytocin system in social recognition has been conserved across perceptual boundaries through evolution, from olfaction in rodents to visual memory in humans.

PMID: 24367110 [PubMed - indexed for MEDLINE]

Attentional switching forms a genetic link between attention problems and autistic traits in adults.

April 4, 2014 - 8:59am
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Attentional switching forms a genetic link between attention problems and autistic traits in adults.

Psychol Med. 2013 Sep;43(9):1985-96

Authors: Polderman TJ, Hoekstra RA, Vinkhuyzen AA, Sullivan PF, van der Sluis S, Posthuma D

Abstract
BACKGROUND: Attention deficit hyperactivity disorder (ADHD) symptoms and autistic traits often occur together. The pattern and etiology of co-occurrence are largely unknown, particularly in adults. This study investigated the co-occurrence between both traits in detail, and subsequently examined the etiology of the co-occurrence, using two independent adult population samples. Method Data on ADHD traits (Inattention and Hyperactivity/Impulsivity) were collected in a population sample (S1, n = 559) of unrelated individuals. Data on Attention Problems (AP) were collected in a population-based family sample of twins and siblings (S2, n = 560). In both samples five dimensions of autistic traits were assessed (social skills, routine, attentional switching, imagination, patterns).
RESULTS: Hyperactive traits (S1) did not correlate substantially with the autistic trait dimensions. For Inattention (S1) and AP (S2), the correlations with the autistic trait dimensions were low, apart from a prominent correlation with the attentional switching scale (0.47 and 0.32 respectively). Analyses in the genetically informative S2 revealed that this association could be explained by a shared genetic factor.
CONCLUSIONS: Our findings suggest that the co-occurrence of ADHD traits and autistic traits in adults is not determined by problems with hyperactivity, social skills, imagination or routine preferences. Instead, the association between those traits is due primarily to shared attention-related problems (inattention and attentional switching capacity). As the etiology of this association is purely genetic, biological pathways involving attentional control could be a promising focus of future studies aimed at unraveling the genetic causes of these disorders.

PMID: 23257114 [PubMed - indexed for MEDLINE]

Associations between single-nucleotide polymorphism in the FNDC3A and autism spectrum disorder in a Korean population.

April 3, 2014 - 8:31am
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Associations between single-nucleotide polymorphism in the FNDC3A and autism spectrum disorder in a Korean population.

Psychiatry Res. 2013 Sep 30;209(2):246-8

Authors: Ro M, Park J, Nam M, Bang HJ, Yang JW, Choi KS, Kim SK, Chung JH, Kwack K

Abstract
Autism spectrum disorder (ASD) is a neurodevelopmental syndrome associated with impairments of reciprocal communication and cognitive function. Associations between single-nucleotide polymorphisms (SNPs) and ASD were analysed by logistic regression. Polymorphisms in fibronectin type III domain-containing 3A (FNDC3A) exhibited significant associations in genotype and diplotype analyses. We conclude that FNDC3A influences the prevalence of ASD.

PMID: 23639254 [PubMed - indexed for MEDLINE]

Chromosomal microarray analysis as a first-tier clinical diagnostic test: Estonian experience.

April 2, 2014 - 8:14am

Chromosomal microarray analysis as a first-tier clinical diagnostic test: Estonian experience.

Mol Genet Genomic Med. 2014 Mar;2(2):166-75

Authors: Zilina O, Teek R, Tammur P, Kuuse K, Yakoreva M, Vaidla E, Mölter-Väär T, Reimand T, Kurg A, Ounap K

Abstract
Chromosomal microarray analysis (CMA) is now established as the first-tier cytogenetic diagnostic test for fast and accurate detection of chromosomal abnormalities in patients with developmental delay/intellectual disability (DD/ID), multiple congenital anomalies (MCA), and autism spectrum disorders (ASD). We present our experience with using CMA for postnatal and prenatal diagnosis in Estonian patients during 2009-2012. Since 2011, CMA is on the official service list of the Estonian Health Insurance Fund and is performed as the first-tier cytogenetic test for patients with DD/ID, MCA or ASD. A total of 1191 patients were analyzed, including postnatal (1072 [90%] patients and 59 [5%] family members) and prenatal referrals (60 [5%] fetuses). Abnormal results were reported in 298 (25%) patients, with a total of 351 findings (1-3 per individual): 147 (42%) deletions, 106 (30%) duplications, 89 (25%) long contiguous stretches of homozygosity (LCSH) events (>5 Mb), and nine (3%) aneuploidies. Of all findings, 143 (41%) were defined as pathogenic or likely pathogenic; for another 143 findings (41%), most of which were LCSH, the clinical significance remained unknown, while 61 (18%) reported findings can now be reclassified as benign or likely benign. Clinically relevant findings were detected in 126 (11%) patients. However, the proportion of variants of unknown clinical significance was quite high (41% of all findings). It seems that our ability to detect chromosomal abnormalities has far outpaced our ability to understand their role in disease. Thus, the interpretation of CMA findings remains a rather difficult task requiring a close collaboration between clinicians and cytogeneticists.

PMID: 24689080 [PubMed]

Incontinentia pigmenti and hypomelanosis of Ito.

April 2, 2014 - 8:14am
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Incontinentia pigmenti and hypomelanosis of Ito.

Handb Clin Neurol. 2013;111:341-7

Authors: Bodemer C

Abstract
Incontinentia pigmenti (IP) is a rare X-linked dominant neurocutaneous disorder affecting ectodermal tissue: skin, eyes, central nervous system, hair, nails, and teeth. It is usually lethal for males in utero. The involved gene is NEMO, an essential component of the nuclear factor-kappa B (NF-κB) signaling pathway. Skin lesions are highly diagnostic, occurring in neonates, with a particular distribution on Blaschko lines. The severity of the disease is related to ocular and neurological impairment. The hallmark of ocular IP is retinal vasculopathy including peripheral retinal vascular nonperfusion, macular infarction and neovascularization, and preretinal neovascularization. CNS involvement consists of seizures, mental retardation, hemiparesis, spasticity, microcephaly, cerebellar ataxia, and coma. It often occurs in neonates. Some patients have persistent pharmacoresistant seizures throughout life. MRI findings consist essentially in: white-matter lesions; scattered cortical neuronal necrosis; multiple cerebral infarctions; cerebral atrophy, hypoplasia of the corpus callosum, encephalomalacia and neuronal heterotopia. A predominant role of vascular occlusive phenomena in small vessels is highly suspected. In fact several intricate mechanisms could be discussed: vascular, inflammatory, developmental mechanisms. Their role and predictive factors of IP CNS involvement in neonatal IP need to be better understood to identify effective innovative therapies. Hypomelanosis of Ito can occur in the neonate, infancy, or childhood, be isolated or diffuse, often following the Blaschko lines, and can fade in childhood or adulthood. It is due to reduced melanin in the epidermis. Eye, central nervous (mental retardation, epilepsy, language disabilities, motor system dysfunction, psychiatric symptoms including autism - with frequent cortical malformations including hemimegalencephaly and white matter involvement), and musculoskeletal systems can also be affected. Mosaicism with various chromosomal rearrangements has been reported.

PMID: 23622185 [PubMed - indexed for MEDLINE]

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