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Microduplication of 15q13.3 and Xq21.31 in a family with Tourette syndrome and comorbidities.

October 23, 2014 - 7:49am
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Microduplication of 15q13.3 and Xq21.31 in a family with Tourette syndrome and comorbidities.

Am J Med Genet B Neuropsychiatr Genet. 2013 Dec;162B(8):825-31

Authors: Melchior L, Bertelsen B, Debes NM, Groth C, Skov L, Mikkelsen JD, Brøndum-Nielsen K, Tümer Z

Abstract
Tourette syndrome (TS) is a childhood onset neurodevelopmental disorder. Although it is widely accepted that genetic factors play a significant role in TS pathogenesis the etiology of this disorder is largely unknown. Identification of rare copy number variations (CNVs) as susceptibility factors in several neuropsychiatric disorders such as attention deficit-hyperactivity disorder (ADHD), autism and schizophrenia, suggests involvement of these rare structural changes also in TS etiology. In a male patient with TS, ADHD, and OCD (obsessive compulsive disorder) we identified two microduplications (at 15q13.3 and Xq21.31) inherited from a mother with subclinical ADHD. The 15q duplication included the CHRNA7 gene; while two genes, PABPC5 and PCDH11X, were within the Xq duplication. The Xq21.31 duplication was present in three brothers with TS including the proband, but not in an unaffected brother, whereas the 15q duplication was present only in the proband and his mother. The structural variations observed in this family may contribute to the observed symptoms, but further studies are necessary to investigate the possible involvement of the described variations in the TS etiology.

PMID: 23894120 [PubMed - indexed for MEDLINE]

Serotonin 2A receptor gene (HTR2A) regulatory variants: possible association with severity of depression symptoms in children with autism spectrum disorder.

October 22, 2014 - 7:38am
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Serotonin 2A receptor gene (HTR2A) regulatory variants: possible association with severity of depression symptoms in children with autism spectrum disorder.

Cogn Behav Neurol. 2014 Jun;27(2):107-16

Authors: Gadow KD, Smith RM, Pinsonneault JK

Abstract
OBJECTIVE AND BACKGROUND: Our aim was to characterize the association of 2 functional single nucleotide polymorphisms (rs6311 and rs6314) in the serotonin 2A receptor gene (HTR2A) with severity of depression symptoms in children with autism spectrum disorder. These polymorphisms have been shown to be associated with depression symptom severity and response to selective serotonin reuptake inhibitor drugs in adults with diagnosed depressive disorder.
METHODS: Parents of 104 children with autism spectrum disorder rated their children's depressive symptoms using a validated scale based on criteria from the Diagnostic and Statistical Manual of Mental Disorders, 4th edition. We compared severity of depression symptoms across the rs6311 and rs6314 genotypes, measured from the children's genomic DNA.
RESULTS: Children homozygous for the G allele of rs6311 had significantly more severe depression symptoms than those with G/A or A/A genotypes (P=0.025). The effect size (partial eta-squared) was small (ηp=0.047) but was somewhat larger when we controlled for severity of generalized anxiety disorder symptoms (P=0.006, ηp=0.072). When we restricted our analyses to white participants, our results were essentially the same as for the entire sample (P=0.004, ηp=0.086). There was no significant association between rs6314 (C/C versus T carriers) and severity of depression.
CONCLUSIONS: Our findings suggest that the HTR2A functional rs6311 polymorphism, which other studies have associated with differential HTR2A mRNA expression, may modulate the severity of depression symptoms in children with autism spectrum disorder. These tentative, hypothesis-generating findings need replication with larger, independent samples.

PMID: 24968012 [PubMed - indexed for MEDLINE]

A girl with tuberous sclerosis complex presenting with severe epilepsy and electrical status epilepticus during sleep, and with high-functioning autism and mutism.

October 22, 2014 - 7:38am
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A girl with tuberous sclerosis complex presenting with severe epilepsy and electrical status epilepticus during sleep, and with high-functioning autism and mutism.

Cogn Behav Neurol. 2014 Jun;27(2):88-95

Authors: Pacheva I, Panov G, Gillberg C, Neville B

Abstract
Most patients with tuberous sclerosis complex (TSC) suffer from epilepsy, and many have cognitive and behavioral problems like severe intellectual disability, autism, and hyperactivity. Only rare patients with TSC and autism have a normal intelligence quotient. We report a 13-year-old girl with definite TSC who had early-onset severe epilepsy, autistic behavior, and moderate developmental delay. By school age, however, she had normal intelligence; her intelligence quotient was at least 70 based on a Stanford-Binet test that she refused to complete. She showed good reading, writing, and language comprehension skills, and the special abilities of hyperlexia, hypermnesia, and hypercalculia. However, she did not speak. Criteria of the Diagnostic and Statistical Manual of Mental Disorders, 4th edition, and her Childhood Autism Rating Scale score of 36 indicated mild to moderate autism. She had severe electroencephalographic abnormalities: hypsarrhythmia, multifocal or generalized epileptiform discharges, and electrical status epilepticus during sleep, with a continuous left temporal focus. Magnetic resonance imaging showed many cortical tubers in all brain lobes, and subependymal nodules. We discuss possible explanations for her lack of speech. Considered as speech apraxia, her mutism could be either a symptom of her TSC or a component of her autism. Another possibility is that long-lasting electrical status epilepticus during sleep led to her autistic behavior and language arrest. Still another possibility is that a disinhibited mammalian target of rapamycin (mTOR) pathway was at the root of all of her neuropsychiatric symptoms.

PMID: 24968009 [PubMed - indexed for MEDLINE]

Altered expression of Alzheimer's disease-related genes in the cerebellum of autistic patients: a model for disrupted brain connectome and therapy.

October 22, 2014 - 7:38am
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Altered expression of Alzheimer's disease-related genes in the cerebellum of autistic patients: a model for disrupted brain connectome and therapy.

Cell Death Dis. 2014;5:e1250

Authors: Zeidán-Chuliá F, de Oliveira BH, Salmina AB, Casanova MF, Gelain DP, Noda M, Verkhratsky A, Moreira JC

Abstract
Autism and Alzheimer's disease (AD) are, respectively, neurodevelopmental and degenerative diseases with an increasing epidemiological burden. The AD-associated amyloid-β precursor protein-α has been shown to be elevated in severe autism, leading to the 'anabolic hypothesis' of its etiology. Here we performed a focused microarray analysis of genes belonging to NOTCH and WNT signaling cascades, as well as genes related to AD and apoptosis pathways in cerebellar samples from autistic individuals, to provide further evidence for pathological relevance of these cascades for autism. By using the limma package from R and false discovery rate, we demonstrated that 31% (116 out of 374) of the genes belonging to these pathways displayed significant changes in expression (corrected P-values <0.05), with mitochondria-related genes being the most downregulated. We also found upregulation of GRIN1, the channel-forming subunit of NMDA glutamate receptors, and MAP3K1, known activator of the JNK and ERK pathways with anti-apoptotic effect. Expression of PSEN2 (presinilin 2) and APBB1 (or F65) were significantly lower when compared with control samples. Based on these results, we propose a model of NMDA glutamate receptor-mediated ERK activation of α-secretase activity and mitochondrial adaptation to apoptosis that may explain the early brain overgrowth and disruption of synaptic plasticity and connectome in autism. Finally, systems pharmacology analyses of the model that integrates all these genes together (NOWADA) highlighted magnesium (Mg(2+)) and rapamycin as most efficient drugs to target this network model in silico. Their potential therapeutic application, in the context of autism, is therefore discussed.

PMID: 24853428 [PubMed - indexed for MEDLINE]

Recommendations for early diagnosis and intervention in autism spectrum disorders: an Italian-Israeli consensus conference.

October 22, 2014 - 7:38am
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Recommendations for early diagnosis and intervention in autism spectrum disorders: an Italian-Israeli consensus conference.

Eur J Paediatr Neurol. 2014 Mar;18(2):107-18

Authors: Zachor DA, Curatolo P, Participants of Italian-Israeli Consensus Conference

Abstract
On April 2013 experts in the field of autism from Italy and Israel convened in Jerusalem to discuss and finalize clinical recommendations for early diagnosis and intervention in Autism Spectrum Disorders (ASDs). In this paper, we summarize the results of this Italian-Israeli consensus conference. ASDs constitute a class of severe and heterogeneous neurodevelopmental conditions caused by atypical brain development beginning during early prenatal life, reflecting many genetic, neurobiological and environmental influences. The first clinical signs of ASDs begin to be evident in children between 12 and 18 months of age, often after a period of relatively typical postnatal development. Recent longitudinal studies reveal substantial diversity in developmental trajectories through childhood and adolescence. Some intervention approaches have been demonstrated to be effective in improving core symptoms of ASDs, even if the heterogeneity and developmental nature of the disorder make it implausible that only one specific treatment will be best for all children with ASDs. More randomized control trials (RCTs) on early intervention are needed to identify the most effective strategies and provide the most efficient allocation of resources during the critical early intervention time period. Future research should focus on linking biological phenotypes with specific genotypes, thus establishing a foundation for the development of diagnostic screening tools and individualization of treatments.

PMID: 24095105 [PubMed - indexed for MEDLINE]

Recurrence rates in autism spectrum disorders--reply.

October 21, 2014 - 7:17am
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Recurrence rates in autism spectrum disorders--reply.

JAMA. 2014 Sep 17;312(11):1155

Authors: Sandin S, Reichenberg A

PMID: 25226487 [PubMed - indexed for MEDLINE]

Recurrence rates in autism spectrum disorders.

October 21, 2014 - 7:17am
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Recurrence rates in autism spectrum disorders.

JAMA. 2014 Sep 17;312(11):1154-5

Authors: Constantino JN

PMID: 25226485 [PubMed - indexed for MEDLINE]

Downregulation of GABAA receptor protein subunits α6, β2, δ, ε, γ2, θ, and ρ2 in superior frontal cortex of subjects with autism.

October 21, 2014 - 7:17am
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Downregulation of GABAA receptor protein subunits α6, β2, δ, ε, γ2, θ, and ρ2 in superior frontal cortex of subjects with autism.

J Autism Dev Disord. 2014 Aug;44(8):1833-45

Authors: Fatemi SH, Reutiman TJ, Folsom TD, Rustan OG, Rooney RJ, Thuras PD

Abstract
We measured protein and mRNA levels for nine gamma-aminobutyric acid A (GABAA) receptor subunits in three brain regions (cerebellum, superior frontal cortex, and parietal cortex) in subjects with autism versus matched controls. We observed changes in mRNA for a number of GABAA and GABAB subunits and overall reduced protein expression for GABAA receptor alpha 6 (GABRα6), GABAA receptor beta 2 (GABRβ2), GABAA receptor delta (GABRδ), GABAA receptor epsilon (GABRε), GABAA receptor gamma 2 (GABRγ2), GABAA receptor theta (GABRθ), and GABAA receptor rho 2 (GABRρ2) in superior frontal cortex from subjects with autism. Our data demonstrate systematic changes in GABAA&B subunit expression in brains of subjects with autism, which may help explain the presence of cognitive abnormalities in subjects with autism.

PMID: 24668190 [PubMed - indexed for MEDLINE]

A twin study of heritable and shared environmental contributions to autism.

October 21, 2014 - 7:17am
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A twin study of heritable and shared environmental contributions to autism.

J Autism Dev Disord. 2014 Aug;44(8):2013-25

Authors: Frazier TW, Thompson L, Youngstrom EA, Law P, Hardan AY, Eng C, Morris N

Abstract
The present study examined genetic and shared environment contributions to quantitatively-measured autism symptoms and categorically-defined autism spectrum disorders (ASD). Participants included 568 twins from the Interactive Autism Network. Autism symptoms were obtained using the Social Communication Questionnaire and Social Responsiveness Scale. Categorically-defined ASD was based on clinical diagnoses. DeFries-Fulker and liability threshold models examined etiologic influences. Very high heritability was observed for extreme autism symptom levels ([Formula: see text]). Extreme levels of social and repetitive behavior symptoms were strongly influenced by common genetic factors. Heritability of categorically-defined ASD diagnosis was comparatively low (.21, 95 % CI 0.15-0.28). High heritability of extreme autism symptom levels confirms previous observations of strong genetic influences on autism. Future studies will require large, carefully ascertained family pedigrees and quantitative symptom measurements.

PMID: 24604525 [PubMed - indexed for MEDLINE]

Palindromic GOLGA8 core duplicons promote chromosome 15q13.3 microdeletion and evolutionary instability.

October 20, 2014 - 6:52am

Palindromic GOLGA8 core duplicons promote chromosome 15q13.3 microdeletion and evolutionary instability.

Nat Genet. 2014 Oct 19;

Authors: Antonacci F, Dennis MY, Huddleston J, Sudmant PH, Steinberg KM, Rosenfeld JA, Miroballo M, Graves TA, Vives L, Malig M, Denman L, Raja A, Stuart A, Tang J, Munson B, Shaffer LG, Amemiya CT, Wilson RK, Eichler EE

Abstract
Recurrent deletions of chromosome 15q13.3 associate with intellectual disability, schizophrenia, autism and epilepsy. To gain insight into the instability of this region, we sequenced it in affected individuals, normal individuals and nonhuman primates. We discovered five structural configurations of the human chromosome 15q13.3 region ranging in size from 2 to 3 Mb. These configurations arose recently (∼0.5-0.9 million years ago) as a result of human-specific expansions of segmental duplications and two independent inversion events. All inversion breakpoints map near GOLGA8 core duplicons-a ∼14-kb primate-specific chromosome 15 repeat that became organized into larger palindromic structures. GOLGA8-flanked palindromes also demarcate the breakpoints of recurrent 15q13.3 microdeletions, the expansion of chromosome 15 segmental duplications in the human lineage and independent structural changes in apes. The significant clustering (P = 0.002) of breakpoints provides mechanistic evidence for the role of this core duplicon and its palindromic architecture in promoting the evolutionary and disease-related instability of chromosome 15.

PMID: 25326701 [PubMed - as supplied by publisher]

Association between autism spectrum disorder in individuals with velocardiofacial (22q11.2 deletion) syndrome and PRODH and COMT genotypes.

October 18, 2014 - 6:18am

Association between autism spectrum disorder in individuals with velocardiofacial (22q11.2 deletion) syndrome and PRODH and COMT genotypes.

Psychiatr Genet. 2014 Oct 16;

Authors: Radoeva PD, Coman IL, Salazar CA, Gentile KL, Higgins AM, Middleton FA, Antshel KM, Fremont W, Shprintzen RJ, Morrow BE, Kates WR

Abstract
Velocardiofacial (VCFS; 22q11.2 deletion) syndrome is a genetic disorder that results from a hemizygous deletion of the q11.2 region on chromosome 22, and is associated with greatly increased risk for psychiatric disorders, including autism spectrum disorder (ASD) and schizophrenia. There is emerging evidence for the involvement of catechol-O-methyltransferase (COMT) and proline dehydrogenase (oxidase) 1 (PRODH) in the psychiatric phenotype of individuals with VCFS. Here, we tested the hypothesis that PRODH and COMT are associated with ASD in youths with VCFS. We found that individuals with VCFS and the low-activity alleles of both PRODH and COMT (rs4819756A and rs4680A) were more likely to present with ASD as compared with individuals with VCFS and the high-activity alleles of these genes [P<0.05; odds ratio=6.0 (95% confidence interval=1.27-28.26; N=87)]. Our results suggest that PRODH and COMT may interact to contribute to the ASD phenotype in individuals with VCFS.

PMID: 25325218 [PubMed - as supplied by publisher]

Towards a new point of view on the phenotype of patients with a 17q12 microdeletion syndrome.

October 18, 2014 - 6:18am

Towards a new point of view on the phenotype of patients with a 17q12 microdeletion syndrome.

Arch Dis Child. 2014 Oct 16;

Authors: Laffargue F, Bourthoumieu S, Llanas B, Baudouin V, Lahoche A, Morin D, Bessenay L, De Parscau L, Cloarec S, Delrue MA, Taupiac E, Dizier E, Laroche C, Bahans C, Yardin C, Lacombe D, Guigonis V

Abstract
OBJECTIVE: 17q12 microdeletion syndrome involves 15 genes, including HNF1B, and is considered to confer a high risk of neuropsychiatric disorders. Patients with HNF1B gene deletion diagnosed secondary to renal disorders are only very rarely reported to have neuropsychiatric disorders. Interestingly, however, when tested, patients with HNF1B gene deletion are found to have 17q12 deletion. This brings into question the extent to which 17q12 deletion is genuinely associated with severe neuropsychological disorders and in which patients. In this study, we sought to confirm 17q12 microdeletion in kidney patients initially diagnosed with HNF1B gene deletion and evaluate neuropsychological disorders in these patients compared with those with HNF1B point mutation.
PATIENTS AND DESIGN: Thirty-nine children with HNF1B disorders (26 with deletions) diagnosed secondary to renal abnormalities were included in this prospective study and tested for 17q12 microdeletion and neuropsychological disorders.
RESULTS: The same 17q12 microdeletion found in patients with neuropsychological disorders was identified in all of our patients with HNF1B deletion. Neurological examinations found no severe impairments except for one patient with autism. No significant differences were found between patients with deletions and those with point mutations as concerns learning abilities and schooling. Nevertheless, patients with deletions tended to have lower developmental quotients and more difficulties at school.
CONCLUSIONS: Complete deletion of the HNF1B gene and 17q12 microdeletion syndrome are actually the same genetic disorder. The neuropsychological phenotype of patients appears less severe when 17q12 deletion is diagnosed secondary to kidney rather than neuropsychological abnormalities. These data may influence antenatal counselling.

PMID: 25324567 [PubMed - as supplied by publisher]

A comparative study of health locus of control in patients with schizophrenia and their first degree relatives.

October 18, 2014 - 6:18am
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A comparative study of health locus of control in patients with schizophrenia and their first degree relatives.

Asian J Psychiatr. 2014 Feb;7(1):34-7

Authors: Thakral S, Bhatia T, Gettig EA, Nimgaonkar VL, Deshpande SN

Abstract
BACKGROUND AND AIMS: An individual's behaviour may be predicted from their beliefs about their locus of control (attribution). A person's "locus" can be internal or external. The present study aimed at comparing the locus of control as measured by Multidimensional Health Locus of Control Scale (MHLC) in patients with schizophrenia and their healthy first degree relatives. We hypothesized that persons with schizophrenia have different locus of control than their first degree relatives.
METHOD: Multidimensional Health Locus of Control Scale (MHLC) was first translated and validated in Hindi by bilingual students (N = 71). Consecutive patients affected with schizophrenia (SZ) (N = 125) and their siblings/offsprings (N = 119) were recruited. Diagnostic Interview for Genetic Studies and MHLC Scale were administered after written informed consent.
RESULTS: There was moderate intra-class correlation between Hindi and English versions of MHLC Scale. Schizophrenia patients were found to have more of 'chance' locus of control (F 6.625, p = 0.011) whereas their first degree relatives have more of 'internal' locus of control (F 6.760, p = 0.010).
CONCLUSION: Patients with SZ attributed their health to external factors which has been found to be associated with poor or late recovery. These findings may provide a theoretical base for developing intervention strategies to promote behavioural changes in patients.

PMID: 24524707 [PubMed - indexed for MEDLINE]

A commonly carried genetic variant, rs9616915, in SHANK3 gene is associated with a reduced risk of autism spectrum disorder: replication in a Chinese population.

October 18, 2014 - 6:18am
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A commonly carried genetic variant, rs9616915, in SHANK3 gene is associated with a reduced risk of autism spectrum disorder: replication in a Chinese population.

Mol Biol Rep. 2014 Mar;41(3):1591-5

Authors: Shao S, Xu S, Yang J, Zhang T, He Z, Sun Z, Song R

Abstract
Autism spectrum disorder (ASD) is one of neurodevelopmental disorders with highly heritability. Recently, abnormality at the synapse is found to be important etiology of ASD. SHANK3 gene is suggested as a strong candidate gene for the pathogenesis of ASD, because it is essential for normally synaptic structure and function. We performed a case-control study to identify association between rs9616915 of the SHANK3 gene and ASD in a Chinese population. Genomic DNA was extracted from oral swabs samples of 212 patients and 636 controls and the SNP genotypes were determined by a polymerase chain reaction-restriction fragment length polymerase assay. Significant difference in genotype distribution of rs9616915 was observed between cases and controls by Pearson's χ(2) test (χ(2) = 6.92, P = 0.031). Genetic analysis of heterozygous model, dominant model and additive model showed an association of the C allele of the rs9616915 with ASD (e.g., additive model, OR 0.582, 95% CI 0.359-0.942, P = 0.028). In conclusion, our results suggested that this commonly genetic variant in SHANK3 gene strikingly decreased the risk of ASD in China.

PMID: 24398551 [PubMed - indexed for MEDLINE]

Copy-number variation in the pathogenesis of autism spectrum disorder.

October 18, 2014 - 6:18am
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Copy-number variation in the pathogenesis of autism spectrum disorder.

Psychiatry Clin Neurosci. 2014 Feb;68(2):85-95

Authors: Shishido E, Aleksic B, Ozaki N

Abstract
Autism spectrum disorder is a neurodevelopmental disorder present in 1% of the population, characterized by impairments in reciprocal social interaction, communication deficits and restricted patterns of behavior. Approximately 10% of the autism spectrum disorder population is thought to have large chromosomal rearrangements. Copy-number variations (CNV) alter the genome structure either by duplication or deletion of a chromosomal region. The association between CNV and autism susceptibility has become more apparent through the use of methods based on comparative genomic hybridization in screening CNV. The nature of the high CNV rate in the human genome is partly explained by non-allelic homologous recombination between flanking repeated sequences derived from multiple copies of transposons or mobile genetic elements. There are hotspots for CNV in the human genome, such as 16p11.2 and 22q11.2. Genes involved in CNV are supposed to have copy-number dose-dependent effects on the behavior of affected individuals. Animal models give insight into the possible interactions between core genetic loci and additional factors contributing to the phenotypes of each individual. If affected genes code for cellular signaling molecules, reducing the dosage in the intracellular signaling pathway may result in the malfunction of the nervous system. The genetic background of autism spectrum disorder is highly heterogenic and most common or rare CNV do not lead to autism spectrum disorders in the majority of cases, but may occasionally increase the risk of developing an autism spectrum disorder.

PMID: 24372918 [PubMed - indexed for MEDLINE]

MTHFR 1298A>C is a risk factor for autism spectrum disorder in the Korean population.

October 18, 2014 - 6:18am
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MTHFR 1298A>C is a risk factor for autism spectrum disorder in the Korean population.

Psychiatry Res. 2014 Jan 30;215(1):258-9

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

PMID: 24295761 [PubMed - indexed for MEDLINE]

Association between the polymorphisms of the selected genes encoding dopaminergic system with ADHD and autism.

October 18, 2014 - 6:18am
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Association between the polymorphisms of the selected genes encoding dopaminergic system with ADHD and autism.

Psychiatry Res. 2014 Jan 30;215(1):260-1

Authors: Nikolac Perkovic M, Nedic Erjavec G, Stefulj J, Muck-Seler D, Pivac N, Kocijan Hercigonja D, Hranilovic D, Curkovic M, Dodig-Curkovic K

PMID: 24210742 [PubMed - indexed for MEDLINE]

Social impairments in chromosome 22q11.2 deletion syndrome (22q11.2DS): autism spectrum disorder or a different endophenotype?

October 18, 2014 - 6:18am
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Social impairments in chromosome 22q11.2 deletion syndrome (22q11.2DS): autism spectrum disorder or a different endophenotype?

J Autism Dev Disord. 2014 Apr;44(4):739-46

Authors: Angkustsiri K, Goodlin-Jones B, Deprey L, Brahmbhatt K, Harris S, Simon TJ

Abstract
High prevalence of autism spectrum disorders (ASD) has been reported in 22q11.2DS, although this has been based solely on parent report measures. This study describes the presence of ASD using a procedure more similar to that used in clinical practice by incorporating history (Social Communication Questionnaire) AND a standardized observation measure (Autism Diagnostic Observation Schedule) and suggests that ASD is not as common as previously reported in 22q11.2DS. Differences in methodology, along with comorbid conditions such as anxiety, likely contribute to false elevations in ASD prevalence and information from multiple sources should be included in the evaluation of ASD.

PMID: 24045981 [PubMed - indexed for MEDLINE]

Cannabinoid receptor type 2, but not type 1, is up-regulated in peripheral blood mononuclear cells of children affected by autistic disorders.

October 18, 2014 - 6:18am
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Cannabinoid receptor type 2, but not type 1, is up-regulated in peripheral blood mononuclear cells of children affected by autistic disorders.

J Autism Dev Disord. 2013 Nov;43(11):2686-95

Authors: Siniscalco D, Sapone A, Giordano C, Cirillo A, de Magistris L, Rossi F, Fasano A, Bradstreet JJ, Maione S, Antonucci N

Abstract
Autistic disorders (ADs) are heterogeneous neurodevelopmental disorders arised by the interaction of genes and environmental factors. Dysfunctions in social interaction and communication skills, repetitive and stereotypic verbal and non-verbal behaviours are common features of ADs. There are no defined mechanisms of pathogenesis, rendering curative therapy very difficult. Indeed, the treatments for autism presently available can be divided into behavioural, nutritional and medical approaches, although no defined standard approach exists. Autistic children display immune system dysregulation and show an altered immune response of peripheral blood mononuclear cells (PBMCs). In this study, we investigated the involvement of cannabinoid system in PBMCs from autistic children compared to age-matched normal healthy developing controls (age ranging 3-9 years; mean age: 6.06 ± 1.52 vs. 6.14 ± 1.39 in autistic children and healthy subjects, respectively). The mRNA level for cannabinoid receptor type 2 (CB2) was significantly increased in AD-PBMCs as compared to healthy subjects (mean ± SE of arbitrary units: 0.34 ± 0.03 vs. 0.23 ± 0.02 in autistic children and healthy subjects, respectively), whereas CB1 and fatty acid amide hydrolase mRNA levels were unchanged. mRNA levels of N-acylphosphatidylethanolamine-hydrolyzing phospholipase D gene were slightly decreased. Protein levels of CB-2 were also significantly increased in autistic children (mean ± SE of arbitrary units: 33.5 ± 1.32 vs. 6.70 ± 1.25 in autistic children and healthy subjects, respectively). Our data indicate CB2 receptor as potential therapeutic target for the pharmacological management of the autism care.

PMID: 23585028 [PubMed - indexed for MEDLINE]

Subclinical inflammatory status in Rett syndrome.

October 17, 2014 - 2:58pm
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Subclinical inflammatory status in Rett syndrome.

Mediators Inflamm. 2014;2014:480980

Authors: Cortelazzo A, De Felice C, Guerranti R, Signorini C, Leoncini S, Pecorelli A, Zollo G, Landi C, Valacchi G, Ciccoli L, Bini L, Hayek J

Abstract
Inflammation has been advocated as a possible common central mechanism for developmental cognitive impairment. Rett syndrome (RTT) is a devastating neurodevelopmental disorder, mainly caused by de novo loss-of-function mutations in the gene encoding MeCP2. Here, we investigated plasma acute phase response (APR) in stage II (i.e., "pseudo-autistic") RTT patients by routine haematology/clinical chemistry and proteomic 2-DE/MALDI-TOF analyses as a function of four major MECP2 gene mutation types (R306C, T158M, R168X, and large deletions). Elevated erythrocyte sedimentation rate values (median 33.0 mm/h versus 8.0 mm/h, P < 0.0001) were detectable in RTT, whereas C-reactive protein levels were unchanged (P = 0.63). The 2-DE analysis identified significant changes for a total of 17 proteins, the majority of which were categorized as APR proteins, either positive (n = 6 spots) or negative (n = 9 spots), and to a lesser extent as proteins involved in the immune system (n = 2 spots), with some proteins having overlapping functions on metabolism (n = 7 spots). The number of protein changes was proportional to the severity of the mutation. Our findings reveal for the first time the presence of a subclinical chronic inflammatory status related to the "pseudo-autistic" phase of RTT, which is related to the severity carried by the MECP2 gene mutation.

PMID: 24511209 [PubMed - indexed for MEDLINE]

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