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Similar white matter but opposite grey matter changes in schizophrenia and high-functioning autism.

April 23, 2016 - 7:35am

Similar white matter but opposite grey matter changes in schizophrenia and high-functioning autism.

Acta Psychiatr Scand. 2016 Apr 22;

Authors: Katz J, d'Albis MA, Boisgontier J, Poupon C, Mangin JF, Guevara P, Duclap D, Hamdani N, Petit J, Monnet D, Le Corvoisier P, Leboyer M, Delorme R, Houenou J

Abstract
OBJECTIVE: High-functioning autism (HFA) and schizophrenia (SZ) are two of the main neurodevelopmental disorders, sharing several clinical dimensions and risk factors. Their exact relationship is poorly understood, and few studies have directly compared both disorders. Our aim was thus to directly compare neuroanatomy of HFA and SZ using a multimodal MRI design.
METHODS: We scanned 79 male adult subjects with 3T MRI (23 with HFA, 24 with SZ and 32 healthy controls, with similar non-verbal IQ). We compared them using both diffusion-based whole-brain tractography and T1 voxel-based morphometry.
RESULTS: HFA and SZ groups exhibited similar white matter alterations in the left fronto-occipital inferior fasciculus with a decrease in generalized fractional anisotropy compared with controls. In grey matter, the HFA group demonstrated bilateral prefrontal and anterior cingulate increases in contrast with prefrontal and left temporal reductions in SZ.
CONCLUSION: HFA and SZ may share common white matter deficits in long-range connections involved in social functions, but opposite grey matter abnormalities in frontal regions that subserve complex cognitive functions. Our results are consistent with the fronto-occipital underconnectivity theory of HFA and the altered connectivity hypothesis of SZ and suggest the existence of both associated and diametrical liabilities to these two conditions.

PMID: 27105136 [PubMed - as supplied by publisher]

Social anxiety and autism spectrum traits among adult FMR1 premutation carriers.

April 23, 2016 - 7:35am

Social anxiety and autism spectrum traits among adult FMR1 premutation carriers.

Clin Genet. 2016 Apr 22;

Authors: López-Mourelo O, Mur E, Madrigal I, Alvarez-Mora MI, Gómez-Ansón B, Pagonabarraga J, Rodriguez-Revenga L, Milà M

Abstract
Behavioral symptoms and traits have been proposed as early markers in neurodegenerative diseases. The aim of this study was to evaluate social anxiety and autism in FMR1 premutation carriers using the Social Phobia Inventory (SPIN) and the Autism-Spectrum Quotient (AQ) questionnaires. Fifty-nine premutation carriers were compared with 50 controls. The SPIN test showed statistically significant differences between female but not male carriers. The AQ questionnaire found statistically significant differences between premutation carriers and controls in the total AQ as well as in the social skills and attention switching subdomains. A gender effect was only observed for the social skills subdomain. Spearman's correlation analysis revealed a moderately positive correlation with the total AQ scores as well as the social skills and communication subdomains. Our results show that FXTAS patients have higher AQ scores. Moreover, this is the first study to find statistically significant differences between FXTAS and no-FXTAS premutation carriers in the communication and the imagination subdomains, suggesting that FXTAS patients present a broader autistic phenotype than premutation carriers without FXTAS. Based on our results a wide range of behavioral/psychiatric traits should be included within the broader phenotypic presentation of individuals with the FMR1 premutation.

PMID: 27102723 [PubMed - as supplied by publisher]

Challenges in understanding psychiatric disorders and developing therapeutics: a role for zebrafish.

April 23, 2016 - 7:35am
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Challenges in understanding psychiatric disorders and developing therapeutics: a role for zebrafish.

Dis Model Mech. 2015 Jul 1;8(7):647-56

Authors: McCammon JM, Sive H

Abstract
The treatment of psychiatric disorders presents three major challenges to the research and clinical community: defining a genotype associated with a disorder, characterizing the molecular pathology of each disorder and developing new therapies. This Review addresses how cellular and animal systems can help to meet these challenges, with an emphasis on the role of the zebrafish. Genetic changes account for a large proportion of psychiatric disorders and, as gene variants that predispose to psychiatric disease are beginning to be identified in patients, these are tractable for study in cellular and animal systems. Defining cellular and molecular criteria associated with each disorder will help to uncover causal physiological changes in patients and will lead to more objective diagnostic criteria. These criteria should also define co-morbid pathologies within the nervous system or in other organ systems. The definition of genotypes and of any associated pathophysiology is integral to the development of new therapies. Cell culture-based approaches can address these challenges by identifying cellular pathology and by high-throughput screening of gene variants and potential therapeutics. Whole-animal systems can define the broadest function of disorder-associated gene variants and the organismal impact of candidate medications. Given its evolutionary conservation with humans and its experimental tractability, the zebrafish offers several advantages to psychiatric disorder research. These include assays ranging from molecular to behavioural, and capability for chemical screening. There is optimism that the multiple approaches discussed here will link together effectively to provide new diagnostics and treatments for psychiatric patients.

PMID: 26092527 [PubMed - indexed for MEDLINE]

Towards understanding the genetics of Autism.

April 22, 2016 - 9:28am
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Towards understanding the genetics of Autism.

Front Biosci (Elite Ed). 2016;8:412-426

Authors: Shailesh H, Gupta I, Sif S, Ouhtit A

Abstract
Autism spectrum disorder (ASD) includes a group of neurodevelopmental disorders that affect communication skills, social interaction and intellectual ability. Despite evidence suggesting a strong genetic link with ASD, the genetic determinant remains unclear. Early studies focusing on candidate genes have shown that several genes associated with neuronal synaptic function are involved in development of ASD. Linkage studies have identified several single nucleotide polymorphisms (SNPs) associated with ASD, and genome-wide association studies have implicated several loci, but failed to recognize a single specific locus with strong significance, indicating heterogeneity in ASD genetic determinants. Detection of de novo copy number variations and single nucleotide variants in several ASD probands has confirmed the genetic heterogeneity of the disease. More interestingly, next generation sequencing approaches have recently identified novel candidate genes and several point mutations in sporadic ASDs, thus increasing our knowledge of ASD etiology. The current review summarizes the findings of recent studies using genetic and genomic approaches to understand the underlying molecular mechanisms of ASD.

PMID: 27100348 [PubMed - as supplied by publisher]

A Pooled Genome-Wide Association Study of Asperger Syndrome.

April 22, 2016 - 9:28am
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A Pooled Genome-Wide Association Study of Asperger Syndrome.

PLoS One. 2015;10(7):e0131202

Authors: Warrier V, Chakrabarti B, Murphy L, Chan A, Craig I, Mallya U, Lakatošová S, Rehnstrom K, Peltonen L, Wheelwright S, Allison C, Fisher SE, Baron-Cohen S

Abstract
Asperger Syndrome (AS) is a neurodevelopmental condition characterized by impairments in social interaction and communication, alongside the presence of unusually repetitive, restricted interests and stereotyped behaviour. Individuals with AS have no delay in cognitive and language development. It is a subset of Autism Spectrum Conditions (ASC), which are highly heritable and has a population prevalence of approximately 1%. Few studies have investigated the genetic basis of AS. To address this gap in the literature, we performed a genome-wide pooled DNA association study to identify candidate loci in 612 individuals (294 cases and 318 controls) of Caucasian ancestry, using the Affymetrix GeneChip Human Mapping version 6.0 array. We identified 11 SNPs that had a p-value below 1x10-5. These SNPs were independently genotyped in the same sample. Three of the SNPs (rs1268055, rs7785891 and rs2782448) were nominally significant, though none remained significant after Bonferroni correction. Two of our top three SNPs (rs7785891 and rs2782448) lie in loci previously implicated in ASC. However, investigation of the three SNPs in the ASC genome-wide association dataset from the Psychiatric Genomics Consortium indicated that these three SNPs were not significantly associated with ASC. The effect sizes of the variants were modest, indicating that our study was not sufficiently powered to identify causal variants with precision.

PMID: 26176695 [PubMed - indexed for MEDLINE]

Reciprocal Relationship between Head Size, an Autism Endophenotype, and Gene Dosage at 19p13.12 Points to AKAP8 and AKAP8L.

April 22, 2016 - 9:28am
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Reciprocal Relationship between Head Size, an Autism Endophenotype, and Gene Dosage at 19p13.12 Points to AKAP8 and AKAP8L.

PLoS One. 2015;10(6):e0129270

Authors: Nebel RA, Kirschen J, Cai J, Woo YJ, Cherian K, Abrahams BS

Abstract
Microcephaly and macrocephaly are overrepresented in individuals with autism and are thought to be disease-related risk factors or endophenotypes. Analysis of DNA microarray results from a family with a low functioning autistic child determined that the proband and two additional unaffected family members who carry a rare inherited 760 kb duplication of unknown clinical significance at 19p13.12 are macrocephalic. Consideration alongside overlapping deletion and duplication events in the literature provides support for a strong relationship between gene dosage at this locus and head size, with losses and gains associated with microcephaly (p=1.11x10(-11)) and macrocephaly (p=2.47x10(-11)), respectively. Data support A kinase anchor protein 8 and 8-like (AKAP8 and AKAP8L) as candidate genes involved in regulation of head growth, an interesting finding given previous work implicating the AKAP gene family in autism. Towards determination of which of AKAP8 and AKAP8L may be involved in the modulation of head size and risk for disease, we analyzed exome sequencing data for 693 autism families (2591 individuals) where head circumference data were available. No predicted loss of function variants were observed, precluding insights into relationship to head size, but highlighting strong evolutionary conservation. Taken together, findings support the idea that gene dosage at 19p13.12, and AKAP8 and/or AKAP8L in particular, play an important role in modulation of head size and may contribute to autism risk. Exome sequencing of the family also identified a rare inherited variant predicted to disrupt splicing of TPTE / PTEN2, a PTEN homologue, which may likewise contribute to both macrocephaly and autism risk.

PMID: 26076356 [PubMed - indexed for MEDLINE]

Investigation of Gene Regulatory Networks Associated with Autism Spectrum Disorder Based on MiRNA Expression in China.

April 22, 2016 - 9:28am
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Investigation of Gene Regulatory Networks Associated with Autism Spectrum Disorder Based on MiRNA Expression in China.

PLoS One. 2015;10(6):e0129052

Authors: Huang F, Long Z, Chen Z, Li J, Hu Z, Qiu R, Zhuang W, Tang B, Xia K, Jiang H

Abstract
Autism spectrum disorder (ASD) comprise a group of neurodevelopmental disorders characterized by deficits in social and communication capacities and repetitive behaviors. Increasing neuroscientific evidence indicates that the neuropathology of ASD is widespread and involves epigenetic regulation in the brain. Differentially expressed miRNAs in the peripheral blood from autism patients were identified by high-throughput miRNA microarray analyses. Five of these miRNAs were confirmed through quantitative reverse transcription-polymerase chain reaction (qRT-PCR) analysis. A search for candidate target genes of the five confirmed miRNAs was performed through a Kyoto encyclopedia of genes and genomes (KEGG) biological pathways and Gene Ontology enrichment analysis of gene function to identify gene regulatory networks. To the best of our knowledge, this study provides the first global miRNA expression profile of ASD in China. The differentially expressed miR-34b may potentially explain the higher percentage of male ASD patients, and the aberrantly expressed miR-103a-3p may contribute to the abnormal ubiquitin-mediated proteolysis observed in ASD.

PMID: 26061495 [PubMed - indexed for MEDLINE]

Bipolar disorder and its relation to major psychiatric disorders: a family-based study in the Swedish population.

April 22, 2016 - 9:28am
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Bipolar disorder and its relation to major psychiatric disorders: a family-based study in the Swedish population.

Bipolar Disord. 2015 Mar;17(2):184-93

Authors: Song J, Bergen SE, Kuja-Halkola R, Larsson H, Landén M, Lichtenstein P

Abstract
OBJECTIVES: Bipolar disorder (BPD) shares genetic components with other psychiatric disorders; however, uncertainty remains about where in the psychiatric spectra BPD falls. To understand the etiology of BPD, we studied the familial aggregation of BPD and co-aggregation between BPD and schizophrenia, depression, anxiety disorders, attention-deficit hyperactivity disorder, drug abuse, personality disorders, and autism spectrum disorders.
METHODS: A population-based cohort was created by linking several Swedish national registers. A total of 54,723 individuals with BPD were identified among 8,141,033 offspring from 4,149,748 nuclear families. The relative risk of BPD in relatives and the co-occurrence of other psychiatric disorders in patients with BPD and their relatives were compared to those of matched-population controls. Structural equation modeling was used to estimate the heritability and tetrachoric correlation.
RESULTS: The familial risks for relatives of BPD probands were 5.8-7.9 in first-degree relatives, and decreased with genetic distance. Co-occurrence risks for other psychiatric disorders were 9.7-22.9 in individuals with BPD and 1.7-2.8 in full siblings of BPD probands. Heritability for BPD was estimated at 58%. The correlations between BPD and other psychiatric disorders were considerable (0.37-0.62) and primarily due to genetic effects. The correlation with depression was the highest (0.62), and was 0.44 for schizophrenia.
CONCLUSIONS: The high familial risks provide evidence that genetic factors play an important role in the etiology of BPD, and the shared genetic determinants suggest pleiotropic effects across different psychiatric disorders. Results also indicate that BPD is in both the mood and psychotic spectra, but possibly more closely related to mood disorders.

PMID: 25118125 [PubMed - indexed for MEDLINE]

Creatine Transporter Deficiency: Screening of Males with Neurodevelopmental Disorders and Neurocognitive Characterization of a Case.

April 21, 2016 - 8:48am

Creatine Transporter Deficiency: Screening of Males with Neurodevelopmental Disorders and Neurocognitive Characterization of a Case.

J Dev Behav Pediatr. 2016 Apr 18;

Authors: Thurm A, Himelstein D, DʼSouza P, Rennert O, Jiang S, Olatunji D, Longo N, Pasquali M, Swedo S, Salomons GS, Carrillo N

Abstract
OBJECTIVE: Creatine transporter deficiency (CTD) is an X-linked, neurometabolic disorder associated with intellectual disability that is characterized by brain creatine (Cr) deficiency and caused by mutations in SLC6A8, the Cr transporter 1 protein gene. CTD is identified by elevated urine creatine/creatinine (Cr/Crn) ratio or reduced Cr peak on brain magnetic resonance spectroscopy; the diagnosis is confirmed by decreased Cr uptake in cultured fibroblasts, and/or identification of a mutation in the SLC6A8 gene. Prevalence studies suggest this disorder may be underdiagnosed. We sought to identify cases from a well-characterized cohort of children diagnosed with neurodevelopmental disorders.
METHOD: Urine screening for CTD was performed on a cohort of 46 males with autism spectrum disorder (ASD) and 9 males with a history of non-ASD developmental delay (DD) classified with intellectual disability.
RESULTS: We identified 1 patient with CTD in the cohort based on abnormal urine Cr/Crn, and confirmed the diagnosis by the identification of a novel frameshift mutation in the SLC6A8 gene. This patient presented without ASD but with intellectual disability, and was characterized by a nonspecific phenotype of early language delay and DD that persisted into moderate-to-severe intellectual disability, consistent with previous descriptions of CTD.
CONCLUSION: Identification of patients with CTD is possible by measuring urine Cr and Crn levels and the current case adds to the growing literature of neurocognitive deficits associated with the disorder that affect cognition, language and behavior in childhood.

PMID: 27096572 [PubMed - as supplied by publisher]

Neurobiology of rodent self-grooming and its value for translational neuroscience.

April 21, 2016 - 8:48am
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Neurobiology of rodent self-grooming and its value for translational neuroscience.

Nat Rev Neurosci. 2016 Jan;17(1):45-59

Authors: Kalueff AV, Stewart AM, Song C, Berridge KC, Graybiel AM, Fentress JC

Abstract
Self-grooming is a complex innate behaviour with an evolutionarily conserved sequencing pattern and is one of the most frequently performed behavioural activities in rodents. In this Review, we discuss the neurobiology of rodent self-grooming, and we highlight studies of rodent models of neuropsychiatric disorders--including models of autism spectrum disorder and obsessive compulsive disorder--that have assessed self-grooming phenotypes. We suggest that rodent self-grooming may be a useful measure of repetitive behaviour in such models, and therefore of value to translational psychiatry. Assessment of rodent self-grooming may also be useful for understanding the neural circuits that are involved in complex sequential patterns of action.

PMID: 26675822 [PubMed - indexed for MEDLINE]

Mouse Model of Chromosome 15q13.3 Microdeletion Syndrome Demonstrates Features Related to Autism Spectrum Disorder.

April 21, 2016 - 8:48am
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Mouse Model of Chromosome 15q13.3 Microdeletion Syndrome Demonstrates Features Related to Autism Spectrum Disorder.

J Neurosci. 2015 Dec 9;35(49):16282-94

Authors: Kogan JH, Gross AK, Featherstone RE, Shin R, Chen Q, Heusner CL, Adachi M, Lin A, Walton NM, Miyoshi S, Miyake S, Tajinda K, Ito H, Siegel SJ, Matsumoto M

Abstract
UNLABELLED: The chromosome 15q13.3 microdeletion is a pathogenic copy number variation conferring epilepsy, intellectual disability, schizophrenia, and autism spectrum disorder (ASD). We generated mice carrying a deletion of 1.2 Mb homologous to the 15q13.3 microdeletion in human patients. Here, we report that mice with a heterozygous deletion on a C57BL/6 background (D/+ mice) demonstrated phenotypes including enlarged/heavier brains (macrocephaly) with enlarged lateral ventricles, decreased social interactions, increased repetitive grooming behavior, reduced ultrasonic vocalizations, decreased auditory-evoked gamma band EEG, and reduced event-related potentials. D/+ mice had normal body weight, activity levels, sensory gating, and cognitive abilities and no signs of epilepsy/seizures. Our results demonstrate that D/+ mice represent ASD-related phenotypes associated with 15q13.3 microdeletion syndrome. Further investigations using this chromosome-engineered mouse model may uncover the common mechanism(s) underlying ASD and other neurodevelopmental/psychiatric disorders representing the 15q13.3 microdeletion syndrome, including epilepsy, intellectual disability, and schizophrenia.
SIGNIFICANCE STATEMENT: Recently discovered pathologic copy number variations (CNVs) from patients with neurodevelopmental/psychiatric disorders show very strong penetrance and thus are excellent candidates for mouse models of disease that can mirror the human genetic conditions with high fidelity. A 15q13.3 microdeletion in humans results in a range of neurodevelopmental/psychiatric disorders, including epilepsy, intellectual disability, schizophrenia, and autism spectrum disorder (ASD). The disorders conferred by a 15q13.3 microdeletion also have overlapping genetic architectures and comorbidity in other patient populations such as those with epilepsy and schizophrenia/psychosis, as well as schizophrenia and ASD. We generated mice carrying a deletion of 1.2 Mb homologous to the 15q13.3 microdeletion in human patients, which allowed us to investigate the potential causes of neurodevelopmental/psychiatric disorders associated with the CNV.

PMID: 26658876 [PubMed - indexed for MEDLINE]

Maternal mid-pregnancy C-reactive protein and risk of autism spectrum disorders: the early markers for autism study.

April 20, 2016 - 7:49am

Maternal mid-pregnancy C-reactive protein and risk of autism spectrum disorders: the early markers for autism study.

Transl Psychiatry. 2016;6:e783

Authors: Zerbo O, Traglia M, Yoshida C, Heuer LS, Ashwood P, Delorenze GN, Hansen RL, Kharrazi M, Van de Water J, Yolken RH, Weiss LA, Croen LA

Abstract
Maternal pregnancy levels of the inflammatory marker C-reactive protein (CRP) has been previously associated with autism spectrum disorder (ASD) in the offspring. We conducted a population-based nested case-control study with 500 children with ASD, 235 with developmental delay (DD) and 580 general population (GP) controls to further investigate whether elevated CRP during pregnancy increases the risk of ASD. Maternal CRP concentration was measured in archived serum collected during 15-19 weeks of pregnancy and genome-wide single-nucleotide polymorphism (SNP) data were generated. The levels of CRP were compared between ASD vs GP and DD vs GP. The genetic associations with CRP were assessed via linear regression. Maternal CRP levels in mid-pregnancy were lower in mothers of ASD compared with controls. The maternal CRP levels in the upper third and fourth quartiles were associated with a 45 and 44% decreased risk of ASD, respectively. Two SNPs at the CRP locus showed strong association with CRP levels but they were not associated with ASD. No difference was found between maternal CRP levels of DD and controls. The reasons for the lower levels of CRP in mothers of ASD are not known with certainty but may be related to alterations in the immune response to infectious agents. The biological mechanisms underlying this association remain to be clarified.

PMID: 27093065 [PubMed - as supplied by publisher]

Looping Genomes: Diagnostic Change and the Genetic Makeup of the Autism Population.

April 20, 2016 - 7:49am

Looping Genomes: Diagnostic Change and the Genetic Makeup of the Autism Population.

AJS. 2016 Mar;121(5):1416-71

Authors: Navon D, Eyal G

Abstract
This article builds on Hacking's framework of "dynamic nominalism" to show how knowledge about biological etiology can interact with the "kinds of people" delineated by diagnostic categories in ways that "loop" or modify both over time. The authors use historical materials to show how "geneticization" played a crucial role in binding together autism as a biosocial community and how evidence from genetics research later made an important contribution to the diagnostic expansion of autism. In the second part of the article, the authors draw on quantitative and qualitative analyses of autism rates over time in several rare conditions that are delineated strictly according to genomic mutations in order to demonstrate that these changes in diagnostic practice helped to both increase autism's prevalence and create its enormous genetic heterogeneity. Thus, a looping process that began with geneticization and involved the social effects of genetics research itself transformed the autism population and its genetic makeup.

PMID: 27092389 [PubMed - in process]

Insulin signaling misregulation underlies circadian and cognitive deficits in a Drosophila fragile X model.

April 20, 2016 - 7:49am

Insulin signaling misregulation underlies circadian and cognitive deficits in a Drosophila fragile X model.

Mol Psychiatry. 2016 Apr 19;

Authors: Monyak RE, Emerson D, Schoenfeld BP, Zheng X, Chambers DB, Rosenfelt C, Langer S, Hinchey P, Choi CH, McDonald TV, Bolduc FV, Sehgal A, McBride SM, Jongens TA

Abstract
Fragile X syndrome (FXS) is an undertreated neurodevelopmental disorder characterized by low intelligence quotent and a wide range of other symptoms including disordered sleep and autism. Although FXS is the most prevalent inherited cause of intellectual disability, its mechanistic underpinnings are not well understood. Using Drosophila as a model of FXS, we showed that select expression of dfmr1 in the insulin-producing cells (IPCs) of the brain was sufficient to restore normal circadian behavior and to rescue the memory deficits in the fragile X mutant fly. Examination of the insulin signaling (IS) pathway revealed elevated levels of Drosophila insulin-like peptide 2 (Dilp2) in the IPCs and elevated IS in the dfmr1 mutant brain. Consistent with a causal role for elevated IS in dfmr1 mutant phenotypes, the expression of dfmr1 specifically in the IPCs reduced IS, and genetic reduction of the insulin pathway also led to amelioration of circadian and memory defects. Furthermore, we showed that treatment with the FDA-approved drug metformin also rescued memory. Finally, we showed that reduction of IS is required at different time points to rescue circadian behavior and memory. Our results indicate that insulin misregulation underlies the circadian and cognitive phenotypes displayed by the Drosophila fragile X model, and thus reveal a metabolic pathway that can be targeted by new and already approved drugs to treat fragile X patients.Molecular Psychiatry advance online publication, 19 April 2016; doi:10.1038/mp.2016.51.

PMID: 27090306 [PubMed - as supplied by publisher]

Hurt, tired and queasy: Specific variants in the ATPase domain of the TRAP1 mitochondrial chaperone are associated with common, chronic "functional" symptomatology including pain, fatigue and gastrointestinal dysmotility.

April 20, 2016 - 7:49am
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Hurt, tired and queasy: Specific variants in the ATPase domain of the TRAP1 mitochondrial chaperone are associated with common, chronic "functional" symptomatology including pain, fatigue and gastrointestinal dysmotility.

Mitochondrion. 2015 Jul;23:64-70

Authors: Boles RG, Hornung HA, Moody AE, Ortiz TB, Wong SA, Eggington JM, Stanley CM, Gao M, Zhou H, McLaughlin S, Zare AS, Sheldon KM, Skolnick J, McKernan KJ

Abstract
Functional disorders are common conditions with a substantial impact on a patients' wellbeing, and can be diagnostically elusive. There are bidirectional associations between functional disorders and mitochondrial dysfunction. In this study, provided clinical information and the exon sequence of the TRAP1 mitochondrial chaperone were retrospectively reviewed with a focus on the functional categories of chronic pain, fatigue and gastrointestinal dysmotility. Very-highly conserved TRAP1 variants were identified in 73 of 930 unrelated patients. Functional symptomatology is strongly associated with specific variants in the ATPase binding pocket. In particular, the combined presence of all three functional categories is strongly associated with p.Ile253Val (OR 7.5, P = 0.0001) and with two other interacting variants (OR 18, P = 0.0005). Considering a 1-2% combined variant prevalence and high odds ratios, these variants may be an important factor in the etiology of functional symptomatology.

PMID: 26022780 [PubMed - indexed for MEDLINE]

A novel maternally inherited 8q24.3 and a rare paternally inherited 14q23.3 CNVs in a family with neurodevelopmental disorders.

April 20, 2016 - 7:49am
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A novel maternally inherited 8q24.3 and a rare paternally inherited 14q23.3 CNVs in a family with neurodevelopmental disorders.

Am J Med Genet A. 2015 Aug;167A(8):1921-6

Authors: Hu J, Sathanoori M, Kochmar S, Azage M, Mann S, Madan-Khetarpal S, Goldstein A, Surti U

Abstract
A 7-year-old female with developmental delay (DD), autism spectrum disorder (ASD), intellectual disability (ID), attention deficit hyperactivity disorder (ADHD), and seizures was referred to our laboratory for oligomicroarray analysis. The analysis revealed a 540 kb microdeletion in the chromosome 8q24.3 region (143,610,058-144,150,241) encompassing multiple genes. Two siblings of the proband were also analyzed. The proband's older sister with DD, seizures, and ASD has a 438 kb intragenic microdeletion of the GPHN gene in the chromosome 14q23.3 region (67,105,512-67,543,291) containing multiple exons, while the proband's older brother with DD, ASD, ID, and ADHD has both the 8q24.3 and the 14q23.3 deletions. All three siblings have a normal karyotype at the 650 G-band level of resolution. Parental FISH analysis indicates that the mother is a carrier for the 8q24.3 deletion and the father is a carrier for the 14q23.3 deletion. The 8q24.3 deletion seen in our patients has not been reported in the literature, while the small deletions of the 14q23.3 region involving multiple exons of the GPHN gene have been reported in a handful of patients in a recent study. The size of the 8q24.3 deletion and its genomic content, as well as the maternal family history, strongly suggest the association between the deletion and the neurodevelopmental disorders. Our study also provides more evidence in support of the association between GPHN deletion and neurodevelopmental disorders.

PMID: 25866352 [PubMed - indexed for MEDLINE]

RPL10 mutation segregating in a family with X-linked syndromic Intellectual Disability.

April 20, 2016 - 7:49am
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RPL10 mutation segregating in a family with X-linked syndromic Intellectual Disability.

Am J Med Genet A. 2015 Aug;167A(8):1908-12

Authors: Thevenon J, Michot C, Bole C, Nitschke P, Nizon M, Faivre L, Munnich A, Lyonnet S, Bonnefont JP, Portes VD, Amiel J

Abstract
Intellectual disability is a neurodevelopmental disorder of impaired adaptive skills and low intelligence quotient. The overall prevalence is estimated at 2-3% in the general population with extreme clinical and genetic heterogeneity, and it has been associated with possibly causative mutations in more than 700 identified genes. In a recent review, among over 100 X-linked intellectual disability causative genes, eight were reported as "awaiting replication." Exome sequencing in a large family identified a missense mutation in RPL10 highly suggestive of X-linked intellectual disability. Herein, we report on the clinical description of four affected males. All patients presented apparent intellectual disability (4/4), psychomotor delay (4/4) with syndromic features including amniotic fluid excess (3/4), microcephaly (2/4), urogenital anomalies (3/4), cerebellar syndrome (2/4), and facial dysmorphism. In the literature, two mutations were reported in three families with affected males presenting with autism. This report confirms the implication of RPL10 mutations in neurodevelopmental disorders and extends the associated clinical spectrum from autism to syndromic intellectual disability.

PMID: 25846674 [PubMed - indexed for MEDLINE]

A clinical case report and literature review of the 3q29 microdeletion syndrome.

April 20, 2016 - 7:49am
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A clinical case report and literature review of the 3q29 microdeletion syndrome.

Clin Dysmorphol. 2015 Jul;24(3):89-94

Authors: Cox DM, Butler MG

Abstract
We report on a 15-year-old male with the 3q29 microdeletion syndrome and summarize the medical literature. He had intellectual disability, autism spectrum disorder, anxiety, obsessive compulsive tendencies, speech delay, delayed walking, a hypernasal voice, gait abnormalities, chronic constipation, gastroesophageal reflux disorder, urinary voiding dysfunction, abnormal skin pigmentation, and dysmorphic features. We present a review of the literature for the 3q29 microdeletion syndrome by comparing both the phenotype and the genetic defects in reported cases. Of the 38 previously reported cases with deletion size information, the most common chromosome deletion was 1.6 Mb in size including ∼ 30 genes. This emerging microdeletion syndrome is characterized by intellectual disability, speech delay, behavioral problems, craniofacial dysmorphism, and musculoskeletal abnormalities.

PMID: 25714563 [PubMed - indexed for MEDLINE]

Salivary proteomics and biomarkers in neurology and psychiatry.

April 20, 2016 - 7:49am
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Salivary proteomics and biomarkers in neurology and psychiatry.

Proteomics Clin Appl. 2015 Oct;9(9-10):899-906

Authors: Wormwood KL, Aslebagh R, Channaveerappa D, Dupree EJ, Borland MM, Ryan JP, Darie CC, Woods AG

Abstract
Biomarkers are greatly needed in the fields of neurology and psychiatry, to provide objective and earlier diagnoses of CNS conditions. Proteomics and other omics MS-based technologies are tools currently being utilized in much recent CNS research. Saliva is an interesting alternative biomaterial for the proteomic study of CNS disorders, with several advantages. Collection is noninvasive and saliva has many proteins. It is easier to collect than blood and can be collected by professionals without formal medical training. For psychiatric and neurological patients, supplying a saliva sample is less anxiety-provoking than providing a blood sample, and is less embarrassing than producing a urine specimen. The use of saliva as a biomaterial has been researched for the diagnosis of and greater understanding of several CNS conditions, including neurodegenerative diseases, autism, and depression. Salivary biomarkers could be used to rule out nonpsychiatric conditions that are often mistaken for psychiatric/neurological conditions, such as fibromyalgia, and potentially to assess cognitive ability in individuals with compromised brain function. As MS and omics technology advances, the sensitivity and utility of assessing CNS conditions using distal human biomaterials such as saliva is becoming increasingly possible.

PMID: 25631118 [PubMed - indexed for MEDLINE]

Autism-Like Behavior and Epigenetic Changes Associated with Autism as Consequences of In Utero Exposure to Environmental Pollutants in a Mouse Model.

April 19, 2016 - 7:10am
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Autism-Like Behavior and Epigenetic Changes Associated with Autism as Consequences of In Utero Exposure to Environmental Pollutants in a Mouse Model.

Behav Neurol. 2015;2015:426263

Authors: Hill DS, Cabrera R, Wallis Schultz D, Zhu H, Lu W, Finnell RH, Wlodarczyk BJ

Abstract
We tested the hypothesis that in utero exposure to heavy metals increases autism-like behavioral phenotypes in adult animals and induces epigenetic changes in genes that have roles in the etiology of autism. Mouse dams were treated with cadmium, lead, arsenate, manganese, and mercury via drinking water from gestational days (E) 1-10. Valproic acid (VPA) injected intraperitoneally once on (E) 8.5 served as a positive control. Young male offspring were tested for behavioral deficits using four standardized behavioral assays. In this study, in utero exposure to heavy metals resulted in multiple behavioral abnormalities that persisted into adulthood. VPA and manganese induced changes in perseverative/impulsive behavior and social dominance behavior, arsenic caused changes only in perseverative/impulsive behavior, and lead induced abnormalities in social interaction in comparison to the control animals. Brain samples from Mn, Pb, and VPA treated and control animals were evaluated for changes in CpG island methylation in promoter regions and associated changes in gene expression. The Chd7 gene, essential for neural crest cell migration and patterning, was found to be hypomethylated in each experimental animal tested compared to water-treated controls. Furthermore, distinct patterns of CpG island methylation yielded novel candidate genes for further investigation.

PMID: 26586927 [PubMed - indexed for MEDLINE]

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