1. Buijsen RA, Visser JA, Kramer P, Severijnen EA, Gearing M, Charlet-Berguerand N, Sherman SL, Berman RF, Willemsen R, Hukema RK. {{Presence of inclusions positive for polyglycine containing protein, FMRpolyG, indicates that repeat-associated non-AUG translation plays a role in fragile X-associated primary ovarian insufficiency}}. {Hum Reprod};2015 (Nov 3)
STUDY QUESTION: Does repeat-associated non-AUG (RAN) translation play a role in fragile X-associated primary ovarian insufficiency (FXPOI), leading to the presence of polyglycine containing protein (FMRpolyG)-positive inclusions in ovarian tissue? SUMMARY ANSWER: Ovaries of a woman with FXPOI and of an Fmr1 premutation (PM) mouse model (exCGG-KI) contain intranuclear inclusions that stain positive for both FMRpolyG and ubiquitin. WHAT IS KNOWN ALREADY: Women who carry the FMR1 PM are at 20-fold increased risk to develop primary ovarian insufficiency (FXPOI). A toxic RNA gain-of-function has been suggested as the underlying mechanism since the PM results in increased levels of mRNA containing an expanded repeat, but reduced protein levels of fragile X mental retardation protein (FMRP). Recently, RAN translation has been shown to occur from FMR1 mRNA that contains PM repeat expansions, leading to FMRpolyG inclusions in brain and non-CNS tissues of fragile X-associated tremor/ataxia syndrome (FXTAS) patients. STUDY DESIGN, SIZE, DURATION: Ovaries of a woman with FXPOI and women without PM (controls), and ovaries from wild-type and exCGG-KI mice were analyzed by immunohistochemistry for the presence of inclusions that stained for ubiquitin and FMRpolyG . The ovaries from wild-type and exCGG-KI mice were further characterized for the number of follicles, Fmr1 mRNA levels and FMRP protein expression. The presence of inclusions was also analyzed in pituitaries of a man with FXTAS and the exCGG-KI mice. PARTICIPANTS/MATERIALS, SETTING, METHODS: Human ovaries from a woman with FXPOI and two control subjects and pituitaries from a man with FXTAS and a control subjects were fixed in 4% formalin. Ovaries and pituitaries of wild-type and exCGG mice were fixed in Bouin’s fluid or 4% paraformaldehyde. Immunohistochemistry was performed on the human and mouse samples using FMRpolyG, ubiquitin and Fmrp antibodies. Fmr1 mRNA and protein expression were determined in mouse ovaries by quantitative RT-PCR and Western blot analysis. Follicle numbers in mouse ovaries were determined in serial sections by microscopy. MAIN RESULTS AND THE ROLE OF CHANCE: FMRpolyG-positive inclusions were present in ovarian stromal cells of a woman with FXPOI but not in the ovaries of control subjects. The FMRpolyG-positive inclusions colocalized with ubiquitin-positive inclusions. Similar inclusions were also observed in the pituitary of a man with FXTAS but not in control subjects. Similarly, ovaries of 40-week-old exCGG-KI mice, but not wild-type mice, contained numerous inclusions in the stromal cells that stained for both FMRpolyG- and ubiquitin, while the ovaries of 20-week-old exCGG-KI contained fewer inclusions. At 40 weeks ovarian Fmr1 mRNA expression was increased by 5-fold in exCGG-KI mice compared with wild-type mice, while Fmrp expression was reduced by 2-fold. With respect to ovarian function in exCGG-KI mice: (i) although the number of healthy growing follicles did not differ between wild-type and exCGG-KI mice, the number of atretic large antral follicles was increased by nearly 9-fold in 40-week old exCGG-KI mice (P < 0.001); (ii) at 40 weeks of age only 50% of exCGG-KI mice had recent ovulations compared with 89% in wild-type mice (P = 0.07) and (iii) those exCGG-KI mice with recent ovulations tended to have a reduced number of fresh corpora lutea (4.8 +/- 1.74 versus 8.50 +/- 0.98, exCGG-KI versus wild-type mice, respectively, P = 0.07). LIMITATIONS, REASONS FOR CAUTION: Although FMRpolyG-positive inclusions were detected in ovaries of both a woman with FXPOI and a mouse model of the FMR1 PM, we only analyzed one ovary from a FXPOI subject. Caution is needed to extrapolate these results to all women with the FMR1 PM. Furthermore, the functional consequence of FMRpolyG-positive inclusions in the ovaries for reproduction remains to be determined. WIDER IMPLICATIONS OF THE FINDINGS: Our results suggest that a dysfunctional hypothalamic-pituitary-gonadal-axis may contribute to FXPOI in FMR1 PM carriers. STUDY FUNDING/COMPETING INTERESTS: This study was supported by grants from NFXF, ZonMW, the Netherlands Brain Foundation and NIH. The authors have no conflict of interest to declare.
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2. Carmeli E, Bachar A, Rom O, Aizenbud D. {{Oxidative Stress and Nitric Oxide in Sedentary Older Adults with Intellectual and Developmental Disabilities}}. {Adv Exp Med Biol};2015 (Nov 6)
Individuals with moderate-to-profound intellectual and developmental disabilities (IDD) are characterized by significant cognitive deficits, abnormal muscle tone, poor posture and balance, and inactive lifestyle. Increased oxidative stress (OS) has been implicated in a variety of chronic diseases, inflammatory conditions, aging, and even following intense physical exercise. Nitric oxide (NO) is a highly reactive mediator that has been shown to play different roles in a variety of different biological process and in aging. The aim of the study was to investigate the serum levels of global OS and NO metabolites (NOx) in sedentary and non-sedentary older adults with IDD. Global OS was measured by CR 3000 instrument, FORM system, and NOx were measured by determination of serum nitrite levels. OS and NOx levels were significantly higher in sedentary IDD comparing non-sedentary controls. The increased of OS and NOx levels suggest their possible involvement in the phenomenon of ‘accelerated aging’ in IDD. Our findings can provide another aspect indicating both OS and NOx as possible biochemical markers and their potential application in minimizing their negative influence through future therapeutic strategies.
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3. Cupolillo D, Hoxha E, Faralli A, De Luca A, Rossi F, Tempia F, Carulli D. {{Autistic-Like Traits and Cerebellar Dysfunction in Purkinje Cell PTEN Knock-Out Mice}}. {Neuropsychopharmacology};2015 (Nov 5)
Autism spectrum disorders (ASDs) are neurodevelopmental disorders characterized by impaired social interaction, isolated areas of interest and insistence on sameness. Mutations in Phosphatase and tensin homolog missing on chromosome 10 (PTEN) have been reported in individuals with ASDs. Recent evidence highlights a crucial role of the cerebellum in the etiopathogenesis of ASDs. In the present study we analyzed the specific contribution of cerebellar Purkinje cell (PC) PTEN loss to these disorders. Using the Cre-loxP recombination system, we generated conditional knockout mice in which PTEN inactivation was induced specifically in PCs. We investigated PC morphology and physiology as well as sociability, repetitive behavior, motor learning and cognitive inflexibility of adult PC PTEN mutant mice. Loss of PTEN in PCs results in autistic-like traits, including impaired sociability, repetitive behavior and deficits in motor learning. Mutant PCs appear hypertrophic and show structural abnormalities in dendrites and axons, decreased excitability, disrupted parallel fiber and climbing fiber synapses and late-onset cell death. Our results unveil new roles of PTEN in PC function and provide the first evidence of a link between the loss of PTEN in PCs and the genesis of ASD-like traits.Neuropsychopharmacology accepted article preview online, 05 November 2015. doi:10.1038/npp.2015.339.
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4. Delobel-Ayoub M, Ehlinger V, Klapouszczak D, Maffre T, Raynaud JP, Delpierre C, Arnaud C. {{Socioeconomic Disparities and Prevalence of Autism Spectrum Disorders and Intellectual Disability}}. {PLoS One};2015;10(11):e0141964.
BACKGROUND AND OBJECTIVES: Study of the impact of socioeconomic status on autism spectrum disorders (ASD) and severe intellectual disabilities (ID) has yielded conflicting results. Recent European studies suggested that, unlike reports from the United States, low socioeconomic status is associated with an increased risk of ASD. For intellectual disabilities, the links with socioeconomic status vary according to the severity. We wished to clarify the links between socioeconomic status and the prevalence of ASD (with or without ID) and isolated severe ID. METHODS: 500 children with ASD and 245 children with severe ID (IQ <50) aged 8 years, born 1995 to 2004, were recruited from a French population-based registry. Inclusions were based on clinical diagnoses reported in medical records according to the International Classification of Diseases, 10th Revision. Socioeconomic status was measured by indicators available at block census level which characterize the population of the child's area of residence. Measures of deprivation, employment, occupation, education, immigration and family structure were used. Prevalences were compared between groups of census units defined by the tertiles of socioeconomic level in the general population. RESULTS: Prevalence of ASD with associated ID was higher in areas with the highest level of deprivation and the highest percentage of unemployed adults, persons with no diploma, immigrants and single-parent families. No association was found when using occupational class. Regarding ASD without associated ID, a higher prevalence was found in areas with the highest percentage of immigrants. No association was found for other socioeconomic indicators. The prevalence of isolated severe ID was likely to be higher in the most disadvantaged groups defined by all indicators. CONCLUSION: The prevalence of ASD with associated ID and of severe isolated ID is more likely to be higher in areas with the highest level of deprivation. Lien vers le texte intégral (Open Access ou abonnement)
5. Dieme B, Mavel S, Blasco H, Tripi G, Bonnet-Brilhault F, Malvy J, Bocca C, Andres CR, Nadal-Desbarats L, Emond P. {{Metabolomics Study of Urine in Autism Spectrum Disorders Using a Multiplatform Analytical Methodology}}. {J Proteome Res};2015 (Nov 23)
Autism spectrum disorder (ASD) is a neurodevelopmental disorder with no clinical biomarker. The aims of this study were to characterize a metabolic signature of ASD and to evaluate multiplatform analytical methodologies in order to develop predictive tools for diagnosis and disease follow-up. Urine samples were analyzed using 1H and 1H-13C NMR-based approaches and LC-HRMS-based approaches (ESI+ and ESI- on HILIC and C18 chromatography columns). Data tables obtained from the six analytical modalities on a training set of 46 urine samples (22 autistic children and 24 controls) were processed by multivariate analysis (orthogonal partial least-squares discriminant analysis, OPLS-DA). The predictions from each of these OPLS-DA models were then evaluated using a prediction set of 16 samples (8 autistic children and 8 controls) and receiver operating characteristic curves. Thereafter, a data fusion block-scaling OPLS-DA model was generated from the 6 best models obtained for each modality. This fused OPLS-DA model showed an enhanced performance (R2Y(cum) = 0.88, Q2(cum) = 0.75) compared to each analytical modality model, as well as a better predictive capacity (AUC = 0.91, p-value = 0.006). Metabolites that are most significantly different between autistic and control children (p < 0.05) are indoxyl sulfate, N-alpha-acetyl-l-arginine, methyl guanidine, and phenylacetylglutamine. This multimodality approach has the potential to contribute to find robust biomarkers and characterize a metabolic phenotype of the ASD population.
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6. Fulceri F, Narzisi A, Apicella F, Balboni G, Baldini S, Brocchini J, Domenici I, Cerullo S, Igliozzi R, Cosenza A, Tancredi R, Muratori F, Calderoni S. {{Application of the Repetitive Behavior Scale-Revised – Italian version – in preschoolers with autism spectrum disorder}}. {Res Dev Disabil};2015 (Nov 2);48:43-52.
Restricted repetitive and stereotyped patterns of behavior, interests, and activities (RRB) are mandatory features for a diagnosis of Autism Spectrum Disorder (ASD) according to the Diagnostic and Statistical Manual of mental disorders-fifth edition (DSM-5). Despite the strong diagnostic role of RRB, their expressiveness and their relationship with other clinical/demographic features in ASD is not fully elucidated. The Italian version of the Repetitive Behavior Scale-Revised (RBS-R) was applied to a relatively large sample of preschool-aged children with ASD who underwent a comprehensive clinical assessment. The relationship between RRB and sex, age, non-verbal IQ, autism severity, as well as the diagnostic accuracy of the RBS-R were explored. Stereotyped and Ritualistic/Sameness behaviors were the most common RRB in preschoolers with ASD, without widespread differences between males and females. No significant correlations between RRB and chronological age, or non-verbal IQ were detected. The expressiveness of ritualistic/sameness behaviors positively correlated with autism severity, assessed through the Calibrated Severity Score (CSS) derived from the Autism Diagnostic Observation Schedule (ADOS). Receiver Operator Characteristic (ROC) analysis showed high diagnostic accuracy using the Global Rating Score, which represents the judgment of the parents of as the RRB affect the child’s life. However, while the Global Rating Score performed well, the remaining subscales did not. This investigation extends the limited research on early pattern and associated features of RRB in young children with ASD. The use of the RBS-R may increase the knowledge of the RRB complexity and variability and in turn improve the diagnostic and therapeutic procedures within the autistic spectrum.
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7. Habibi NM, Dodangi NM, Nazeri AM. {{Efficacy and Safety of Aripiprazole for Treatment of Irritability in Children with Autistic Disorder: An Open-Label Study}}. {Iran J Med Sci};2015 (Nov);40(6):548-549.
8. Lawson RP, Aylward J, White S, Rees G. {{A striking reduction of simple loudness adaptation in autism}}. {Sci Rep};2015;5:16157.
Reports of sensory disturbance, such as loudness sensitivity or sound intolerance, are ubiquitous in Autism Spectrum Disorder (ASD) but a mechanistic explanation for these perceptual differences is lacking. Here we tested adaptation to loudness, a process that regulates incoming sensory input, in adults with ASD and matched controls. Simple loudness adaptation (SLA) is a fundamental adaptive process that reduces the subjective loudness of quiet steady-state sounds in the environment over time, whereas induced loudness adaptation (ILA) is a means of generating a reduction in the perceived volume of louder sounds. ASD participants showed a striking reduction in magnitude and rate of SLA relative to age and ability-matched typical adults, but in contrast ILA remained intact. Furthermore, rate of SLA predicted sensory sensitivity coping strategies in the ASD group. These results provide the first evidence that compromised neural mechanisms governing fundamental adaptive processes might account for sound sensitivity in ASD.
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9. Li J, You Y, Yue W, Yu H, Lu T, Wu Z, Jia M, Ruan Y, Liu J, Zhang D, Wang L. {{Chromatin remodeling gene EZH2 involved in the genetic etiology of autism in Chinese Han population}}. {Neurosci Lett};2015 (Nov 6)
Autism spectrum disorder (ASD) is a group of severe neurodevelopmental disorders. Epigenetic factors play a critical role in the etiology of ASD. Enhancer of zest homolog 2 (EZH2), which encodes a histone methyltransferase, plays an important role in the process of chromatin remodeling during neurodevelopment. Further, EZH2 is located in chromosome 7q35-36, which is one of the linkage regions for autism. However, the genetic relationship between autism and EZH2 remains unclear. To investigate the association between EZH2 and autism in Chinese Han population, we performed a family-based association study between autism and three tagged single nucleotide polymorphisms (SNPs) that covered 95.4% of the whole region of EZH2. In the discovery cohort of 239 trios, two SNPs (rs740949 and rs6464926) showed a significant association with autism. To decrease false positive results, we expanded the sample size to 427 trios. A SNP (rs6464926) was significantly associated with autism even after Bonferroni correction (p=0.008). Haplotype G-T (rs740949 and rs6464926) was a risk factor for autism (Z = 2.655, p=0.008, Global p=0.024). In silico function prediction for SNPs indicated that these two SNPs might be regulatory SNPs. Expression pattern of EZH2 showed that it is highly expressed in human embryonic brains. In conclusion, our findings demonstrate that EZH2 might contribute to the genetic etiology of autism in Chinese Han population.
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10. Marchese M, Valvo G, Moro F, Sicca F, Santorelli FM. {{Targeted Gene Resequencing (Astrochip) to Explore the Tripartite Synapse in Autism-Epilepsy Phenotype with Macrocephaly}}. {Neuromolecular Med};2015 (Nov 4)
The frequent co-occurrence of autism spectrum disorders (ASD) and epilepsy, or paroxysmal EEG abnormalities, defines a condition termed autism-epilepsy phenotype (AEP). This condition results, in some cases , from dysfunctions of glial inwardly rectifying potassium channels (Kir), which are mainly expressed in astrocytes where they mediate neuron-glia communication. Macrocephaly is also often comorbid with autism-epilepsy (autism-epilepsy phenotype with macrocephaly, MAEP), and it is tempting to hypothesize that shared pathogenic mechanisms might explain concurrence of these conditions. In the present study, we assessed whether protein pathways involved, along with Kir channels, in astrocyte-neuron interaction at the tripartite synapse play a role in the etiopathogenesis of MAEP. Using a targeted resequencing methodology, we investigated the coding regions of 35 genes in 61 patients and correlated genetic results with clinical features. Variants were subdivided into 12 classes and clustered into four groups. We detected rare or previously unknown predicted deleterious missense changes in GJA1, SLC12A2, SNTA1, EFNA3, CNTNAP2, EPHA4, and STXBP1 in seven patients and two high-frequency variants in DLG1 in six individuals. We also found that a group of variants (predicted deleterious and non-coding), segregating with the comorbid MAEP/AEP subgroups, belong to proteins specifically involved in glutamate transport and metabolism (namely, SLC17A6, GRM8, and GLUL), as well as in potassium conductance (KCNN3). This « endophenotype-oriented » study, performed using a targeted strategy, helped to further delineate part of the complex genetic background of ASD, particularly in the presence of coexisting macrocephaly and/or epilepsy/paroxysmal EEG, and suggests that use of stringent clinical clustering might be an approach worth adopting in order to unravel the complex genomic data in neurodevelopmental disorders.
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11. McCleery JP. {{Comment on Technology-Based Intervention Research for Individuals on the Autism Spectrum}}. {J Autism Dev Disord};2015 (Dec);45(12):3832-3835.
The purpose of this letter to the editor is to comment on several review papers recently published in the current Journal of Autism and Developmental Disorders, Special Issue on Technology: Software, Robotics, and Translational Science. These reviews address a variety of aspects relating to technology-aided intervention and instruction for individuals with Autism Spectrum Disorders (ASDs). Here, I comment on and evaluate the overall status of research and development in this area, including reflection on current challenges in this area in the context of previous challenges and resolutions in behavioral intervention research. From these reviews and the current evaluation, I further discuss important next steps for the field which may be critical for guiding progress toward meaningful impacts upon individuals with ASD.
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12. McCollum M, LaVesser P, Berg C. {{Participation in Daily Activities of Young Adults with High Functioning Autism Spectrum Disorder}}. {J Autism Dev Disord};2015 (Nov 4)
Young adults with an autism spectrum disorder (ASD) struggle to assume adult roles. This research assessed the feasibility of using the Adolescent and Young Adult Activity Card Sort (AYA-ACS) with emerging adults with high functioning ASD. Two phases were utilized during this research: (1) comparing the activity participation reported by emerging adults with an ASD and that reported by their caring adult; (2) examining the barriers to participation reported. Preliminary results demonstrate that the AYA-ACS appears to be a reliable and valid method of identifying emerging adults’ participation strengths as well as personal and environmental challenges in a variety of age-appropriate activities. The AYA-ACS could assist service providers by providing an understanding of the challenges to participation faced by this population and aid in developing client centered interventions.
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13. Primeau M, Gershon A, Talbot L, Cotto I, Lotspeich L, Hardan A, Hallmayer J, O’Hara R. {{Individuals With Autism Spectrum Disorders Have Equal Success Rate But Require Longer Periods of Systematic Desensitization Than Control Patients to Complete Ambulatory Polysomnography}}. {J Clin Sleep Med};2015 (Nov 6)
ABSTRACT: Polysomnography (PSG) is the gold standard for the assessment of sleep, and provides valuable information for researchers and clinicians alike. However, the extensive apparatus required for monitoring with PSG can be difficult to tolerate, particularly in children. Clinical populations, such as those with anxiety or tactile sensitivity, may have even greater difficulty tolerating the PSG equipment. A protocol using ambulatory PSG and systematic desensitization is described that was developed to study sleep in individuals with autism spectrum disorders (ASD) or developmental delay (DD), as well as typically developing controls (TD). Using this procedure, PSG was successfully attained in 144 subjects (89.4%). Individuals with ASD were equally able to obtain successful PSG; however, they did take significantly longer to desensitize to the equipment than DD or TD subjects. Age, sex, IQ, and tactile sensitivity did not predict the duration of time required for successful desensitization. Clinicians and researchers might consider use of a similar protocol to facilitate future sleep investigations.
14. Verhaeghe L, Dereu M, Warreyn P, De Groote I, Vanhaesebrouck P, Roeyers H. {{Extremely Preterm Born Children at Very High Risk for Developing Autism Spectrum Disorder}}. {Child Psychiatry Hum Dev};2015 (Nov 6)
This study aimed to provide a more comprehensive picture of the prevalence of autism spectrum disorder (ASD) in a geographic cohort of extremely preterm born adolescents by using established diagnostic instruments in addition to screening instruments. 53 participants passed a screening procedure with two screening instruments and a diagnostic evaluation with a semi-structured assessment and a parent interview. 28 % of the adolescents had a community based clinical diagnosis of ASD. When research diagnoses were also taken into account, this rate increased to 40 %. Intellectual disability, language impairment and behavioural difficulties are characteristic for these children with ASD. This study is to our knowledge the first to use ASD-specific diagnostic instruments to confirm ASD diagnoses in extremely preterm born children in early adolescence. The study expands findings of previous research and raises the need for follow-up into late childhood and early adolescence.
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15. Wakeford S, Hinvest N, Ring H, Brosnan M. {{Autistic characteristics in adults with epilepsy and perceived seizure activity}}. {Epilepsy Behav};2015 (Nov);52(Pt A):244-250.
The prevalence of autism spectrum disorders in epilepsy is approximately 15%-47%, with previous research by Wakeford and colleagues reporting higher autistic traits in adults with epilepsy. The aim of this study was to investigate autistic characteristics and their relationship to having seizures by employing two behavioral assessments in two samples: adults with epilepsy and controls. METHOD: The study employed the Social Responsiveness Scale – Shortened (SRS-S) (patients with epilepsy (n=76), control (n=19)) and the brief Repetitive Behavior Scale – Revised (RBS-R) (patients with epilepsy (n=47), control (n=21)). This study employed a unique method to quantify the extent to which autistic characteristics are related to perceived mild seizure activity. Adults with epilepsy were instructed to rate their usual behavior on each assessment and, at the same time, rate their behavior again when they perceived that they were having mild seizure activity. RESULTS: Significantly higher SRS-S scores were related to having a diagnosis of epilepsy and were perceived by adults with epilepsy to increase during mild seizure activity. These scores positively correlated with antiepileptic drug control. No difference was found for RBS-R scores in adults with epilepsy compared with controls. CONCLUSION: Together, these results suggest that adults with epilepsy have higher autistic characteristics measured by the social responsiveness scale, while sameness behaviors remain unimpaired. The autistic characteristics measured by the social responsiveness scale were reported by adults with epilepsy to be more severe during their mild seizure activity.
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16. Watanabe T, Rees G. {{Age-associated changes in rich-club organisation in autistic and neurotypical human brains}}. {Sci Rep};2015;5:16152.
Macroscopic structural networks in the human brain have a rich-club architecture comprising both highly inter-connected central regions and sparsely connected peripheral regions. Recent studies show that disruption of this functionally efficient organisation is associated with several psychiatric disorders. However, despite increasing attention to this network property, whether age-associated changes in rich-club organisation occur during human adolescence remains unclear. Here, analysing a publicly shared diffusion tensor imaging dataset, we found that, during adolescence, brains of typically developing (TD) individuals showed increases in rich-club organisation and inferred network functionality, whereas individuals with autism spectrum disorders (ASD) did not. These differences between TD and ASD groups were statistically significant for both structural and functional properties. Moreover, this typical age-related changes in rich-club organisation were characterised by progressive involvement of the right anterior insula. In contrast, in ASD individuals, did not show typical increases in grey matter volume, and this relative anatomical immaturity was correlated with the severity of ASD social symptoms. These results provide evidence that rich-club architecture is one of the bases of functionally efficient brain networks underpinning complex cognitive functions in adult human brains. Furthermore, our findings suggest that immature rich-club organisation might be associated with some neurodevelopmental disorders.
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17. Yui K, Imataka G, Kawasaki Y, Yamada H. {{Down-regulation of a signaling mediator in association with lowered plasma arachidonic acid levels in individuals with autism spectrum disorders}}. {Neurosci Lett};2015 (Nov 6)
Previous studies have indicated that the altered composition of polyunsaturated fatty acids (PUFAs) might contribute to the pathophysiology of autism spectrum disorder (ASD). We examined the relationship between the plasma fatty acid levels, expressed as mug/ml, and the plasma levels of biomarkers of AA-related signaling mediators, such as ceruloplasmin, transferrin and superoxide dismutase, and assessed the behavioral symptoms of 30 individuals with ASD (mean age, 13.6 +/- 4.3 years old) compared with 20 age- and gender-matched normal controls (mean age, 13.2 +/- 5.4 years old) using Aberrant Behavior Checklists (ABC). The plasma levels of EPA and the plasma ratios of EPA/AA were significantly higher, while the plasma levels of AA and metabolites, such as 5,8,11,14-eicosatetraenoic acid, adrenic acid, and ceruloplasmin (Cp), were significantly lower in the 30 individuals with ASD compared with the 20 normal controls. The ABC scores were significantly increased in the ASD group compared with those of the control group. Thus, the results of the present study revealed that reduced plasma levels of AA and metabolites in association with high plasma EPA/AA ratios might down-regulate AA-related signaling mediators, such as Cp. Subsequently, reduced plasma Cp levels might reduce the protective capacity for brain damage, resulting in the pathophysiology underlying the behavioral symptoms in individuals with ASD. These findings suggest that reduced plasma AA levels may downregulate Cp.
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18. Zhang Y, Kong W, Gao Y, Liu X, Gao K, Xie H, Wu Y, Wang J, Gao F, Wu X, Jiang Y. {{Gene Mutation Analysis in 253 Chinese Children with Unexplained Epilepsy and Intellectual/Developmental Disabilities}}. {PLoS One};2015;10(11):e0141782.
OBJECTIVE: Epilepsy and intellectual/developmental disabilities (ID/DD) have a high rate of co-occurrence. Here, we investigated gene mutations in Chinese children with unexplained epilepsy and ID/DD. METHODS: We used targeted next-generation sequencing to detect mutations within 300 genes related to epilepsy and ID/DD in 253 Chinese children with unexplained epilepsy and ID/DD. A series of filtering criteria was used to find the possible pathogenic variations. Validation and parental origin analyses were performed by Sanger sequencing. We reviewed the phenotypes of patients with each mutated gene. RESULTS: We identified 32 novel and 16 reported mutations within 24 genes in 46 patients. The detection rate was 18% (46/253) in the whole group and 26% (17/65) in the early-onset (before three months after birth) epilepsy group. To our knowledge, we are the first to report KCNAB1 is a disease-causing gene of epilepsy by identifying a novel de novo mutation (c.1062dupCA p.Leu355HisfsTer5) within this gene in one patient with early infantile epileptic encephalopathy (EIEE). Patients with an SCN1A mutation accounted for the largest proportion, 17% (8/46). A total of 38% (9/24) of the mutated genes re-occurred at least 2 times and 63% (15/24) occurred only one time. Ion channel genes are the most common (8/24) and genes related to synapse are the next most common to occur (5/24). SIGNIFICANCE: We have established genetic diagnosis for 46 patients of our cohort. Early-onset epilepsy had the highest detection rate. KCNAB1 mutation was first identified in EIEE patient. We expanded the phenotype and mutation spectrum of the genes we identified. The mutated genes in this cohort are mostly isolated. This suggests that epilepsy and ID/DD phenotypes occur as a consequence of brain dysfunction caused by a highly diverse population of mutated genes. Ion channel genes and genes related to synapse were more common mutated in this patient cohort.
