1. Al-Ayadhi L, Halepoto DM. {{Role of proteomics in the discovery of autism biomarkers}}. {J Coll Physicians Surg Pak};2013 (Feb);23(2):137-143.
The epidemiology of autism is continuously increasing all over the world with social, behavioural and economical burdens. Autism is considered as a multi-factorial disorder, influenced by genetic, neurological, environmental and immunological aspects. Autism is still believed to be incurable disorder with little information about the role of proteins patterns in the diagnosis of the disease. Knowing the applications of proteomic tools, it is possible to identify quantitative and qualitative protein patterns in a wide variety of tissues and body fluids such as blood, urine, saliva and cerebrospinal fluid in order to establish specific diagnostic and prognostic biomarkers. The aim of this review is to provide an overview of the various protocols available for proteomics by using mass spectrometry analysis, discuss reports in which these techniques have been previously applied in biomarker discovery for the diagnosis of autism, and consider the future development of this area of research.
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2. Au J, Scott Akins R, Berkowitz-Sutherland L, Tang HT, Chen Y, Boyd A, Tassone F, Nguyen DV, Hagerman R. {{Prevalence and Risk of Migraine Headaches in Adult Fragile X Premutation Carriers}}. {Clin Genet};2013 (Feb 1)
FMR1 premutation carriers are common in the general population (1/130-260 females and 1/250 – 810 males) and can be affected by fragile X-associated tremor ataxia syndrome (FXTAS), fragile X-associated primary ovarian insufficiency (FXPOI), anxiety, depression, hypertension, sleep apnea, fibromyalgia, and hypothyroidism. Here we report the results of a pilot study to assess the prevalence and risk of migraine in FMR1 premutation carriers. 315 carriers (203 females; 112 males) and 154 controls (83 females; 71 males) were seen sequentially as part of a family study. A standardized medical history, physical examination and confirmation of diagnosis of migraine headaches were performed by a physician. The prevalence of migraine was 54.2% in female carriers (mean age/SD: 49.60/13.73) and 26.79% in male carriers (mean age/SD: 59.94/ 14.27). This prevalence was higher compared to female (25.3%;mean age/SD: 47.60/15.21;p = 0.0001) and male controls (15.5%; mean age/SD; 53.88/13.31;p = 0.0406) who underwent the same protocol and were confirmed to be negative for the FMR1 mutation by DNA testing. We hypothesize that the increased prevalence of migraine headaches in FMR1 premutation carriers is likely related to the mitochondrial abnormalities that have recently been reported. Screening for migraine should be considered when evaluating FMR1 premutation carriers in the future.
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3. Eack SM, Bahorik AL, Hogarty SS, Greenwald DP, Litschge MY, Mazefsky CA, Minshew NJ. {{Brief Report: Is Cognitive Rehabilitation Needed in Verbal Adults with Autism? Insights from Initial Enrollment in a Trial of Cognitive Enhancement Therapy}}. {J Autism Dev Disord};2013 (Feb 5)
Cognitive rehabilitation is an emerging set of potentially effective interventions for the treatment of autism spectrum disorder, yet the applicability of these approaches for « high functioning » adults who have normative levels of intelligence remains unexplored. This study examined the initial cognitive performance characteristics of 40 verbal adults with autism enrolled in a pilot trial of Cognitive Enhancement Therapy to investigate the need for cognitive rehabilitation in this population. Results revealed marked and broad deficits across neurocognitive and social-cognitive domains, despite above-average IQ. Areas of greatest impairment included processing speed, cognitive flexibility, and emotion perception and management. These findings indicate the need for comprehensive interventions designed to enhance cognition among verbal adults with autism who have intact intellectual functioning.
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4. Elsabbagh M, Fernandes J, Jane Webb S, Dawson G, Charman T, Johnson MH. {{Disengagement of Visual Attention in Infancy Is Associated with Emerging Autism in Toddlerhood}}. {Biol Psychiatry};2013 (Jan 29)
BACKGROUND: Early emerging characteristics of visual orienting have been associated with a wide range of typical and atypical developmental outcomes. In the current study, we examined the development of visual disengagement in infants at risk for autism. METHODS: We measured the efficiency of disengaging from a central visual stimulus to orient to a peripheral one in a cohort of 104 infants with and without familial risk for autism by virtue of having an older sibling with autism. RESULTS: At 7 months of age, disengagement was not robustly associated with later diagnostic outcomes. However, by 14 months, longer latencies to disengage in the subset of the risk group later diagnosed with autism was observed relative to other infants at risk and the low-risk control group. Moreover, between 7 months and 14 months, infants who were later diagnosed with autism at 36 months showed no consistent increases in the speed and flexibility of visual orienting. However, the latter developmental effect also characterized those infants who exhibited some form of developmental concerns (but not meeting criteria for autism) at 36 months. CONCLUSIONS: Infants who develop autism or other developmental concerns show atypicality in the development of visual attention skills from the first year of life.
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5. Girirajan S, Dennis MY, Baker C, Malig M, Coe BP, Campbell CD, Mark K, Vu TH, Alkan C, Cheng Z, Biesecker LG, Bernier R, Eichler EE. {{Refinement and Discovery of New Hotspots of Copy-Number Variation Associated with Autism Spectrum Disorder}}. {Am J Hum Genet};2013 (Jan 30)
Rare copy-number variants (CNVs) have been implicated in autism and intellectual disability. These variants are large and affect many genes but lack clear specificity toward autism as opposed to developmental-delay phenotypes. We exploited the repeat architecture of the genome to target segmental duplication-mediated rearrangement hotspots (n = 120, median size 1.78 Mbp, range 240 kbp to 13 Mbp) and smaller hotspots flanked by repetitive sequence (n = 1,247, median size 79 kbp, range 3-96 kbp) in 2,588 autistic individuals from simplex and multiplex families and in 580 controls. Our analysis identified several recurrent large hotspot events, including association with 1q21 duplications, which are more likely to be identified in individuals with autism than in those with developmental delay (p = 0.01; OR = 2.7). Within larger hotspots, we also identified smaller atypical CNVs that implicated CHD1L and ACACA for the 1q21 and 17q12 deletions, respectively. Our analysis, however, suggested no overall increase in the burden of smaller hotspots in autistic individuals as compared to controls. By focusing on gene-disruptive events, we identified recurrent CNVs, including DPP10, PLCB1, TRPM1, NRXN1, FHIT, and HYDIN, that are enriched in autism. We found that as the size of deletions increases, nonverbal IQ significantly decreases, but there is no impact on autism severity; and as the size of duplications increases, autism severity significantly increases but nonverbal IQ is not affected. The absence of an increased burden of smaller CNVs in individuals with autism and the failure of most large hotspots to refine to single genes is consistent with a model where imbalance of multiple genes contributes to a disease state.
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6. Gonzalez C, Martin JM, Minshew NJ, Behrmann M. {{Practice Makes Improvement: How Adults with Autism Out-Perform Others in a Naturalistic Visual Search Task}}. {J Autism Dev Disord};2013 (Feb 5)
People with autism spectrum disorder (ASD) often exhibit superior performance in visual search compared to others. However, most studies demonstrating this advantage have employed simple, uncluttered images with fully visible targets. We compare the performance of high-functioning adults with ASD and matched controls on a naturalistic luggage screening task. Although the two groups were equally accurate in detecting targets, the ASD adults improve in their correct elimination of target-absent bags faster than controls. This feature of their behavior is extremely important for many real-world monitoring tasks that require sustained attention for long time periods. Further analyses suggest that this improvement is attributable neither to the motor speed nor to the level of intelligence of the adults with ASD. These findings may have possible implications for employment opportunities of adult individuals with ASD.
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7. Koldewyn K, Jiang YV, Weigelt S, Kanwisher N. {{Global/Local Processing in Autism: Not a Disability, but a Disinclination}}. {J Autism Dev Disord};2013 (Feb 3)
It is widely suggested that ASD is characterized by atypical local/global processing, but the published findings are contradictory. In an effort to resolve this question, we tested a large group of children on both a free-choice task and an instructed task using hierarchical local-global stimuli. We find that although children with autism showed a reduced preference to report global properties of a stimulus when given a choice, their ability to process global properties when instructed to do so is unimpaired. These findings support prior claims that people with ASD show a disinclination, not a disability, in global processing, and highlight the broader question of whether other characteristics of autism may also reflect disinclinations rather than disabilities.
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8. Korzeniewski SJ, Pinto-Martin JA, Whitaker AH, Feldman JF, Lorenz JM, Levy SE, Movsas TZ, Pappas A, Paneth N. {{Association between transient hypothyroxinaemia of prematurity and adult autism spectrum disorder in a low-birthweight cohort: an exploratory study}}. {Paediatr Perinat Epidemiol};2013 (Mar);27(2):182-187.
BACKGROUND: Transient hypothyroxinaemia of prematurity (THOP) is associated with increased risk of cerebral palsy and lower IQ in low-birthweight infants. This study explores whether THOP is also associated with increased risk of autism spectrum disorders (ASD). METHODS: This secondary analysis uses data from a birth cohort of newborns weighing 500 -2000 g (n = 1105) who were followed to age 21 years, when they were assessed for ASD in the second of a two-stage process. Of the 187 assessed at age 21, 14 had ASD. Neonatal thyroxine results were available for 12/14 and 165/173 participants diagnosed with and without ASD, respectively. THOP was defined as thyroxine z-score <-2.6. Unadjusted relative risks (RR) and confidence intervals (CI) were calculated. RESULTS: The mean neonatal thyroxine z-score in young adults diagnosed with ASD was 0.5 SD lower [95% CI -0.16, 1.06] than in those without ASD. Participants with THOP were at 2.5-fold greater risk of ASD (RR 2.5 [95% CI 0.7, 8.4]). While neither of these differences was statistically significant, in a secondary subgroup analysis of those whose mothers did not have hypertension during pregnancy, THOP significantly increased the RR for ASD (5.0 [95% CI 1.2, 20.5]). CONCLUSION: While the primary relation between THOP and ASD found here is not statistically significant, the magnitude of association and significant relationship observed in the subgroup whose mothers did not have hypertension during pregnancy suggest that it is worthy of further investigation.
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9. Lopaczynski W. {{Translational research and behavioral sciences in developmental medicine: metabolic conditions of pregnancy versus autism spectrum disorders}}. {Med Wieku Rozwoj};2012 (Jul-Sep);16(3):171-174.
Recently, scientific literature informed that metabolic conditions in pregnant women may be associated with increased risk for autism and other neurodevelopmental disorders in their offspring. In a cohort study of more than 1000 children between the ages of 2 and 5 years, those who had mothers classified as having « metabolic conditions » (which included diabetes, hypertension, and obesity) during pregnancy were at a significantly higher risk for developing an autism spectrum disorder (ASD) and neurodevelopmental delays. In addition, mothers with obesity were 1.6 times more likely to have a child with ASD and more than twice as likely to have a child with other developmental problems. In the United States, the prevalence of obesity among women of childbearing age is 34%. Moreover, with obesity rates rising steadily, these results appear to raise serious public health implications. The main objective of this Editorial is to propagate the health care improvement based on the translation research approach from basic behavioral sciences and relevant integrative neuroscience to pressing clinical issues that include an understanding of the etiology and assessment of disorders, and the assessment of functioning and development of innovative and culturally appropriate preventive treatment. Behavioral interventions for weight management in pregnancy may include the Transtheoretical Model (TTM) employed in obese pregnant women and then, the comparison with elements of the ecological model. A comparative effectiveness design is to test the effect of tailoring while including one of the most important predictors of screening-physician recommendation: after careful selection of analyzed behaviors from the TTM approach. However, there is also a risk that the evidence may not be conclusive for sustained weigh loss as a primary outcome of the proposed intervention, although the TTM in combination of physical activity and diet tended to produce significant results. Therefore, physicians might use the TTM to convince pregnant women to regulate weight and educate future parents on how to deal with autism at an early age of their children using watchful waiting management.
10. Lynch CJ, Uddin LQ, Supekar K, Khouzam A, Phillips J, Menon V. {{Default Mode Network in Childhood Autism: Posteromedial Cortex Heterogeneity and Relationship with Social Deficits}}. {Biol Psychiatry};2013 (Jan 31)
BACKGROUND: The default mode network (DMN), a brain system anchored in the posteromedial cortex, has been identified as underconnected in adults with autism spectrum disorder (ASD). However, to date there have been no attempts to characterize this network and its involvement in mediating social deficits in children with ASD. Furthermore, the functionally heterogeneous profile of the posteromedial cortex raises questions regarding how altered connectivity manifests in specific functional modules within this brain region in children with ASD. METHODS: Resting-state functional magnetic resonance imaging and an anatomically informed approach were used to investigate the functional connectivity of the DMN in 20 children with ASD and 19 age-, gender-, and IQ-matched typically developing (TD) children. Multivariate regression analyses were used to test whether altered patterns of connectivity are predictive of social impairment severity. RESULTS: Compared with TD children, children with ASD demonstrated hyperconnectivity of the posterior cingulate and retrosplenial cortices with predominately medial and anterolateral temporal cortex. In contrast, the precuneus in ASD children demonstrated hypoconnectivity with visual cortex, basal ganglia, and locally within the posteromedial cortex. Aberrant posterior cingulate cortex hyperconnectivity was linked with severity of social impairments in ASD, whereas precuneus hypoconnectivity was unrelated to social deficits. Consistent with previous work in healthy adults, a functionally heterogeneous profile of connectivity within the posteromedial cortex in both TD and ASD children was observed. CONCLUSIONS: This work links hyperconnectivity of DMN-related circuits to the core social deficits in young children with ASD and highlights fundamental aspects of posteromedial cortex heterogeneity.
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11. Matson J. {{Narrative overview of systematic reviews and meta-analyses: evidence on many treatments for psychopathology in people with developmental disabilities is limited}}. {Evid Based Ment Health};2013 (Feb 1)
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12. May T, Rinehart N, Wilding J, Cornish K. {{The Role of Attention in the Academic Attainment of Children with Autism Spectrum Disorder}}. {J Autism Dev Disord};2013 (Feb 3)
Academic attainment in children with Autism Spectrum Disorder (ASD) is under-studied, with associated factors largely undetermined. Parent-reported attention symptoms, attentional-switching and sustained-attention tasks were examined to determine relationships with mathematics and reading attainment in 124 children aged 7-12 years; sixty-four with high-functioning ASD, half girls, and sixty age- and gender-matched typical children (TYP). With full-scale IQ controlled there were no differences in mathematics, reading, attentional switching or sustained attention. In regression analysis, attentional switching was related to mathematics achievement in ASD but not TYP children. Findings highlight attentional switching difficulties are linked with poorer mathematics outcomes in ASD.
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13. Narzisi A, Calderoni S, Maestro S, Calugi S, Mottes E, Muratori F. {{Child Behavior Check List 1(1/2)-5 as a tool to identify toddlers with Autism Spectrum Disorders: A case-control study}}. {Res Dev Disabil};2013 (Jan 31);34(4):1179-1189.
Tools to identify toddlers with autism in clinical settings have been recently developed. This study evaluated the sensitivity and specificity of the Child Behavior Check List 1(1/2)-5 (CBCL 1(1/2)-5) in the detection of toddlers subsequently diagnosed with an Autism Spectrum Disorder (ASD), ages 18-36 months. The CBCL of 47 children with ASD were compared to the CBCL of 47 toddlers with Other Psychiatric Disorders (OPD) as well as the CBCL of 47 toddlers with Typical Development (TD) in a case control study. One-way analysis of variance (ANOVA) and logistic regression with odds ratio (OR) analyses were performed. In order to establish the optimal threshold able to discriminate children with ASD from children with OPD and TD, Receiver Operating Characteristic (ROC) analyses were performed. One-way ANOVA revealed significant differences between the three groups. Logistic regression analysis showed that the Withdrawn and the Pervasive Developmental Problems (PDP) subscales can recognize toddlers subsequently identified as ASD from both children with TD (p<0.001) and OPD (p<0.001). ROC analyses showed very high sensitivity and specificity for the PDP (0.98 and 0.91) and Withdrawn (0.92 and 0.97) subscales when ASD was compared to TD. Sensitivity and specificity of Withdrawn (0.90 and 0.83) and PDP (0.85 and 0.83) remained high when comparing ASD versus OPD. In conclusion, the CBCL 1(1/2)-5 seemed to be able to identify toddlers subsequently diagnosed with ASD from children with TD and OPD. Its high sensitivity and specificity, coupled with its efficiency in terms of time and cost, suggest this broadband tool should be tested in a pilot screening survey of toddlers in the general population.
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14. Raz R, Lerner-Geva L, Leon O, Chodick G, Gabis LV. {{A Survey of Out-of-Pocket Expenditures for Children with Autism Spectrum Disorder in Israel}}. {J Autism Dev Disord};2013 (Feb 5)
We describe a survey of children with ASD aged 4-10 years. The main dependent variables were out-of-pocket expenditures for health services and hours of therapy. Multivariable logistic regression models were used in order to find independent predictors for service utilization. Parents of 178 of the children (87 %) agreed to participate. The average annual out-of-pocket cost was $8,288, with a median of $4,473 and a range of $0-89,754. Higher severity of ASD and a parent with an academic degree were associated with higher expenditure. Having at least one older sibling, siblings without developmental disorders, regular education setting, lower parent education and low income were associated with lower expenditure.
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15. Sato K. {{Placenta-derived hypo-serotonin situations in the developing forebrain cause autism}}. {Med Hypotheses};2013 (Jan 31)
Autism is a pervasive developmental disorder that is characterized by the behavioral traits of impaired social cognition and communication, and repetitive and/or obsessive behavior and interests. Although there are many theories and speculations about the pathogenetic causes of autism, the disruption of the serotonergic system is one of the most consistent and well-replicated findings. Recently, it has been reported that placenta-derived serotonin is the main source in embryonic day (E) 10-15 mouse forebrain, after that period, the serotonergic fibers start to supply serotonin into the forebrain. E 10-15 is the very important developing period, when cortical neurogenesis, migration and initial axon targeting are processed. Since all these events have been considered to be involved in the pathogenesis of autism and they are highly controlled by serotonin signals, the paucity of placenta-derived serotonin should have potential importance when the pathogenesis of autism is considered. I, thus, postulate a hypothesis that placenta-derived hypo-serotonin situations in the developing forebrain cause autism. The hypothesis is as follows. Various factors, such as inflammation, dysfunction of the placenta, together with genetic predispositions cause a decrease of placenta-derived serotonin levels. The decrease of placenta-derived serotonin levels leads to hypo-serotonergic situations in the forebrain of the fetus. The paucity of serotonin in the forebrain leads to mis-wiring in important regions which are responsible for the theory of mind. The paucity of serotonin in the forebrain also causes over-growth of serotonergic fibers. These disturbances result in network deficiency and aberration of the serotonergic system, leading to the autistic phenotypes.
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16. Steinman G, Mankuta D. {{Insulin-like growth factor and the etiology of autism}}. {Med Hypotheses};2013 (Jan 30)
The basic hypothesis for this study is that reduced peripartum level of insulin-like growth factor-1 (IGF) due to genetic, epigenetic, or environmental factors is a sentinel biomarker of increased probability of later development of autism. The central objective of the resultant proposed study described here is examining if a correlation exists between the serum level of IGF in the fetus/newborn and the probability of autism developing later in the child. Mechanisms possibly causing such a decrease are considered. This would define a prospective biomarker for and possible etiology of this disorder. Insulin-like growth factor-1 directly affects the rate at which oligodendrocytes promote myelination in the central nervous system, especially in the brain. Factors which reduce the production or availability of IGF could retard normal nerve programming in the fetus or neonate. Thus, it would be desirable to arrest the pathologic processes of autism in the early neonatal stage before irreversible nerve damage occurs.
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17. Watanabe H, Nakamura M, Ohno T, Itahashi T, Tanaka E, Ohta H, Yamada T, Kanai C, Iwanami A, Kato N, Hashimoto R. {{Altered orbitofrontal sulcogyral patterns in adult males with high-functioning autism spectrum disorders}}. {Soc Cogn Affect Neurosci};2013 (Feb 5)
Functions of the orbitofrontal cortex include diverse social, cognitive, and affective processes, many of which are abnormal in autism spectrum disorders (ASD). Recently, altered orbitofrontal sulcogyral patterns have been revealed in several psychiatric conditions such as schizophrenia, indicating a possibility that altered orbitofrontal sulcogyral morphology reflects abnormal neurodevelopment. However, the presence of sulcal alterations in ASD remains unexplored. Using structural MRI, subtypes of the « H-shaped » sulcus (Type I, II, and III, in order of frequency), posterior orbital sulcus (POS), and intermediate orbital sulcus were identified in each hemisphere of adult males with ASD (n=51) and matched normal controls (n=55) based on Chiavaras and Petrides (2000). ASD showed a significantly altered distribution of H-shaped sulcal subtypes in both hemispheres, with a significant increase of Type III. A significant alteration in the distribution of sulcal subtypes was also identified in the right hemisphere POS of ASD. Categorical regression analysis revealed that Type I and II expressions predicted a reduced total Autism-Spectrum Quotient score. Furthermore, Type I expression was associated with a reduced « attention to detail » subscale score. The results demonstrate that altered sulcogyral morphology can be a marker for abnormal neurodevelopment leading to the increased risk of developing autism.
