1. Ali A, Cui X, Alexander S, Eyles D. {{The placental immune response is dysregulated developmentally vitamin D deficient rats: Relevance to autism}}. {The Journal of steroid biochemistry and molecular biology}. 2018.
Emerging evidence suggests that maternal or developmental vitamin D (DVD) deficiency is a risk factor for Autism Spectrum Disorders. A well-established association has also been found between gestational infection and increased incidence of autism. Placenta mediates the maternal immune response in respect to the foetus. The placenta is also a major source of vitamin D and locally produced vitamin D is an essential regulator of immune function during pregnancy. Here we investigate the effects of DVD-deficiency on baseline placental immune status and in response to the well-known viral and bacterial immune activating agents polyriboinosinic-polyribocytidylic acid (poly(I:C) and lipopolysaccharide (LPS). We show DVD-deficiency does not affect baseline inflammatory cytokines in placenta. However, when challenged with poly(I:C) but not LPS, DVD-deficient placentas from male foetuses had higher production of IL-6 and 1L-1beta compared to control placentas. This suggests the developing DVD-deficient male foetus may be particularly vulnerable to maternal viral exposures. This in turn may have adverse implications for the developing male brain. In conclusion, a dysregulated placental immune response may provide a plausible mechanism for both the epidemiological links between DVD-deficiency and increased male incidence of developmental conditions such as autism.
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2. Al-Otaish H, Al-Ayadhi L, Bjorklund G, Chirumbolo S, Urbina MA, El-Ansary A. {{Relationship between absolute and relative ratios of glutamate, glutamine and GABA and severity of autism spectrum disorder}}. {Metabolic brain disease}. 2018.
Autism spectrum disorder (ASD) is a neurodevelopmental pathology characterized by an impairment in social interaction, communication difficulties, and repetitive behaviors. Glutamate signaling abnormalities are thought to be considered as major etiological mechanisms leading to ASD. The search for amino-acidic catabolytes related to glutamate in patients with different levels of ASD might help current research to clarify the mechanisms underlying glutamate signaling and its disorders, particularly in relation to ASD. In the present study, plasma levels of the amino acids and their derivatives glutamate, glutamine, and gamma-aminobutyric acid (GABA), associated with their relative ratios, were evaluated using an enzyme-linked immunosorbent assay (ELISA) technique in 40 male children with ASD and in 38 age- and gender-matched neurotypical health controls. The Social Responsiveness Scale (SRS) was used to evaluate social cognition, and the Childhood Autism Rating Scale (CARS) was used to assess subjects’ behaviors. Children with ASD exhibited a significant elevation of plasma GABA and glutamate/glutamine ratio, as well as significantly lower levels of plasma glutamine and glutamate/GABA ratios compared to controls. No significant correlation was found between glutamate levels and the severity of autism, measured by CARS and SRS. In receiver operating characteristic (ROC) curve analysis, the area under the curve for GABA compared to other parameters was close to one, indicating its potential use as a biomarker. Glutamine appeared as the best predictive prognostic markers in the present study. The results of the present study indicate a disturbed balance between GABAergic and glutamatergic neurotransmission in ASD. The study also indicates that an increased plasma level of GABA can be potentially used as an early diagnostic biomarker for ASD.
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3. Bitar T, Mavel S, Emond P, Nadal-Desbarats L, Lefevre A, Mattar H, Soufia M, Blasco H, Vourc’h P, Hleihel W, Andres CR. {{Identification of metabolic pathway disturbances using multimodal metabolomics in autistic disorders in a Middle Eastern population}}. {Journal of pharmaceutical and biomedical analysis}. 2018; 152: 57-65.
We analyzed for the first time the metabolic profile of Lebanese children affected by autistic disorders to compare this profile to other metabolomics studies and to identify the associated metabolic disturbances. Urine samples of 40 patients with Autism spectrum disorder (ASD) and 40 healthy matched controls were analyzed using nuclear magnetic resonance (NMR) and liquid chromatography coupled to high-resolution mass spectrometry (LC-MS). Multivariate analysis on analytical data fusion was conducted on the training set of 50 urine samples, and then validated with a test set of 30 samples, this repeated 10 times. The model was also evaluated using a receiver operating characteristic curve showing a specificity and a sensitivity of 86% and 80%, respectively. Among the most significant metabolites that contributed to the discrimination between ASD and controls, we confirmed the perturbations of tyrosine, 2-hydroxybutyrate, creatine and glutamate. We found new metabolites such as trigonelline, cysteic acid and guanine. We found metabolic perturbations including amino acids, carbohydrates and oxidative stress pathways which added value for the contribution of known metabolic disturbances in ASD observed in populations of other ethnic and geographic origins.
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4. Dominick KC, Wink LK, Pedapati EV, Shaffer R, Sweeney JA, Erickson CA. {{Risperidone Treatment for Irritability in Fragile X Syndrome}}. {J Child Adolesc Psychopharmacol}. 2018.
OBJECTIVE: The goal of this study was to assess the effectiveness of risperidone monoantipsychotic therapy targeting irritability in patients with Fragile X syndrome (FXS) in a naturalistic outpatient clinical setting. METHODS: We examined the use of risperidone, predominantly in combination with other nonantipsychotic psychotropic agents, targeting irritability in 21 male patients with FXS with a retrospective analysis of a prospectively collected large developmental disabilities-specific treatment database. Mean age at start of treatment, treatment duration, final dose, body mass index (BMI), and Clinical Global Impressions-Improvement (CGI-I) Scale score at final visit were determined, and changes with treatment were analyzed using paired t-tests. RESULTS: Mean age at start of treatment was 14.0 years. The final mean dose of risperidone was 2.5 mg/day. The mean duration of treatment was 22 months. Seven (33.33%) participants were considered treatment responders based on the CGI-I. Change in BMI between initiation and cessation of treatment episode was not significant, however, these data were only available for a subset (n = 11) of patients. CONCLUSIONS: Risperidone may be effective in the treatment of irritability in males with FXS. The overall effectiveness of monoantipsychotic treatment with risperidone was limited in this study compared with previous published reports; however, this may be the result of differences in outcome measures as well as a reflection of the level of functioning and severity of irritability in this sample.
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5. Leser KA, Pirie PL, Ferketich AK, Havercamp SM, Wewers ME. {{Smoking behaviors of adults with developmental disabilities and their direct support professional providers}}. {Disability and health journal}. 2018.
BACKGROUND: People with developmental disabilities are not immune from the addictive effects and poor health outcomes associated with cigarette use. Direct support professionals often play a large role in the social environments of people with developmental disabilities and the literature suggests that one’s environment can influence behavior. OBJECTIVES: To examine the relationship between the smoking behaviors of people with developmental disabilities and their direct support professional providers. Two exploratory aims of the study were to assess how direct support professionals facilitate smoking behaviors and to describe the use of home smoking policies. METHODS: The Ohio Department of Disabilities’ online provider search database was used to randomly select participants. A total of 398 direct support professionals completed an online survey about smoking. Direct support professionals served as proxy reporters for the smoking behaviors of those with developmental disabilities. Descriptive statistics were calculated and Chi-Square tests were used. RESULTS: Findings suggest that there was no significant relationship (chi1(2)=0.300, p=0.584) between the current smoking behaviors of people with developmental disabilities and their direct support providers. Direct support professionals were most likely to facilitate smoking behaviors by allowing people with developmental disabilities to smoke in front of them and waiting for them to finish smoking before moving on to a new activity. Approximately 46% of people with developmental disabilities were reported to have some type of home smoking policy. CONCLUSIONS: Future research is needed to better understand the reasons why people with developmental disabilities initially start smoking and continue to smoke.
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6. Mazurek MO, Lu F, Macklin EA, Handen BL. {{Factors associated with DSM-5 severity level ratings for autism spectrum disorder}}. {Autism}. 2018: 1362361318755318.
The newest edition of the Diagnostic and Statistical Manual of Mental Disorders (5th ed., DSM-5) introduced substantial changes to the diagnostic criteria for autism spectrum disorder, including new severity level ratings for social communication and restricted and repetitive behavior domains. The purpose of this study was to evaluate the use of these new severity ratings and to examine their relation to other measures of severity and clinical features. Participants included 248 children with autism spectrum disorder who received diagnostic evaluations at one of six Autism Treatment Network sites. Higher severity ratings in both domains were associated with younger age, lower intelligence quotient, and greater Autism Diagnostic Observation Schedule-Second Edition domain-specific symptom severity. Greater restricted and repetitive behavior severity was associated with higher parent-reported stereotyped behaviors. Severity ratings were not associated with emotional or behavioral problems. The new DSM-5 severity ratings in both domains were significantly associated with behavioral observations of autism severity but not with measures of other behavioral or emotional symptoms. However, the strong associations between intelligence quotient and DSM-5 severity ratings in both domains suggest that clinicians may be including cognitive functioning in their overall determination of severity. Further research is needed to examine clinician decision-making and interpretation of these specifiers.
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7. Mitroi AF, Aschie M, Apostol A, Brinzan C, Cozaru G, Mitroi AN. {{A boy with 13.34-Mb interstitial deletion of chromosome 4p15: A new case report and review of the literature}}. {Medicine}. 2017; 96(51): e9301.
RATIONALE: To date, >40 cases have been described with interstitial deletions involving the 4p15 region. PATIENT CONCERNS AND DIAGNOSIS: We report a case of a 3-year-old boy with an interstitial de novo deletion of approximately 13.34 Mb in 4p15.1-15.31 having mild developmental delay and multiple minor congenital abnormalities. LESSONS: This case presents a clinical manifestation that is similar but not identical to other reported cases. In this report, we have provided a detailed description of a 3-year-old patient with an interstitial 4p deletion and mildly affected phenotype. We discuss the possible involvement of SLIT2, KCNIP4, and LGI2 in cortical development and RBPJ in skeletal abnormalities.
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8. Neumeyer AM, Cano Sokoloff N, McDonnell EI, Macklin EA, McDougle CJ, Holmes TM, Hubbard JL, Misra M. {{Nutrition and Bone Density in Boys with Autism Spectrum Disorder}}. {Journal of the Academy of Nutrition and Dietetics}. 2018.
BACKGROUND: Boys with autism spectrum disorder (ASD) have lower bone mineral density (BMD) than typically developing controls. Differences in diet and exercise may contribute to low BMD. OBJECTIVE: Our aim was to examine macro- and micronutrient intakes and self-reported physical activity in boys with ASD compared to TDC and the relationship of these variables with BMD. DESIGN/METHODS: We conducted a cross-sectional study of 49 boys (25 ASD, 24 typically developing controls) assessed for 3-day food records and physical activity records, and BMD of the whole body less head, hip, and spine using dual-energy x-ray absorptiometry. Fasting levels of 25(OH) vitamin D and calcium were obtained. PARTICIPANTS: Participants were adolescent boys, aged 8 to 17 years, recruited from a clinic population (ASD) or community advertisements (ASD and typically developing controls) matched for age. RESULTS: ASD participants were approximately 9 months younger than typically developing control participants on average. Body mass index and serum vitamin D and calcium levels were similar. Boys with ASD consumed 16% fewer calories, with a larger percentage obtained from carbohydrates, and 37% less animal protein and 20% less fat than typically developing controls. A lower proportion of ASD participants were categorized as « very physically active » (27% vs 79%; P<0.001). BMD z scores were 0.7 to 1.2 standard deviations lower in ASD than typically developing controls at all locations. Higher animal protein, calcium, and phosphorus intakes were associated positively with bone density measures in boys with ASD. CONCLUSIONS: Compared to typically developing controls, boys with ASD had lower protein, calcium, and phosphorus intakes, activity levels, and BMD z scores at the lumbar spine, femoral neck, total hip, and whole body less head. Protein, calcium, and phosphorus intakes were associated positively with BMD. Lien vers le texte intégral (Open Access ou abonnement)
9. Pascolini G, Agolini E, Majore S, Novelli A, Grammatico P, Digilio MC. {{Helsmoortel-Van der Aa Syndrome as emerging clinical diagnosis in intellectually disabled children with autistic traits and ocular involvement}}. {European journal of paediatric neurology : EJPN : official journal of the European Paediatric Neurology Society}. 2018.
A recent syndromic condition with craniofacial dysmorphisms, comprising congenital ocular defect and neurodevelopmental delay named Helsmoortel-Van der Aa Syndrome (HVDAS) (OMIM#615873), has been described and molecularly defined, identifying pathogenic mutations in the ADNP gene (OMIM#611386) as biological cause. We report on two children, displaying intellectual disability (ID) and peculiar congenital eyes anomalies, both carrying a de novo nonsense mutation in the ADNP gene. The review of present and literature reports, suggests that the diagnosis of HVDAS should be suspected in patients with ID accompanied by behavioral features in the Autism Spectrum Disorder and distinctive craniofacial phenotype. Among dysmorphisms due to malformation of the periorbital region, ptosis appears to be particularly recurrent in HVDAS. Furthermore, the present patients could support the inclusion of the HVDAS associated with specific mutations clustering within a small ADNP genomic region among clinical conditions reminiscent of the blepharophimosis/mental retardation syndromes (BMRS).
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10. Quadros EV, Sequeira JM, Brown WT, Mevs C, Marchi E, Flory M, Jenkins EC, Velinov MT, Cohen IL. {{Folate receptor autoantibodies are prevalent in children diagnosed with autism spectrum disorder, their normal siblings and parents}}. {Autism Res}. 2018.
Folate deficiency can affect fetal and neonatal brain development Considering the reported association of Folate receptor alpha (FRalpha) autoantibodies (Abs) with autism and developmental disorders, we sought to confirm this in families of 82 children with ASD, 53 unaffected siblings, 65 fathers, and 70 mothers, along with 52 unrelated normal controls. Overall, 76% of the affected children, 75% of the unaffected siblings, 69% of fathers and 59% of mothers were positive for either blocking or binding Ab, whereas the prevalence of this Ab in the normal controls was 29%. The Ab was highly prevalent in affected families including unaffected siblings. The appearance of these antibodies may have a familial origin but the risk of developing ASD is likely influenced by other mitigating factors since some siblings who had the antibodies were not affected. The antibody response appears heritable with the blocking autoantibody in the parents and affected child increasing the risk of ASD. Autism Res 2018. (c) 2018 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: Folate is an essential nutrient during fetal and infant development. Autoantibodies against the folate receptor alpha can block folate transport from the mother to the fetus and to the brain in infants. Children diagnosed with autism and their immediate family members were evaluated for the prevalence of folate receptor autoantibodies. The autoantibody was highly prevalent in affected families with similar distribution in parents, normal siblings and affected children. The presence of these antibodies appears to have a familial origin and may contribute to developmental deficits when combined with other factors.
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11. Ramelli V, Perlini R, Zanda N, Mascetti G, Rizzi E, Ramelli GP. {{Early identification of autism spectrum disorders using the two-step Modified Checklist for Autism: experience in Southern Switzerland}}. {European journal of pediatrics}. 2018; 177(4): 477-8.
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12. Rose S, Bennuri SC, Davis JE, Wynne R, Slattery JC, Tippett M, Delhey L, Melnyk S, Kahler SG, MacFabe DF, Frye RE. {{Butyrate enhances mitochondrial function during oxidative stress in cell lines from boys with autism}}. {Translational psychiatry}. 2018; 8(1): 42.
Butyrate (BT) is a ubiquitous short-chain fatty acid (SCFA) principally derived from the enteric microbiome. BT positively modulates mitochondrial function, including enhancing oxidative phosphorylation and beta-oxidation and has been proposed as a neuroprotectant. BT and other SCFAs have also been associated with autism spectrum disorders (ASD), a condition associated with mitochondrial dysfunction. We have developed a lymphoblastoid cell line (LCL) model of ASD, with a subset of LCLs demonstrating mitochondrial dysfunction (AD-A) and another subset of LCLs demonstrating normal mitochondrial function (AD-N). Given the positive modulation of BT on mitochondrial function, we hypothesized that BT would have a preferential positive effect on AD-A LCLs. To this end, we measured mitochondrial function in ASD and age-matched control (CNT) LCLs, all derived from boys, following 24 and 48 h exposure to BT (0, 0.1, 0.5, and 1 mM) both with and without an in vitro increase in reactive oxygen species (ROS). We also examined the expression of key genes involved in cellular and mitochondrial response to stress. In CNT LCLs, respiratory parameters linked to adenosine triphosphate (ATP) production were attenuated by 1 mM BT. In contrast, BT significantly increased respiratory parameters linked to ATP production in AD-A LCLs but not in AD-N LCLs. In the context of ROS exposure, BT increased respiratory parameters linked to ATP production for all groups. BT was found to modulate individual LCL mitochondrial respiration to a common set-point, with this set-point slightly higher for the AD-A LCLs as compared to the other groups. The highest concentration of BT (1 mM) increased the expression of genes involved in mitochondrial fission (PINK1, DRP1, FIS1) and physiological stress (UCP2, mTOR, HIF1alpha, PGC1alpha) as well as genes thought to be linked to cognition and behavior (CREB1, CamKinase II). These data show that the enteric microbiome-derived SCFA BT modulates mitochondrial activity, with this modulation dependent on concentration, microenvironment redox state, and the underlying mitochondrial function of the cell. In general, these data suggest that BT can enhance mitochondrial function in the context of physiological stress and/or mitochondrial dysfunction, and may be an important metabolite that can help rescue energy metabolism during disease states. Thus, insight into this metabolic modulator may have wide applications for both health and disease since BT has been implicated in a wide variety of conditions including ASD. However, future clinical studies in humans are needed to help define the practical implications of these physiological findings.
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13. Tordjman S, Cohen D, Anderson GM, Botbol M, Canitano R, Coulon N, Roubertoux PL. {{Repint of « Reframing autism as a behavioral syndrome and not a specific mental disorder: Implications of genetic and phenotypic heterogeneity »}}. {Neurosci Biobehav Rev}. 2018.
Clinical and molecular genetics have advanced current knowledge on genetic disorders associated with autism. A review of diverse genetic disorders associated with autism is presented and for the first time discussed extensively with regard to possible common underlying mechanisms leading to a similar cognitive-behavioral phenotype of autism. The possible role of interactions between genetic and environmental factors, including epigenetic mechanisms, is in particular examined. Finally, the pertinence of distinguishing non-syndromic autism (isolated autism) from syndromic autism (autism associated with genetic disorders) will be reconsidered. Given the high genetic and etiological heterogeneity of autism, autism can be viewed as a behavioral syndrome related to known genetic disorders (syndromic autism) or currently unknown disorders (apparent non-syndromic autism), rather than a specific categorical mental disorder. It highlights the need to study autism phenotype and developmental trajectory through a multidimensional, non-categorical approach with multivariate analyses within autism spectrum disorder but also across mental disorders, and to conduct systematically clinical genetic examination searching for genetic disorders in all individuals (children but also adults) with autism.
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14. Zhang X, Zhou M, Yin H, Dai Y, Li Y. {{The predictive value of early oral motor assessments for neurodevelopmental outcomes of moderately and late preterm infants}}. {Medicine}. 2017; 96(50): e9207.
Oral motor assessment is used to identify abnormal sucking patterns which may reflect neurodevelopmental problems in preterm infants, but few studies have focused on moderately and late preterm infants. We enrolled 118 moderately and late preterm infants (mean gestational age, 35.04 weeks; mean birth weight, 2347.59 g) and analyzed the relationship between the Neonatal Oral-Motor Assessment Scale scores of these infants and the Chinese revision of Bayley Scales of Infant Development outcomes at 6 months corrected age. And the infants with abnormal sucking pattern had significantly lower Mental Development Index and Psychomotor Development Index and showed a higher rate of below average scores than control group (P = .003, P = .029, P = .022). The incoordination of suck-swallow-respiration was a risk factor for adverse neurodevelopment (RR = 3.67, 95% CI: 1.42-9.45). These indicate that abnormal sucking patterns in moderately and late preterm infants might provide some predictive value for short-term neurodevelopmental outcomes, but the clinical predictive value for developmental delay need to be determined in a longer term follow-up. This finding may offer a basis for early intervention.
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15. Zhang Y, Lian Y, Xie N. {{Early onset epileptic encephalopathy with a novel GABRB3 mutation treated effectively with clonazepam: A case report}}. {Medicine}. 2017; 96(50): e9273.
RATIONALE: Early onset epileptic encephalopathy (EOEE) is one of the most serious early onset epilepsies. The etiopathology of this condition remains unclear, and recent evidence indicated that gamma-aminobutyric acid (GABA) A receptor, subunit beta 3 (GABRB3) gene mutations might be associated with EOEE. Furthermore, the therapeutic regimen for EOEE has yet to be well elucidated. Herein, we reported the clinical and genetic features of a case with GABRB3-related EOEE. PATIENT CONCERNS: A 6-year-old girl developed epileptic seizures 3 days after birth. She presented with multiple seizure types including myoclonic seizures, spasms, and absence seizures. Serial electroencephalographic examinations showed variable abnormalities, and intellectual evaluation revealed significant development retardation. Conventional antiepileptic drugs were ineffective for the seizure controlling. Genetic screening identified a novel nonsense mutation (C.5G > A, p.W2X) in the GABRB3 gene. DIAGNOSES: Early onset epileptic encephalopathy. INTERVENTIONS: We changed the antiepileptic strategy to oral clonazepam (0.5mg twice daily). The patient was followed up once a week and significant declining in the attack frequency was noted 1 week later (2-3 times daily). Subsequently, the dosage was doubled (1mg twice daily), and complete cessation of seizures was achieved 20 days later. OUTCOMES: Through a 9-month follow up,the girl remained seizure-free. LESSONS: This study identified a novel nonsensemutation (C.5G>A) in the exon 1 of GABRB3 Gene, which may be associated with EOEE. To our knowledge, this is the first report to use clonazepam in the patient with GABRB3-related EOEE with favorable outcome. Our finding suggested that clonazepam might be a choice for patient with GABRB3-related EOEE. The remarkable efficacy of clonazepam in the control of seizures indicated a potential GABRB3- or GABA-related mechanism involved in the development of EOEE.
