Pubmed du 13/03/21

samedi 13 mars 2021

1. Baba R, Matsuda S, Arakawa Y, Yamada R, Suzuki N, Ando T, Oki H, Igaki S, Daini M, Hattori Y, Matsumoto S, Ito M, Nakatani A, Kimura H. LSD1 enzyme inhibitor TAK-418 unlocks aberrant epigenetic machinery and improves autism symptoms in neurodevelopmental disorder models. Science advances. 2021 ; 7(11).

Persistent epigenetic dysregulation may underlie the pathophysiology of neurodevelopmental disorders, such as autism spectrum disorder (ASD). Here, we show that the inhibition of lysine-specific demethylase 1 (LSD1) enzyme activity normalizes aberrant epigenetic control of gene expression in neurodevelopmental disorders. Maternal exposure to valproate or poly I:C caused sustained dysregulation of gene expression in the brain and ASD-like social and cognitive deficits after birth in rodents. Unexpectedly, a specific inhibitor of LSD1 enzyme activity, 5-((1R,2R)-2-((cyclopropylmethyl)amino)cyclopropyl)-N-(tetrahydro-2H-pyran-4-yl)thiophene-3-carboxamide hydrochloride (TAK-418), almost completely normalized the dysregulated gene expression in the brain and ameliorated some ASD-like behaviors in these models. The genes modulated by TAK-418 were almost completely different across the models and their ages. These results suggest that LSD1 enzyme activity may stabilize the aberrant epigenetic machinery in neurodevelopmental disorders, and the inhibition of LSD1 enzyme activity may be the master key to recover gene expression homeostasis. TAK-418 may benefit patients with neurodevelopmental disorders.

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2. Bardhan M, Polavarapu K, Bevinahalli NN, Veeramani PK, Anjanappa RM, Arunachal G, Shingavi L, Vengalil S, Nashi S, Chawla T, Nagabhushan D, Mohan D, Horvath R, Nishino I, Atchayaram N. Megaconial congenital muscular dystrophy secondary to novel CHKB mutations resemble atypical Rett syndrome. Journal of human genetics. 2021.

Megaconial congenital muscular dystrophy (CMD)(OMIM #602541), related to CHKB mutation, is a rare autosomal recessive disorder. To date, only 35 confirmed patients are recorded. We present a detailed description of the clinical, histopathological, imaging, and genetic findings of five children from four Indian families. The children had moderate-to-severe autistic behavior, hand stereotypies, and global developmental delay mimicking atypical Rett syndrome. In addition, generalized hypotonia was a common initial finding. The progression of muscle weakness was variable, with two patients having a milder phenotype and three having a severe form. Interestingly, the majority did not attain sphincter control. Only patient 1 had classical ichthyotic skin changes. Muscle biopsy in two patients showed a myopathic pattern with characteristic peripherally placed enlarged mitochondria on modified Gomori trichrome stain and electron microscopy. Genetic analysis in these patients identified three novel null mutations in CHKB [c.1027dupA (p.Ser343LysfsTer86) ;c.224 + 1G > T (5’ splice site) ; c.1123C > T (p.Gln375Ter)] and one reported missense mutation, c.581G > A (p.Arg194Gln), all in the homozygous state. Megaconial CMD, although rare, forms an important group with a complex phenotypic presentation and accounted for 5.5% of our genetically confirmed CMD patients. Atypical Rett syndrome-like presentation may be a clue towards CHKB-related disorder.

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3. Davidovitch M, Shmueli D, Rotem RS, Bloch AM. Diagnosis despite clinical ambiguity : physicians’ perspectives on the rise in Autism Spectrum disorder incidence. BMC Psychiatry. 2021 ; 21(1) : 150.

BACKGROUND : To provide insight on physicians’ perspectives concerning recent changes in the incidence and diagnostic process of Autism Spectrum Disorder (ASD) compared to other mental and neurodevelopmental disorders. METHOD : A questionnaire was sent to 191 specialists in child neurology and child development, and 200 child psychiatrists in Israel. Information was collected on professional background, as well as on physicians’ opinions concerning the accuracy and rate of ASD diagnosis compared to that of cerebral palsy (CP), mental illness, and Attention Deficit Hyperactivity Disorder (ADHD). For each closed-ended question, a global chi-square test for categorical variables was performed. RESULTS : 115 (60.2%) of specialists in child neurology and development, and 59 (29.5%) of child psychiatrists responded. Most physicians (67.2%) indicated that there was a moderate/significant increase in the incidence of ASD, which was higher than similar responses provided for CP (2.9%, p < 0.01) and mental illnesses (14.4%, p < 0.01), and similar to responses provided for ADHD (70.1%, p = 0.56). 52.8% of physicians believed that in more than 10% of clinical assessments, an ASD diagnosis was given despite an inconclusive evaluation (CP : 8.6%, p < 0.01 ; mental illnesses : 25.8%, p = 0.03 ; ADHD : 68.4%, p = 0.03). CONCLUSION : The clinicians perceive both ASD and ADHD as over-diagnosed disorders. The shared symptomology between ASD and other disorders, coupled with heightened awareness and public de-stigmatization of ASD and with the availability of ASD-specific services that are not accessible to children diagnosed with other conditions, might lead clinicians to over-diagnose ASD. It is advisable to adopt an approach in which eligibility for treatments is conditional on function, rather than solely on a diagnosis. The medical community should strive for accurate diagnoses and a continuous review of diagnostic criteria.

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4. Hansen JB, Bilenberg N, Timmermann CAG, Jensen RC, Frederiksen H, Andersson AM, Kyhl HB, Jensen TK. Prenatal exposure to bisphenol A and autistic- and ADHD-related symptoms in children aged 2 and5 years from the Odense Child Cohort. Environmental health : a global access science source. 2021 ; 20(1) : 24.

BACKGROUND : Bisphenol A (BPA) is a non-persistent chemical with endocrine disrupting abilities used in a variety of consumer products. Fetal exposure to BPA is of concern due to the elevated sensitivity, which particularly relates to the developing brain. Several epidemiological studies have investigated the association between prenatal BPA exposure and neurodevelopment, but the results have been inconclusive. OBJECTIVE : To assess the association between in utero exposure to BPA and Attention Deficit/Hyperactivity Disorder (ADHD-) symptoms and symptoms of Autism Spectrum Disorder (ASD) in 2 and 5-year old Danish children. METHOD : In the prospective Odense Child Cohort, BPA was measured in urine samples collected in gestational week 28 and adjusted for osmolality. ADHD and ASD symptoms were assessed with the use of the ADHD scale and ASD scale, respectively, derived from the Child Behaviour Checklist preschool version (CBCL/1½-5) at ages 2 and 5 years. Negative binomial and multiple logistic regression analyses were performed to investigate the association between maternal BPA exposure (continuous ln-transformed or divided into tertiles) and the relative differences in ADHD and ASD problem scores and the odds (OR) of an ADHD and autism score above the 75th percentile adjusting for maternal educational level, maternal age, pre-pregnancy BMI, parity and child age at evaluation in 658 mother-child pairs at 2 years of age for ASD-score, and 427 mother-child pairs at 5 years of age for ADHD and ASD-score. RESULTS : BPA was detected in 85.3% of maternal urine samples even though the exposure level was low (median 1.2 ng/mL). No associations between maternal BPA exposure and ASD at age 2 years or ADHD at age 5 years were found. Trends of elevated Odds Ratios (ORs) were seen among 5 year old children within the 3rd tertile of BPA exposure with an ASD-score above the 75th percentile (OR = 1.80, 95% CI 0.97,3.32), being stronger for girls (OR = 3.17, 95% CI 1.85,9.28). A dose-response relationship was observed between BPA exposure and ASD-score at 5 years of age (p-trend 0.06) in both boys and girls, but only significant in girls (p-trend 0.03). CONCLUSION : Our findings suggest that prenatal BPA exposure even in low concentrations may increase the risk of ASD symptoms which may predict later social abilities. It is therefore important to follow-up these children at older ages, measure their own BPA exposure, and determine if the observed associations persist.

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5. Howells K, Sivaratnam C, Lindor E, He J, Hyde C, McGillivray J, Wilson RB, Rinehart N. Can a Community-Based Football Program Benefit Motor Ability in Children with Autism Spectrum Disorder ? A Pilot Evaluation Considering the Role of Social Impairments. J Autism Dev Disord. 2021.

This non-randomised pilot study evaluated the impact of a community football program on motor ability in children aged 5-12 years with autism spectrum disorder. Sixteen children were evaluated at baseline-and-post attendance in a football program for a varied number of weeks and compared to 19 children engaging in treatment-as-usual. Primary analyses indicated a statistically significant increase in total MABC-2, aiming and catching, and balance scores for the intervention group, with no changes in scores in the comparison group. There were no changes in manual dexterity across either group. At a between group level, the changes in aiming and catching scores were significantly greater for the intervention group. Further analyses highlighted the potential importance of social impairments regarding aiming and catching.

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6. Rahmani Z, Fayyazi Bordbar MR, Dibaj M, Alimardani M, Moghbeli M. Genetic and molecular biology of autism spectrum disorder among Middle East population : a review. Human genomics. 2021 ; 15(1) : 17.

BACKGROUND : Autism spectrum disorder (ASD) is a neurodevelopmental disease, characterized by impaired social communication, executive dysfunction, and abnormal perceptual processing. It is more frequent among males. All of these clinical manifestations are associated with atypical neural development. Various genetic and environmental risk factors are involved in the etiology of autism. Genetic assessment is essential for the early detection and intervention which can improve social communications and reduce abnormal behaviors. Although, there is a noticeable ASD incidence in Middle East countries, there is still a lack of knowledge about the genetic and molecular biology of ASD among this population to introduce efficient diagnostic and prognostic methods. MAIN BODY : In the present review, we have summarized all of the genes which have been associated with ASD progression among Middle East population. We have also categorized the reported genes based on their cell and molecular functions. CONCLUSIONS : This review clarifies the genetic and molecular biology of ASD among Middle East population and paves the way of introducing an efficient population based panel of genetic markers for the early detection and management of ASD in Middle East countries.

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7. Wieckowski AT, Hamner T, Nanovic S, Porto KS, Coulter KL, Eldeeb SY, Chen CA, Fein DA, Barton ML, Adamson LB, Robins DL. Early and Repeated Screening Detects Autism Spectrum Disorder. The Journal of pediatrics. 2021.

OBJECTIVE : To evaluate timing and accuracy of early and repeated screening for autism spectrum disorder (ASD) during well-child visits. STUDY DESIGN : Using a longitudinal study design, toddlers (n=5784) were initially screened at 12 (n=1504), 15 (n=1228), or 18 (n=3052) months during well-child visits, and rescreened at 18, 24, and 36 months. Of those screened, 368 toddlers attended an ASD evaluation after a positive screen and/or a provider concern for ASD at any visit. RESULTS : Screens initiated at 12 months yielded an ASD diagnosis significantly earlier than at 15 months (P = .003, d = 0.99) and 18 months (P < .001, d = 0.97). Cross-group overall sensitivity of the initial screen was .715 and specificity was .959. Repeat screening improves sensitivity (82.1%), without notably decreasing specificity (all > 93.5%). Screening at 18 months resulted in significantly higher positive predictive value (PPV) than at 12 months (X(2) (1, n=221) = 9.87, P = .002, OR = 2.60) and 15 months (X(2) (1, n=208) = 14.57, P < .001, OR = 3.67). With repeat screening, PPV increased for all screen groups but the increase was not significant. CONCLUSION : Screening as early as 12 months effectively identifies many children at risk for ASD. Children screened at 12 months receive a diagnosis of ASD significantly earlier than peers who are first screened at later ages, facilitating earlier intervention. However, as the sensitivity is lower for a single screen, screening needs to be repeated.

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