1. Berger K, Pearl M, Kharrazi M, Li Y, DeGuzman J, She J, Behniwal P, Lyall K, Windham G. The association of in utero tobacco smoke exposure, quantified by serum cotinine, and Autism Spectrum Disorder. Autism research : official journal of the International Society for Autism Research. 2021; 14(9): 2017-26.

Previous studies on in utero exposure to maternal environmental tobacco smoke (ETS) or maternal active smoking and Autism Spectrum Disorder (ASD) have not been entirely consistent, and no studies have examined in utero cotinine concentrations as an exposure classification method. We measured cotinine in stored second trimester maternal serum for 498 ASD cases and 499 controls born in California in 2011-2012. We also obtained self-reported maternal cigarette smoking during and immediately prior to pregnancy, as well as covariate data, from birth records. Using unconditional logistic regression, we found no association between log10 cotinine concentrations and odds for developing ASD among children of non-smokers (aOR: 0.93 [95% CI: 0.69, 1.25] per ng/ml), which represents exposure to ETS, though there may be a possible interaction with race. We found no association between cotinine-defined smoking (≥3.08 ng/ml vs. <3.08 ng/ml) (adjusted odds ratio [aOR]: 0.73 (95% confidence interval [95% CI]: 0.35, 1.54)) or self-reported smoking (aOR: 1.64 [95% CI: 0.65, 4.16]) and ASD. In one of the few studies of ETS and the first with measured cotinine, our results indicate no overall relationship between in utero exposure to tobacco smoke from maternal ETS exposure or active smoking, and development of ASD. LAY SUMMARY: This study found that women who smoke or are exposed to tobacco smoke during pregnancy are not more likely to have children with Autism Spectrum Disorder (ASD). This is the first ASD study to measure a chemical in the mother's blood during pregnancy to identify exposure to tobacco smoke.

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2. Cartwright JE, Mount KB. Adjunctive Parental Support Within Manualized Parent Training for Children with Autism Spectrum Disorder. Child psychiatry and human development. 2021.

Parent training is a central focus of behavioral intervention, with emphasis on teaching parents to become change agents for their children by using behavioral management skills. However, its effectiveness is limited by a parent’s ability to engage in the learning process. Parents managing external stressors, psychopathology, or poverty often do not gain the skills and thus, the treatment may minimally impacts parent and child behavior. In order to increase a parent’s ability to acquire and implement new skills accurately, referred to as parent treatment integrity, the current study added a parent-support component to the RUBI Autism Network’s Parent Training for Disruptive Behaviors protocol. The parent-support component was intended to remove barriers to skill acquisition during the parent training session by alleviating some of the interfering parental stress. In an alternating treatments design, a community-based sample of five parent-child dyads (average age of child = 32 months) participated in the parent-training protocol; half of the intervention sessions included a 15-min parent-support component. The addition of the parent-support component increased parent engagement, treatment integrity, and learned parenting skills, like parent praise. Results support a model of change for parenting behavior. Inclusion of a parent-support component is supported as an effective practice for parent training.

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3. Choi L, An JY. Genetic architecture of autism spectrum disorder: Lessons from large-scale genomic studies. Neuroscience and biobehavioral reviews. 2021; 128: 244-57.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder with a strong genetic component. Recently developed genomic technologies, including microarray and next-generation sequencing (NGS), have enabled researchers to genetic analyses aimed at identifying genetic variations associated with ASD and to elucidate the genetic architecture of the disorder. Large-scale microarray, exome sequencing analyses, and robust statistical methods have resulted in successful gene discovery and identification of high-confidence ASD genes from among de novo and inherited variants. Efforts have been made to understand the genetic architecture of ASD using whole-genome sequencing and genome-wide association studies aimed at identifying noncoding mutations and common variants associated with ASD. In addition, the development of systems biology approaches has resulted in the integration of genetic findings with functional genomic datasets, thereby providing a unique insight into the functional convergence of ASD risk genes and their neurobiology. In this review, we summarize the latest findings of ASD genetic studies involving large cohorts and discuss their implications in ASD neurobiology and in clinical practice.

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4. Ghotra S, Feeny D, Barr R, Yang J, Saigal S, Vincer M, Afifi J, Shah PS, Lee SK, Synnes AR. Parent-reported health status of preterm survivors in a Canadian cohort. Archives of disease in childhood Fetal and neonatal edition. 2022; 107(1): 87-93.

OBJECTIVES: Health status (HS)/ health-related quality of life measures, completed by self or proxy, are important outcome indicators. Most HS literature on children born preterm includes adolescents and adults with limited data at preschool age. This study aimed to describe parent-reported HS in a large national cohort of extreme preterm children at preschool age and to identify clinical and sociodemographic variables associated with HS. METHODS: Infants born before 29 weeks’ gestation between 2009 and 2011 were enrolled in a prospective longitudinal national cohort study through the Canadian Neonatal Network (CNN) and the Canadian Neonatal Follow-Up Network (CNFUN). HS, at 36 months’ corrected age (CA), was measured with the Health Status Classification System for Pre-School Children tool completed by parents. Information about HS predictors was extracted from the CNN and CNFUN databases. RESULTS: Of 811 children included, there were 79, 309 and 423 participants in 23-24, 25-26 and 27-28 weeks’ gestational age groups, respectively. At 36 months’ CA, 78% had a parent-reported health concern, mild in >50% and severe in 7%. Most affected HS attributes were speech (52.1%) and self-care (41.4%). Independent predictors of HS included substance use during pregnancy, infant male sex, Score for Neonatal Acute Physiology-II, bronchopulmonary dysplasia, severe retinopathy of prematurity, caregiver employment and single caregiver. CONCLUSION: Most parents expressed no or mild health concerns for their children at 36 months’ CA. Factors associated with health concerns included initial severity of illness, complications of prematurity and social factors.

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5. Janjua K, Hillwig-Garcia J, Baweja R. Bupropion-Associated Neurotoxicity in Adolescent With Autism Spectrum Disorder on Stable Dose of Amantadine. Journal of clinical psychopharmacology. 2021; 41(4): 493-5.

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6. Mazahery S, Soleymani Z, Jalaie S. Preliminary psychometric properties of the Autism Classification System of Functioning: Social Communication (ACSF: SC) in Farsi speaking children. Applied neuropsychology Child. 2021: 1-6.

BACKGROUND: Autism Classification System of Functioning: Social Communication (ACSF: SC) assesses typical performance and capacity of communication. Farsi version of ACSF: SC was developed and its psychometric properties investigated. MATERIAL AND METHODS: The English version of ACSF: SC was translated into Farsi and cultural adaptation was completed. The content validity of the adapted version was evaluated by experts and parents. The back-translated version was approved by www.canchild.ca. Therapists and parents assessed face validity. Correlation between ACSF: SC and the Children’s Communication Checklist (CCC) was analyzed to determine concurrent validity. For inter-rater reliability, 5 speech and language pathologists, 5 occupational therapists, and 35 parents participated to assess the communication level of 35 autistic children aged 3-6. The test-retest reliability was performed at the interval of 14 days. RESULT: The results of analyses for typical performance and capacity showed the communication levels of children in ACSF: CS were directly related to subscales of CCC including inappropriate initiation (r ≥ 0.46) and stereotypical conversation (r ≥ 0.45). The weighted kappa inter-rater reliability ranged from good (0.54) to excellent (0.77); and the test-retest reliability varied from good (0.63) to excellent (0.85). CONCLUSION: Adapted version of ACSF: CS is able to estimate the communication function of Farsi- speaking autism spectrum disorder children.

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7. Rodan LH, Spillmann RC, Kurata HT, Lamothe SM, Maghera J, Jamra RA, Alkelai A, Antonarakis SE, Atallah I, Bar-Yosef O, Bilan F, Bjorgo K, Blanc X, Van Bogaert P, Bolkier Y, Burrage LC, Christ BU, Granadillo JL, Dickson P, Donald KA, Dubourg C, Eliyahu A, Emrick L, Engleman K, Gonfiantini MV, Good JM, Kalser J, Kloeckner C, Lachmeijer G, Macchiaiolo M, Nicita F, Odent S, O’Heir E, Ortiz-Gonzalez X, Pacio-Miguez M, Palomares-Bralo M, Pena L, Platzer K, Quinodoz M, Ranza E, Rosenfeld JA, Roulet-Perez E, Santani A, Santos-Simarro F, Pode-Shakked B, Skraban C, Slaugh R, Superti-Furga A, Thiffault I, van Jaabrsveld RH, Vincent M, Wang HG, Zacher P, Rush E, Pitt GS, Au PYB, Shashi V. Phenotypic expansion of CACNA1C-associated disorders to include isolated neurological manifestations. Genetics in medicine : official journal of the American College of Medical Genetics. 2021; 23(10): 1922-32.

PURPOSE: CACNA1C encodes the alpha-1-subunit of a voltage-dependent L-type calcium channel expressed in human heart and brain. Heterozygous variants in CACNA1C have previously been reported in association with Timothy syndrome and long QT syndrome. Several case reports have suggested that CACNA1C variation may also be associated with a primarily neurological phenotype. METHODS: We describe 25 individuals from 22 families with heterozygous variants in CACNA1C, who present with predominantly neurological manifestations. RESULTS: Fourteen individuals have de novo, nontruncating variants and present variably with developmental delays, intellectual disability, autism, hypotonia, ataxia, and epilepsy. Functional studies of a subgroup of missense variants via patch clamp experiments demonstrated differential effects on channel function in vitro, including loss of function (p.Leu1408Val), neutral effect (p.Leu614Arg), and gain of function (p.Leu657Phe, p.Leu614Pro). The remaining 11 individuals from eight families have truncating variants in CACNA1C. The majority of these individuals have expressive language deficits, and half have autism. CONCLUSION: We expand the phenotype associated with CACNA1C variants to include neurodevelopmental abnormalities and epilepsy, in the absence of classic features of Timothy syndrome or long QT syndrome.

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8. Turbitt E, D’Amanda C, Hyman S, Weber JD, Bridges JFP, Peay HL, Biesecker BB. Parent clinical trial priorities for fragile X syndrome: a best-worst scaling. European journal of human genetics : EJHG. 2021; 29(8): 1245-51.

An expansion in the availability of clinical drug trials for genetic neurodevelopmental conditions is underway. Delineating patient priorities is key to the success of drug development and clinical trial design. There is a lack of evidence about parent decision-making in the context of clinical drug trials for genetic neurodevelopmental conditions. We assessed parents’ priorities when making a decision whether to enroll their child with fragile X syndrome (FXS) in a clinical drug trial. An online survey included a best-worst scaling method for parents to prioritize motivating and discouraging factors for child enrollment. Parents were recruited through the National Fragile X Foundation and FRAXA. Sequential best-worst with conditional logit analysis was used to determine how parents prioritize motivating and discouraging factors about trial enrollment decisions. Respondents (N = 354) were largely biological mothers (83%) of an individual with FXS who ranged in age from under 5 to over 21 years. The highest motivating factor was a trial to test a drug targeting the underlying FXS mechanism (coeff = 3.28, p < 0.001), followed by the potential of the drug to help many people (coeff = 3.03, p < 0.001). Respondents rated requirement of blood draws (coeff = -3.09, p < 0.001), loss of access to the drug post trial (coeff = -3.01, p < 0.001), and drug side effects (coeff = -2.96, p < 0.001) as most discouraging. The priorities defined by parents can be incorporated into evidence-based trial design and execution to enhance the enrollment process.

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9. Uguen K, Krysiak K, Audebert-Bellanger S, Redon S, Benech C, Viora-Dupont E, Tran Mau-Them F, Rondeau S, Elsharkawi I, Granadillo JL, Neidich J, Soares CA, Tkachenko N, S MA, Engleman K, Boland A, Deleuze JF, Bezieau S, Odent S, Toutain A, Bonneau D, Gilbert-Dussardier B, Faivre L, Rio M, Le Marechal C, Ferec C, Repnikova E, Cao Y. Heterozygous HMGB1 loss-of-function variants are associated with developmental delay and microcephaly. Clinical genetics. 2021; 100(4): 386-95.

13q12.3 microdeletion syndrome is a rare cause of syndromic intellectual disability. Identification and genetic characterization of patients with 13q12.3 microdeletion syndrome continues to expand the phenotypic spectrum associated with it. Previous studies identified four genes within the approximately 300 Kb minimal critical region including two candidate protein coding genes: KATNAL1 and HMGB1. To date, no patients carrying a sequence-level variant or a single gene deletion in HMGB1 or KATNAL1 have been described. Here we report six patients with loss-of-function variants involving HMGB1 and who had phenotypic features similar to the previously described 13q12.3 microdeletion syndrome cases. Common features included developmental delay, language delay, microcephaly, obesity and dysmorphic features. In silico analyses suggest that HMGB1 is likely to be intolerant to loss-of-function, and previous in vitro data are in line with the role of HMGB1 in neurodevelopment. These results strongly suggest that haploinsufficiency of the HMGB1 gene may play a critical role in the pathogenesis of the 13q12.3 microdeletion syndrome.

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10. Xiang J, Chen Y, Roussy M. Behavioral Inflexibility from a Neuronal Population Perspective. The Journal of neuroscience : the official journal of the Society for Neuroscience. 2021; 41(25): 5350-2.

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11. Zaki MS, Accogli A, Mirzaa G, Rahman F, Mohammed H, Porras-Hurtado GL, Efthymiou S, Maqbool S, Shukla A, Vincent JB, Hussain A, Mir A, Beetz C, Leubauer A, Houlden H, Gleeson JG, Maroofian R. Pathogenic variants in PIDD1 lead to an autosomal recessive neurodevelopmental disorder with pachygyria and psychiatric features. European journal of human genetics : EJHG. 2021; 29(8): 1226-34.

The PIDDosome is a multiprotein complex, composed by the p53-induced death domain protein 1 (PIDD1), the bipartite linker protein CRADD (also known as RAIDD) and the proform of caspase-2 that induces apoptosis in response to DNA damage. In the recent years, biallelic pathogenic variants in CRADD have been associated with a neurodevelopmental disorder (MRT34; MIM 614499) characterized by pachygyria with a predominant anterior gradient, megalencephaly, epilepsy and intellectual disability. More recently, biallelic pathogenic variants in PIDD1 have been described in a few families with apparently nonsydnromic intellectual disability. Here, we aim to delineate the genetic and radio-clinical features of PIDD1-related disorder. Exome sequencing was carried out in six consanguineous families. Thorough clinical and neuroradiological evaluation was performed for all the affected individuals as well as reviewing all the data from previously reported cases. We identified five distinct novel homozygous variants (c.2584C>T p.(Arg862Trp), c.1340G>A p.(Trp447*), c.2116_2120del p.(Val706Hisfs*30), c.1564_1565delCA p.(Gln522fs*44), and c.1804_1805del p.(Gly602fs*26) in eleven subjects displaying intellectual disability, behaviorial and psychiatric features, and a typical anterior-predominant pachygyria, remarkably resembling the CRADD-related neuroimaging pattern. In summary, we outlin`e the phenotypic and molecular spectrum of PIDD1 biallelic variants supporting the evidence that the PIDD1/CRADD/caspase-2 signaling is crucial for normal gyration of the developing human neocortex as well as cognition and behavior.

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