1. Al-Beltagi M. Autism medical comorbidities. World journal of clinical pediatrics. 2021; 10(3): 15-28.

Medical comorbidities are more common in children with autism spectrum disorders (ASD) than in the general population. Some genetic disorders are more common in children with ASD such as Fragile X syndrome, Down syndrome, Duchenne muscular dystrophy, neurofibromatosis type I, and tuberous sclerosis complex. Children with autism are also more prone to a variety of neurological disorders, including epilepsy, macrocephaly, hydrocephalus, cerebral palsy, migraine/headaches, and congenital abnormalities of the nervous system. Besides, sleep disorders are a significant problem in individuals with autism, occurring in about 80% of them. Gastrointestinal (GI) disorders are significantly more common in children with ASD; they occur in 46% to 84% of them. The most common GI problems observed in children with ASD are chronic constipation, chronic diarrhoea, gastroesophageal reflux and/or disease, nausea and/or vomiting, flatulence, chronic bloating, abdominal discomfort, ulcers, colitis, inflammatory bowel disease, food intolerance, and/or failure to thrive. Several categories of inborn-errors of metabolism have been observed in some patients with autism including mitochondrial disorders, disorders of creatine metabolism, selected amino acid disorders, disorders of folate or B12 metabolism, and selected lysosomal storage disorders. A significant proportion of children with ASD have evidence of persistent neuroinflammation, altered inflammatory responses, and immune abnormalities. Anti-brain antibodies may play an important pathoplastic mechanism in autism. Allergic disorders are significantly more common in individuals with ASD from all age groups. They influence the development and severity of symptoms. They could cause problematic behaviours in at least a significant subset of affected children. Therefore, it is important to consider the child with autism as a whole and not overlook possible symptoms as part of autism. The physician should rule out the presence of a medical condition before moving on to other interventions or therapies. Children who enjoy good health have a better chance of learning. This can apply to all children including those with autism.

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2. Campbell K, Cunningham S, Neeley A, Young PC, Stoddard G, Stone B, Carbone PS. Ratings of Physician Communication by Caregivers of Hospitalized Children With and Without Autism. Hospital pediatrics. 2021; 11(6): 547-53.

BACKGROUND AND OBJECTIVES: To investigate caregivers’ perceptions of physician communication and hospital ratings for hospitalized children with and without autism and assess associations between perceived quality of physician communication and overall ratings of the hospital. METHODS: We studied survey data from caregivers of 543 patients with autism compared with a 2:1 matched control sample of 1086 patients with similar characteristics but without autism from a single children’s hospital. We analyzed survey items related to physician communication and hospital ratings from the Consumer Assessment of Healthcare Physicians and Systems Child Hospital Survey. We constructed multivariable regression models to examine the relationship between caregiver-perceived physician communication and caregivers’ overall ratings of the hospital. RESULTS: A similar proportion of caregivers of children with and without autism reported that doctors « always » listened carefully to them (71.4% vs 74.3%; adjusted prevalence ratio 0.96; 95% confidence interval 0.90-1.03) and « always » treated them with respect (80.0% vs 84.1%; adjusted prevalence ratio 0.95; 95% confidence interval 0.90-1.00). Caregivers of children with autism were less likely to « definitely » recommend the hospital (87.0% vs 92.3%; adjusted prevalence ratio 0.94; 95% confidence interval 0.91-0.98). All items related to caregiver-perceived physician communication were associated with the highest hospital rating and the highest recommendation of the hospital in both groups. CONCLUSIONS: When matched on the basis of medical and social factors, caregivers of children with and without autism reported similar frequencies of highest-quality physician communication. Improvement of physician communication with caregivers of medically and socially complex children with and without autism may improve caregivers’ overall ratings of the hospital.

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3. Cao Q, Mu W, Sun D, Zhu J, Ge J, Peng Y, Zhang J. [Significance and case analysis of FMR1 mutation screening during early and middle pregnancy]. Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics. 2021; 38(5): 450-3.

OBJECTIVE: To screen for mutations of fragile X mental retardation 1 (FMR1) gene during early and middle pregnancy and provide prenatal diagnosis for those carrying high-risk CGG trinucleotide expansions. METHODS: Peripheral blood samples of 2316 pregnant women at 12 to 21(+6) gestational weeks were collected for the extraction of genomic DNA. CGG repeats of the FMR1 gene were detected by fluorescence PCR and capillary electrophoresis. Genetic counseling and prenatal diagnosis were provided for 3 women carrying the premutations. RESULTS: The carrier rate of CGG repeats of the FMR1 gene was 1 in 178 for the intermediate type and 1 in 772 for the premutation types. The highest frequency allele of CGG was 29 repeats, which accounted for 49.29%, followed by 30 repeats (28.56%) and 36 repeats (8.83%). In case 1, the fetus had a karyotype of 45,X, in addition with premutation type of CGG expansion of the FMR1 gene. Following genetic counseling, the couple chose to terminate the pregnancy through induced labor. The numbers of CGG repeats were respectively 70/- and 29/30 for the husband and wife. In case 2, amniocentesis was performed at 20 weeks of gestation. The number of CGG repeats of the FMR1 gene was 29/-. No abnormality was found in the fetal karyotype and chromosomal copy number variations. The couple chose to continue with the pregnancy. Case 3 refused prenatal diagnosis after genetic counseling and gave birth to a girl at full term, who had a birth weight of 2440 g and no obvious abnormality found during follow-up. CONCLUSION: Pregnant women should be screened for FMR1 gene mutations during early and middle pregnancy, and those with high-risk CGG expansions should undergo prenatal diagnosis, genetic counseling and family study.

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4. Dionne O, Lortie A, Gagnon F, Corbin F. Rates of protein synthesis are reduced in peripheral blood mononuclear cells (PBMCs) from fragile X individuals. PloS one. 2021; 16(5): e0251367.

BACKGROUND: Fragile X syndrome (FXS) is the leading inherited cause of intellectual disability and is caused by the loss of expression of the Fragile X mental retardation protein (FMRP). In animal model of FXS, the absence of FMRP leads to an aberrant rate of neuronal protein synthesis, which in turn is believed to be at the origin of defects regarding spine morphology and synaptic plasticity. Normalisation of protein synthesis in these models has been associated with a rescue of FXS behavioral and biochemicals phenotype, thus establishing the rate of protein synthesis as one of the most promising monitoring biomarker for FXS. However, rate of protein synthesis alteration in fragile X individuals is not well characterized. METHOD: We applied a robust radiolabeled assay to measure rate of protein synthesis in freshly extracted peripheral blood mononuclear cells (PBMCs) and blood platelets. We ultimately settle on PBMCs to measure and compare rate of protein synthesis in 13 males with fragile X and 14 matched controls individuals. RESULTS: Using this method, we measured a 26.9% decrease (p = 0,0193) in the rate of protein synthesis in fragile X individuals PBMCs. Furthermore, the rate of protein synthesis measurements obtained were highly reproducible, highlighting the robustness of the method. CONCLUSION: Our work presents the first evidence of a diminution of the rate of protein synthesis in a human peripheral model of fragile X. Our results also support the finding of previous studies using brain PET imaging in Fragile X individuals. Since our assay only requires a simple venous puncture, it could be used in other cases of intellectual disability in order to determine if an aberrant rate of protein synthesis is a common general mechanism leading to impairment in synaptic plasticity and to intellectual disability.

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5. Doehring P. Does the Arc of Science Bend Towards Impact? Four Decades of Empirical Research Published in JADD Since the DSM-III. Journal of autism and developmental disorders. 2021; 51(12): 4411-21.

The present study explored the shift from understanding to intervention to population impact in the empirical research published in this journal at five points of time over 40 years since the release of DSM-III. Two-thirds of the more than 600 original studies identified involved basic research, a pattern that is consistent with previous analyses of research funding allocations and that did not change over time. One of every eight studies involved intervention research, which occurred in community-based programs only about one-quarter of the time. These gaps in intervention research and community impact did not improve over time. The findings underscore the need to broaden the training and experience of researchers, and to re-consider priorities for research funding and publication.

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6. Gasser BA, Kurz J, Dick B, Mohaupt MG. A reply to ‘Alteration of steroidogenesis in boys with autism spectrum disorders’. Translational psychiatry. 2021; 11(1): 278.

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7. Gui A, Bussu G, Tye C, Elsabbagh M, Pasco G, Charman T, Johnson MH, Jones EJH. Correction: Attentive brain states in infants with and without later autism. Translational psychiatry. 2021; 11(1): 277.

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8. Johari AN. Watchwords for management of developmental disabilities in developing countries. Developmental medicine and child neurology. 2021; 63(6): 629.

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9. Leader G, Glynn C, Kirkpatrick B, Chen JL, O’Súilleabháin PS, Mannion A. Familial sleep and autism spectrum disorder: a pilot actigraphy study of sleep quality, quality of life and psychological distress. Irish journal of psychological medicine. 2021: 1-11.

OBJECTIVES: Sleep problems are common among children with autism spectrum disorder (ASD) and can have a negative impact on the child’s behaviour and daytime functioning. The current pilot study examined objective measurements of child and parent sleep as factors associated with the stress, anxiety, depressive symptoms, social support and quality of life of parents of children with ASD. METHODS: Participants were nine children with ASD and their parents (nine mothers and three fathers). Participants wore an actigraph for 7 consecutive days and nights. Measures of sleep habits and quality were used to ascertain child and parent sleep. Measures of parenting stress, anxiety, depressive symptoms, quality of life and social support were collated. RESULTS: Results indicated the emergence of high parental stress, anxiety and depressive symptoms. Significant correlations were observed between parent depressive symptoms, and both subjective sleep quality and child sleep disruptions. CONCLUSIONS: The present study found that parental well-being is affected by child sleep problems.

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10. Leader G, Moore R, Chen JL, Caher A, Arndt S, Maher L, Naughton K, Clune R, Mannion A. Attention deficit hyperactivity disorder (ADHD) symptoms, comorbid psychopathology, behaviour problems and gastrointestinal symptoms in children and adolescents with autism spectrum disorder. Irish journal of psychological medicine. 2021: 1-11.

OBJECTIVES: The study aims to investigate attention deficit hyperactivity disorder (ADHD) symptoms, gastrointestinal (GI) symptoms, comorbid psychopathology and behaviour problems in children and adolescents with autism spectrum disorder (ASD). METHODS: Parents of 147 children and adolescents with ASD aged 6-18 years completed the Conners 3 Parent-Short Form, Gastrointestinal Symptom Inventory, Behavior Problems Inventory-Short Form and Autism Spectrum Disorder-Comorbid for Children. RESULTS: Fifty-six per cent of children and adolescents had a comorbid diagnosis of ADHD, yet over 70% presented with clinically significant ADHD symptoms. Forty per cent of participants received a diagnosis of ADHD before ASD and 25.6% received a diagnosis of ASD first. Relationships were found between ADHD symptoms and comorbid psychopathology, GI symptoms, and behaviour problems. CONCLUSIONS: The outcomes suggest that ADHD is being underestimated as a comorbid disorder of ASD. This may have implications on treatment and interventions for children and adolescents who have a diagnosis of both ASD and ADHD.

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11. Leming MJ, Baron-Cohen S, Suckling J. Single-participant structural similarity matrices lead to greater accuracy in classification of participants than function in autism in MRI. Molecular autism. 2021; 12(1): 34.

BACKGROUND: Autism has previously been characterized by both structural and functional differences in brain connectivity. However, while the literature on single-subject derivations of functional connectivity is extensively developed, similar methods of structural connectivity or similarity derivation from T1 MRI are less studied. METHODS: We introduce a technique of deriving symmetric similarity matrices from regional histograms of grey matter volumes estimated from T1-weighted MRIs. We then validated the technique by inputting the similarity matrices into a convolutional neural network (CNN) to classify between participants with autism and age-, motion-, and intracranial-volume-matched controls from six different databases (29,288 total connectomes, mean age = 30.72, range 0.42-78.00, including 1555 subjects with autism). We compared this method to similar classifications of the same participants using fMRI connectivity matrices as well as univariate estimates of grey matter volumes. We further applied graph-theoretical metrics on output class activation maps to identify areas of the matrices that the CNN preferentially used to make the classification, focusing particularly on hubs. LIMITATIONS: While this study used a large sample size, the majority of data was from a young age group; furthermore, to make a viable machine learning study, we treated autism, a highly heterogeneous condition, as a binary label. Thus, these results are not necessarily generalizable to all subtypes and age groups in autism. RESULTS: Our models gave AUROCs of 0.7298 (69.71% accuracy) when classifying by only structural similarity, 0.6964 (67.72% accuracy) when classifying by only functional connectivity, and 0.7037 (66.43% accuracy) when classifying by univariate grey matter volumes. Combining structural similarity and functional connectivity gave an AUROC of 0.7354 (69.40% accuracy). Analysis of classification performance across age revealed the greatest accuracy in adolescents, in which most data were present. Graph analysis of class activation maps revealed no distinguishable network patterns for functional inputs, but did reveal localized differences between groups in bilateral Heschl’s gyrus and upper vermis for structural similarity. CONCLUSION: This study provides a simple means of feature extraction for inputting large numbers of structural MRIs into machine learning models. Our methods revealed a unique emphasis of the deep learning model on the structure of the bilateral Heschl’s gyrus when characterizing autism.

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12. Luo S, He W, Liao Y, Tang W, Li X, Hu L, Du J, Zhang Q, Tan Y, Lin G, Li W. [Analysis and prenatal diagnosis of FMR1 gene mutations among patients with unexplained mental retardation]. Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics. 2021; 38(5): 439-45.

OBJECTIVE: To analyze the (CGG)n repeats of FMR1 gene among patients with unexplained mental retardation. METHODS: For 201 patients with unexplained mental retardation, the (CGG)n repeats of the FMR1 gene were analyzed by PCR and FragilEase(TM) PCR. Prenatal diagnosis was provided to carriers of pre- and full-mutations. The pattern of X chromosome inactivation (XCI) was determined for women with mental retardation and full mutations. RESULTS: For the 201 patients with unexplained mental retardation, 15 were identified with full mutations of the FMR1 gene. The prevalence of fragile X syndrome (FXS) in patients with unexplained mental retardation was determined as 7.5% (15/201). Prenatal diagnosis was provided for 6 pregnant women with pre- or full mutations. Analysis revealed that women with mental retardation and full FMR1 mutations exhibited a skewed XCI pattern with primary expression of the X chromosome carrying the mutant allele. CONCLUSION: FXS has a high incidence among patients with unexplained mental retardation. Analysis of FMR1 gene (CGG)n repeats in patients with unexplained mental retardation can facilitate genetic counseling and prenatal diagnosis for their families. FMR1 gene (CGG)n repeats screening should be recommended for patients with unexplained mental retardation.

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13. Maruccia F, Gomáriz L, Rosas K, Durduran T, Paredes-Carmona F, Sahuquillo J, Poca MA. Neurodevelopmental profile in children with benign external hydrocephalus syndrome. A pilot cohort study. Child’s nervous system : ChNS : official journal of the International Society for Pediatric Neurosurgery. 2021; 37(9): 2799-806.

PURPOSE: The management of children with benign external hydrocephalus (BEH) remains controversial. Most BEH children do well in the long-term, but a substantial number have temporary or permanent psychomotor delays. The study aims to assess the prevalence and pattern of neurodevelopmental delay in a cohort of children with BEH. METHODS: We conducted a cohort study of 42 BEH children (30 boys and 12 girls, aged 6 to 38 months). A pediatric neurosurgeon performed a first clinical evaluation to confirm/reject the diagnosis according to the clinical features and neuroimaging studies. Two trained evaluators assessed the child’s psychomotor development using the third edition of the Bayley Scales of Infant and Toddler Development (Bayley-III). Developmental delay was defined as a scaled score < 7 according to the simple scale and/or a composite score < 85. RESULTS: Eighteen children (43%) presented statistically lower scores in the gross motor and composite motor of the Bayley-III scales compared to their healthy peers. CONCLUSION: In BEH, it is important to establish a diagnostic algorithm that helps to discriminate BEH patients that have self-limiting delays from those at risk of a persistent delay that should be referred for additional studies and/or interventions that might improve the natural evolution of a disease with high impact on the children and adult's quality of life.

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14. Sevik MO, Aykut A, Şahin Ö. Resolution of cystoid macular edema with topical carbonic anhydrase inhibitor in a patient with retinal dystrophy associated with Cohen syndrome. Ophthalmic genetics. 2021; 42(5): 619-23.

Background: Cohen Syndrome (CS) is an autosomal recessive multisystemic disorder characterized by various ophthalmologic findings, including retinal dystrophy and associated cystoid macular edema (CME), in which there was no known effective treatment approach.Material and Methods: We describe a CS patient with a homozygous c.62 T > G, p.(Leu21*) mutation in the VPS13B gene with a topical carbonic anhydrase inhibitor (CAI; brinzolamide %1, thrice daily) responding CME.Case Description: A seven-year-old girl with an established diagnosis of CS was referred with a primary complaint of nyctalopia. On ophthalmologic examination, bilateral decreased visual acuity and normal-appearing macula with mild optic disc pallor were present. However, the detailed evaluation revealed bilateral blunted foveal reflexes, barely visible foveal pigmentation, and slightly attenuated retinal vessels without any peripheral retinal pigmentary changes in dilated fundus examination, and CME on optical coherence tomography. Bilateral topical brinzolamide thrice daily was initiated for CME. Visual acuity increased, and CME was resolved except for minimal schisis at the inner nuclear layer level at the third-month follow-up visit and remained stable up to one-year follow-up. CME reappeared after five months of self-discontinuation of the patient’s therapy but resolved again with treatment resumption.Conclusion: We report the first case of CME secondary to rod-cone dystrophy associated with CS showing improvement in anatomy and visual acuity with a topical CAI.

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15. Treffert DA, Treffert DA. The Sudden Savant: A New Form of Extraordinary Abilities. WMJ : official publication of the State Medical Society of Wisconsin. 2021; 120(1): 69-73.

INTRODUCTION: Savant Syndrome previously has been characterized as either congenital or acquired. This report describes sudden savant syndrome in which neurotypical persons have the sudden emergence of savant skills without underlying disability or brain injury and without prior interest or ability in the newly emerged skill areas. CASE PRESENTATION: Eleven cases are described in which savant abilities suddenly and unexpectedly surfaced in neurotypical persons with no special prior interest or ability in the new skills, accompanied by an obsessive interest with and compulsive need to display the new abilities. All participants completed an online survey to record their demographics and skill characteristics. DISCUSSION: The acquired savant, and now the sudden savant, raise questions about the dormant potential for such buried skills in everyone. The challenge is to be able to tap such latent abilities without head injury or other precipitating events. CONCLUSION: This paper documents 11 cases of sudden savant syndrome, which is a new and additional form of savant abilities surfacing in neurotypical persons without developmental disabilities (such as autism) or head or other brain injury (acquired savant syndrome). It opens new paths of inquiry for exploration of extraordinary abilities perhaps within everyone.

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16. Walls M, Zuckerman KE, Broder-Fingert S. Recommendations for Improving the Family Experience for Hospitalized Children With Autism. Hospital pediatrics. 2021; 11(6): e101-e3.

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17. Wang JF, Han JH, Zhang ZC. Behavioral analyses in mouse models of autism spectrum disorders. Yi chuan = Hereditas. 2021; 43(5): 501-19.

Autism spectrum disorder is a group of genetically-related developmental disorders of the nervous system. Patients mainly present with core symptoms such as social behavior defects, repetitive stereotyped behaviors, and learning and memory disorders. The mouse models are critical for the studies of the pathogenic mechanisms and potential therapeutic strategies of autism spectrum disorder. The assessments of mouse behaviors provide understandings of the effects of different genetic manipulations as well as pathogenic mechanisms of these diseases. This article describes various mouse behavioral assays corresponding to the core symptoms of ASD patients and provides a detailed description of protocols, cautions, and data analysis for those assays, thereby helping researchers to establish their own experimental designs. In addition, behavioral phenotypes of currently known ASD mouse models are summarized to provide a reference for researchers in the field.

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18. Xie X, Yu J, Qi Z, Bao L, Shen Y, Chen T, Li P. [Experience and lessons on guiding and governing clinical applications of chromosome microarray analysis in the United States]. Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics. 2021; 38(5): 419-24.

Chromosome microarray analysis (CMA) has become the first-tier testing for chromosomal abnormalities and copy number variations (CNV). This review described the clinical validation of CMA, the development and updating of technical standards and guidelines and their diagnostic impacts. The main focuses were on the development and updating of expert consensus, practice resources, and a series of technical standards and guidelines through systematic review of case series with CMA application in the literature. Expert consensus and practice resource supported the use of CMA as the first-tier testing for detecting chromosomal abnormalities and CNV in developmental and intellectual disabilities, multiple congenital anomalies and autism. The standards and guidelines have been applied to pre- and postnatal testing for constitutional CNV and tumor testing for acquired CNV. CMA has significantly improved the diagnostic yields but still needs to overcome its technical limitations and face challenges of new technologies. Guiding and governing CMA through expert consensus, practice resource, standards and guidelines in the United States has provided effective and safe diagnostic services to patients and their families, reliable diagnosis on related genetic diseases for clinical database and basic research, and references for clinical translation of new technologies.

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