1. Agrawal N, Mandal K. Rare case of dual diagnosis in consanguineous family: a case report. Clinical dysmorphology. 2021; 30(3): 164-6.

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2. Albajara Sáenz A, Villemonteix T, Van Schuerbeek P, Baijot S, Septier M, Defresne P, Delvenne V, Passeri G, Raeymaekers H, Victoor L, Willaye E, Peigneux P, Deconinck N, Massat I. Motor Abnormalities in Attention-Deficit/Hyperactivity Disorder and Autism Spectrum Disorder Are Associated With Regional Grey Matter Volumes. Frontiers in neurology. 2021; 12: 666980.

Attention-Deficit/Hyperactivity Disorder (ADHD) and Autism Spectrum Disorder (ASD) are associated with motor impairments, with some children holding a comorbid diagnosis of Developmental Coordination Disorder (DCD). However, DCD is underdiagnosed in these populations and the volume abnormalities that contribute to explaining these motor impairments are poorly understood. In this study, motor abilities as measured by the Developmental Coordination Disorder Questionnaire (DCDQ) were compared between children with ADHD, children with ASD and typically developing (TD) children, aged 8-12 years old. Additionally, the association between the DCDQ scores (general coordination, fine motor/handwriting, control during movement, total) and regional volume abnormalities were explored in 6 regions of interest (pre-central gyrus, post-central gyrus, inferior parietal cortex, superior frontal gyrus, middle frontal gyrus, medial frontal gyrus), within each group and across all participants. Children with ASD and children with ADHD showed impaired motor abilities in all the DCDQ-derived scores compared to TD children. Additionally, most children with ASD or ADHD had an indication or suspicion of DCD. Within the ASD group, coordination abilities were associated with the volume of the right medial frontal gyrus, and within the ADHD group, the total DCDQ score was associated with the volume of the right superior frontal gyrus. This study underlines the importance of routinely checking motor abilities in populations with ASD or ADHD in clinical practise and contributes to the understanding of structural abnormalities subtending motor impairments in these disorders.

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3. Carotti S, Zingariello M, Francesconi M, D’Andrea L, Latasa MU, Colyn L, Fernandez-Barrena MG, Flammia RS, Falchi M, Righi D, Pedini G, Pantano F, Bagni C, Perrone G, Rana RA, Avila MA, Morini S, Zalfa F. Fragile X mental retardation protein in intrahepatic cholangiocarcinoma: regulating the cancer cell behavior plasticity at the leading edge. Oncogene. 2021; 40(23): 4033-49.

Intrahepatic cholangiocarcinoma (iCCA) is a rare malignancy of the intrahepatic biliary tract with a very poor prognosis. Although some clinicopathological parameters can be prognostic factors for iCCA, the molecular prognostic markers and potential mechanisms of iCCA have not been well investigated. Here, we report that the Fragile X mental retardation protein (FMRP), a RNA binding protein functionally absent in patients with the Fragile X syndrome (FXS) and also involved in several types of cancers, is overexpressed in human iCCA and its expression is significantly increased in iCCA metastatic tissues. The silencing of FMRP in metastatic iCCA cell lines affects cell migration and invasion, suggesting a role of FMRP in iCCA progression. Moreover, we show evidence that FMRP is localized at the invasive front of human iCCA neoplastic nests and in pseudopodia and invadopodia protrusions of migrating and invading iCCA cancer cells. Here FMRP binds several mRNAs encoding key proteins involved in the formation and/or function of these protrusions. In particular, we find that FMRP binds to and regulates the expression of Cortactin, a critical regulator of invadopodia formation. Altogether, our findings suggest that FMRP could promote cell invasiveness modulating membrane plasticity and invadopodia formation at the leading edges of invading iCCA cells.

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4. Dabrowski AK, Carrasco M, Gatti JR, Barreto ARF, Parkinson C, Robinson S, Tekes A, Sun LR. Neonatal Subpial Hemorrhage: Clinical Factors, Neuroimaging, and Outcomes in a Quaternary Care Children’s Center. Pediatric neurology. 2021; 120: 52-8.

BACKGROUND: Subpial hemorrhages are underrecognized, underreported, and poorly understood. The spectrum of their clinical manifestations and consequences in neonates has not been fully described. Here, we describe the demographic, clinical, and radiographic characteristics of neonates with subpial hemorrhages. METHODS: We reviewed the medical records and neuroimaging studies of neonates with subpial hemorrhage who were admitted to our neonatal intensive care unit between September 2009 and December 2020. RESULTS: Of 114 neonates with intracranial hemorrhage, 31 (27%) had subpial hemorrhage. The majority of neonates in our cohort were male (68%) and born at term (55%). The most common imaging indication was apneas and/or seizures in 58%. Common comorbid conditions included cardiorespiratory failure (42%), hypoxic-ischemic encephalopathy (26%), and coagulopathy (23%). Subpial hemorrhages were multifocal in 45% of neonates, located in the temporal lobe in 45% of neonates, and tended to be larger in neonates with coagulopathy, birth trauma, or hydrocephalus requiring neurosurgical intervention. Subpial hemorrhage was associated with another type of intracranial bleed in 77% of cases and with arterial ischemic stroke in 16% of cases. Of 17 patients with more than one year of follow-up data, 14 (82%) have developmental delay and four (24%) have epilepsy. Of 14 patients with follow-up imaging, 10 (71%) had encephalomalacia subjacent to the subpial hemorrhage. CONCLUSIONS: This is the largest cohort of neonates with subpial hemorrhages to date. Outcome data are limited by duration of follow-up and may be confounded by comorbid conditions and other concurrent hemorrhages. Further study is needed to define the spectrum of risk factors and expected neurological outcomes.

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5. Hegarty M, Morrison PJ. A proximal 300kb deletion further defining critical regions in 4q25 syndrome. Clinical dysmorphology. 2021; 30(3): 137-8.

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6. Hong J, Kapoor A, DaWalt LS, Maltman N, Kim B, Berry-Kravis EM, Almeida D, Coe C, Mailick M. Stress and genetics influence hair cortisol in FMR1 premutation carrier mothers of children with fragile X syndrome. Psychoneuroendocrinology. 2021; 129: 105266.

To investigate genetic and environmental influences on cortisol levels, mothers of children with fragile X syndrome (FXS) were studied four times over a 7.5-year period. All participants (n = 84) were carriers of the FMR1 « premutation », a genetic condition associated with impaired HPA axis functioning. Genetic variation was indicated by expansions in the number of CGG (cytosine-guanine-guanine) repeats in the FMR1 gene (67-138 repeats in the present sample). The environmental factor was cumulative exposure to adverse life events during the study period. Cortisol was measured at the beginning of the study via saliva samples and at the end of the study via hair samples; hormone values from these two specimen types were significantly correlated. The interactions between CGG repeat number and adverse life events significantly predicted hair cortisol concentration, including after accounting for the initial salivary cortisol level. For those with fewer CGG repeats, stress exposure was associated with elevated cortisol, the expected response to stress, although women with a higher number of CGGs had a reduced cortisol response to adverse events, which might be related to HPA dysfunction. These results indicate that both exogenous and endogenous factors affect HPA functioning in this population of women.

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7. Kotsopoulos SI, Karaivazoglou K, Florou IS, Gyftogianni MI, Papadaki EJ, Kotsopoulou A. Systematic Intervention for Children with Autism Spectrum Disorder and Integration in Regular School Classes: A Naturalistic Study. Global pediatric health. 2021; 8: 2333794×211012988.

Objective of the present study was the assessment of the effect of a systematic community intervention offered at an early age to 32 children with autism spectrum disorder (ASD), 2 to 5 year after completion of treatment while attending public school classes. The intervention had been offered at a community Day Centre and lasted 3 years. On assessment all children showed clinical improvement and significant results on Childhood Autism Rating Scale (CARS) and Vineland Adaptive Scales and 13 scored below criteria for autism on Autism Diagnostic Observation Scale-2 (ADOS-2). Most performed adequately at school whilst 12 required academic assistance. No major disruptive behavior difficulties were reported.

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8. Kouo T, Bharadwaj N, Kouo J, Tackett S, Ryan L. Assessing Ease of Delivering Emergency Care for Patients with Autism Spectrum Disorders. Journal of developmental and behavioral pediatrics : JDBP. 2021; 42(9): 704-10.

OBJECTIVE: The aim of this study was to develop a method for objectively assessing the delivery of care to children with autism spectrum disorder (ASD) in the emergency department (ED). METHODS: A case-control study of patients ages 2 to 18 years admitted to the hospital from January 2016 to January 2018. Cases were defined as patients with an International Classification of Diseases, Tenth Revision diagnosis of ASD or other pervasive developmental disorder (F84) in their medical record and were matched 1:1 with neurotypical controls. The primary outcome was ability to complete several core tasks clinically necessary within an ED visit and summarized into a Task Completion Index (TCI). RESULTS: Overall, children with ASD had higher median TCIs of 0.25 (interquartile range [IQR] 0-0.45) versus 0 (IQR 0-0.25) when compared with children without ASD (p < 0.01). Children with ASD were 5 times more likely to have difficulty with triage vitals, 3 times more likely to require additional staff for peripheral intravenous placement, and 4 times more likely to experience delays or disruptions to their plan of care. The TCI was also associated with 8-fold increased odds of receiving pharmacologic or physical restraint. CONCLUSIONS: The TCI reflects difficulty accomplishing core tasks necessary to complete an ED visit. Children with ASD have higher TCIs than neurotypical controls, which puts them at higher risk for care disruptions. Evaluation of initiatives to improve quality of care for children with ASD should focus not only on metrics of overall experience and satisfaction but also how these initiatives affect the ability to effectively administer care.

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9. Lai KYC, Yuen ECW, Hung SF, Leung PWL. Autism Diagnostic Interview-Revised Within DSM-5 Framework: Test of Reliability and Validity in Chinese Children. Journal of autism and developmental disorders. 2022; 52(4): 1807-20.

This study examines the psychometric properties of the Autism Diagnostic Interview-Revised (ADI-R) in the context of DSM-5 in a sample of Chinese children. Using re-mapped ADI-R items and algorithms matched to DSM-5 criteria, and administering to children with autism spectrum disorder (ASD) with and without intellectual disability, attention-deficit hyperactivity disorder, and typically developing, it evidenced high sensitivity and specificity. However, similar to DSM-IV algorithm, the DSM-5 algorithms were better at classifying ASD among children with intellectual disability than among those without intellectual disability. With the DSM-5’s recognition of the spectrum nature of ASD, the performance of the ADI-R can be improved by having finer gradations in the ADI-R scoring and adding more items on the restricted and repetitve behavior domain.

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10. Malhi P, Saini S, Bharti B, Attri S, Sankhyan N. Sensory Processing Dysfunction and Mealtime Behavior Problems in Children With Autism. Indian pediatrics. 2021; 58(9): 842-5.

OBJECTIVE: To compare sensory processing and mealtime problem behaviors among children with autism spectrum disorder (ASD) and typically developing controls, and to examine the relationship between atypical sensory processing and eating problems in children with ASD. METHODS: 50 children (4-10 years) with a diagnosis of ASD as per DSM-5 were recruited from the pediatric psychology clinic of a tertiary care center in India. The Brief Assessment of Mealtime Behavior in Children (BAMBIC) and the Short Sensory Profile (SSP) were administered to measure feeding and sensory processing problems, respectively. Parents were interviewed about their child’s dietary intake using a 3-day dietary recall. RESULTS: The ASD group showed greater mealtime behavior problems than the control group and had significantly higher total scores on the BAMBIC (P<0.001), and on two of the three subscales including food refusal (P<0.001) and disruptive behavior (P<0.001). The ASD group, relative to the neurotypical children, showed atypical response on majority of the subscales of the short sensory profile including tactile sensitivity (P<0.001), taste sensitivity (P<0.001), movement sensitivity (P<0.001), under responsiveness (P<0.001), auditory filtering (P<0.001), low weak/energy (P=0.02), and visual/auditory sensitivity (P<0.001). CONCLUSIONS: The study underscores the need for detailed evaluation of sensory processing and feeding problems of children with ASD so that the interventions can be tailored to address their unique sensory characteristics.

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11. Royer-Bertrand B, Cisarova K, Niel Bütschi F, Foletti G, Guinchat V, Tran C, Superti-Furga A, Good JM. CNOT2 haploinsufficiency in a 40-year-old man with intellectual disability, autism, and seizures. American journal of medical genetics Part A. 2021; 185(8): 2602-6.

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12. Saber Sotoodeh M, Taheri-Torbati H. A Point-Light Display Model for Teaching Motor Skills to Children With Autism Spectrum Disorder: An Eye-Tracking Study. Perceptual and motor skills. 2021; 128(4): 1485-503.

People with autism spectrum disorder (ASD) have limitations in their attention and working memory that affect their motor learning. The aim of current study was to compare point-light display (PLD) to video observation as instructional models for teaching motor skills to children with ASD versus typically developing (TD) children. We randomly assigned 24 children with ASD aged 6-17-years-old and 24 age paired typically developing (TD) children to four groups: (a) ASD-Video, (b) ASD-PLD, (c) TD-Video, and (d) TD-PLD. After twenty training blocks (200 trials), all participants entered into late retention and transfer testing. We recorded all participants’ visual gazes when observing each PLD and Video condition. Both PLD groups had better performance in the acquisition phase, and on retention and transfer tests. Also, gaze recordings revealed that children with ASD paid more attention to relevant demonstration points in the PLD than in the video condition. We discuss possible mechanisms and implications of these findings.

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13. Sabir AH, Sheikh J, Gowda V, Wallis C, Singham S, Durve D, Cocca A, Holder-Espinasse M, Irving M. KIAA0753-related skeletal ciliopathy: a ninth case, extending the phenotype and reporting a novel variant. Clinical dysmorphology. 2021; 30(3): 142-6.

KIAA0753-related skeletal ciliopathy is a recently described recessive disorder causing skeletal dysplasia and overlapping features of certain ciliopathies; Joubert, Jeune and Oro-facial-digital syndromes. We describe a ninth case that expands the phenotype; a 10-year-old girl with rhizomelic short stature (-5.6 SD), macrocephaly, developmental delay, CNS anomalies (thin corpus callosum, bilateral ventriculomegaly), cone-rod dystrophy, nystagmus, mild conductive hearing loss and recurrent chest infections secondary to confirmed ciliary dyskinesia. Testing for FGFR3 achondroplasia-related hotspots and mucopolysaccharidosis were negative. Whole-exome sequencing, aged eight, via skeletal dysplasia panel analysis and subsequent whole-genome sequencing (via the 100,000 genomes project) found no cause. WGS data reanalysis using exomiser uncovered compound heterozygous pathogenic KIAA0753 variants (frameshift and splice site). Further clinical and radiological surveys were consistent with the expected phenotype. We discuss the emerging phenotype of this uncommon disorder. This report details the sixth published case of skeletal dysplasia in all cases of KIAA0753-related disease and the first case to describe a novel c.1830-2A>G splice variant. Our case is the eldest woman reported to date (aged ten years) and the only known case to report associated hearing loss, leg-length discrepancy, pectus carinatum, respiratory ciliary dyskinesia and late-onset (9 years old) neuro-degenerative regression.

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14. Salehinejad MA, Paknia N, Hosseinpour AH, Yavari F, Vicario CM, Nitsche MA, Nejati V. Contribution of the right temporoparietal junction and ventromedial prefrontal cortex to theory of mind in autism: A randomized, sham-controlled tDCS study. Autism research : official journal of the International Society for Autism Research. 2021; 14(8): 1572-84.

Theory of mind (ToM) is the ability to attribute subjective mental states to oneself and others and is significantly impaired in autism spectrum disorder (ASD). A frontal-posterior network of regions including the ventromedial prefrontal cortex (vmPFC) and temporoparietal junction (TPJ) is involved in ToM. Previous studies show an underactivation of these regions in ASD. Transcranial direct current stimulation (tDCS) is a noninvasive brain stimulation method for causally investigating brain-behavior relationships via induction of cortical excitability alterations. tDCS, mostly over the dorsolateral prefrontal cortex, has been increasingly applied for improving behavioral problems in ASD leaving other potentially interesting regions untouched. Here we investigated contribution of the vmPFC and right TPJ in ToM abilities of ASD children via tDCS in a pilot study. Sixteen children with ASD (mean age = 10.7 ± 1.9) underwent three tDCS sessions (1 mA, 20 min) in a randomized, sham-controlled design. Stimulation protocols included: (a) anodal vmPFC tDCS, (b) anodal r-TPJ tDCS, and (c) sham tDCS. ToM abilities were explored during tDCS using the theory of mind test (TOMT). Our results show that activation of the vmPFC with anodal tDCS significantly improved ToM in children with ASD compared with both, r-TPJ tDCS, and sham stimulation. Specifically, precursors of ToM (e.g., emotion recognition, perception, and imitation) and elementary ToM skills (e.g., first-order mental state reasoning) were significantly improved by anodal vmPFC tDCS. Based on these results, the vmPFC could be a potential target region for the reduction of ASD symptoms via noninvasive brain stimulation, which should be examined in larger detail in future studies. LAY SUMMARY: Theory of mind (ToM) is the ability to infer mental states of oneself and others, which is impaired in autism. Brain imaging studies have shown involvement of two brain regions in ToM (ventromedial prefrontal cortex, temporoparietal junction) which are underactivated in autism. We increased activation of these regions via noninvasive brain stimulation in this experiment to see how it would affect ToM abilities in autism. We found that increased activation of the ventromedial prefrontal cortex improved ToM abilities in children with autism.

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15. Trevino CE, Rounds JC, Charen K, Shubeck L, Hipp HS, Spencer JB, Johnston HR, Cutler DJ, Zwick ME, Epstein MP, Murray A, Macpherson JN, Mila M, Rodriguez-Revenga L, Berry-Kravis E, Hall DA, Leehey MA, Liu Y, Welt C, Warren ST, Sherman SL, Jin P, Allen EG. Identifying susceptibility genes for primary ovarian insufficiency on the high-risk genetic background of a fragile X premutation. Fertility and sterility. 2021; 116(3): 843-54.

OBJECTIVE: To identify modifying genes that explains the risk of fragile X-associated primary ovarian insufficiency (FXPOI). DESIGN: Gene-based, case/control association study, followed by a functional screen of highly ranked genes using a Drosophila model. SETTING: Participants were recruited from academic and clinical settings. PATIENT(S): Women with a premutation (PM) who experienced FXPOI at the age of 35 years or younger (n = 63) and women with a PM who experienced menopause at the age of 50 years or older (n = 51) provided clinical information and a deoxyribonucleic acid sample for whole genome sequencing. The functional screen was on the basis of Drosophila TRiP lines. INTERVENTION(S): Clinical information and a DNA sample were collected for whole genome sequencing. MAIN OUTCOME MEASURES: A polygenic risk score derived from common variants associated with natural age at menopause was calculated and associated with the risk of FXPOI. Genes associated with the risk of FXPOI were identified on the basis of the P-value from gene-based association test and an altered level of fecundity when knocked down in the Drosophila PM model. RESULTS: The polygenic risk score on the basis of common variants associated with natural age at menopause explained approximately 8% of the variance in the risk of FXPOI. Further, SUMO1 and KRR1 were identified as possible modifying genes associated with the risk of FXPOI on the basis of an untargeted gene analysis of rare variants. CONCLUSIONS: In addition to the large genetic effect of a PM on ovarian function, the additive effects of common variants associated with natural age at menopause and the effect of rare modifying variants appear to play a role in FXPOI risk.

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16. Widenka H, Kadner A. Right axillary minithoracotomy: An alternative access to close an ASD. Multimedia manual of cardiothoracic surgery : MMCTS. 2021; 2021.

A vertical right axillary thoracotomy is a favorable alternative to a median sternotomy for surgical correction of common congenital heart defects in patients of all ages. The right-sided heart structures can be approached through a 4- to 5-cm vertical incision in the midaxillary line. In contrast to a midline sternotomy, osseous thoracic structures can be preserved through a muscle-sparing approach simply by retracting the ribs. Consequently, recovery is usually faster, and the resulting scar is completely hidden under the resting arm. In addition, there is no need for special equipment. The entire operation can be performed with established techniques. Operative outcome and long-term results have been shown by several research groups to be comparable to those obtained with a median sternotomy. This tutorial demonstrates the stepwise performance of an axillary thoracotomy and the extracorporeal circulation setup by the example of the closure of an atrial septal defect.

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17. Young DJ, Meydan S, Guydosh NR. 40S ribosome profiling reveals distinct roles for Tma20/Tma22 (MCT-1/DENR) and Tma64 (eIF2D) in 40S subunit recycling. Nature communications. 2021; 12(1): 2976.

The recycling of ribosomes at stop codons for use in further rounds of translation is critical for efficient protein synthesis. Removal of the 60S subunit is catalyzed by the ATPase Rli1 (ABCE1) while removal of the 40S is thought to require Tma64 (eIF2D), Tma20 (MCT-1), and Tma22 (DENR). However, it remains unclear how these Tma proteins cause 40S removal and control reinitiation of downstream translation. Here we used a 40S ribosome footprinting strategy to directly observe intermediate steps of ribosome recycling in cells. Deletion of the genes encoding these Tma proteins resulted in broad accumulation of unrecycled 40S subunits at stop codons, directly establishing their role in 40S recycling. Furthermore, the Tma20/Tma22 heterodimer was responsible for a majority of 40S recycling events while Tma64 played a minor role. Introduction of an autism-associated mutation into TMA22 resulted in a loss of 40S recycling activity, linking ribosome recycling and neurological disease.

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