1. Bishop SK, Moore JW, Dart EH, Radley K, Brewer R, Barker LK, Quintero L, Litten S, Gilfeather A, Newborne B, Toche C. {{Further investigation of increasing vocalizations of children with autism with a speech-generating device}}. {J Appl Behav Anal};2019 (Mar 22)
We replicated and extended the findings of Gervarter et al. (2016) by using prompting and reinforcement to produce increased vocal speech with 3 young children diagnosed with autism spectrum disorder (ASD) who used a speech generating device (SGD). We extended Gervarter et al. by adopting a more robust experimental design, conducting session-by-session preference assessments, and measuring the emergence of novel vocalizations. The frequency of vocalizations increased for all 3 participants after the introduction of an echoic prompt. These results suggest that SGD-based interventions may lead to increased vocal output for children with ASD.
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2. Cai X, Arif M, Wan H, Kornreich R, Edelmann LJ. {{Clinical Genetic Testing for Fragile X Syndrome by Polymerase Chain Reaction Amplification and Southern Blot Analyses}}. {Methods Mol Biol};2019;1942:11-27.
Fragile X syndrome (FXS) is characterized by mental retardation and in the vast majority of cases it is caused by expansion of CGG trinucleotide repeats in the 5′ untranslated region (or UTR) in the FMR1 gene on the X chromosome. The size and methylation status of CGG repeats are correlated with the clinical phenotype of FMR1-related disorders. The methods used for clinical genetic testing of FXS include polymerase chain reaction (PCR) amplification and Southern blot analyses, which effectively detect alleles with repeats in the normal, intermediate, premutation, and full mutation size ranges, as well as the methylation status of FMR1 promoter region.
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3. Chabeda-Barthe J, Wambua T, Chege WL, Hwaga D, Gakuo T, Rotich GC. {{Child Developmental Disabilities, Caregivers’ Role in Kenya and Its Implications on Global Migration}}. {Int J Environ Res Public Health};2019 (Mar 20);16(6)
Background: This paper is a summary of the findings from an ethnographic study on child developmental disabilities conducted partly in Nairobi and Kiambu Counties in Kenya. Methods: Quantitative and qualitative data collection methods were applied for the period between mid August and mid November 2018. The study was conducted through the Kenya Institute of Special Education (KISE) situated in Nairobi County. Results: There are parents who are willing to migrate in search of better education and healthcare options for their children who have developmental disabilities (DDs). However, there are also government reforms taking place in the field of disability that may help to support the caregiving role for children with special needs. The challenges, bargaining position and power play between parents or guardians and other actors implicated in the debates on inclusion and integration of persons with developmental disabilities in Kenya has been brought to the forefront. Conclusions: In Kenya, more needs to be done to change the attitude towards disability from the medical and moral (religious/cultural) models to an approach leaning towards the social model, so that developmental disabilities are not viewed negatively.
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4. Deshpande RR, Dungarwal PP, Bagde KK, Thakur PS, Gajjar PM, Kamath AP. {{Comparative evaluation of salivary zinc concentration in autistic and healthy children in mixed dentition age group-pilot study}}. {Indian J Dent Res};2019 (Jan-Feb);30(1):43-46.
Context: Autism prevalence is increasing, with current estimates at 1/68-1/50 individuals diagnosed with autism. Diagnosis is based on behavioral assessments. Early diagnosis and intervention are known to greatly improve functional outcomes in people with autism. Diagnosis, treatment monitoring, and prognosis of autistic children’s symptoms could be facilitated with biomarkers to complement behavioral assessments. Aims: The aim of this study is to compare and evaluate salivary zinc concentration in saliva samples of autistic and healthy children in mixed dentition age group. Settings and Design: Cross-sectional comparative study carried out in dental college and special child school. Unstimulated whole saliva collected for finding a biomarker. Subjects and Methods: Unstimulated whole saliva sample was collected from 10 autistic and 10 healthy children in mixed dentition age group. Diluted saliva sample was then subjected to inductively coupled plasma emission spectroscopy for the estimation of salivary zinc concentration. Statistical Analysis Used: Mann-Whitney U-test. Results: In children with autism salivary zinc concentration showed a linear equation when compared to healthy children. Conclusions: The low salivary zinc concentration in autistic children can reveal the pathogenesis of autism.
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5. Elizur SE, Friedman Gohas M, Dratviman-Storobinsky O, Cohen Y. {{Pathophysiology Mechanisms in Fragile-X Primary Ovarian Insufficiency}}. {Methods Mol Biol};2019;1942:165-171.
Women who carry the FMR1 premutation may suffer from ongoing deterioration of ovarian function. The lucidity of the molecular mechanism of FXTAS is emerging and findings from research in the field of FXTAS could elucidate the pathogenesis of FXPOI. To date there are three possible mechanisms for ovarian dysfunction in FMR1 permutation carriers. The first is the RNA toxic gain-of-function mechanism initiating loss of function of over 30 specific RNA-binding proteins. The second is associated to the formation of an abnormal polyglycine-containing protein (FMRpolyG), and the third is related to novel lncRNAs, named FMR4 and FMR6. Herein we describe our laboratory methodology, focusing on the culturing and manipulation of granulosa cells from human female premutation carriers, trying to reveal the actual possible mechanisms liable to FXPOI. Detecting the precise pathways in premutation carrier might facilitate in offering these women the opportunity to make an informed decision regarding their reproductive and family planning.
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6. Garg P, Sharp AJ. {{Screening for rare epigenetic variations in autism and schizophrenia}}. {Hum Mutat};2019 (Mar 21)
While many studies have led to the identification of rare sequence variants linked with susceptibility to autism and schizophrenia, the contribution of rare epigenetic variations (epivariations) in these disorders remains largely unexplored. Previously we presented evidence that epivariations occur relatively frequently in the human genome, and likely contribute to a subset of congenital and neurodevelopmental disorders through the disruption of dosage-sensitive genes. Here we extend this approach, studying methylation profiles from 297 samples with autism and 767 cases with schizophrenia, identifying 84 and 268 rare epivariations in these two cohorts, respectively, that were absent from 4,860 population controls. We observed multiple features associated with these epivariations that support their pathogenic relevance, including (a) a significant enrichment for epivariations in schizophrenic individuals at genes previously linked with schizophrenia, (b) increased brain expression of genes associated with epivariations found in autism cases compared with controls, (c) in autism families, a significant excess of epivariations found specifically in affected versus unaffected sibs, (d) Gene Ontology terms linked with epivariations found in autism, including « D1 dopamine receptor binding. » Our study provides additional evidence that rare epivariations likely contribute to the mutational spectra underlying neurodevelopmental disorders.
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7. Hayward BE, Usdin K. {{Assays for Determining Repeat Number, Methylation Status, and AGG Interruptions in the Fragile X-Related Disorders}}. {Methods Mol Biol};2019;1942:49-59.
Knowledge of the CGG*CCG-repeat number, AGG interruption status, and the extent of DNA methylation of the FMR1 gene are vital for both diagnosis of the fragile X-related disorders and for basic research into disease mechanisms. We describe here assays that we use in our laboratory to assess these parameters. Our assays are PCR-based and include one for repeat size that can also be used to assess the extent of methylation and a related assay that allows the AGG interruption pattern to be reliably determined even in women. A second more quantitative methylation assay is also described. We also describe our method for cloning of repeats to generate the reference standards necessary for the accurate determination of repeat number and AGG interruption status.
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8. Kong HE, Lim J, Jin P. {{Application of Drosophila Model Toward Understanding the Molecular Basis of Fragile X Syndrome}}. {Methods Mol Biol};2019;1942:141-153.
Drosophila melanogaster is an ideal model to study Fragile X syndrome (FXS) as it presents us with a toolbox to identify genetic modifiers and to investigate the molecular mechanisms of FXS. Here we describe some of the methods that have been used to study FXS, ranging from reverse genetic screening using the GAL4-UAS system, to mushroom body staining and courtship behavioral assays to examine the learning and memory deficits associated with FXS.
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9. Kuhlthau KA, Luberto CM, Traeger L, Millstein RA, Perez GK, Lindly OJ, Chad-Friedman E, Proszynski J, Park ER. {{A Virtual Resiliency Intervention for Parents of Children with Autism: A Randomized Pilot Trial}}. {J Autism Dev Disord};2019 (Mar 21)
Parents of children with Autism experience high levels of stress. Resiliency is the ability to cope and adapt when faced with stressful events. This randomized, waitlist controlled pilot trial examines the feasibility, acceptability, and preliminary efficacy of an adapted virtual mind-body group intervention for parents of children with ASD. The intervention was feasible and acceptable. The immediate treatment group showed no difference in distress and greater improvement in resiliency and stress reactivity/coping relative to the delayed treatment group, (M difference 5.78; p = .038 and M difference 7.78; p = .001 respectively). Findings showed promising feasibility, acceptability, and preliminary efficacy for parents of children with ASD.
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10. Okazaki K, Yamamuro K, Iida J, Kishimoto T. {{Guanfacine monotherapy for ADHD/ASD comorbid with Tourette syndrome: a case report}}. {Ann Gen Psychiatry};2019;18:2.
Background: Patients with attention deficit/hyperactivity disorder (ADHD) often experience comorbid conditions, such as autism spectrum disorder (ASD) and Tourette syndrome (TS). Although pharmacotherapies are effective for treating ADHD, they are likely to elicit a variety of adverse effects. It is, thus, important to select an effective and well-tolerated pharmacotherapeutic treatment for patients with ADHD/ASD comorbid with TS. Case presentation: We report the case of a 10-year-old boy with ADHD/ASD comorbid with TS who was treated with guanfacine (GUAN). He experienced several side effects of atomoxetine (ATX) and methylphenidate (MPH) before being treated with GUAN. In the presented case, symptoms of ADHD as well as tic symptoms were improved by treatment with GUAN. Conclusion: GUAN might be effective and well tolerated in the treatment of patients with ADHD/ASD comorbid with TS who experience side effects of ATX and MPH.
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11. Port RG, Dipiero MA, Ku M, Liu S, Blaskey L, Kuschner ES, Edgar JC, Roberts TPL, Berman J. {{Children with ASD demonstrate regionally specific altered resting-state phase-amplitude coupling}}. {Brain Connect};2019 (Mar 22)
Studies suggest that individuals with autism spectrum disorder (ASD) exhibit altered electrophysiological alpha to gamma phase-amplitude coupling (PAC). Preliminary reports with small samples report conflicting findings regarding the directionality of the alpha to gamma PAC alterations in ASD. The present study examined resting-state activity throughout the brain in a relatively large sample of 119 children with ASD and 47 typically developing (TD) children. Children with ASD demonstrated regionally specific abnormalities in alpha to low-gamma PAC, with increased alpha to low-gamma PAC for a central midline source and decreased PAC at lateral sources. Group differences in local gamma-band power did not account for the regional group differences in alpha to low-gamma PAC. Moreover, local alpha power did not significantly modulate alpha to low-gamma PAC estimates. Finally, PAC estimates were correlated with SRS indicating clinical relevance of the PAC metric. In conclusion, alpha to low-gamma PAC alterations in ASD demonstrate a heterogeneous spatial profile consistent with previous studies and were related to symptom severity.
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12. Reches A. {{Fragile X Syndrome: Introduction}}. {Methods Mol Biol};2019;1942:3-10.
Fragile X syndrome (FXS) is one of the most common reasons for intellectual disability (ID). First described in the 1940s, it took many years to understand the disease. The awe-inspiring breakthroughs in both science and technology facilitated the recognition of the unique inheritance pattern and the genetic mechanism of fragile X. In this chapter we describe the history and evolution of our understanding of FXS as mirrored by advances in genetics.
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13. Svedberg L, Herngren B, Michno P. {{How reconstructive surgery combined with physiotherapy for a painful nontraumatic patellar dislocation enabled a woman with Rett syndrome to become pain free and remain physically active: A case report}}. {Clin Case Rep};2019 (Mar);7(3):542-545.
The effects of orthopedic measures, with the exception of scoliosis surgery, are rarely described in individuals with Rett syndrome. In this case, treating a painful dislocation of the patella with combined orthopedic and physiotherapeutic measures enabled a woman with Rett syndrome to become pain free and remain physically active.
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14. Telias M. {{Fragile X Syndrome Pre-Clinical Research: Comparing Mouse- and Human-Based Models}}. {Methods Mol Biol};2019;1942:155-162.
Despite almost 30 years of biomedical research, a treatment or cure for fragile X syndrome (FXS) is not yet available. The reasons behind this are varied, and among them are discrepancies in both research methodologies and research models. For many years, the fmr1 knockout mouse model dominated the field, and was used to draw important conclusions. The establishment of FXS-human cellular models called these conclusions into question, showing conflicting evidence. Discrepancies in FXS research, between mouse and human, might arise from differences inherent to each species, and from the use of different methodologies. This chapter summarizes these discrepancies and evaluates their impact on the current status of clinical trials.
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15. Telias M. {{Molecular Mechanisms of Synaptic Dysregulation in Fragile X Syndrome and Autism Spectrum Disorders}}. {Front Mol Neurosci};2019;12:51.
Fragile X syndrome (FXS) is the most common form of monogenic hereditary cognitive impairment. FXS patient exhibit a high comorbidity rate with autism spectrum disorders (ASDs). This makes FXS a model disease for understanding how synaptic dysregulation alters neuronal excitability, learning and memory, social behavior, and more. Since 1991, with the discovery of fragile X mental retardation 1 (FMR1) as the sole gene that is mutated in FXS, thousands of studies into the function of the gene and its encoded protein FMR1 protein (FMRP), have been conducted, yielding important information regarding the pathophysiology of the disease, as well as insight into basic synaptic mechanisms that control neuronal networking and circuitry. Among the most important, are molecular mechanisms directly involved in plasticity, including glutamate and gamma-aminobutyric acid (GABA) receptors, which can control synaptic transmission and signal transduction, including short- and long-term plasticity. More recently, several novel mechanisms involving growth factors, enzymatic cascades and transcription factors (TFs), have been proposed to have the potential of explaining some of the synaptic dysregulation in FXS. In this review article, I summarize the main mechanisms proposed to underlie synaptic disruption in FXS and ASDs. I focus on studies conducted on the Fmr1 knock-out (KO) mouse model and on FXS-human pluripotent stem cells (hPSCs), emphasizing the differences and even contradictions between mouse and human, whenever possible. As FXS and ASDs are both neurodevelopmental disorders that follow a specific time-course of disease progression, I highlight those studies focusing on the differential developmental regulation of synaptic abnormalities in these diseases.
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16. Telias M, Segal M. {{Patch-Clamp Recordings from Human Embryonic Stem Cells-Derived Fragile X Neurons}}. {Methods Mol Biol};2019;1942:131-139.
Performing electrophysiological recordings from human neurons that have been differentiated in vitro, as compared to primary cultures, raises many challenges. However, patch-clamp recording from neurons derived from stem cells provides an abundance of valuable information, reliably and fast. Here, we describe a protocol that is used successfully in our lab for recording from both control and Fragile X neurons, derived in vitro from human embryonic stem cells.
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17. Wijker C, Leontjevas R, Spek A, Enders-Slegers MJ. {{Effects of Dog Assisted Therapy for Adults with Autism Spectrum Disorder: An Exploratory Randomized Controlled Trial}}. {J Autism Dev Disord};2019 (Mar 21)
Effective treatments of highly prevalent stress-related outcomes such as depression and anxiety are understudied in adults with autism spectrum disorder (ASD). A randomized controlled trial with baseline, post-intervention, and 10-week follow-up, that explores the effects of animal assisted therapy (AAT) was conducted. In total, 53 adults with ASD with normal to high intelligence were randomized in an intervention (N = 27) versus waiting list control group (N = 26). The remarkable adherence to the therapy program by study participants and the program’s clinically relevant effects indicate that AAT with dogs can be used to reduce perceived stress and symptoms of agoraphobia, and to improve social awareness and communication in adults with ASD with normal to high intelligence.
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18. Zafarullah M, Tassone F. {{Fragile X-Associated Tremor/Ataxia Syndrome (FXTAS)}}. {Methods Mol Biol};2019;1942:173-189.
Individuals carrying an FMR1 expansion between 55 and 200 CGG repeats, are at risk of developing the Fragile X-associated tremor/ataxia syndrome (FXTAS), a late onset neurodegenerative disorder characterized by cerebellar gait ataxia, intentional tremor, neuropathy, parkinsonism, cognitive decline, and psychological disorders, such as anxiety and depression. In addition, brain atrophy, white matter disease, and hyperintensities of the middle cerebellar peduncles can also be present. The neuropathological distinct feature of FXTAS is represented by the presence of eosinophilic intranuclear inclusions in neurons and astrocytes throughout the brain and in other tissues. In this chapter, protocols for available diagnostic tools, in both humans and mice, the clinical features and the basic molecular mechanisms leading to FXTAS and the animal models proposed to study this disorder are discussed.
