Variability of Coordination in Typically Developing Children Versus Children with Autism Spectrum Disorder with and without Rhythmic Signal.

Motor coordination deficit is a cardinal feature of autism spectrum disorder (ASD). Theevaluation of coordination of children with ASD is either lengthy, subjective (via observationalanalysis), or requires cumbersome post analysis. We therefore aimed to use tri-axial accelerometersto compare inter-limb coordination measures between typically developed (TD) children and childrenASD, while jumping with and without a rhythmic signal. Children aged 5-6 years were recruited tothe ASD group (n = 9) and the TD group (n = 19). Four sensors were strapped to their ankles and wristand they performed at least eight consecutive jumping jacks twice: at a self-selected rhythm and witha metronome. The primary outcome measures were the timing lag (TL), the timing difference of themaximal acceleration of the left and right limbs, and the lag variability (LV), the variation of TL acrossthe 5 jumps. The LV of the legs of children with ASD was higher compared to the LV of the legs of TDchildren during self-selected rhythm jumping (p < 0.01). Additionally, the LV of the arms of childrenwith ASD, jumping with the rhythmic signal, was higher compared to that of the TD children (p <0.05). There were no between-group differences in the TL parameter. Our preliminary findingssuggest that the simple protocol presented in this study might allow an objective and accuratequantification of the intra-subject variability of children with ASD via actigraphy.

Benefits of medical clowning in the treatment of young children with autism spectrum disorder.

We investigated the contribution of group therapy delivered by a medical clown to young children diagnosed with autism spectrum disorder (ASD). So far, scientific publications regarding medical clowning focus on general health advantages. The current study is the first controlled research examining the use of medical clowning in the therapy for children with ASD. Twenty-four children aged 2-6 years old with ASD enrolled in our special education intensive program were examined before and after group sessions with clown intervention (CI) and other intervention (OI). We tested stereotypic behaviors, verbal expression, play reciprocity, and social smiles. Data was collected during 12 weeks of intervention, and the trajectory of change was evaluated in addition to the pre-/post-intervention.Conclusion: improvement over time in all measures: Significant increase in word production, play reciprocity, and amount of social smiles during CI as compared with OI. We also found a reduction in frequency of stereotypic behaviors during and following CI as compared with before CI. These preliminary results indicate that medical clowning may be beneficial for young children with ASD, since it promotes communication and social reciprocity in a fun and lively interventional setting. What is Known: • Many therapies are used and proven as efficacious interventions for children with ASD. • So far, medical clowning was not tested as an intervention or therapy for ASD. What is New: • Medical clowning sessions with children with ASD elicited enhanced communication during the interventions as compared with other interventions. • Medical clowning sessions contributed to a decrease in frequency of stereotypic movements over time, in children with ASD.

Prolonged Time Lag to Final Diagnosis of Fragile X Syndrome.

OBJECTIVE: To evaluate the diagnostic process in children ultimately diagnosed with fragile X syndrome (FXS), with an emphasis on the time lag between initial presentation and on diagnosis in female vs male children. STUDY DESIGN: Interviews were conducted with 89 families of children with a final diagnosis of FXS and assessment of time intervals between initial presentation and confirmed molecular diagnosis. RESULTS: Screening of 117 patients (25 female patients) from the 89 families revealed that less than 20% of patients obtained a diagnosis within the first year of seeking medical attention. Mean age at the time of initial presentation was 12.3 months in male patients and 23 months in female patients, while definitive diagnosis of FXS was made at a mean of 4 and 9 years, respectively. Presenting symptoms of developmental delays were recognized by 72% of parents, and 84% had another child with FXS before the index case diagnosis. Average age of diagnosis for children with FXS born since 2007 was significantly lower at 31.9 months, compared with 69.5 months for children born before 2007. CONCLUSIONS: Although FXS is a significant and prevalent cause of disability in children, it is underdiagnosed and diagnosed late, especially in female patients. In every male and female patient presenting with developmental delay or autism, FXS should be considered. Dysmorphic physical features may not be present in infancy, and the absence of those features cannot exclude a diagnosis of FXS.

[FROM GENETICS OF FRAGILE X SYNDROME TO DEVELOPMENT OF TARGETED AND PERSONALIZED DRUG THERAPY].

INTRODUCTION: At the end of the last century Fragile X syndrome was identified, and the main syndrome characteristics were discovered. The syndrome is caused from a flaw in the number of nucleotide repeats that encodes for a regulatory protein which is critical for neural connectivity and normal brain development. The syndrome is characterized by neurodevelopmental and intellectual disabilities, autism spectrum features and other clinical features associated with the same gene aberration. The number of trinucleotide repeats have a direct effect on the outcome and the need for genetic counseling. We advocate performing genetic tests for every child with developmental delay, learning disabilities, autism spectrum disorders and especially, intellectual impairment. It is also advisable to check the number of nucleotide repeats of the gene, in every woman suffering from infertility or early menopause. In addition, genetic testing should be performed on older adults manifesting early symptoms of Parkinson's disease, balance instability, tremor or cognitive dysfunction with unknown etiology. Due to the tremendous progress in understanding the biological mechanisms of the syndrome, new molecules/drugs have been proposed and are tested, in order to find a way to bypass the defect mechanism underlying the disorder. We will review the most commonly used drugs in the treatment of Fragile X syndrome and many medications that are currently under investigation as a more targeted treatment.

Fragile X Premutation Carrier Epidemiology and Symptomatology in Israel-Results from a Tertiary Child Developmental Center.

Fragile X syndrome (FXS) is the most prevalent known genetically inherited cause for autism and intellectual disability. Premutation state can cause several clinical disorders as well. We aimed to perform a nesting approach to acquire data with regard to first degree relatives of index fragile X cases at the largest child development center in Israel in order to map characteristics of Israeli FXS permutation women carriers. Seventy-nine women were referred due to a related fragile X syndrome patient, mainly an offspring or sibling. General information regarding demographics, ethnicity, and associated medical conditions were collected using interviews and structured questionnaires. Thirteen (17 %) of the women who were referred as "carrier" were proven to be actually full mutation. The mean years of education were 14 (±1.51, range 12-17). Twenty-one women (27 %) originated from Tunisia (mainly from the island of Djerba). Ten women (13 %) reported delivery of their affected offspring beyond 41 gestational weeks. Twenty-two percent of women with premutation reported symptoms consistent with learning difficulties, mainly dyscalculia, and 14 % reported ADHD symptoms. Awareness about clinical disorders of the carriers was existent only in 25 % of the patients. Increased awareness and knowledge dissemination concerning premutation symptomatology and associated medical conditions are warranted. We suggest a national registry to be installed in different countries in order to identify fragile X premutation carriers at increased risk for various medical complications.

An escalating continuum of learning and attention difficulties from premutation to full mutation in female carriers of FMR1 expansion.

Objective: Carriers of Fragile X premutation may have associated medical comorbidities, such as Fragile X-associated tremor and ataxia (FXTAS) and Fragile X-associated premature ovarian insufficiency (FXPOI). We examined the Fragile X premutation effect on cognition, and we assumed that there is a direct correlation between the continuous spectrum of specific learning and attention deficits to the number of CGG repeats on the FMR1 gene. Methods: A total of 108 women were referred to our center due to a related Fragile X syndrome (FXS) patient, 79 women carried a premutation of 56-199 repeats, and 19 women carried a full mutation of more than 200 CGG repeats on FMR1 gene. Genetic results of CGG repeats, demographic information, structured questionnaires for ADHD, learning disabilities of language and mathematics, and independence level were analyzed in women carrying the FMR1 premutation and compared to the group carrying the full mutation. Women with FXS and FXTAS were excluded. Results: When analyzed as a continuum, there was a significant increase in the following complaints which were associated with a higher number of repeats: specific daily function skills such as driving a car, writing checks, disorientation in directions, and also specific learning difficulties such as spelling and math difficulties. Additionally, when tested as a categorical independent variable, we observe that women with the full mutation were more likely to have ADHD or other learning disability diagnoses in the past than during premutation (<200 CGG repetitions). Conclusion: Specific learning and attention difficulties and resulting daily function difficulties correlate with an increased number of CGG repeats and are more likely to be associated as a common feature of premutation and full mutation in a female premutation carrier. Despite evidence of learning and attention difficulties, it is encouraging that most female carriers of the premutation and full mutation function well in most areas. Nevertheless, they face significant difficulties in specific areas of functioning such as driving, and confusion in times and schedules. Those daily function skills are mostly impacted by dyscalculia, right and left disorientation, and attention difficulties. This may aid to design specific interventions to address specific learning deficits in order to improve daily function skills and quality of life.

The myth of vaccination and autism spectrum.

BACKGROUND: Among all of the studied potential causes of autism, vaccines have received some of the most scrutiny and have been the topic of many evidence-based studies. These efforts have led the great majority of scientists, physicians, and public health researchers to refute causation between vaccines and autism. RATIONALE: This presumed association and concern has been a major contributor to parents' refusal to immunize their children and has become a major threat to public health in secluded populations over the last two decades, even prior to the COVID-19 pandemic. With the emergence of COVID-19 immunizations, sentiments towards this topic were addressed as a public health concern that may influence the ability to overcome the Corona virus worldwide. SCIENTIFIC REVIEW OF DATA: Despite the overwhelming data demonstrating that there is no link between vaccines and autism, many parents are hesitant to immunize their children because of the alleged association. Other contributing factors to the myths and conspiracy theories surrounding the association between vaccines and autism include the fact that the diagnosis of autism is typically made after the age of receiving the main childhood immunizations, as well as the occasional occurrence of regression after the age of first year vaccinations. In spite of vast evidence that the main contribution to the increase in incidence is from improvement of the diagnostic process, this rapid and publicized rise in autism diagnoses feeds parental concerns regarding any medical intervention that may be associated with the health of their children. RECOMMENDATIONS: It is plausible that with more evidence-based studies linking autism to specific etiologies the myth will diminish and disappear eventually. In an era where conspiracy theories are prevalent on social media, it is critical that evidence-based studies relating autism to specific etiologies be made public, and that information concerning autism diagnosis and causes be made more readily available through social media and parental organizations.

The Weak Link: Hypotonia in Infancy and Autism Early Identification.

Background: Presenting symptoms and age specific differential diagnosis of Autism Spectrum Disorder (ASD), determine the age of initial assessment and the age of a definite diagnosis. The AAP recommends screening all children for ASD at 18 and 24 months followed by a comprehensive evaluation for children with developmental concerns. More recently it has been recommended that the evaluation should be performed at a younger age, with a diagnosis being made as early as the beginning of the second year of life resulting in earlier intensive intervention. Objective: To assess early developmental milestones in a cohort of children diagnosed with Autism Spectrum Disorder (ASD) in order to find an objective and reliable early marker. We suggest that low muscle tone- hypotonia, is a sign that meets the above criteria of consistency and reliability and may be related to early diagnosis. Methods: We compared age distributions of ASD diagnosis in the presence of hypotonia in a dataset of 5,205 children diagnosed at Keshet Center. One thousand, one hundred eighty-two children (953 males) were diagnosed with ASD and compared to other developmental diagnoses. Within the ASD cohort we further analyzed for gender and pre-maturity differences. Results: In the presence of hypotonia, the mean age for ASD diagnosis was significantly lower (by 1.5 years for males and females) and this effect increased in children born at term as compared to pre-maturity. Conclusions: Hypotonia is a recognizable marker of ASD and may serve as a "red flag" to prompt earlier recognition and neurodevelopmental evaluation toward an autism diagnosis.

[Gastrointestinal symptoms in pediatric patients with attention deficit and hyperactivity disorders].

BACKGROUND: Only a few studies have addressed the subject of physical manifestations in children with attention deficit hyperactivity disorder (ADHD) and gastrointestinal (GI) complaints, although pharmacological treatments for ADHD may have GI symptoms as a main side effect. AIM: The goal of this study was to assess whether children with ADHD have a higher frequency of GI symptoms compared with healthy children in the general population. METHOD: The study group included 62 children with ADHD and 57 healthy children as a control group. The childrens' parents were asked to report on abdominal pain, diarrhea, constipation, encopresis, food intolerance or allergy. Height, weight and the medical data of the two groups were compared. RESULTS: A higher frequency of food allergies was found in the ADHD group, but the relationship was at near significant levels only (p = 0.06), and open to criticism. CONCLUSION: This study showed no obvious correlation between GI symptoms and ADHD in Israeli children.

Ethical Dilemmas Linked to Fragile X Testing of Minors-a Preliminary Survey Among Professionals.

Asymptomatic female carriers of the FMR1 premutation at childbearing age have been mostly identified through prenatal genetic testing, which is routinely proposed in Israel. During the last few years, a premutation phenotype in males and females has been defined-FXAND, including neuropsychiatric disorder, learning difficulties, endocrine dysfunction, and premature ovarian failure. So when a family at risk is identified, should individuals be tested for premutation even if minors? In order to understand what professionals' views are with regard to testing FMR1 premutation in minors, we performed a questionnaire testing both ethical attitudes and knowledge. Eighty-two percent of professionals would positively consider fragile X testing in minors, and an additional 15.4% would consider it in boys only. The specific phenotype of full mutation is recognized well by health professionals, while the premutation phenotype is not well known. There is a need to expand awareness on the fragile X premutation phenotype through better information. Testing of fragile X premutation status in minors should be considered, when at risk due to family history.

Autism risk linked to prematurity is more accentuated in girls.

INTRODUCTION: Prematurity has been identified as a risk factor for Autism Spectrum Disorder (ASD). The link between Autism Spectrum Disorder (ASD) and birth-week has not been strongly evidenced. We evaluated the correlation between the degree of prematurity and the incidence of autism in a cohort of 871 children born prematurely and followed from birth. The cohort was reduced to 416 premature infants born between 2011-2017 who were followed for 2-14 years, and analyzed according to birth week (degree of prematurity), and according to gender. RESULTS: 43 children (10.3%) received a definite diagnosis of ASD. There was a significant correlation between birth week and the risk of ASD, with 22.6% of children diagnosed with ASD when born at 25 weeks, versus 6% of ASD diagnoses at 31 weeks of prematurity. For children born after 32 weeks, the incidence decreased to 8-12.5%. A strong link was found between earlier birth week and increased autism risk; the risk remained elevated during near-term prematurity in boys. A correlation between early birth week and an elevated risk for ASD was seen in all children, but accentuated in females, gradually decreasing as birth week progresses; in males the risk for ASD remains elevated for any birth week. CONCLUSION: A statistically significant increase in rates of autism was found with each additional week of prematurity. Females drove this direct risk related to degree of prematurity, while males had an elevated risk throughout prematurity weeks, even at near-term. We recommend including ASD screening in follow up of infants born prematurely, at all levels of prematurity.

Improvement of Language in Children with Autism with Combined Donepezil and Choline Treatment.

The safety and efficacy of a novel combination treatment of AChE inhibitors and choline supplement was initiated and evaluated in children and adolescents with autism spectrum disorder (ASD). Safety and efficacy were evaluated on 60 children and adolescents with ASD during a 9-month randomized, double-blind, placebo-controlled trial comprising 12 weeks of treatment preceded by baseline evaluation, and followed by 6 months of washout, with subsequent follow-up evaluations. The primary exploratory measure was language, and secondary measures included core autism symptoms, sleep and behavior. Significant improvement was found in receptive language skills 6 months after the end of treatment as compared to placebo. The percentage of gastrointestinal disturbance reported as a side effect during treatment was higher in the treatment group as compared to placebo. The treatment effect was enhanced in the younger subgroup (younger than 10 years), occurred already at the end of the treatment phase, and was sustained at 6 months post treatment. No significant side effects were found in the younger subgroup. In the adolescent subgroup, no significant improvement was found, and irritability was reported statistically more often in the adolescent subgroup as compared to placebo. Combined treatment of donepezil hydrochloride with choline supplement demonstrates a sustainable effect on receptive language skills in children with ASD for 6 months after treatment, with a more significant effect in those under the age of 10 years.

Prolonged auditory brainstem responses in infants with autism.

Numerous studies have attempted to identify early physiological abnormalities in infants and toddlers who later develop autism spectrum disorder (ASD). One potential measure of early neurophysiology is the auditory brainstem response (ABR), which has been reported to exhibit prolonged latencies in children with ASD. We examined whether prolonged ABR latencies appear in infancy, before the onset of ASD symptoms, and irrespective of hearing thresholds. To determine how early in development these differences appear, we retrospectively examined clinical ABR recordings of infants who were later diagnosed with ASD. Of the 118 children in the participant pool, 48 were excluded due to elevated ABR thresholds, genetic aberrations, or old testing age, leaving a sample of 70 children: 30 of which were tested at 0-3 months, and 40 were tested at toddlerhood (1.5-3.5 years). In the infant group, the ABR wave-V was significantly prolonged in those who later developed ASD as compared with case-matched controls (n = 30). Classification of infants who later developed ASD and case-matched controls using this measure enabled accurate identification of ASD infants with 80% specificity and 70% sensitivity. In the group of toddlers with ASD, absolute and interpeak latencies were prolonged compared to clinical norms. Findings indicate that ABR latencies are significantly prolonged in infants who are later diagnosed with ASD irrespective of their hearing thresholds; suggesting that abnormal responses might be detected soon after birth. Further research is needed to determine if ABR might be a valid marker for ASD risk. Autism Res 2016, 9: 689-695. © 2015 The Authors Autism Research published by Wiley Periodicals, Inc. on behalf of International Society for Autism Research.

Long-Term Maternal Stress and Post-traumatic Stress Symptoms Related to Developmental Outcome of Extremely Premature Infants.

In this study, we examined the relations between the severity of developmental outcomes of extremely low birth weight (ELBW) children and their mothers' stress and post-traumatic stress disorder (PTSD) symptoms, 4-16 years after birth. Israeli mothers (N = 78) of a cohort of extremely premature infants (24-27 weeks) born 4-16 years earlier were asked to report about the medical and developmental condition of their child and their current perceived stress and PTSD symptoms. Results show that mothers of ELBW children with normal development reported the lowest perceived stress compared with mothers of ELBW children with developmental difficulties. We also found that 25.6% of the mothers had the potential to suffer from PTSD following the birth of an ELBW child. Furthermore, the severity of prematurity developmental outcomes made a significant contribution to mothers' perceived stress. To sum, mothers of ELBW infants' perceived stress is related to their children's severity of prematurity developmental outcomes, 4-16 years after birth. Clinical implications of these findings are discussed.

Balance deficit enhances anxiety and balance training decreases anxiety in vestibular mutant mice.

Treatment of anxiety disorders by either pharmacological or behavioral means is applied with the intention to directly target the limbic system or high brain centers that down-regulate limbic activity. In spite of intense and long treatment, remission is not achieved in many patients, suggesting that their pathophysiology is not addressed by either of the above treatments. An alternative pathophysiology may be a disordered vestibular system, which may be studied in the context of comorbidity of balance and anxiety disorders. Here we studied whether mutant vestibular Headbanger (Hdb) mice demonstrate elevated anxiety and whether physical treatment of balance alleviates the behavioral symptoms of anxiety. Hdb and wildtype (Wt) mice were raised in either balance training or standard cages and were subjected repeatedly at 1-3 months of age to balance and anxiety-related tests. Results demonstrated progressive deterioration of balance performance and parallel elevation of anxiety in untrained Hdb as compared to untrained Wt mice. Training significantly improved balance performance of Hdb mice and in parallel, decreased the level of anxiety compared to untrained Hdb mice. These findings confirm that vestibular pathophysiology may be causally related to development of anxiety and suggest that in some clinical cases of anxiety, the appropriate treatment is physical rehabilitation of balance.

Assessment of Abilities and Comorbidities in Children With Cerebral Palsy.

This study examines major comorbidities in children with severe cerebral palsy and the feasibility of psychological tests for measuring abilities in a more impaired population. Eighty psychological evaluations of children with cerebral palsy aged 1.8 to 15.4 years (mean = 5.6) were analyzed. Major comorbid disorders were correlated with severity of motor disability. More than half of the cohort were diagnosed with severe cerebral palsy according to the Gross Motor Function Classification System. Multiple subtests were combined in order to assess the intellectual level. Normal intelligence was found in 22.5%, and 41.3% had moderate or severe intellectual impairment. Epilepsy occurred in 32.5% and attention-deficit hyperactivity disorder (ADHD) in 22.5%. Intellectual disability correlated with motor ability and with epilepsy. In a logistic regression model, epilepsy and motor ability score predicted 29.9% of IQ score variance. Intellectual impairment and epilepsy are common comorbidities. Subtests from different scales should be applied and interpreted with caution.

Progressive vestibular mutation leads to elevated anxiety.

Anxiety disorders are among the most common mental disorders, and are comorbid with balance disorders in a significant proportion of these individuals. Presently, it is unclear whether anxiety and balance disorders are causally related, and what direction this causality may take. We argue that balance disorders may predispose an individual to anxiety and that demonstration of such causality may be informative to the development of preferred treatment for such individuals. To demonstrate that balance disorders may predispose to anxiety, we studied headbanger (Hdb) mutant mice in which the balance disorder is due to progressive vestibular impairment and wildtype (Wt) mice. Balance was assessed by swim and tail-hang tests that demonstrated clear behavioral balance deficits in the Hdb mice. Anxiety was assessed by open-field and elevated plus-maze tests, which confirmed elevated anxiety in the Hdb mice. These findings demonstrate that congenital vestibular genotype predisposes the animal to elevated levels of anxiety in space-related tests. Similar causality in clinics may redirect treatment strategies in afflicted patients.