DNA mutational events are increasingly being identified in autism spectrum disorder (ASD), but the potential additional role of dysregulation of the epigenome in the pathogenesis of the condition ...remains unclear. The epigenome is of interest as a possible mediator of environmental effects during development, encoding a cellular memory reflected by altered function of progeny cells. Advanced maternal age (AMA) is associated with an increased risk of having a child with ASD for reasons that are not understood. To explore whether AMA involves covert aneuploidy or epigenetic dysregulation leading to ASD in the offspring, we tested a homogeneous ectodermal cell type from 47 individuals with ASD compared with 48 typically developing (TD) controls born to mothers of ≥35 years, using a quantitative genome-wide DNA methylation assay. We show that DNA methylation patterns are dysregulated in ectodermal cells in these individuals, having accounted for confounding effects due to subject age, sex and ancestral haplotype. We did not find mosaic aneuploidy or copy number variability to occur at differentially-methylated regions in these subjects. Of note, the loci with distinctive DNA methylation were found at genes expressed in the brain and encoding protein products significantly enriched for interactions with those produced by known ASD-causing genes, representing a perturbation by epigenomic dysregulation of the same networks compromised by DNA mutational mechanisms. The results indicate the presence of a mosaic subpopulation of epigenetically-dysregulated, ectodermally-derived cells in subjects with ASD. The epigenetic dysregulation observed in these ASD subjects born to older mothers may be associated with aging parental gametes, environmental influences during embryogenesis or could be the consequence of mutations of the chromatin regulatory genes increasingly implicated in ASD. The results indicate that epigenetic dysregulatory mechanisms may complement and interact with DNA mutations in the pathogenesis of the disorder.
Abstract Background In 2003, several hundred Israeli infants risked thiamine deficiency after being fed a soy-based formula deficient in thiamine. Approximately 20 patients were seriously affected, ...and three of them died. We report the clinical presentation of acute encephalopathy in 11 children and the long-term sequelae of eight children who initially survived. Patients In the acute phase, six had bulbar signs, five had ophthalmologic signs and two had phrenic neuropathy. Three of the five patients with cardiac involvement had cardiomyopathy and died in the acute phase. One patient presented with a complete atrioventricular block. Results In the long-term, one patient, who was in a chronic vegetative state, died after 6 years. Seven children exhibited mental retardation and motor abnormalities, six developed severe epilepsy, two early kyphoscoliosis, and one patient remained with a complete atrioventricular block. Conclusions Infants who survive severe infantile thiamine deficiency have serious residual motor and cognitive sequelae as well as epilepsy.
Abstract Postnatal microcephaly is defined as normal head circumference at birth, which progressively declines to more than 2 standard deviations below the average for the patient’s age and sex. We ...describe four patients from three consanguineous families of Arab Bedouin origin who presented with autosomal recessive inheritance of progressive microcephaly, spasticity, thin corpus callosum, pyramidal signs, and intellectual disability. Homozygosity mapping (Human Mapping Nsp I 250K arrays, Affymetrix, Santa Clara, CA) placed the disease locus at 8q23.2-q24.12. The candidate region includes 22 known or predicted genes, including RAD21 , which is related to the cohesion complex EIF3H , which is involved in translation initiation, and TAF2 , which may be involved in intellectual disability. Identification of the causative gene in our reported family will shed light on the pathogenesis of this severe condition.
Benign hereditary chorea is an autosomal dominant disease with an early onset of symptoms. In some families, symptoms tend to decrease in adulthood, suggesting that the disorder results from a ...developmental disturbance in the brain. Individuals with benign hereditary chorea, a nonprogressive disease, have normal or slightly below normal intelligence. The locus for benign hereditary chorea is on chromosome 14. Benign hereditary chorea is a result of mutations in the thyroid transcription factor 1 gene. Previous neuroimaging and pathological investigations of the brain showed no notable abnormalities in patients with this condition. In this study, 5 patients from 1 family with typical clinical features of benign hereditary chorea are presented. Clinical severity varied considerably in the family. Brain magnetic resonance imaging results were normal. Brain single photon emission computed tomography in 3 children, performed 1 hour after intravenous injection of 0.35 mCi/kg of body weight of technetium 99m ethyl cysteinate dimer, showed markedly decreased uptake in the right striatum and the right thalamus in 1 child. The oldest child had mildly reduced uptake in the right putamen and the left thalamus. Brain single photon emission computed tomographic findings in the youngest child were normal. Contrary to other reports of radionuclide brain imaging, notable brain single photon emission computed tomography changes were detected in 2 of 5 patients. Brain single photon emission computed tomography findings did not seem to correlate with the clinical status of the children.
Environmental factors, such as nutritional status, physical activity, and drug therapy, can affect bone mineralization. Our objective was to evaluate the relationship between nutritional status, ...physical activity, and bone mineralization as assessed by multisite quantitative ultrasound technology in children. The study group comprised 67 children, aged 6–17 years (mean, 9.4), attending a primary care clinic. Data on calcium intake and physical activity were collected using a detailed questionnaire. Speed of sound measurements were performed at the distal 1/3 radius and the midshaft tibia using Sunlight Omnisense apparatus. The reported mean calcium intake was 1105 mg/day. There was a significant difference in Z-scores at the radius and tibia between the low-and high-calcium-intake groups (
P
= 0.004,
P
= 0.035, respectively). A similar difference was found between the low-and normal-physical-activity groups (
P
= 0.015,
P
= 0.036, respectively). In this pilot study, a positive association was found between calcium intake, physical activity, and bone status, as assessed by the quantitative ultrasound technique.
Epilepsy and attention-deficit hyperactivity disorder (ADHD) were reported to co-occur at rates higher than expected for coincidental findings. This study investigated the prevalence of both ...disorders in community-based primary care practice. The central database of the second-largest health maintenance organization in Israel was searched for all children aged 6 to 13 years (n = 284 419; 51.5% males) diagnosed as having ADHD according to the physicians’ records and/or the filling of at least 10 prescriptions for antiepileptic medications according to pharmacy records. The prevalence of epilepsy in the total population was 5 out of 1000 children, and the prevalence of ADHD was 12.6%. More than one-fourth (27.7%) of the epileptic children were also diagnosed as having ADHD. On multivariate analysis, children with ADHD had almost twice the risk of epilepsy than children without ADHD. This study supports hospital-based findings of a strong interrelationship between ADHD and epilepsy. The high rate of ADHD in Israeli children warrants further investigation.
Background: Developmental and behavioral pediatrics has emerged as an area of special interest and new responsibility for pediatricians. The aim of this study was to evaluate the impact of training, ...experience, and other factors on pediatricians’ satisfaction with their abilities to care for children with developmental, behavioral and psychosocial problems.
Methods: A questionnaire was sent to 211 pediatricians working in primary care clinics in the community in Israel. Items included personal characteristics and experience, practice and satisfaction with the care of children with developmental, behavioral and psychosocial problems. Overall, pediatrician satisfaction with their personal abilities in this domain was defined as the dependent variable on multivariate analysis.
Results: The response rate was 76.3% (n = 161). Pediatricians’ satisfaction with their overall professional ability to care for children with developmental, behavioral and psychosocial problems was significantly and positively associated with the following independent variables: (i) satisfaction with training received in the child development field; (ii) satisfaction with psychiatric updates; (iii) general satisfaction with the available child development services; (iv) prescription of methylphenidate to children with attention deficit/hyperactivity disorder; and (v) having completed their medical studies in a country in which the issue is emphasized.
Conclusions: Imparting more knowledge and skills in child development and behavioral pediatrics in pediatric residency and continuing education programs will help improve the attitudes of primary care pediatricians towards developmental and behavioral problems, encourage them to treat these patients and their families, and better the quality of care.
A 14-year-old male sustained neck trauma during a fight at school. Torticollis developed immediately afterwards, followed by axial dystonia and camptocormia. Thorough evaluation for etiology or ...background disease, including psychiatric examination, was negative except for the recent trauma. Antidystonia medications, administered after significant worsening of the symptoms, led to improvement. Dystonia and camptocormia resulting from trauma are rare presentations in childhood and adolescence.
Abstract Objective To evaluate the rate of depressive symptomatology and possible underlying factors in adoptive mothers during the transition to motherhood. Design Cohort survey. Setting General ...Community. Participants Thirty-nine adoptive mothers of reproductive age registered with international adoption agencies. Interventions All women completed the Edinburgh Postnatal Depression Scale (EPDS), the Beck Depression Inventory (BDI), and the Brief Symptom Inventory (BSI) before and 6 weeks after the adoption. Main outcome measures Responses were compared between the study group and published findings for biological mothers in the general population, and within the study group, before and after adoption. Results Symptoms of depression were found in 15.4% of the study group. This rate was similar to that for postpartum depression in the general population, and lower than the rate recorded in the study group before adoption (25.6%). All women with symptoms of depression after the adoption had also shown evidence of depressive features before the adoption. Similar findings were noted for other psychopathologies as well. Conclusion Adopting a child does not cause new-onset, reactive depression among adoptive mothers. It may even lead to a decrease in depressive features, perhaps in response to relief from other adjustment difficulties.
The 22q11.2 deletion syndrome (22q11.2DS) is the most common hemizygous deletion syndrome in humans. In addition to a wide range of physical abnormalities 22q11.2DS subjects show high prevalence of ...several psychiatric disorders. In our previous study we showed that the low-activity allele (158Met) of the COMT gene is a risk factor for attention deficit hyperactivity disorder (ADHD) and obsessive–compulsive disorder (OCD) in 22q11.2DS individuals. In the present study we have genotyped fifty-five 22q11.2DS individuals and 95 of their parents for eight SNPs in and around the COMT gene. A haplotype composed of three SNPs rs2097603; rs4680 (158Val/Met); rs165599 representing the major linkage disequilibrium blocks in COMT and previously implicated in functional variation, was found to be associated with ADHD and OCD in 22q11.2DS individuals. A common risk haplotype (G-A-A) was significantly associated with both ADHD (OR 3.13, χ2=4.38, p=0.036) and OCD (OR 4.00, χ2=6.41, p=0.011) in 22q11.2DS individuals. Interestingly, the same haplotype was recently found to be associated with efficient prefrontal performance in the general population. The risk haplotype was not found to be associated with IQ scores in our 22q11.2DS sample. Parental origin of the deletion did not affect the susceptibility to ADHD and OCD in the 22q11.2DS subjects. This study demonstrated the association of a particular COMT haplotype with susceptibility to both ADHD and OCD in 22q11.2DS and supports the hypothesis that COMT gene variations contribute to genetic predisposition to psychiatric disorders in the general population.
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