Whole Genome Analysis of Dizygotic Twins With Autism Reveals Prevalent Transposon Insertion Within Neuronal Regulatory Elements: Potential Implications for Disease Etiology and Clinical Assessment.

Transposable elements (TEs) have been implicated in autism spectrum disorder (ASD). However, our understanding of their roles is far from complete. Herein, we explored de novo TE insertions (dnTEIs) and de novo variants (DNVs) across the genomes of dizygotic twins with ASD and their parents. The neuronal regulatory elements had a tendency to harbor dnTEIs that were shared between twins, but ASD-risk genes had dnTEIs that were unique to each twin. The dnTEIs were 4.6-fold enriched in enhancers that are active in embryonic stem cell (ESC)-neurons (p < 0.001), but DNVs were 1.5-fold enriched in active enhancers of astrocytes (p = 0.0051). Our findings suggest that dnTEIs and DNVs play a role in ASD etiology by disrupting enhancers of neurons and astrocytes.

Alternative splicing and gene co-expression network-based analysis of dizygotic twins with autism-spectrum disorder and their parents.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder with high heritability, however, understanding the complexity of the underlying genetic basis has proven to be a challenging task. We hypothesized that dissecting the aberrations in alternative splicing (AS) and their effects on expression networks might provide insight. Therefore, we performed AS and co-expression analyses of total RNA isolated from Peripheral Blood Mononuclear Cells (PBMCs) of two pairs of dizygotic (DZ) twins with non-syndromic autism and their parents. We identified 183 differential AS events in 146 genes, seven of them being Simons Foundation Autism Research Initiative (SFARI) Category 1-3 genes, three of which had previously been reported to be alternatively spliced in ASD post-mortem brains. Gene co-expression analysis identified 7 modules with 513 genes, 5 of which were SFARI Category 1 or Category 2 genes. Among differentially AS genes within the modules, ZNF322 and NR4A1 could be potentially interesting targets for further investigations.

Genetic imaging study with [Tc-99m] TRODAT-1 SPECT in adolescents with ADHD using OROS-methylphenidate.

AIM: To examine theeffects on the brain of 2-month treatment withamethylphenidate extended-release formulation (OROS-MPH) using [Tc-99m] TRODAT-1SPECT in a sample of treatment-naïve adolescents with Attention Deficit/Hyperactivity Disorder (ADHD). In addition, to assess whether risk alleles (homozygosity for 10-repeat allele at the DAT1 gene were associated with alterations in striatal DAT availability. METHODS: Twenty adolescents with ADHD underwent brain single-photon emission computed tomography (SPECT) scans with [Tc-99m] TRODAT-1 at baseline and two months after starting OROS-MPH treatment with dosages up to 1 mg/kg/day. Severity of illness was estimated using the Clinical Global Impression Scale (CGI-S) and DuPaul ADHD Rating Scale-Clinician version (ARS) before treatment,1 month and 2 months after initiating OROS-MPH treatment. RESULTS: Decreased DAT availability was found in both the right caudate (pretreatment DAT binding: 224.76 ±â€¯33.77, post-treatment DAT binding: 208.86 ±â€¯28.75, p = 0.02) and right putamen (pre-treatment DAT binding: 314.41 ±â€¯55.24, post-treatment DAT binding: 285.66 ±â€¯39.20, p = 0.05) in adolescents with ADHD receiving OROS-MPH treatment. Adolescents with ADHD who showed a robust response to OROS-MPH (n = 7) had significantly greater reduction of DAT density in the right putamen than adolescents who showed less robust response to OROS-MPH (n = 13) (p = 0.02). However, between-group differences by treatment responses were not related with DAT density in the right caudate. Risk alleles (homozygosity for the 10-repeat allele of DAT1 gene) in the DAT1 gene were not associated with alterations in striatal DAT availability. CONCLUSION: Two months of OROS-MPH treatment decreased DAT availability in both the right caudate and putamen. Adolescents with ADHD who showed a robust response to OROS-MPH had greater reduction of DAT density in the right putamen. However,our findings did not support an association between homozygosity for a 10-repeat allele in the DAT1 gene and DAT density, assessedusing[Tc-99m] TRODAT-1SPECT.

A Comparison of DSM-IV-TR and DSM-5 Diagnostic Classifications in the Clinical Diagnosis of Autistic Spectrum Disorder.

Aim of this study was to compare children diagnosed with Pervasive Developmental Disorder (PDD) according to DSM-IV-TR and DSM-5 diagnostic systems. One hundred fifty children aged between 3 and 15 years diagnosed with PDD by DSM-IV-TR were included. PDD symptoms were reviewed through psychiatric assessment based on DSM-IV-TR and DSM-5 criteria. Clinical severity was determined using Childhood Autism Rating Scale (CARS) and Autism Behavior Checklist (ABC). A statistically significant decrease (19.3 %) was detected in the diagnostic ratio with DSM-5. Age and symptom severity differed significantly between those who were and were not diagnosed with PDD using DSM-5. B4 criteria in DSM-5 was most common criterion. Results indicate that individuals diagnosed with PDD by DSM-IV-TR criteria may not be diagnosed using DSM-5 criteria.

Atomoxetine treatment may decrease striatal dopaminergic transporter availability after 8 weeks: pilot SPECT report of three cases.

Attention deficit/hyperactivity disorder is one of the most common neurodevelopmental disorders. The pathophysiology is thought to involve noradrenaline and dopamine. The role of dopamine transporter (DAT) was evaluated in imaging studies using mostly dopamine reuptake inhibitors. Atomoxetine is a selective noradrenaline reuptake inhibitor. Here we report the results of a pilot study conducted to evaluate changes in striatal DAT after 8 weeks of atomoxetine treatment. Our results suggest that 8 weeks of atomoxetine treatment may change striatal DAT bioavailability as measured via SPECT but that change was not correlated with genotype or clinical improvement.

Establishment of interdisciplinary child protection teams in Turkey 2002-2006: identifying the strongest link can make a difference!

OBJECTIVES: The University of Iowa Child Protection Program collaborated with Turkish professionals to develop a training program on child abuse and neglect during 2002-2006 with the goals of increasing professional awareness and number of multidisciplinary teams (MDT), regional collaborations, and assessed cases. This paper summarizes the 5-year outcome. METHODS: A team of instructors evaluated needs and held training activities in Turkey annually, and provided consultation when needed. Descriptive analysis was done via Excel and SPSS software. RESULTS: Eighteen training activities were held with 3,570 attendees. Over the study period, the number of MDTs increased from 4 to 14. The MDTs got involved in organizing training activities in their institutions and communities. The number of medical curriculum lectures taught by MDTs to medical students/residents, conferences organized by the MDTs, and lectures to non-medical professional audiences increased significantly (R(2)=91.4%, 83.8%, and 69.2%, respectively). The number of abuse cases assessed by the MDTs increased by five times compared to pre-training period. CONCLUSIONS: A culturally competent training program had a positive impact on professional attitudes and behaviors toward recognition and management of child abuse and neglect in Turkey. The need to partner with policy makers to revise current law in favor of a greater human services orientation became clear. PRACTICE IMPLICATIONS: Pioneers in developing countries may benefit from collaborating with culturally competent instructors from countries with more developed child protection systems to develop training programs so that professional development can improve recognition and management of child abuse and neglect.

[Neurocognitive features of the frontal lobe in parents of autistic children]. / Otistik çocuklarin ana babalarinda frontal loba özgü nörobilissel özellikler.

OBJECTIVE: The aim of this study was to examine the neurocognitive functions of the frontal lobe in parents of autistic children. METHOD: The study group included 64 parents of children (aged 4-18 years) diagnosed with autism, according to DSM-IV criteria, that were followed-up at the child and adolescent psychiatry outpatient clinic. Parents of children with Down syndrome (n = 60) were selected as the control group. We administered the Wisconsin Card Sorting Test (WCST), Stroop Test, and Wechsler Adult Intelligence Test (WAIS) to both groups in order to evaluate executive functions, attention, inhibition, and intelligence. RESULTS: Mothers of children with autism performed better than the control group mothers on the executive function measures of WCST. There were no group differences in Stroop Test measures of attention and inhibition, or in the verbal and performance intelligence subtests of WAIS. Fathers of children with severe autistic symptoms performed better on some WAIS subtests compared to other; however, there were no significant differences in IQ between the parents in both groups. CONCLUSION: The results suggest that parents of autistic children could display different cognitive styles, but we did not observe any distinctive cognitive profile pertaining to frontal lobe functions. The cognitive ability of parents of autistic children and its neurobiological basis should be further investigated.

Technetium-99m HMPAO brain SPECT in autistic children and their families.

The purpose of the study was to investigate perfusion patterns in autistic children (AC) and their families. Ten AC (9 boys, 1 girl; mean age: 6.9+/-1.7 years) with autistic disorder defined by DSM-III-R criteria, five age-matched children (3 boys, 2 girls) as a control group, and the immediate family members of eight AC (8 mothers, 8 fathers, 7 siblings; mean ages: 39+/-4 years, 36+/-5 years and 13+/-5 years, respectively) were included in the study. Age- and sex-matched control groups for both the parents and the siblings were also included in the study. Brain perfusion images were obtained 1 h after the intravenous injection of an adjusted dose of Tc-99m HMPAO to children and the adults. Visual and semiquantitative evaluations were performed. Hypoperfusion was seen in the right posterior parietal cortex in three AC, in bilateral parietal cortex in one AC, bilateral frontal cortex in two AC, left parietal and temporal cortex in one AC, and right parietal and temporal cortex in one AC. Asymmetric perfusion was observed in the caudate nucleus in four AC. In semiquantitative analyses, statistically significant hypoperfusion was found in the right inferior and superior frontal, left superior frontal, right parietal, right mesial temporal and right caudate nucleus. In parents of AC, significant hypoperfusion was noted in the right parietal and bilateral inferior frontal cortex. In siblings of AC, perfusion in the right frontal cortex, right nucleus caudate and left parietal cortex was significantly decreased. This preliminary study suggests the existence of regional brain perfusion alterations in frontal, temporal, and parietal cortex and in caudate nucleus in AC and in their first-degree family members.

Risperidone versus haloperidol in children and adolescents with AD : a randomized, controlled, double-blind trial.

OBJECTIVE: The aim of the study was to compare safety, efficacy and tolerability of risperidone with haloperidol in the treatment of Autistic Disorder (AD). METHOD: This study was designed as a double-blind, prospective, for a 12-week period. A total of 30 subjects, between the ages of 8 and 18 with AD based on DSM IV criteria, were included in the study. Behavioral Rating Scales were performed by the investigators and the parents. Safety assessment included vital signs, electrocardiogram, electroencephalogram, adverse events, laboratory tests, extrapyramidal symptoms and the side effects. Both treatments were applied in a once daily dosage regimen of 0.01-0.08 mg/kg/day. RESULTS: The reduction from baseline in Ritvo-Freeman Real Life Rating Scale (RF-RLRS), sensory motor (subscale I) and language (subscale V) scores were significant in risperidone group (P < 0.05). Compared to haloperidol, risperidone led to a significantly greater reduction in the Aberrant Behavior Checklist (ABC) and Turgay DSM-IV Pervasive Developmental Disorder (PDD) scale scores (P < 0.05 and P < 0.01). There was a greater increase of prolactin in the risperidone group, while alanine amino transferase (ALT) had further increased in the haloperidol group. Sensory motor behaviors (subscale I) and language at the end of the 12th week, RF-RLRS sensory motor and language subscale scores decreased in the risperidone group further than the other group (P < 0.05). CONCLUSIONS: Risperidone was found to be more effective than haloperidol in the treatment of behavioral symptoms, impulsivity, language skills, and impaired social relations in children with AD. These results demonstrated that both drugs were safe and well tolerated in the treatment of AD.

Comparison of long-term efficacy and safety of risperidone and haloperidol in children and adolescents with autistic disorder. An open label maintenance study.

BACKGROUND: The aim of the study was to investigate safety, efficacy and tolerability of risperidone in comparison with haloperidol in the long-term treatment of autistic disorder. METHODS: This was an open-label continuation study of the randomized, double-blind, controlled trial of risperidone and haloperidol study for 12 week in autistic children and adolescents. A total of 28 subjects between 8 and 18 ages with autistic disorder were enrolled to the open label phase of the study. Behavioral rating scales (Clinical Global Impression Scale [CGI-I], Ritvo-Freeman Real Life Rating Scale [RF-RLRS]), Aberrant Behavior Checklist [ABC], Turgay DSM-IV Pervasive Developmental Disorder Rating Scale [TPDDRS]) and safety assessment scales (Extrapyramidal Symptoms Rating Scale [ESRS], UKU-Side Effect Rating Scale) were performed at 12, 16, 20 and 24 weeks, following the 12 week double-blind phase. Risperidone and haloperidol treatments were applied with a once daily dosage regimen as 0.01-0.08 mg/kg/day. RESULTS: Risperidone led to a significant greater reduction on CGI scale. There was significant improvement on RF-RLRS sensory motor and language subscale and ABC scores in risperidone group. Weight gain was observed more frequently in the haloperidol group at week 24. CONCLUSIONS: These results demonstrate that risperidone is more efficacious and well tolerated than haloperidol in the long-term maintenance treatment of autistic disorder.

Effects of long-term methylphenidate treatment: a pilot follow-up clinical and SPECT study.

BACKGROUND: Although abnormalities in the regional cerebral blood flow (rCBF) responses to methylphenidate (MPH) treatment have been reported in children with attention deficit hyperactivity disorder (ADHD), there are few prospective longitudinal studies assessing the long-term effects of MPH and discontinuation effects after chronic treatment. METHODS: The authors studied ten drug-naive children (2 girls, 8 boys, mean age+/-S.D.=9.60+/-1.96) diagnosed with ADHD by the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) diagnostic criteria, using (99m)Tc-HMPAO-single photon emission computed tomography (SPECT). Patients were studied at baseline (visit 1), after 2 months of MPH treatment (visit 2) and after a drug-free period of 2 months following 12 months of MPH treatment (visit 3) at doses of 1 mg/kg/day. We evaluated SPECT data visually and semi-quantitatively. RESULTS: Two months of chronic MPH treatment resulted in visually detectable improvement in hypoperfusion in the right frontal cortex and all areas of temporal cortex with the exception of left lateral temporal cortex. This improvement was still detectable on visual evaluations of SPECT data after 2 months of treatment discontinuation. The treatment effects that were detected visually were not statistically significant in semi-quantitative analyses. CONCLUSIONS: Treatment effects of chronic MPH treatment may persist long after the discontinuation of the treatment.

Suspected child abuse among victims of home accidents being admitted to the emergency department: a prospective survey from Turkey.

OBJECTIVES: Association between home injuries and child abuse has received interest in Western countries. Inasmuch as it is now known that cultural differences may have an impact on child-rearing practices and the definition of maltreatment, we aimed to assess the suspected physical abuse in children presenting to the emergency department with home injuries and determine the risk factors associated with suspected child maltreatment in our region. METHOD: The study is prospective in design. The sample was composed of 87 children younger than 72 months with presenting histories of home accidents. Data were collected by interview with the parents and by application of various questionnaires and inventories to both children and their parents. RESULTS: Suspected physical abuse was identified in 16.1% of cases presenting with home injuries. The significant factors associated with suspected abuse were child's age younger than 12 months, having developmental delays in the social and self-care domains, younger paternal age, paternal alcohol abuse, marital discordancy, repeated history of home injuries, and requirement for radiological examination. CONCLUSION: A missed diagnosis of child abuse can result in repeated injury, cause severe morbidity, and even result in death. This research indicates the features of "victims of accidents" who require special attention to recognize suspected abuse at the emergency department. Cultural factors might also provide additional indications that might aid in determining the cases of child maltreatment.

Development and behavior of non-handicapped preterm children from a developing country.

BACKGROUND: There are many studies, mainly conducted in industrialized countries, concerning developmental and behavioral outcomes of preterm children. However, little is known about the outcomes of preterm children from developing countries. METHOD: Forty-three non-handicapped Turkish preterm children, 15 with very low birth weight and 28 with low birth weight at preschool age, as well as 36 term controls were compared on rates of developmental, emotional and behavioral impairments. Data were collected by review of hospital records and application of various questionnaires and inventories to both children and their parents. RESULTS: Preterm children had significant delays in general development and significant rise in somatic complaints with unknown medical etiologies. The very low birth weight group also had significant delay in language and cognitive development. Parents of the preterm children displayed significantly higher rates of democratic attitudes. Developmental outcome was significantly associated with birth weight and authoritarian parental attitudes where behavioral outcome was significantly influenced by birth weight. CONCLUSION: Presence of developmental delay is in accordance with existing data on the outcomes of preterm children from industrialized countries. An isolated increase in somatic complaints is an uncommon finding which might also be related to cultural factors.

Assessment of child neurology outpatients with headache, dizziness, and fainting.

Neurologic symptoms such as headache, vertigo, dizziness, and fainting can create a diagnostic problem in pediatric neurology practice because they are also the most common presenting symptoms of psychiatric disorders. Children, especially adolescents, who are often admitted with such autonomic symptoms, are frequently misdiagnosed. In this study, we aimed to investigate the psychiatric morbidity and comorbidity rate in children and adolescents presenting with neurologic symptoms such as headache, vertigo, and syncope. We investigated 31 children who presented with these symptoms. All children were evaluated for their medical history and had a physical and neurologic examination. We attempted to rule out a possible organic etiology. All patients received a complete laboratory examination (blood count, electroencephalography), pediatric cardiology and otorhinolaryngology consultations, and a caloric test. All patients were assessed according to Diagnostic and Statistical Manual of Mental Disorders-IV (DSM-IV) criteria. The majority of the patients (93.5%) received a psychiatric diagnosis according to the DSM-IV criteria. Most of these patients were adolescents and female. Psychosocial stressors such as academic problems, familial dysfunction, parental psychopathology, and child sexual abuse were associated with somatic symptoms. The results of this study demonstrated the importance of differential diagnosis and psychiatric comorbidity in a pediatric neurologic outpatient population. Treatment should be directed at biopsychosocial integrity, and a multidisciplinary treatment approach should be applied.

Technetium-99m HMPAO brain SPECT in children with attention deficit hyperactivity disorder.

Attention deficit hyperactivity disorder (ADHD) is a developmental, neurobehavioral syndrome with an onset in childhood. The aim of this study was to investigate the existence of regional perfusion changes in ADHD by means of Tc-99m HMPAO brain SPECT. Thirteen children with a diagnosis of ADHD and 7 healthy, age-matched controls were included in this study. Hypoperfusion was observed on the right temporal cortex in 9, and on the left temporal cortex in 3 children. The distribution of the lesions showed right lateral temporal cortex involvement in 3, right medial temporal cortex in 9 and left medial temporal cortex in 8 children. Asymmetric perfusion was seen on the caudate nucleus in 4, on the thalamus in 3 and on the frontal cortex in 6 children. There was a significant difference between children with ADHD and controls in right medial temporal cortex: cerebellum and right lateral temporal cortex: cerebellum ratios. Hypoperfusion in the right medial temporal cortex was significantly and inversely correlated with Du Paul teachers' questionnaire rating scale (r = -0.71, p = 0.006). It has been postulated that difficulty in self regulating response to stimuli in ADHD is mediated by underfunctioning of the orbital frontal cortex and subsequent connection to the limbic system. Decreased temporal cortex perfusion may dysfunction of the limbic system or the orbito-frontal-limbic axis.