1. Becker KG, Schultz ST. {{Similarities in features of autism and asthma and a possible link to acetaminophen use}}. {Med Hypotheses}. Jan;74(1):7-11.
Autism and autism spectrum disorders are enigmatic conditions that have their origins in the interaction of genes and environmental factors. In this hypothesis, genes statistically associated with autism are emphasized to be important in inflammation and in innate immune pathways, including pathways for susceptibility to asthma. The role of acetaminophen (paracetamol) in an increased risk for asthma is described and a possible similar link to an increased risk for autism is suggested.
2. Blatt J, Deal AM, Mesibov G. {{Autism in children and adolescents with cancer}}. {Pediatr Blood Cancer}. Jan;54(1):144-7.
BACKGROUND: The causes of autistic disorders (AD) are not known. Abnormalities of tumor suppressor genes have suggested that these genes may be important to the development of autism in some cases, and result in an increased risk of developing cancer or other neoplasms. We explore possible associations between AD and childhood cancer. PROCEDURE: We reviewed our institutional pediatric cancer database for all new cancer diagnoses 1997-2007. Medical records from patients older than 2 years at last visit were reviewed for a diagnosis of AD. The prevalence of AD was estimated for neoplasms overall and for specific tumor types, and compared with that in the general pediatric population. RESULTS: Of 702 eligible patients, 7 (1%; 95% CI: (0.4%, 2.04%)) were labeled as AD, not different than the prevalence of AD in North Carolina’s general population (0.65%, P = 0.35). Cancer diagnoses for these 7 children were acute lymphoblastic leukemia (n = 1), acute nonlymphocytic leukemia (n = 2), non-Hodgkin lymphoma (n = 1), Hodgkin Disease (n = 1), brain tumor (n = 1), osteogenic sarcoma (n = 1). CONCLUSIONS: These data do not suggest that there is a high concordance between AD and childhood cancer. However, studies of large rigorously characterized AD cohorts will be needed to definitively address this issue.
3. Chen AY, Kim SE, Houtrow AJ, Newacheck PW. {{Prevalence of obesity among children with chronic conditions}}. {Obesity (Silver Spring)}. Jan;18(1):210-3.
New evidence suggests that children with chronic conditions may be predisposed to overweight and obesity. This study provides prevalence estimate of obesity for children and adolescents with select chronic conditions. We analyzed reported height and weight and the corresponding BMI from 46,707 subjects aged 10-17 years collected by the National Survey of Children’s Health (NSCH-2003). Our main outcome measure was the prevalence of obesity (defined as >/=95th percentile of the sex-specific BMI for age growth charts), adjusted for underlying demographic and socioeconomic factors. We found that the prevalence of obesity among children 10-17 years of age without a chronic condition was 12.2% (95% confidence interval (CI) 11.5-13.0); the prevalence of obesity for children with asthma was 19.7% (19.5-19.9); with a hearing/vision condition was 18.4% (18.2-18.5); with learning disability was 19.3% (19.2-19.4); with autism was 23.4% (23.2-23.6); and with attention-deficit/hyperactivity disorder was 18.9% (18.7-19.0). Our findings suggest that children 10-17 years of age with select chronic conditions were at increased risk for obesity compared to their counterparts without a chronic condition.
4. Dhir A. {{Novel discoveries in understanding the complexities of epilepsy and major depression}}. {Expert Opin Ther Targets}. Jan;14(1):109-15.
The 39th Annual meeting of the Society for Neuroscience was held in Chicago, Illinois, USA from 17 to 21 October, 2009. The conference was attended by more than 33,000 delegates from across the globe including scientists from both basic and clinical settings. Co-incidentally, this year, the scientific community is commemorating the 200th anniversary of the birth of the famous English naturalist and biologist, Charles Darwin, who described the theory of natural selection. Keeping its traditions, the congress discussed various new advances in the area of neuroscience. The topics were divided into symposia, mini-symposia, nano-symposia, special lectures and poster sessions. The main areas of discussion were novel discoveries in Alzheimer’s, Parkinson’s, drug addiction, autism, epilepsy and major depression. According to the WHO, neurological disorders are one of the greatest threats to public health. There are many unknown and challenging facts in the field of neuroscience that needs exploration. It is unfortunate that despite the availability of various drugs for treating these disorders, a sizeable population still do not achieve complete remission. Therefore, organizing such events and addressing the latest developments may open new treatment vistas for patients suffering from these disorders. The present review discusses some of the outcomes of the deliberations in the field of epilepsy and major depression.
5. Ecker C, Rocha-Rego V, Johnston P, Mourao-Miranda J, Marquand A, Daly EM, Brammer MJ, Murphy C, Murphy DG. {{Investigating the predictive value of whole-brain structural MR scans in autism: a pattern classification approach}}. {Neuroimage}. Jan 1;49(1):44-56.
Autistic spectrum disorder (ASD) is accompanied by subtle and spatially distributed differences in brain anatomy that are difficult to detect using conventional mass-univariate methods (e.g., VBM). These require correction for multiple comparisons and hence need relatively large samples to attain sufficient statistical power. Reports of neuroanatomical differences from relatively small studies are thus highly variable. Also, VBM does not provide predictive value, limiting its diagnostic value. Here, we examined neuroanatomical networks implicated in ASD using a whole-brain classification approach employing a support vector machine (SVM) and investigated the predictive value of structural MRI scans in adults with ASD. Subsequently, results were compared between SVM and VBM. We included 44 male adults; 22 diagnosed with ASD using « gold-standard » research interviews and 22 healthy matched controls. SVM identified spatially distributed networks discriminating between ASD and controls. These included the limbic, frontal-striatal, fronto-temporal, fronto-parietal and cerebellar systems. SVM applied to gray matter scans correctly classified ASD individuals at a specificity of 86.0% and a sensitivity of 88.0%. Cases (68.0%) were correctly classified using white matter anatomy. The distance from the separating hyperplane (i.e., the test margin) was significantly related to current symptom severity. In contrast, VBM revealed few significant between-group differences at conventional levels of statistical stringency. We therefore suggest that SVM can detect subtle and spatially distributed differences in brain networks between adults with ASD and controls. Also, these differences provide significant predictive power for group membership, which is related to symptom severity.
6. Ekinci O, Arman AR, Isik U, Bez Y, Berkem M. {{EEG abnormalities and epilepsy in autistic spectrum disorders: Clinical and familial correlates}}. {Epilepsy Behav}. 2009 Dec 28.
Our aim was to examine the characteristics of EEG findings and epilepsy in autistic spectrum disorders (ASD) and the associated clinical and familial risk factors. Fifty-seven children (86% male) with ASD, mean age 82+/-36.2months, were included in the study. Thirty-nine (68.4%) children had the diagnosis of autism, 15 (26.3%) had Pervasive Developmental Disorder Not Otherwise Specified, and 3 (5.3%) had high-functioning autism. One hour of sleep and/or awake EEG recordings was obtained for each child. All patients were evaluated with respect to clinical and familial characteristics and with the Childhood Autism Rating Scale, the Autism Behavior Checklist, and the Aberrant Behavior Checklist. The frequency of interictal epileptiform EEG abnormalities (IIEAs) was 24.6% (n=14), and the frequency of epilepsy was 14.2% (n=8). IIEAs were associated with a diagnosis of epilepsy (P=0.0001), Childhood Autism Rating Scale Activity scores (P=0.047), and a history of asthma and allergy (P=0.044). Epilepsy was associated with a family history of epilepsy (P=0.049) and psychiatric problems in the mother during pregnancy (P=0.0026). Future studies with larger samples will help to clarify the possible associations of epilepsy/IIEAs with asthma/allergy, hyperactivity, and familial factors in ASD.
7. Enstrom AM, Onore CE, Van de Water JA, Ashwood P. {{Differential monocyte responses to TLR ligands in children with autism spectrum disorders}}. {Brain Behav Immun}. Jan;24(1):64-71.
Autism spectrum disorders (ASD) are characterized by impairment in social interactions, communication deficits, and restricted repetitive interests and behaviors. Recent evidence has suggested that impairments of innate immunity may play an important role in ASD. To test this hypothesis, we isolated peripheral blood monocytes from 17 children with ASD and 16 age-matched typically developing (TD) controls and stimulated these cell cultures in vitro with distinct toll-like receptors (TLR) ligands: TLR 2 (lipoteichoic acid; LTA), TLR 3 (poly I:C), TLR 4 (lipopolysaccharide; LPS), TLR 5 (flagellin), and TLR 9 (CpG-B). Supernatants were harvested from the cell cultures and pro-inflammatory cytokine responses for IL-1beta, IL-6, IL-8, TNFalpha, MCP-1, and GM-CSF were determined by multiplex Luminex analysis. After in vitro challenge with TLR ligands, differential cytokine responses were observed in monocyte cultures from children with ASD compared with TD control children. In particular, there was a marked increase in pro-inflammatory IL-1beta, IL-6, and TNFalpha responses following TLR 2, and IL-1beta response following TLR 4 stimulation in monocyte cultures from children with ASD (p<0.04). Conversely, following TLR 9 stimulation there was a decrease in IL-1beta, IL-6, GM-CSF, and TNFalpha responses in monocyte cell cultures from children with ASD compared with controls (p<0.05). These data indicate that, monocyte cultures from children with ASD are more responsive to signaling via select TLRs. As monocytes are key regulators of the immune response, dysfunction in the response of these cells could result in long-term immune alterations in children with ASD that may lead to the development of adverse neuroimmune interactions and could play a role in the pathophysiology observed in ASD.
8. Farmer CA, Aman MG. {{Psychometric properties of the Children’s Scale of Hostility and Aggression: Reactive/Proactive (C-SHARP)}}. {Res Dev Disabil}. Jan-Feb;31(1):270-80.
Although often lacking « malice », aggression is fairly common in children with intellectual or developmental disability (I/DD). Despite this, there are no scales available that are appropriate for an in-depth analysis of aggressive behavior in this population. Such scales are needed for the study of aggressive behavior, which is a common target symptom in clinical trials. We assessed the reliability and validity of the Children’s Scale of Hostility and Aggression: Reactive/Proactive (C-SHARP), a new aggression scale created for children with I/DD. Data are presented from a survey of 365 children with I/DD aged 3-21 years. Interrater reliability was very high for the Problem Scale, which characterizes type of aggression. Reliability was lower but largely acceptable for the Provocation Scale, which assesses motivation. Validity of the Problem Scale was supported by expected differences in children with autism, Down syndrome, comorbid disruptive behavior disorders (DBDs) and ADHD. The Provocation Scale, which categorizes behavior as proactive or reactive, showed expected differences in children with DBD, but was less effective in those with ADHD. The C-SHARP appears to have fundamentally sound psychometric characteristics, although more research is needed.
9. Fava L, Strauss K. {{Multi-sensory rooms: comparing effects of the Snoezelen and the Stimulus Preference environment on the behavior of adults with profound mental retardation}}. {Res Dev Disabil}. Jan-Feb;31(1):160-71.
The present study examined whether Snoezelen and Stimulus Preference environments have differential effects on disruptive and pro-social behaviors in adults with profound mental retardation and autism. In N=27 adults these target behaviors were recorded for a total of 20 sessions using both multi-sensory rooms. Three comparison groups were created by diagnosis and motor respective linguistic abilities. Each client was exposed to only one multi-sensory room. Results showed that Snoezelen intervention decreased disruptive behaviors only in individuals with autism, while Stimulus Preference increased pro-social behaviors only in participants with profound mental retardation with co-occurring poor motor and linguistic abilities. Furthermore, several trend analyses of the improved behaviors were conducted throughout all sessions toward short and mid term effects of the multi-sensory room applications. These findings support both the prudence of using the Snoezelen room in individuals with developmental disabilities and the importance of using a Stimulus Preference assessment in multi-sensory environments in clients with profound mental retardation.
10. Freeth M, Ropar D, Chapman P, Mitchell P. {{The eye gaze direction of an observed person can bias perception, memory, and attention in adolescents with and without autism spectrum disorder}}. {J Exp Child Psychol}. Jan-Feb;105(1-2):20-37.
The reported experiments aimed to investigate whether a person and his or her gaze direction presented in the context of a naturalistic scene cause perception, memory, and attention to be biased in typically developing adolescents and high-functioning adolescents with autism spectrum disorder (ASD). A novel computerized image manipulation program presented a series of photographic scenes, each containing a person. The program enabled participants to laterally maneuver the scenes behind a static window, the borders of which partially occluded the scenes. The gaze direction of the person in the scenes spontaneously cued attention of both groups in the direction of gaze, affecting judgments of preference (Experiment 1a) and causing memory biases (Experiment 1b). Experiment 2 showed that the gaze direction of a person cues visual search accurately to the exact location of gaze in both groups. These findings suggest that biases in preference, memory, and attention are caused by another person’s gaze direction when viewed in a complex scene in adolescents with and without ASD.
11. Freitag CM, Agelopoulos K, Huy E, Rothermundt M, Krakowitzky P, Meyer J, Deckert J, von Gontard A, Hohoff C. {{Adenosine A(2A) receptor gene (ADORA2A) variants may increase autistic symptoms and anxiety in autism spectrum disorder}}. {Eur Child Adolesc Psychiatry}. Jan;19(1):67-74.
Autism spectrum disorders (ASDs) are heterogeneous disorders presenting with increased rates of anxiety. The adenosine A(2A) receptor gene (ADORA2A) is associated with panic disorder and is located on chromosome 22q11.23. Its gene product, the adenosine A(2A) receptor, is strongly expressed in the caudate nucleus, which also is involved in ASD. As autistic symptoms are increased in individuals with 22q11.2 deletion syndrome, and large 22q11.2 deletions and duplications have been observed in ASD individuals, in this study, 98 individuals with ASD and 234 control individuals were genotyped for eight single-nucleotide polymorphisms in ADORA2A. Nominal association with the disorder was observed for rs2236624-CC, and phenotypic variability in ASD symptoms was influenced by rs3761422, rs5751876 and rs35320474. In addition, association of ADORA2A variants with anxiety was replicated for individuals with ASD. Findings point toward a possible mediating role of ADORA2A variants on phenotypic expression in ASD that need to be replicated in a larger sample.
12. Genuis SJ, Bouchard TP. {{Celiac disease presenting as autism}}. {J Child Neurol}. Jan;25(1):114-9.
Gluten-restricted diets have become increasingly popular among parents seeking treatment for children diagnosed with autism. Some of the reported response to celiac diets in children with autism may be related to amelioration of nutritional deficiency resulting from undiagnosed gluten sensitivity and consequent malabsorption. A case is presented of a 5-year-old boy diagnosed with severe autism at a specialty clinic for autistic spectrum disorders. After initial investigation suggested underlying celiac disease and varied nutrient deficiencies, a gluten-free diet was instituted along with dietary and supplemental measures to secure nutritional sufficiency. The patient’s gastrointestinal symptoms rapidly resolved, and signs and symptoms suggestive of autism progressively abated. This case is an example of a common malabsorption syndrome associated with central nervous system dysfunction and suggests that in some contexts, nutritional deficiency may be a determinant of developmental delay. It is recommended that all children with neurodevelopmental problems be assessed for nutritional deficiency and malabsorption syndromes.
13. Greimel E, Schulte-Ruther M, Kircher T, Kamp-Becker I, Remschmidt H, Fink GR, Herpertz-Dahlmann B, Konrad K. {{Neural mechanisms of empathy in adolescents with autism spectrum disorder and their fathers}}. {Neuroimage}. Jan 1;49(1):1055-65.
A deficit in empathy has been repeatedly described in individuals with autism spectrum disorder (ASD) and also, albeit less markedly, in their unaffected relatives. Here, we aimed to investigate the neural mechanisms of empathy in ASD, and to explore familial contributions to empathy correlates. Using functional magnetic resonance imaging, 15 boys with ASD, 11 fathers of adolescents with ASD, and two control groups comparable for age and IQ (n=15 typically developing boys and their fathers (n=9)) were investigated during an empathy task. Emotional faces were presented and participants were either asked to infer the emotional state from the face (other-task) or to judge their own emotional response to the face (self-task). When attributing emotions to self and other, the ASD group showed diminished fusiform gyrus activation compared to controls. Neural activity in the fusiform gyrus was inversely related to social deficits in ASD subjects. Moreover, when ASD subjects inferred their own emotional response to faces, they showed less congruent reactions and inferior frontal gyrus activity was decreased. Although fathers of ASD children scored higher on a self-rating scale for autistic symptoms compared to control fathers, their task performance was unimpaired. However, neurally, fathers of affected children also showed reduced fusiform gyrus activation when inferring others’ emotions. Shared abnormalities in fusiform gyrus activation in affected adolescents and first-degree relatives suggest that this dysfunction constitutes a fundamental deviation in ASD. Moreover, the findings provide evidence that both aberrant neural face and mirroring mechanisms are implicated in empathy impairments in ASD.
14. Hagberg BS, Miniscalco C, Gillberg C. {{Clinic attenders with autism or attention-deficit/hyperactivity disorder: cognitive profile at school age and its relationship to preschool indicators of language delay}}. {Res Dev Disabil}. Jan-Feb;31(1):1-8.
Many studies have shown that children with autism spectrum disorders (ASD) and attention-deficit/hyperactivity disorder (ADHD) have had early indicators of language delay. The aim of the present study was to examine the cognitive profile of school age children referred to a specialist clinic for ASD, ADHD, or both, and relate this profile specifically to the age at which these children were first flagged up (or not) as suspected from language delay during the preschool years. Forty clinic children with ASD, ADHD, or the combination of the two (without clinical suspicion of learning disability) were assessed cognitively and as regards language development and language function at a mean age of 7.3 years. They were contrasted with a group of 21 children from the community who had been flagged at 2.5 years as suspected of language delay, and who had been followed up neuropsyhiatrically/neuropsychologically and in respect of language at a mean age of 7.9 years. Mean WISC-III full scale IQ was lower than population norms (in spite of the exclusion in both samples of cases with obvious learning disability) and similar across diagnostic groups (ASD and ADHD), and across settings (clinic and community). WISC-III Kaufman factor profiles separated the diagnostic groups as regards Perceptual Organisation. Early concern about language delay was a strong predictor of lower IQ and of distinguishing between « pure » cases of ASD and ADHD. School age clinic children who present with ASD and ADHD have a similar cognitive and early language development profile as do those children from the community, followed prospectively, who present with a suspicion of early preschool language delay and are shown at school age to suffer from ASD or ADHD. Concern about early language delay in the preschool age should prompt assessments (psychiatric and cognitively) for ASD and ADHD in a multidisciplinary setting much more often than is currently the case. In many cases early language delay, even in the absence of clear learning disability should be taken as a signal that – regardless of specific diagnosis – intellectual functioning might be in the low average range.
15. Haldeman-Englert CR, Chapman KA, Kruger H, Geiger EA, McDonald-McGinn DM, Rappaport E, Zackai EH, Spinner NB, Shaikh TH. {{A de novo 8.8-Mb deletion of 21q21.1-q21.3 in an autistic male with a complex rearrangement involving chromosomes 6, 10, and 21}}. {Am J Med Genet A}. Jan;152A(1):196-202.
We report here on a normal-appearing male with pervasive developmental disorder who was found to have a de novo, apparently balanced complex rearrangement involving chromosomes 6, 10, and 21: 46,XY,ins(21;10)(q11.2;p11.2p13)t(6;21)(p23;q11.2). Further analysis by high-density oligonucleotide microarray was performed, showing an 8.8-Mb heterozygous deletion at 21q21.1-q21.3. Interestingly, the deletion is distal to the translocation breakpoint on chromosome 21. The deletion involves 19 genes, including NCAM2 and GRIK1, both of which are associated with normal brain development and function, and have been considered as possible candidate genes in autism and other neurobehavioral disorders. This case underscores the utility of genomewide microarray analysis for the detection of copy number alterations in patients with apparently balanced complex rearrangements and abnormal phenotypes.
16. Johansson M, Gillberg C, Rastam M. {{Autism spectrum conditions in individuals with Mobius sequence, CHARGE syndrome and oculo-auriculo-vertebral spectrum: diagnostic aspects}}. {Res Dev Disabil}. Jan-Feb;31(1):9-24.
As part of multidisciplinary surveys of three Behavioural Phenotype Conditions (BPCs); Mobius sequence (Mobius), CHARGE syndrome (CHARGE) and oculo-auriculo-vertebral spectrum (OAV), autism spectrum conditions (ASCs) was diagnosed in 45%, 68% and 42% of the individuals, respectively. Diagnostic difficulties due to additional dysfunctions such as mental retardation (MR), impaired vision, reduced hearing and cranial nerve dysfunction, were experienced in all three BPC groups. The applicability of current autism diagnostic instruments, such as the Autism Diagnostic Interview-Revised (ADI-R), the Childhood Autism Rating Scale (CARS) and the Autistic Behaviour Checklist (ABC), in individuals with ASCs and Mobius/CHARGE/OAV was analysed. Use of an extensive battery of diagnostic instruments, including both observational schedules and parent interviews, and, if possible, independent judgements from two clinicians, is essential in the diagnostics of ASCs in these individuals. Further, in individuals who are deaf and blind the applicability of current autism diagnostic instruments is highly questionable.
17. Jones TB, Bandettini PA, Kenworthy L, Case LK, Milleville SC, Martin A, Birn RM. {{Sources of group differences in functional connectivity: an investigation applied to autism spectrum disorder}}. {Neuroimage}. Jan 1;49(1):401-14.
An increasing number of fMRI studies are using the correlation of low-frequency fluctuations between brain regions, believed to reflect synchronized variations in neuronal activity, to infer « functional connectivity ». In studies of autism spectrum disorder (ASD), decreases in this measure of connectivity have been found by focusing on the response to task modulation, by using only the rest periods, or by analyzing purely resting-state data. This difference in connectivity, however, could result from a number of different mechanisms–differences in noise, task-related fluctuations, task performance, or spontaneous neuronal activity. In this study, we investigate the difference in functional connectivity between adolescents with high-functioning ASD and typically developing control subjects by examining the residual fluctuations occurring on top of the fMRI response to an overt verbal fluency task. We find decreased correlations of these residuals (a decreased « connectivity ») in ASD subjects. Furthermore, we find that this decrease was not due to task-related effects, block-to-block variations in task performance, or increased noise, and the difference was greatest when primarily rest periods are considered. These findings suggest that the estimate of disrupted functional connectivity in ASD is likely driven by differences in task-unrelated neuronal fluctuations.
18. Kinney DK, Barch DH, Chayka B, Napoleon S, Munir KM. {{Environmental risk factors for autism: do they help cause de novo genetic mutations that contribute to the disorder?}}. {Med Hypotheses}. Jan;74(1):102-6.
Recent research has discovered that a number of genetic risk factors for autism are de novo mutations. Advanced parental age at the time of conception is associated with increased risk for both autism and de novo mutations. We investigated the hypothesis that other environmental factors associated with increased risk for autism might also be mutagenic and contribute to autism by causing de novo mutations. A survey of the research literature identified 9 environmental factors for which increased pre-conceptual exposure appears to be associated with increased risk for autism. Five of these factors–mercury, cadmium, nickel, trichloroethylene, and vinyl chloride–are established mutagens. Another four–including residence in regions that are urbanized, located at higher latitudes, or experience high levels of precipitation–are associated with decreased sun exposure and increased risk for vitamin D deficiency. Vitamin D plays important roles in repairing DNA damage and protecting against oxidative stress–a key cause of DNA damage. Factors associated with vitamin D deficiency will thus contribute to higher mutation rates and impaired repair of DNA. We note how de novo mutations may also help explain why the concordance rate for autism is so markedly higher in monozygotic than dizygotic twins. De novo mutations may also explain in part why the prevalence of autism is so remarkably high, given the evidence for a strong role of genetic factors and the low fertility of individuals with autism–and resultant selection pressure against autism susceptibility genes. These several lines of evidence provide support for the hypothesis, and warrant new research approaches–which we suggest–to address limitations in existing studies. The hypothesis has implications for understanding possible etiologic roles of de novo mutations in autism, and it suggests possible approaches to primary prevention of the disorder, such as addressing widespread vitamin D deficiency and exposure to known mutagens.
19. Kirby RS, Lane JB, Childers J, Skinner SA, Annese F, Barrish JO, Glaze DG, Macleod P, Percy AK. {{Longevity in Rett syndrome: analysis of the North American Database}}. {J Pediatr}. Jan;156(1):135-8 e1.
OBJECTIVE: To determine longevity in Rett syndrome (RTT) from a large cohort. STUDY DESIGN: The North American RTT Database allows the examination of longevity in a large cohort of individuals with RTT from the United States and Canada. This database contains information on 1928 individuals, 85.5% with typical RTT, 13.4% with atypical RTT, and 1.1% with a mutation in the methyl-CpG-binding protein 2 gene (MECP2) but not RTT. Kaplan-Meier analyses were performed to assess longevity. RESULTS: Earlier decennial cohorts exhibited better survival than recent cohorts, with most participants surviving into middle age. Comparing overall survival in persons with typical RTT and atypical RTT revealed greater mortality in typical RTT across the observed lifespan (P < .0001). Comparing survival in persons with RTT and identified MECP2 mutations and persons with unknown MECP2 status demonstrated greater mortality in the latter group (P < .0001, log-rank test). CONCLUSIONS: This analysis provides strong evidence for significant longevity in RTT and indicates the need for careful planning for long-term care of these women. The disproportionately greater survival seen in earlier time periods and in persons with atypical RTT may be attributed to more severely affected individuals dying before diagnosis in the former and to greater numbers with milder variants (ie, preserved speech and delayed onset) in the latter.
20. Levav-Rabkin T, Melamed O, Clarke G, Farber M, Cryan JF, Dinan TG, Grossman Y, Golan HM. {{A Sensitive Period of Mice Inhibitory System to Neonatal GABA Enhancement by Vigabatrin is Brain Region Dependent}}. {Neuropsychopharmacology}. 2009 Dec 30.
Neurodevelopmental disorders, such as schizophrenia and autism, have been associated with disturbances of the GABAergic system in the brain. We examined immediate and long-lasting influences of exposure to the GABA-potentiating drug vigabatrin (GVG) on the GABAergic system in the hippocampus and cerebral cortex, before and during the developmental switch in GABA function (postnatal days P1-7 and P4-14). GVG induced a transient elevation of GABA levels. A feedback response to GABA enhancement was evident by a short-term decrease in glutamate decarboxylase (GAD) 65 and 67 levels. However, the number of GAD65/67-immunoreactive (IR) cells was greater in 2-week-old GVG-treated mice. A long-term increase in GAD65 and GAD67 levels was dependent on brain region and treatment period. Vesicular GABA transporter was insensitive to GVG. The overall effect of GVG on the Cl(-) co-transporters NKCC1 and KCC2 was an enhancement of their synthesis, which was dependent on the treatment period and brain region studied. In addition, a short-term increase was followed by a long-term decrease in KCC2 oligomerization in the cell membrane of P4-14 hippocampi and cerebral cortices. Analysis of the Ca(2+) binding proteins expressed in subpopulations of GABAergic cells, parvalbumin and calbindin, showed region-specific effects of GVG during P4-14 on parvalbumin-IR cell density. Moreover, calbindin levels were elevated in GVG mice compared to controls during this period. Cumulatively, these results suggest a particular susceptibility of the hippocampus to GVG when exposed during days P4-14. In conclusion, our studies have identified modifications of key components in the inhibitory system during a critical developmental period. These findings provide novel insights into the deleterious consequences observed in children following prenatal and neonatal exposure to GABA-potentiating drugs.Neuropsychopharmacology advance online publication, 30 December 2009; doi:10.1038/npp.2009.219.
21. Marshall V, Long BC. {{Coping processes as revealed in the stories of mothers of children with autism}}. {Qual Health Res}. Jan;20(1):105-16.
Copious research evidence identifies the many stressors faced by mothers of children with autism. The aim of this study was to examine the ways in which coping is revealed in the content and structure of stories told by five mothers of children with autism. Narrative data were analyzed using both holistic-form and categorical-content approaches. Manifestations of coping were revealed in the macrostructures of stories. Cognitive coping strategies were particularly apparent in the life stories, which tended to focus on the emotional and cognitive journeys of the storytellers. Stories of discrete coping episodes added information about behavioral coping strategies employed in specific situations. Analysis of form, particularly of the structure of the life stories, yielded strategies the mothers employed to make meaning of autism in their lives.
22. Momoi T, Fujita E, Senoo H, Momoi M. {{Genetic factors and epigenetic factors for autism: endoplasmic reticulum stress and impaired synaptic function}}. {Cell Biol Int}. Jan;34(1):13-9.
The molecular pathogenesis of ASD (autism spectrum disorder), one of the heritable neurodevelopmental disorders, is not well understood, although over 15 autistic-susceptible gene loci have been extensively studied. A major issue is whether the proteins that these candidate genes encode are involved in general function and signal transduction. Several mutations in genes encoding synaptic adhesion molecules such as neuroligin, neurexin, CNTNAP (contactin-associated protein) and CADM1 (cell-adhesion molecule 1) found in ASD suggest that impaired synaptic function is the underlying pathogenesis. However, knockout mouse models of these mutations do not show all of the autism-related symptoms, suggesting that gain-of-function in addition to loss-of-function arising from these mutations may be associated with ASD pathogenesis. Another finding is that family members with a given mutation frequently do not manifest autistic symptoms, which possibly may be because of gender effects, dominance theory and environmental factors, including hormones and stress. Thus epigenetic factors complicate our understanding of the relationship between these mutated genes and ASD pathogenesis. We focus in the present review on findings that ER (endoplasmic reticulum) stress arising from these mutations causes a trafficking disorder of synaptic receptors, such as GABA (gamma-aminobutyric acid) B-receptors, and leads to their impaired synaptic function and signal transduction. In the present review we propose a hypothesis that ASD pathogenesis is linked not only to loss-of-function but also to gain-of-function, with an ER stress response to unfolded proteins under the influence of epigenetic factors.
23. Mulder EJ, Anderson GM, Kemperman RF, Oosterloo-Duinkerken A, Minderaa RB, Kema IP. {{Urinary excretion of 5-hydroxyindoleacetic acid, serotonin and 6-sulphatoxymelatonin in normoserotonemic and hyperserotonemic autistic individuals}}. {Neuropsychobiology}.61(1):27-32.
OBJECTIVE: A substantial proportion of individuals with autism have elevated levels of platelet serotonin (5-HT). We examined whether platelet hyperserotonemia is associated with increased gut 5-HT synthesis, altered 5-HT catabolism or altered melatonin production. METHODS: Urinary excretion of 5-hydroxyindoleacetic acid (5-HIAA) and 5-HT was compared in 10 normoserotonemic and 10 hyperserotonemic age-matched autistic individuals. The relationship of urinary 6-sulfatoxymelatonin (6-SM) excretion to platelet 5-HT, and to urinary 5-HT and 5-HIAA excretion, was also examined. RESULTS: In the hyperserotonemic group, significant increases at trend level in urinary excretion of 5-HIAA (p = 0.061) and 5-HT (p = 0.071) and a significant decrease for 6-SM were found (p = 0.027). The urinary 5-HIAA:5-HT ratio was similar in the normo- versus the hyperserotonemic groups. CONCLUSIONS: The catabolism of 5-HT does not differ in the groups, but greater exposure of the platelet to 5-HT cannot be ruled out as a cause of the platelet hyperserotonemia of autism. Although only trend level significant, the data point to a need for larger studies to examine more thoroughly the relationships between platelet hyperserotonemia, gut 5-HT synthesis and melatonin production.
24. Muskett T, Perkins M, Clegg J, Body R. {{Inflexibility as an interactional phenomenon: Using conversation analysis to re-examine a symptom of autism}}. {Clin Linguist Phon}. Jan;24(1):1-16.
Many accounts of autism spectrum disorder (ASD) imply that the condition’s behavioural ‘symptoms’ are direct reflexes of underlying deficits. In doing so, however, they invariably overlook the social contexts in which symptomatic behaviours occur and are identified as pathological. This study addresses this issue, using conversation analysis (CA) to examine the emergence of inflexibility, a behavioural trait symptomatic of ASD, during play involving an adult and diagnosed child. We argue that ‘inflexibility’ is the product of the child’s strategic attempts to retain control over the unfolding interaction, within a context where such attempts breach normative expectations about adult-child play. Furthermore, it demonstrates that the adult does not resist these attempts, on occasion even explicitly providing opportunity for subsequent inflexibility. This challenges the assumption that ASD’s behavioural profile solely represents the endpoint of underlying deficit, and demonstrates how ‘non-impaired’ speakers can be implicated in the manifestation of symptomatic behaviours.
25. New JJ, Schultz RT, Wolf J, Niehaus JL, Klin A, German TC, Scholl BJ. {{The scope of social attention deficits in autism: prioritized orienting to people and animals in static natural scenes}}. {Neuropsychologia}. Jan;48(1):51-9.
A central feature of autism spectrum disorder (ASD) is an impairment in ‘social attention’–the prioritized processing of socially relevant information, e.g. the eyes and face. Socially relevant stimuli are also preferentially attended in a broader categorical sense, however: observers orient preferentially to people and animals (compared to inanimate objects) in complex natural scenes. To measure the scope of social attention deficits in autism, observers viewed alternating versions of a natural scene on each trial, and had to ‘spot the difference’ between them–where the difference involved either an animate or inanimate object. Change detection performance was measured as an index of attentional prioritization. Individuals with ASD showed the same prioritized social attention for animate categories as did control participants. This could not be explained by lower level visual factors, since the effects disappeared when using blurred or inverted images. These results suggest that social attention – and its impairment in autism – may not be a unitary phenomenon: impairments in visual processing of specific social cues may occur despite intact categorical prioritization of social agents.
26. Odent M. {{Attention deficit hyperactivity disorder (ADHD) and obesity: two facets of the same disease?}}. {Med Hypotheses}. Jan;74(1):139-41.
We hypothesize that when two pathological conditions or personality traits share the same critical period for gene-environment interaction, we should expect further similarities, particularly from clinical and pathophysiological perspectives. They should therefore be considered as two facets of the same disease. To test this hypothesis we compiled data included in the Primal Health Research Database. This database (www.primalhealthresearch.com) is specialised in studies exploring correlations between what happens during the ‘primal period’ (fetal life, perinatal period and year following birth) and what happens later on in life in terms of health and personality traits. After mentioning the links between autism and anorexia nervosa, we explore more in depth the links between attention deficit hyperactivity disorder (ADHD) and obesity. We suggest from such examples that the nature of an environmental factor is often less important than the timing of the interaction. We conclude that the concept of gene expression, combined with Primal Health Research, might lead to reconsider conventional nosological classifications. Some previously well-defined pathological entities should be included into the framework of multifaceted diseases. On the other hand some existing pathological entities should be dismantled.
27. Palmieri L, Papaleo V, Porcelli V, Scarcia P, Gaita L, Sacco R, Hager J, Rousseau F, Curatolo P, Manzi B, Militerni R, Bravaccio C, Trillo S, Schneider C, Melmed R, Elia M, Lenti C, Saccani M, Pascucci T, Puglisi-Allegra S, Reichelt KL, Persico AM. {{Altered calcium homeostasis in autism-spectrum disorders: evidence from biochemical and genetic studies of the mitochondrial aspartate/glutamate carrier AGC1}}. {Mol Psychiatry}. Jan;15(1):38-52.
Autism is a severe developmental disorder, whose pathogenetic underpinnings are still largely unknown. Temporocortical gray matter from six matched patient-control pairs was used to perform post-mortem biochemical and genetic studies of the mitochondrial aspartate/glutamate carrier (AGC), which participates in the aspartate/malate reduced nicotinamide adenine dinucleotide shuttle and is physiologically activated by calcium (Ca(2+)). AGC transport rates were significantly higher in tissue homogenates from all six patients, including those with no history of seizures and with normal electroencephalograms prior to death. This increase was consistently blunted by the Ca(2+) chelator ethylene glycol tetraacetic acid; neocortical Ca(2+) levels were significantly higher in all six patients; no difference in AGC transport rates was found in isolated mitochondria from patients and controls following removal of the Ca(2+)-containing postmitochondrial supernatant. Expression of AGC1, the predominant AGC isoform in brain, and cytochrome c oxidase activity were both increased in autistic patients, indicating an activation of mitochondrial metabolism. Furthermore, oxidized mitochondrial proteins were markedly increased in four of the six patients. Variants of the AGC1-encoding SLC25A12 gene were neither correlated with AGC activation nor associated with autism-spectrum disorders in 309 simplex and 17 multiplex families, whereas some unaffected siblings may carry a protective gene variant. Therefore, excessive Ca(2+) levels are responsible for boosting AGC activity, mitochondrial metabolism and, to a more variable degree, oxidative stress in autistic brains. AGC and altered Ca(2+) homeostasis play a key interactive role in the cascade of signaling events leading to autism: their modulation could provide new preventive and therapeutic strategies.
28. Radua J, Phillips ML, Russell T, Lawrence N, Marshall N, Kalidindi S, El-Hage W, McDonald C, Giampietro V, Brammer MJ, David AS, Surguladze SA. {{Neural response to specific components of fearful faces in healthy and schizophrenic adults}}. {Neuroimage}. Jan 1;49(1):939-46.
Perception of fearful faces is associated with functional activation of cortico-limbic structures, which has been found altered in individuals with psychiatric disorders such as schizophrenia, autism and major depression. The objective of this study was to isolate the brain response to the features of standardized fearful faces by incorporating principal component analysis (PCA) into the analysis of neuroimaging data of healthy volunteers and individuals with schizophrenia. At the first stage, the visual characteristics of morphed fearful facial expressions (FEEST, Young et al., 2002) were classified with PCA, which produced seven orthogonal factors, with some of them related to emotionally salient facial features (eyes, mouth, brows) and others reflecting non-salient facial features. Subsequently, these PCA-based factors were included into the functional magnetic resonance imaging (fMRI) analysis of 63 healthy volunteers and 32 individuals with schizophrenia performing a task that involved implicit processing of FEEST stimuli. In healthy volunteers, significant neural response was found to visual characteristics of eyes, mouth or brows. In individuals with schizophrenia, PCA-based analysis enabled us to identify several significant clusters of activation that were not detected by the standard approach. These clusters were implicated in processing of visual and emotional information and were attributable to the perception of eyes and brows. PCA-based analysis could be useful in isolating brain response to salient facial features in psychiatric populations.
29. Ring RH, Schechter LE, Leonard SK, Dwyer JM, Platt BJ, Graf R, Grauer S, Pulicicchio C, Resnick L, Rahman Z, Sukoff Rizzo SJ, Luo B, Beyer CE, Logue SF, Marquis KL, Hughes ZA, Rosenzweig-Lipson S. {{Receptor and behavioral pharmacology of WAY-267464, a non-peptide oxytocin receptor agonist}}. {Neuropharmacology}. Jan;58(1):69-77.
The widely reported effects of oxytocin (OT) on CNS function has generated considerable interest in the therapeutic potential for targeting this system for a variety of human psychiatric diseases, including anxiety disorders, autism, schizophrenia, and depression. The utility of synthetic OT, as both a research tool and neurotherapeutic, is limited by the physiochemical properties inherent in most neuropeptides, notably its short half-life and poor blood brain barrier penetration. Subsequently, the discovery and development of non-peptide molecules that act as selective agonists of the oxytocin receptor (OTR) has been an important goal of the field. In this study, we report the receptor and behavioral pharmacology of WAY-267464, a first generation small-molecule OTR agonist. WAY-267464 is a high-affinity, potent, and selective (vs. V1a, V2, V1b) agonist of the OTR. In assays measuring both behavioral (four-plate test, elevated zero maze) and autonomic (stress-induced hyperthermia) parameters of the anxiety response, WAY-267464 exhibits an anxiolytic-like profile similar to OT. We have demonstrated that the anxiolytic-like profile of WAY-267464 is mediated through central sites of action. WAY-267464 also significantly reverses disruption in prepulse inhibition of the acoustic startle reflex induced by either MK-801 or amphetamine, similar to the antipsychotic-like effects previously reported for OT. Interestingly, in the mouse tail suspension test, WAY-267464 failed to produce changes in immobility that are seen with OT, raising the question of whether the antidepressant-like activity of OT may be working independently of the OTR. A selective OTR antagonist also failed to block the effects of OT on immobility in the TST. The significance of these findings for shaping the clinical development of OTR agonists is discussed.
30. Ruta L, Mugno D, D’Arrigo VG, Vitiello B, Mazzone L. {{Obsessive-compulsive traits in children and adolescents with Asperger syndrome}}. {Eur Child Adolesc Psychiatry}. Jan;19(1):17-24.
The objective of this study is to examine the occurrence and characteristic features of obsessive-compulsive behaviours in children and adolescents with Asperger syndrome (AS), with respect to a matched obsessive compulsive disorder group (OCD) and a typically developing control group (CG). For this purpose, 60 subjects (20 OCD; 18 AS; 22 CG), aged 8-15 years, matched for age, gender and IQ were compared. AS and OCD patients were diagnosed according to the DSM-IV-TR criteria. The Autism Diagnostic Interview-Revised and the Autism Diagnostic Observation Schedule were used to assist in the AS diagnosis; the WISC-R was administered to assess IQ. Obsessive and compulsive symptoms were evaluated by using the Children’s Yale-Brown Obsessive-Compulsive Scale (CY-BOCS). None of the AS children received a formal diagnosis of OCD. The AS group presented significantly higher frequencies of Hoarding obsessions and Repeating, Ordering and Hoarding compulsions compared to CG. The OCD group, in turn, reported significantly higher frequencies of Contamination and Aggressive obsessions and Checking compulsions compared to both the AS group and CG. As expected, the OCD group displayed a higher severity of symptoms (Moderate level of severity) than did the AS group (Mild level of severity). Finally, in our sample, neither the OCD group nor the AS group demonstrated a completely full awareness of the intrusive, unreasonable and distressing nature of symptoms, and the level of insight did not differ between the OCD group and CG, although an absence of insight was observed in the AS group. Children with AS showed higher frequencies of obsessive and compulsive symptoms than did typically developing children, and these features seem to cluster around Hoarding behaviours. Additionally, different patterns of symptoms emerged between the OCD and AS groups. Finally, in our sample, the level of insight was poor in both the OCD and the AS children. Further research should be conducted to better understand the characteristics of repetitive thoughts and behaviours in autism spectrum disorders, and to clarify the underlying neurobiological basis of these symptoms.
31. Sahyoun CP, Belliveau JW, Soulieres I, Schwartz S, Mody M. {{Neuroimaging of the functional and structural networks underlying visuospatial vs. linguistic reasoning in high-functioning autism}}. {Neuropsychologia}. Jan;48(1):86-95.
High-functioning individuals with autism have been found to favor visuospatial processing in the face of typically poor language abilities. We aimed to examine the neurobiological basis of this difference using functional magnetic resonance imaging and diffusion tensor imaging. We compared 12 children with high functioning autism (HFA) to 12 age- and IQ-matched typically developing controls (CTRL) on a pictorial reasoning paradigm under three conditions: V, requiring visuospatial processing; S, requiring language (i.e., semantic) processing; and V+S, a hybrid condition in which language use could facilitate visuospatial transformations. Activated areas in the brain were chosen as endpoints for probabilistic diffusion tractography to examine tract integrity (FA) within the structural network underlying the activation patterns. The two groups showed similar networks, with linguistic processing activating inferior frontal, superior and middle temporal, ventral visual, and temporo-parietal areas, whereas visuospatial processing activated occipital and inferior parietal cortices. However, HFA appeared to activate occipito-parietal and ventral temporal areas, whereas CTRL relied more on frontal and temporal language regions. The increased reliance on visuospatial abilities in HFA was supported by intact connections between the inferior parietal and the ventral temporal ROIs. In contrast, the inferior frontal region showed reduced connectivity to ventral temporal and middle temporal areas in this group, reflecting impaired activation of frontal language areas in autism. The HFA group’s engagement of posterior brain regions along with its weak connections to frontal language areas suggest support for a reliance on visual mediation in autism, even in tasks of higher cognition.
32. Souders MC, Mason TB, Valladares O, Bucan M, Levy SE, Mandell DS, Weaver TE, Pinto-Martin J. {{Sleep behaviors and sleep quality in children with autism spectrum disorders}}. {Sleep}. 2009 Dec 1;32(12):1566-78.
STUDY OBJECTIVES: (1) Compare sleep behaviors of children with autism spectrum disorders (ASD) with sleep behaviors of typically developing (TD) children using the Children’s Sleep Habits Questionnaire (CSHQ); (2) compare sleep quality–defined as mean activity, sleep latency, number of awakenings, sleep efficiency and total sleep time–of the cohort of children with ASD and TD, as measured by 10 nights of actigraphy; and (3) estimate the prevalence of sleep disturbances in the ASD and TD cohorts. DESIGN: Descriptive cross-sectional study. SETTING: The Children’s Hospital of Philadelphia. PARTICIPANTS: Randomly selected children from the Regional Autism Center. The ASD cohort of 59 children, aged 4 to 10 years, (26 with autism, 21 with pervasive developmental disorder-not otherwise specified [PDD-NOS], and 12 with Asperger disorder) were compared with 40 TD control subjects. MEASUREMENTS AND RESULTS: The CSHQ, sleep diaries, and 10 nights of actigraphy using the Sadeh algorithm of children with ASD and TD control subjects were compared. CSHQ showed 66.1% of parents of children with ASD (62.5% autism, 76.2% PDD-NOS, 58.3% Asperger disorder) and 45% of parents of the control subjects reported that their children had sleep problems. Actigraphic data showed that 66.7% of children with ASD (75% autism, 52.4% PDD-NOS, 75% Asperger disorder) and 45.9% of the control subjects had disturbed sleep. CONCLUSIONS: The prevalence estimate of 45% for mild sleep disturbances in the TD cohort highlights pediatric sleep debt as a public health problem of concern. The prevalence estimate of 66% for moderate sleep disturbances in the ASD cohort underscores the significant sleep problems that the families of these children face. The predominant sleep disorders in the ASD cohort were behavioral insomnia sleep-onset type and insomnia due to PDD.
33. Steinman KJ, Mostofsky SH, Denckla MB. {{Toward a narrower, more pragmatic view of developmental dyspraxia}}. {J Child Neurol}. Jan;25(1):71-81.
Apraxia traditionally refers to impaired ability to carry out skilled movements in the absence of fundamental sensorimotor, language, or general cognitive impairment sufficient to preclude them. The child neurology literature includes a much broader and varied usage of the term developmental dyspraxia. It has been used to describe a wide range of motor symptoms, including clumsiness and general coordination difficulties, in various developmental disorders (including autistic spectrum disorders, developmental language disorders, and perinatal stroke). We argue for the need to restrict use of the term developmental dyspraxia to describe impaired performance of skilled gestures, recognizing that, unlike acquired adult-onset apraxia, coexisting sensory and motor problems can also be present.
34. Tiemeier H, Lenroot RK, Greenstein DK, Tran L, Pierson R, Giedd JN. {{Cerebellum development during childhood and adolescence: a longitudinal morphometric MRI study}}. {Neuroimage}. Jan 1;49(1):63-70.
In addition to its well-established role in balance, coordination, and other motor skills, the cerebellum is increasingly recognized as a prominent contributor to a wide array of cognitive and emotional functions. Many of these capacities undergo dramatic changes during childhood and adolescence. However, accurate characterization of co-occurring anatomical changes has been hindered by lack of longitudinal data and methodologic challenges in quantifying subdivisions of the cerebellum. In this study we apply an innovative image analysis technique to quantify total cerebellar volume and 11 subdivisions (i.e. anterior, superior posterior, and inferior posterior lobes, corpus medullare, and three vermal regions) from anatomic brain MRI scans from 25 healthy females and 25 healthy males aged 5-24 years, each of whom was scanned at least three times at approximately 2-year intervals. Total cerebellum volume followed an inverted U shaped developmental trajectory peaking at age 11.8 years in females and 15.6 years in males. Cerebellar volume was 10% to 13% larger in males depending on the age of comparison and the sexual dimorphism remained significant after covarying for total brain volume. Subdivisions of the cerebellum had distinctive developmental trajectories with more phylogenetically recent regions maturing particularly late. The cerebellum’s unique protracted developmental trajectories, sexual dimorphism, preferential vulnerability to environmental influences, and frequent implication in childhood onset disorders such as autism and ADHD make it a prime target for pediatric neuroimaging investigations.
35. Verhoeven JS, De Cock P, Lagae L, Sunaert S. {{Neuroimaging of autism}}. {Neuroradiology}. Jan;52(1):3-14.
Neuroimaging studies done by means of magnetic resonance imaging (MRI) have provided important insights into the neurobiological basis for autism. The aim of this article is to review the current state of knowledge regarding brain abnormalities in autism. Results of structural MRI studies dealing with total brain volume, the volume of the cerebellum, caudate nucleus, thalamus, amygdala and the area of the corpus callosum are summarised. In the past 5 years also new MRI applications as functional MRI and diffusion tensor imaging brought considerable new insights in the pathophysiological mechanisms of autism. Dysfunctional activation in key areas of verbal and non-verbal communication, social interaction, and executive functions are revised. Finally, we also discuss white matter alterations in important communication pathways in the brain of autistic patients.
36. Wallace DC, Fan W. {{Energetics, epigenetics, mitochondrial genetics}}. {Mitochondrion}. Jan;10(1):12-31.
The epigenome has been hypothesized to provide the interface between the environment and the nuclear DNA (nDNA) genes. Key factors in the environment are the availability of calories and demands on the organism’s energetic capacity. Energy is funneled through glycolysis and mitochondrial oxidative phosphorylation (OXPHOS), the cellular bioenergetic systems. Since there are thousands of bioenergetic genes dispersed across the chromosomes and mitochondrial DNA (mtDNA), both cis and trans regulation of the nDNA genes is required. The bioenergetic systems convert environmental calories into ATP, acetyl-Coenzyme A (acetyl-CoA), s-adenosyl-methionine (SAM), and reduced NAD(+). When calories are abundant, ATP and acetyl-CoA phosphorylate and acetylate chromatin, opening the nDNA for transcription and replication. When calories are limiting, chromatin phosphorylation and acetylation are lost and gene expression is suppressed. DNA methylation via SAM can also be modulated by mitochondrial function. Phosphorylation and acetylation are also pivotal to regulating cellular signal transduction pathways. Therefore, bioenergetics provides the interface between the environment and the epigenome. Consistent with this conclusion, the clinical phenotypes of bioenergetic diseases are strikingly similar to those observed in epigenetic diseases (Angelman, Rett, Fragile X Syndromes, the laminopathies, cancer, etc.), and an increasing number of epigenetic diseases are being associated with mitochondrial dysfunction. This bioenergetic-epigenomic hypothesis has broad implications for the etiology, pathophysiology, and treatment of a wide range of common diseases.
37. Warren SF, Brady N, Sterling A, Fleming K, Marquis J. {{Maternal responsivity predicts language development in young children with fragile x syndrome}}. {Am J Intellect Dev Disabil}. Jan;115(1):54-75.
The relationship between early maternal responsivity and later child communication outcomes in young children with fragile X syndrome was investigated. Data were obtained from 55 mother-child dyads over a 36-month period. Performance data were obtained at each measurement point from video observations of four different contexts. These were coded for (a) child communication behaviors, (b) parent responsivity, and (c) behavior management behaviors. Results indicate that early maternal responsivity predicts the level of four important child language outcomes at 36 months of age after controlling for child developmental level and autism symptomology.
38. Williams EL, Casanova MF. {{Autism and dyslexia: a spectrum of cognitive styles as defined by minicolumnar morphometry}}. {Med Hypotheses}. Jan;74(1):59-62.
There is a continuum of cognitive styles amongst humans, defined by differences in minicolumnar numbers/width and arcuate/commissural white matter connectivities. Specifically, it is the connectivity within and between modular cortical circuits that defines conditions such as autism and developmental dyslexia. In autism, a model of local hyperconnectivity and long-range hypoconnectivity explains many of the behavioral and cognitive traits present in the condition, while the inverse arrangement of local hypoconnectivity and long-range hyperconnectivity in dyslexia sheds light on that condition as well. We propose that the cognitive styles present in autism and developmental dyslexia typify the extremes of a minicolumnar spectrum in humans.
39. Yavas G, Koyuturk M, Ozsoyoglu M, Gould MP, Laframboise T. {{Cokgen: a software for the identification of rare copy number variation from SNP microarrays}}. {Pac Symp Biocomput}.371-82.
Until fairly recently, it was believed that essentially all human cells harbor two copies of each locus in the autosomal genome. However, studies have now shown that there are segments of the genome that are polymorphic with regard to genomic copy number. These copy number variations (CNVs) have a role in various diseases such as Alzheimer disease, Crohn’s disease, autism and schizophrenia. In the effort to scan the entire genome for these gains and losses of DNA, single nucleotide polymorphism (SNP) arrays have emerged as an important tool. As such, CNV identification from SNP array data is attracting considerable attention as an algorithmic problem, and many methods have been published over the last few years. However, many of the existing model-based methods train their models based on common variations and are therefore less successful in the identification of rare CNVs, detection of which may be very important in personalized genomics applications. In this paper, we formulate CNV identification explicitly as an optimization problem with an objective function that is characterized by several adjustable parameters. These parameters can be configured based on the characteristics of the experimental platform and target application, so that the solution to the optimization problem is the most accurate set of CNV calls. Our method, termed COKGEN, efficiently solves this problem using a variant of the well-known heuristic simulated annealing. We apply COKGEN to data from hundreds of samples, and demonstrate its ability to detect known CNVs at a high level of sensitivity without sacrificing specificity, not only for common but also rare CNVs. Furthermore, we show that it performs better than other publicly-available methods. The configurability of COKGEN, its computational efficiency, and its accuracy in calling rare CNVs make it particularly useful for personalized genomics applications. COKGEN is implemented as an R package and is freely available at http://mendel.gene.cwru.edu/laframboiselab/software.php.
40. Zhang X, Cui N, Wu Z, Su J, Tadepalli JS, Sekizar S, Jiang C. {{Intrinsic membrane properties of locus coeruleus neuronsin Mecp2-null mice}}. {Am J Physiol Cell Physiol}. 2009 Dec 30.
Rett syndrome caused by mutations in Mecp2 gene shows abnormalities in autonomic functions in which brainstem norepinephrinergic systems play an important role. Here we present systematic comparisons of intrinsic membrane properties of locus coeruleus (LC) neurons between Mecp2( horizontal line /Y) and wild-type (WT) mice. Whole-cell current clamp was performed in brain slices of 3-4 week-old mice. Mecp2( horizontal line /Y) neurons showed stronger inward rectification and had shorter time constant than WT cells. The former was likely due to over-expression of Kir4.1 channel, and the latter was attributable to the smaller cell surface area. The action potential duration was prolonged in Mecp2( horizontal line /Y) cells with an extended rise time. This was associated with a significant reduction in the voltage-activated Na(+) current density. Following action potentials, over 60% Mecp2( horizontal line /Y) neurons displayed fast and medium afterhyperpolarizations (fAHP and mAHP), while nearly 90% WT neurons showed only mAHP. The mAHP amplitude was smaller in Mecp2( horizontal line /Y) neurons. The firing frequency was higher in neurons with mAHP, and the frequency variation was greater in cells with both fAHP and mAHP in Mecp2( horizontal line /Y) mice. Small but significant differences in spike frequency adaption and delayed excitation were found in Mecp2( horizontal line /Y) neurons. These results indicate that there are several electrophysiological abnormalities in LC neurons of Mecp2( horizontal line /Y) mice, which may contribute to the dysfunction of norepinephrine system in the central nervous system.
