http://www.jneurodevdisorders.com The latest research articles published by Journal of Neurodevelopmental Disorders 2013-05-10T00:00:00Z Background: From a young age the typical development of social functioning relies upon the allocation of attention to socially relevant information, which in turn allows experience at processing such information and thus enhances social cognition. As such, research has attempted to identify the developmental processes that are derailed in some neuro-developmental disorders that impact upon social functioning. Williams syndrome (WS) and autism are disorders of development that are characterized by atypical yet divergent social phenotypes and atypicalities of attention to people. Methods: We used eye tracking to explore how individuals with WS and autism attended to, and subsequently interpreted, an actor's eye gaze cue within a social scene. Images were presented for 3 seconds, initially with an instruction simply to look at the picture. The images were then shown again, with the participant asked to identify the object being looked at. Allocation of eye gaze in each condition was analyzed by analysis of variance and accuracy of identification was compared with t tests. Results: Participants with WS allocated more gaze time to face and eyes than their matched controls, both with and without being asked to identify the item being looked at; while participants with autism spent less time on face and eyes in both conditions. When cued to follow gaze, participants with WS increased gaze to the correct targets; those with autism looked more at the face and eyes but did not increase gaze to the correct targets, while continuing to look much more than their controls at implausible targets. Both groups identified fewer objects than their controls. Conclusions: The atypicalities found are likely to be entwined with the deficits shown in interpreting social cognitive cues from the images. WS and autism are characterized by atypicalities of social attention that impact upon socio-cognitive expertise, but, importantly, the type of atypicality is syndrome specific. http://www.jneurodevdisorders.com/content/5/1/13 Deborah Riby Peter Hancock Nicola Jones Mary Hanley Journal of Neurodevelopmental Disorders 2013, null:13 2013-05-10T00:00:00Z doi:10.1186/1866-1955-5-13 /content/figures/1866-1955-5-13-toc.gif Journal of Neurodevelopmental Disorders 1866-1955 ${item.volume} 13 2013-05-10T00:00:00Z PDF Background: Following from previous work suggesting that neurobehavioral features distinguish fragile X and idiopathic variants of autism, we investigated the relationships between four forms of repetitive behavior (stereotypy, self-injury, compulsivity, ritual behavior) and caudate nuclei volume in two groups: boys with fragile X syndrome, a subset of whom met criteria for autism, and a comparison group of boys with idiopathic autism. Methods: Bilateral caudate nuclei volumes were measured in boys aged 3 to 6 years with fragile X syndrome (n = 41), the subset of boys with fragile X syndrome and autism (n = 16), and boys with idiopathic autism (n = 30). Repetitive behaviors were measured using the Repetitive Behavior Scales-Revised. Results: For boys with idiopathic autism, left caudate volume was modestly associated with self-injury, while both compulsive and ritual behaviors showed significant positive correlations with bilateral caudate nuclei volumes, replicating previous results. For boys with fragile X syndrome, there was no such association between caudate volume and compulsive behaviors. However, we did identify significant positive correlations between self-injury total scores and number of self-injury topographies with bilateral caudate nuclei volumes. Conclusions: These findings suggest a specific role for the caudate nucleus in the early pathogenesis of self-injurious behavior associated with both idiopathic autism and fragile X syndrome. Results further indicate that the caudate may be differentially associated with compulsive behavior, highlighting the utility of isolating discrete brain-behavior associations within and between subtypes of autism spectrum disorder. http://www.jneurodevdisorders.com/content/5/1/12 Jason Wolff Heather Hazlett Amy Lightbody Allan Reiss Joseph Piven Journal of Neurodevelopmental Disorders 2013, null:12 2013-05-02T00:00:00Z doi:10.1186/1866-1955-5-12 /content/figures/1866-1955-5-12-toc.gif Journal of Neurodevelopmental Disorders 1866-1955 ${item.volume} 12 2013-05-02T00:00:00Z XML Background: Features of the Broad Autism Phenotype (BAP) are disproportionately prevalent in parents of a child with autism, highlighting familial patterns indicative of heritability. It is unclear, however, whether the presence of BAP features in both parents confers an increased liability for autism. The current study explores whether the presence of BAP features in two biological parents occurs more frequently in parents of a child with autism relative to comparison parents, whether parental pairs of a child with autism more commonly consist of one or two parents with BAP features, and whether these features are associated with severity of autism behaviors in probands.MethodSeven hundred eleven parents of a child with an autism spectrum disorder and 981 comparison parents completed the Broad Autism Phenotype Questionnaire. Parents of a child with autism also completed the Social Communication Questionnaire. Results: Although parental pairs of a child with autism were more likely than comparison parental pairs to have both parents characterized by the presence of the BAP, they more commonly consisted of a single parent with BAP features. The presence of the BAP in parents was associated with the severity of autism behaviors in probands, with the lowest severity occurring for children of parental pairs in which neither parent exhibited a BAP feature. Severity did not differ between children of two affected parents and those of just one. Conclusions: Collectively, these findings indicate that parental pairs of children with autism frequently consist of a single parent with BAP characteristics and suggest that future studies searching for implicated genes may benefit from a more narrow focus that identifies the transmitting parent. The evidence of intergenerational transmission reported here also provides further confirmation of the high heritability of autism that is unaccounted for by the contribution of de novo mutations currently emphasized in the field of autism genetics. http://www.jneurodevdisorders.com/content/5/1/11 Noah Sasson Kristen Lam Morgan Parlier Julie Daniels Joseph Piven Journal of Neurodevelopmental Disorders 2013, null:11 2013-05-02T00:00:00Z doi:10.1186/1866-1955-5-11 /content/figures/1866-1955-5-11-toc.gif Journal of Neurodevelopmental Disorders 1866-1955 ${item.volume} 11 2013-05-02T00:00:00Z XML Background: Death receptor 6 (DR6) is highly expressed in the human brain: it has been shown to induce axon pruning and neuron death via distinct caspases and to mediate axonal degeneration through binding to N-terminal beta amyloid precursor protein (N-APP). Methods: We investigated the expression of DR6 during prenatal and postnatal development in human hippocampus and temporal cortex by immunocytochemistry and Western blot analysis (118 normal human brain specimens; 9 to 41 gestational weeks; 1 day to 7 months postnatally; 3 to 91 years). To investigate the role of N-APP/DR6/caspase 6 pathway in the development of hippocampal Alzheimer's disease (AD)-associated pathology, we examined DR6 immunoreactivity (IR) in the developing hippocampus from patients with Down syndrome (DS; 48 brain specimens; 14 to 41 gestational weeks; 7 days to 8 months postnatally; 15 to 64 years) and in adults with DS and AD. Results: DR6 was highly expressed in human adult hippocampus and temporal cortex: we observed consistent similar temporal and spatial expression in both control and DS brain. Western blot analysis of total homogenates of temporal cortex and hippocampus showed developmental regulation of DR6. In the hippocampus, DR6 IR was first apparent in the stratum lacunosum-moleculare at 16 weeks of gestation, followed by stratum oriens, radiatum, pyramidale (CA1 to CA4) and molecular layer of the dentate gyrus between 21 and 23 gestational weeks, reaching a pattern similar to adult hippocampus around birth. Increased DR6 expression in dystrophic neurites was detected focally in a 15-year-old DS patient. Abnormal DR6 expression pattern, with increased expression within dystrophic neurites in and around amyloid plaques was observed in adult DS patients with widespread AD-associated neurodegeneration and was similar to the pattern observed in AD hippocampus. Double-labeling experiments demonstrated the colocalization, in dystrophic neurites, of DR6 with APP. We also observed colocalization with hyper-phosphorylated Tau and with caspase 6 (increased in hippocampus with AD pathology) in plaque-associated dystrophic neurites and within the white matter. Conclusions: These findings demonstrate a developmental regulation of DR6 in human hippocampus and suggest an abnormal activation of the N-APP/DR6/caspase 6 pathway, which can contribute to initiation or progression of hippocampal AD-associated pathology. http://www.jneurodevdisorders.com/content/5/1/10 Anand Iyer Jackelien van Scheppingen Jasper Anink Ivan Milenkovic Gabor Kovács Eleonora Aronica Journal of Neurodevelopmental Disorders 2013, null:10 2013-04-24T00:00:00Z doi:10.1186/1866-1955-5-10 /content/figures/1866-1955-5-10-toc.gif Journal of Neurodevelopmental Disorders 1866-1955 ${item.volume} 10 2013-04-24T00:00:00Z PDF Background: Minocycline is a tetracycline derivative that readily crosses the blood brain barrier and appears to have beneficial effects on neuroinflammation, microglial activation and neuroprotection in a variety of neurological disorders. Both microglial activation and neuroinflammation have been reported to be associated with autism. The study was designed to evaluate the effects of minocycline treatment on markers of neuroinflammation and autism symptomatology in children with autism and a history of developmental regression. Methods: Eleven children were enrolled in an open-label trial of six months of minocycline (1.4 mg/kg). Ten children completed the trial. Behavioral measures were collected and cerebrospinal fluid (CSF), serum and plasma were obtained before and at the end of minocycline treatment and were analyzed for markers of neuroinflammation. Results: Clinical improvements were negligible. The laboratory assays demonstrated significant changes in the expression profile of the truncated form of brain derived neurotrophic factor (BDNF) (P = 0.042) and hepatic growth factor (HGF) (P = 0.028) in CSF. In serum, the ratio of the truncated BDNF form and α-2 macroglobulin (α-2 M), was also significantly lower (P = 0.028) while the mature BDNF/α-2 M ratio revealed no difference following treatment. Only the chemokine CXCL8 (IL-8) was significantly different (P = 0.047) in serum while no significant changes were observed in CSF or serum in chemokines such as CCL2 (MCP-1) or cytokines such as TNF-α, CD40L, IL-6, IFN-γ and IL-1β when pre- and post-treatment levels of these proteins were compared. No significant pre- and post-treatment changes were seen in the profiles of plasma metalloproteinases, putative targets of the effects of minocycline. Conclusions: Changes in the pre- and post-treatment profiles of BDNF in CSF and blood, HGF in CSF and CXCL8 (IL-8) in serum, suggest that minocycline may have effects in the CNS by modulating the production of neurotrophic growth factors. However, in this small group of children, no clinical improvements were observed during or after the six months of minocycline administration.Trial registrationNCT00409747 http://www.jneurodevdisorders.com/content/5/1/9 Carlos Pardo Ashura Buckley Audrey Thurm Li-Ching Lee Arun Azhagiri David Neville Susan Swedo Journal of Neurodevelopmental Disorders 2013, null:9 2013-04-08T00:00:00Z doi:10.1186/1866-1955-5-9 /content/figures/1866-1955-5-9-toc.gif Journal of Neurodevelopmental Disorders 1866-1955 ${item.volume} 9 2013-04-08T00:00:00Z XML Background: Hypermethylation of the fragile X mental retardation 1 gene FMR1 results in decreased expression of FMR1 protein FMRP, which is the underlying cause of Fragile X syndrome – an incurable neurological disorder characterized by mental retardation, anxiety, epileptic episodes and autism. Disease-modifying therapies for Fragile X syndrome are thus aimed at treatments that increase the FMRP expression levels in the brain. We describe the development and characterization of two assays for simple and quantitative detection of FMRP protein.MethodAntibodies coupled to fluorophores that can be employed for time-resolved Förster’s resonance energy transfer were used for the development of homogeneous, one-step immunodetection. Purified recombinant human FMRP and patient cells were used as control samples for assay development. Results: The assays require small sample amounts, display high stability and reproducibility and can be used to quantify endogenous FMRP in human fibroblasts and peripheral blood mononuclear cells. Application of the assays to FXS patient cells showed that the methods can be used both for the characterization of clinical FXS patient samples as well as primary readouts in drug-discovery screens aimed at increasing endogenous FMRP levels in human cells. Conclusion: This study provides novel quantitative detection methods for FMRP in FXS patient cells. Importantly, due to the simplicity of the assay protocol, the method is suited to be used in screening applications to identify compounds or genetic interventions that result in increased FMRP levels in human cells. http://www.jneurodevdisorders.com/content/5/1/8 Gabi Schutzius Dorothee Bleckmann Sandra Kapps-Fouthier Francesco di Giorgio Bernd Gerhartz Andreas Weiss Journal of Neurodevelopmental Disorders 2013, null:8 2013-04-02T00:00:00Z doi:10.1186/1866-1955-5-8 /content/figures/1866-1955-5-8-toc.gif Journal of Neurodevelopmental Disorders 1866-1955 ${item.volume} 8 2013-04-02T00:00:00Z XML Background: People with Prader-Willi syndrome (PWS) demonstrate social dysfunction and increased risk of autism spectrum disorder, especially those with the maternal uniparental disomy (mUPD) versus paternal deletion genetic subtype. This study compared the neural processing of social (faces) and nonsocial stimuli, varying in emotional valence, across genetic subtypes in 24 adolescents and adults with PWS. Methods: Upright and inverted faces, and nonsocial objects with positive and negative emotional valence were presented to participants with PWS in an oddball paradigm with smiling faces serving as targets. Behavioral and event-related potential (ERP) data were recorded. Results: There were no genetic subtype group differences in accuracy, and all participants performed above chance level. ERP responses revealed genetic subtype differences in face versus object processing. In those with deletions, the face-specific posterior N170 response varied in size for face stimuli versus inverted faces versus nonsocial objects. Persons with mUPD generated N170 of smaller amplitude and showed no stimulus differentiation. Brain responses to emotional content did not vary by subtype. All participants elicited larger posterior and anterior late positive potential responses to positive objects than to negative objects. Emotion-related differences in response to faces were limited to inverted faces only in the form of larger anterior late positive potential amplitudes to negative emotions over the right hemisphere. Detection of the target smiling faces was evident in the increased amplitude of the frontal and central P3 responses but only for inverted smiling faces. Conclusion: Persons with the mUPD subtype of PWS may show atypical face versus object processes, yet both subtypes demonstrated potentially altered processing, attention to and/or recognition of faces and their expressions. http://www.jneurodevdisorders.com/content/5/1/7 Alexandra Key Dorita Jones Elisabeth Dykens Journal of Neurodevelopmental Disorders 2013, null:7 2013-03-27T00:00:00Z doi:10.1186/1866-1955-5-7 /content/figures/1866-1955-5-7-toc.gif Journal of Neurodevelopmental Disorders 1866-1955 ${item.volume} 7 2013-03-27T00:00:00Z XML Contributing reviewersThe editors of Journal of Neurodevelopmental Disorders would like to thank all of our reviewers who have contributed to the journal in volume 4 (2012). High quality and timely reviews are critical to the overall quality of the journal. We are committed to providing a unique and important outlet for scholarship regarding neurodevelopmental disorders and are indebted to the outstanding reviewers who have contributed their time over the last year in helping us to reach this goal. Joseph Piven Journal of Neurodevelopmental Disorders 2013, null:5 2013-03-21T00:00:00Z doi:10.1186/1866-1955-5-5 /content/figures/1866-1955-5-5-toc.gif Journal of Neurodevelopmental Disorders 1866-1955 ${item.volume} 5 2013-03-21T00:00:00Z XML Background: Maternal alcohol consumption is known to adversely affect fetal neurodevelopment. While it is known that alcohol dose and timing play a role in the cognitive and behavioral changes associated with prenatal alcohol exposure, it is unclear what developmental processes are disrupted that may lead to these phenotypes. Methods: Mice (n=6 per treatment per developmental time) were exposed to two acute doses of alcohol (5 g/kg) at neurodevelopmental times representing the human first, second, or third trimester equivalent. Mice were reared to adulthood and changes to their adult brain transcriptome were assessed using expression arrays. These were then categorized based on Gene Ontology annotations, canonical pathway associations, and relationships to interacting molecules. Results: The results suggest that ethanol disrupts biological processes that are actively occurring at the time of exposure. These include cell proliferation during trimester one, cell migration and differentiation during trimester two, and cellular communication and neurotransmission during trimester three. Further, although ethanol altered a distinct set of genes depending on developmental timing, many of these show interrelatedness and can be associated with one another via ‘hub’ molecules and pathways such as those related to huntingtin and brain-derived neurotrophic factor. Conclusions: These changes to brain gene expression represent a ‘molecular footprint’ of neurodevelopmental alcohol exposure that is long-lasting and correlates with active processes disrupted at the time of exposure. This study provides further support that there is no neurodevelopmental time when alcohol cannot adversely affect the developing brain. http://www.jneurodevdisorders.com/content/5/1/6 Morgan Kleiber Katarzyna Mantha Randa Stringer Shiva Singh Journal of Neurodevelopmental Disorders 2013, null:6 2013-03-13T00:00:00Z doi:10.1186/1866-1955-5-6 /content/figures/1866-1955-5-6-toc.gif Journal of Neurodevelopmental Disorders 1866-1955 ${item.volume} 6 2013-03-13T00:00:00Z XML Neurodevelopmental disorders are classified as diseases that cause abnormal functions of the brain or central nervous system. Children with neurodevelopmental disorders show impaired language and speech abilities, learning and memory damage, and poor motor skills. However, we still know very little about the molecular etiology of these disorders. Recent evidence implicates the bromodomain-containing proteins (BCPs) in the initiation and development of neurodevelopmental disorders. BCPs have a particular domain, the bromodomain (Brd), which was originally identified as specifically binding acetyl-lysine residues at the N-terminus of histone proteins in vitro and in vivo. Other domains of BCPs are responsible for binding partner proteins to form regulatory complexes. Once these complexes are assembled, BCPs alter chromosomal states and regulate gene expression. Some BCP complexes bind nucleosomes, are involved in basal transcription regulation, and influence the transcription of many genes. However, most BCPs are involved in targeting. For example, some BCPs function as a recruitment platform or scaffold through their Brds-binding targeting sites. Others are recruited to form a complex to bind the targeting sites of their partners. The regulation mediated by these proteins is especially critical during normal and abnormal development. Mutant BCPs or dysfunctional BCP-containing complexes are implicated in the initiation and development of neurodevelopmental disorders. However, the pathogenic molecular mechanisms are not fully understood. In this review, we focus on the roles of regulatory BCPs associated with neurodevelopmental disorders, including mental retardation, Fragile X syndrome (FRX), Williams syndrome (WS), Rett syndrome and Rubinstein-Taybi syndrome (RTS). A better understanding of the molecular pathogenesis, based upon the roles of BCPs, will lead to screening of targets for the treatment of neurodevelopmental disorders. http://www.jneurodevdisorders.com/content/5/1/4 Junlin Li Guifang Zhao Xiaocai Gao Journal of Neurodevelopmental Disorders 2013, null:4 2013-02-20T00:00:00Z doi:10.1186/1866-1955-5-4 /content/figures/1866-1955-5-4-toc.gif Journal of Neurodevelopmental Disorders 1866-1955 ${item.volume} 4 2013-02-20T00:00:00Z XML