1. Abdala AP, Dutschmann M, Bissonnette JM, Paton JF. {{Correction of respiratory disorders in a mouse model of Rett syndrome}}. {Proc Natl Acad Sci U S A} (Oct 4)
Rett syndrome (RTT) is an autism spectrum disorder caused by mutations in the X-linked gene that encodes the transcription factor methyl-CpG-binding protein 2 (MeCP2). A major debilitating phenotype in affected females is frequent apneas, and heterozygous Mecp2-deficient female mice mimic the human respiratory disorder. GABA defects have been demonstrated in the brainstem of Mecp2-deficient mice. Here, using an intact respiratory network, we show that apnea in RTT mice is characterized by excessive excitatory activity in expiratory cranial and spinal nerves. Augmenting GABA markedly improves the respiratory phenotype. In addition, a serotonin 1a receptor agonist that depresses expiratory neuron activity also reduces apnea, corrects the irregular breathing pattern, and prolongs survival in MeCP2 null males. Combining a GABA reuptake blocker with a serotonin 1a agonist in heterozygous females completely corrects their respiratory defects. The results indicate that GABA and serotonin 1a receptor activity are candidates for treatment of the respiratory disorders in Rett syndrome.
2. Barnea-Goraly N, Lotspeich LJ, Reiss AL. {{Similar white matter aberrations in children with autism and their unaffected siblings: a diffusion tensor imaging study using tract-based spatial statistics}}. {Arch Gen Psychiatry} (Oct);67(10):1052-1060.
CONTEXT: Autism is a neurobiological condition with a strong genetic component. Recent diffusion tensor imaging (DTI) studies have indicated that white matter structure is aberrant in autism. To date, white matter structure has not been assessed in family members of children with autism. OBJECTIVE: To determine whether white matter structure is aberrant in children with autism and their unaffected siblings compared with controls, and to test the hypothesis that white matter structure in autism is correlated with autism spectrum symptomatology. DESIGN: Cross-sectional, case-control, voxel-based, whole-brain DTI analysis using Tract-Based Spatial Statistics. SETTING: University research center. Patients A sample of 37 children: 13 subjects with autism, 13 of their unaffected siblings, and 11 controls. Controls were age- and intelligence quotient-matched to the unaffected siblings; all groups were age matched. Main Outcome Measure Fractional anisotropy (FA) and axial and radial diffusivities. In addition, behavioral correlation analyses were conducted using the Autism Diagnostic Interview and Autism Diagnostic Observation Schedule subscales and FA values, as well as axial diffusivity values in the autism group. RESULTS: Compared with the control group, both the autism and sibling groups had widespread, significantly reduced white matter FA values (P </= .05, corrected) in the frontal parietal and temporal lobes and included, but were not restricted to, regions known to be important for social cognition. Within regions of reduced FA, significant reductions in axial diffusivity, but not radial diffusivity, were observed. There were no significant differences in white matter structure between the autism and sibling groups. There were no significant correlations between autism symptomatology and white matter FA or axial diffusivity. CONCLUSIONS: Our findings suggest that white matter structure may represent a marker of genetic risk for autism or vulnerability to development of this disorder.
3. Courchesne E, Campbell K, Solso S. {{Brain Growth Across the Life Span in Autism: Age-Specific Changes in Anatomical Pathology}}. {Brain Res} (Oct 1)
Autism is marked by overgrowth of the brain at the earliest ages but not at older ages when decreases in structural volumes and neuron numbers are observed instead. This has lead to the theory of age-specific anatomic abnormalities in autism. Here we report age-related changes in brain size in autistic and typical subjects from 12 months to 50 years of age based on analyses of 586 longitudinal and cross-sectional MRI scans. This dataset is several times larger than the largest autism study to date. Results demonstrate early brain overgrowth during infancy and the toddler years in autistic boys and girls, followed by an accelerated rate of decline in size and perhaps degeneration from adolescence to late middle age in this disorder. We theorize that underlying these age-specific changes in anatomic abnormalities in autism there may also be age-specific changes in gene expression, molecular, synaptic, cellular and circuit abnormalities. A peak age for detecting and studying the earliest fundamental biological underpinnings of autism is prenatal life and the first three postnatal years. Studies of the older autistic brain may not address original causes but are essential to discovering how best to help the older aging autistic person. Lastly, the theory of age-specific anatomic abnormalities in autism has broad implications for a wide range of work on the disorder including the design, validation and interpretation of animal model, lymphocyte gene expression, brain gene expression, and genotype/CNV-anatomic phenotype studies.
4. Dodds L, Fell DB, Shea S, Armson BA, Allen AC, Bryson S. {{The Role of Prenatal, Obstetric and Neonatal Factors in the Development of Autism}}. {J Autism Dev Disord} (Oct 5)
We conducted a linked database cohort study of infants born between 1990 and 2002 in Nova Scotia, Canada. Diagnoses of autism were identified from administrative databases with relevant diagnostic information to 2005. A factor representing genetic susceptibility was defined as having an affected sibling or a mother with a history of a psychiatric or neurologic condition. Among 129,733 children, there were 924 children with an autism diagnosis. The results suggest that among those with low genetic susceptibility, some maternal and obstetric factors may have an independent role in autism etiology whereas among genetically susceptible children, these factors appear to play a lesser role. The role of pre-pregnancy obesity and excessive weight gain during pregnancy on autism risk require further investigation.
5. Downs J, Bebbington A, Kaufmann WE, Leonard H. {{Longitudinal Hand Function in Rett Syndrome}}. {J Child Neurol} (Oct 4)
Loss of hand function is a core feature of Rett syndrome. This article describes longitudinal hand function at 3 time points for 72 subjects participating in the Australian Rett Syndrome Database. Approximately 40% of subjects with some grasping abilities lost skill over the 3- to 4-year period between video assessments. In these subjects, a decrease in hand function was seen less frequently in girls 13 to 19 years old than in those younger than 8 years, in subjects with some mobility compared with those who were wheelchair bound, and in those who had previously been able to finger feed. Relationships with the magnitude of change reflected these findings. Change in hand function did not vary with clinical severity. The results for all subjects were similar to results obtained when analysis was restricted to those with a pathogenic mutation. Variability in the longitudinal course of hand function in Rett syndrome was observed.
6. Ghanizadeh A. {{Targeting neurotensin as a potential novel approach for the treatment of autism}}. {J Neuroinflammation} (Oct 1);7(1):58.
ABSTRACT: The pathophysiology of autism remains obscure. Recently, serum neurotensin levels in children with autistic disorder have been found to be higher than those of normal children. Neurotensin is known to intensify neuronal NMDA-mediated glutamate signaling, which may cause apoptosis in autism. Further, an imbalance of glutamate/GABAergic system in autism has been described. These observations lead to a postulate that neurotensin may accentuate the hyperglutaminergic state in autism, leading to apoptosis. Targeting neurotensin might be a possible novel approach for the treatment of autism.
7. Kotulska K, Jozwiak S. {{Autism in monogenic disorders}}. {Eur J Paediatr Neurol} (Oct 1)
8. Lin LY. {{Factors associated with caregiving burden and maternal pessimism in mothers of adolescents with an autism spectrum disorder in Taiwan}}. {Occup Ther Int} (Oct 6)
9. Pop-Jordanova N, Zorcec T, Demerdzieva A, Gucev Z. {{QEEG characteristics and spectrum weighted frequency for children diagnosed as autistic spectrum disorder}}. {Nonlinear Biomed Phys} (Sep 30);4(1):4.
ABSTRACT: BACKGROUND: Autistic spectrum disorders are a group of neurological and developmental disorders associated with social, communication, sensory, behavioral and cognitive impairments, as well as restricted, repetitive patterns of behavior, activities, or interests. The aim of this study was a) to analyze QEEG findings of autistic patients and to compare the results with data base; and b) to introduce the calculation of spectrum weighted frequency (brain rate) as an indicator of general mental arousal in these patients. RESULTS: Results for Q-EEG shows generally increased delta-theta activity in frontal region of the brain. Changes in QEEG pattern appeared to be in a non-linear correlation with maturational processes. Brain rate measured in CZ shows slow brain activity (5. 86) which is significantly lower than normal and corresponds to low general mental arousal. Recent research has shown that autistic disorders have as their basis disturbances of neural connectivity. Neurofeedback seems capable of remediating such disturbances when these data are considered as part of treatment planning. CONCLUSIONS: Prognosis of this pervasive disorder depends on the intellectual abilities: the better intellectual functioning, the possibilities for life adaptation are higher QEEG shows generally increased delta-theta activity in frontal region of the brain which is related to poor cognitive abilities. Brain rate measured in CZ shows slow brain activity related to under arousal. Pharmacotherapy combined with behavior therapy, social support and especially neurofeedback technique promise slight improvements.
10. Wu H, Tao J, Chen PJ, Shahab A, Ge W, Hart RP, Ruan X, Ruan Y, Sun YE. {{Genome-wide analysis reveals methyl-CpG-binding protein 2-dependent regulation of microRNAs in a mouse model of Rett syndrome}}. {Proc Natl Acad Sci U S A} (Oct 4)
MicroRNAs (miRNAs) are a class of small, noncoding RNAs that function as posttranscriptional regulators of gene expression. Many miRNAs are expressed in the developing brain and regulate multiple aspects of neural development, including neurogenesis, dendritogenesis, and synapse formation. Rett syndrome (RTT) is a progressive neurodevelopmental disorder caused by mutations in the gene encoding methyl-CpG-binding protein 2 (MECP2). Although Mecp2 is known to act as a global transcriptional regulator, miRNAs that are directly regulated by Mecp2 in the brain are not known. Using massively parallel sequencing methods, we have identified miRNAs whose expression is altered in cerebella of Mecp2-null mice before and after the onset of severe neurological symptoms. In vivo genome-wide analyses indicate that promoter regions of a significant fraction of dysregulated miRNA transcripts, including a large polycistronic cluster of brain-specific miRNAs, are DNA-methylated and are bound directly by Mecp2. Functional analysis demonstrates that the 3′ UTR of messenger RNA encoding Brain-derived neurotrophic factor (Bdnf) can be targeted by multiple miRNAs aberrantly up-regulated in the absence of Mecp2. Taken together, these results suggest that dysregulation of miRNAs may contribute to RTT pathoetiology and also may provide a valuable resource for further investigations of the role of miRNAs in RTT.
