1. Brendel C, Belakhov V, Werner H, Wegener E, Gartner J, Nudelman I, Baasov T, Huppke P. {{Readthrough of nonsense mutations in Rett syndrome: evaluation of novel aminoglycosides and generation of a new mouse model}}. {J Mol Med};2010 (Dec 1)
Thirty-five percent of patients with Rett syndrome carry nonsense mutations in the MECP2 gene. We have recently shown in transfected HeLa cells that readthrough of nonsense mutations in the MECP2 gene can be achieved by treatment with gentamicin and geneticin. This study was performed to test if readthrough can also be achieved in cells endogenously expressing mutant MeCP2 and to evaluate potentially more effective readthrough compounds. A mouse model was generated carrying the R168X mutation in the MECP2 gene. Transfected HeLa cells expressing mutated MeCP2 fusion proteins and mouse ear fibroblasts isolated from the new mouse model were treated with gentamicin and the novel aminoglycosides NB30, NB54, and NB84. The localization of the readthrough product was tested by immunofluorescence. Readthrough of the R168X mutation in mouse ear fibroblasts using gentamicin was detected but at lower level than in HeLa cells. As expected, the readthrough product, full-length Mecp2 protein, was located in the nucleus. NB54 and NB84 induced readthrough more effectively than gentamicin, while NB30 was less effective. Readthrough of nonsense mutations can be achieved not only in transfected HeLa cells but also in fibroblasts of the newly generated Mecp2 ( R168X ) mouse model. NB54 and NB84 were more effective than gentamicin and are therefore promising candidates for readthrough therapy in Rett syndrome patients.
2. Ekas NV, Whitman TL. {{Adaptation to Daily Stress Among Mothers of Children With an Autism Spectrum Disorder: The Role of Daily Positive Affect}}. {J Autism Dev Disord};2010 (Dec 2)
Raising a child with an autism spectrum disorder is a challenging experience that can impact maternal well-being. Using a daily diary methodology, this study investigates (1) the relationship between stress and negative affect, and (2) the role of daily positive affect as a protective factor in the stress and negative affect relationship. Results from hierarchical linear models revealed that higher levels of stress were associated with decreased negative affect, both within and across days. Daily positive affect buffered the immediate and longer-lasting negative impact of stress on days of low to moderate levels of stress. Implications of the present study are discussed with regard to theoretical models of positive affect, the development of intervention programs, and directions for future research.
3. Giulivi C, Zhang YF, Omanska-Klusek A, Ross-Inta C, Wong S, Hertz-Picciotto I, Tassone F, Pessah IN. {{Mitochondrial dysfunction in autism}}. {JAMA};2010 (Dec 1);304(21):2389-2396.
CONTEXT: Impaired mitochondrial function may influence processes highly dependent on energy, such as neurodevelopment, and contribute to autism. No studies have evaluated mitochondrial dysfunction and mitochondrial DNA (mtDNA) abnormalities in a well-defined population of children with autism. OBJECTIVE: To evaluate mitochondrial defects in children with autism. DESIGN, SETTING, AND PATIENTS: Observational study using data collected from patients aged 2 to 5 years who were a subset of children participating in the Childhood Autism Risk From Genes and Environment study in California, which is a population-based, case-control investigation with confirmed autism cases and age-matched, genetically unrelated, typically developing controls, that was launched in 2003 and is still ongoing. Mitochondrial dysfunction and mtDNA abnormalities were evaluated in lymphocytes from 10 children with autism and 10 controls. MAIN OUTCOME MEASURES: Oxidative phosphorylation capacity, mtDNA copy number and deletions, mitochondrial rate of hydrogen peroxide production, and plasma lactate and pyruvate. RESULTS: The reduced nicotinamide adenine dinucleotide (NADH) oxidase activity (normalized to citrate synthase activity) in lymphocytic mitochondria from children with autism was significantly lower compared with controls (mean, 4.4 [95% confidence interval {CI}, 2.8-6.0] vs 12 [95% CI, 8-16], respectively; P = .001). The majority of children with autism (6 of 10) had complex I activity below control range values. Higher plasma pyruvate levels were found in children with autism compared with controls (0.23 mM [95% CI, 0.15-0.31 mM] vs 0.08 mM [95% CI, 0.04-0.12 mM], respectively; P = .02). Eight of 10 cases had higher pyruvate levels but only 2 cases had higher lactate levels compared with controls. These results were consistent with the lower pyruvate dehydrogenase activity observed in children with autism compared with controls (1.0 [95% CI, 0.6-1.4] nmol x [min x mg protein](-1) vs 2.3 [95% CI, 1.7-2.9] nmol x [min x mg protein](-1), respectively; P = .01). Children with autism had higher mitochondrial rates of hydrogen peroxide production compared with controls (0.34 [95% CI, 0.26-0.42] nmol x [min x mg of protein](-1) vs 0.16 [95% CI, 0.12-0.20] nmol x [min x mg protein](-1) by complex III; P = .02). Mitochondrial DNA overreplication was found in 5 cases (mean ratio of mtDNA to nuclear DNA: 239 [95% CI, 217-239] vs 179 [95% CI, 165-193] in controls; P = 10(-4)). Deletions at the segment of cytochrome b were observed in 2 cases (ratio of cytochrome b to ND1: 0.80 [95% CI, 0.68-0.92] vs 0.99 [95% CI, 0.93-1.05] for controls; P = .01). CONCLUSION: In this exploratory study, children with autism were more likely to have mitochondrial dysfunction, mtDNA overreplication, and mtDNA deletions than typically developing children.
4. Lange N, Dubray MB, Lee JE, Froimowitz MP, Froehlich A, Adluru N, Wright B, Ravichandran C, Fletcher PT, Bigler ED, Alexander AL, Lainhart JE. {{Atypical diffusion tensor hemispheric asymmetry in autism}}. {Autism Res};2010 (Dec 2)
Background: Biological measurements that distinguish individuals with autism from typically developing individuals and those with other developmental and neuropsychiatric disorders must demonstrate very high performance to have clinical value as potential imaging biomarkers. We hypothesized that further study of white matter microstructure (WMM) in the superior temporal gyrus (STG) and temporal stem (TS), two brain regions in the temporal lobe containing circuitry central to language, emotion, and social cognition, would identify a useful combination of classification features and further understand autism neuropathology. Methods: WMM measurements from the STG and TS were examined from 30 high-functioning males satisfying full criteria for idiopathic autism aged 7-28 years and 30 matched controls and a replication sample of 12 males with idiopathic autism and 7 matched controls who participated in a previous case-control diffusion tensor imaging (DTI) study. Language functioning, adaptive functioning, and psychotropic medication usage were also examined. Results: In the STG, we find reversed hemispheric asymmetry of two separable measures of directional diffusion coherence, tensor skewness, and fractional anisotropy. In autism, tensor skewness is greater on the right and fractional anisotropy is decreased on the left. We also find increased diffusion parallel to white matter fibers bilaterally. In the right not left TS, we find increased omnidirectional, parallel, and perpendicular diffusion. These six multivariate measurements possess very high ability to discriminate individuals with autism from individuals without autism with 94% sensitivity, 90% specificity, and 92% accuracy in our original and replication samples. We also report a near-significant association between the classifier and a quantitative trait index of autism and significant correlations between two classifier components and measures of language, IQ, and adaptive functioning in autism.
5. Leaf JB, Sheldon JB, Sherman JA. {{Comparison of simultaneous prompting and no-no prompting in two-choice discrimination learning with children with autism}}. {J Appl Behav Anal};2010 (Summer);43(2):215-228.
This study compared no-no prompting procedures to simultaneous prompting procedures for 3 children with autism. Using a parallel treatments design, researchers taught rote math skills, receptive labels, or answers to « wh- » questions with both prompting systems. Results indicated that no-no prompting was effective in teaching all skills. By contrast, simultaneous prompting was effective in teaching only one pair of skills to 1 participant in the same amount of teaching time and trials. Researchers conducted a preference assessment to determine which of the two prompting procedures the 3 participants preferred. The participants showed mixed preferences for the two procedures.
6. Lionello-Denolf KM, Dube WV, McIlvane WJ. {{Evaluation of Resistance to Change under Different Disrupter Conditions in Children with Autism and Severe Intellectual Disability}}. {J Exp Anal Behav};2010 (May);93(3):369-383.
Translational research inspired by behavioral momentum theory in the area of developmental disabilities has shown effects in individuals over a range of functioning levels. In the current study, behavioral momentum was assessed in 6 children diagnosed with autism and severe intellectual disability. In a repeated measures design, participants were exposed to relatively rich versus lean reinforcement contingencies in a multiple schedule with food reinforcers. This was followed by exposure to each of four disrupting conditions: prefeeding, presentation of a concurrent alternative stimulus, presentation of a movie, and the presence of a researcher dispensing response-independent reinforcers on a variable-time schedule. Consistently greater resistance to disruption in the component with the richer schedule occurred with the alternative stimulus disrupter but not with the other disrupters. These results suggest parameters that may be more (or less) effective if behavioral momentum inspired techniques are to be exploited in therapeutic environments.
7. Nakamura K, Iwata Y, Anitha A, Miyachi T, Toyota T, Yamada S, Tsujii M, Tsuchiya KJ, Iwayama Y, Yamada K, Hattori E, Matsuzaki H, Matsumoto K, Suzuki K, Suda S, Takebayashi K, Takei N, Ichikawa H, Sugiyama T, Yoshikawa T, Mori N. {{Replication study of Japanese cohorts supports the role of STX1A in autism susceptibility}}. {Prog Neuropsychopharmacol Biol Psychiatry};2010 (Nov 27)
Autism is a pervasive developmental disorder diagnosed in early childhood. Abnormalities of serotonergic neurotransmission have been reported in autism. Serotonin transporter (5-HTT), which modulates serotonin levels, is a major therapeutic target in autism. Therefore, factors that regulate 5-HTT expression might be implicated in autism. One candidate 5-HTT-regulatory protein is the presynaptic protein, syntaxin 1A (STX1A). We examined the association of STX1A with autism in a trio association study using DNA samples from Japanese trios with autistic probands. In TDT analysis, rs69510130 (p=0.027) showed nominal associations with autism; modest haplotype association was also observed. We further compared STX1A mRNA expression between the autistic and control groups in the postmortem brain. In the anterior cingulate gyrus region, STX1A expression in the autism group was found to be significantly lower than that of the control group. Thus, we suggest a possible role of STX1A in the pathogenesis of autism.
8. Napolitano DA, Smith T, Zarcone JR, Goodkin K, McAdam DB. {{Increasing response diversity in children with autism}}. {J Appl Behav Anal};2010 (Summer);43(2):265-271.
Repetitive and invariant behavior is a diagnostic feature of autism. We implemented a lag reinforcement schedule to increase response diversity for 6 participants with autism aged 6 to 10 years, 4 of whom also received prompting plus additional training. These procedures appeared to increase the variety of building-block structures, demonstrating that an intervention that includes differential reinforcement can increase response diversity for children with an autism spectrum disorder.
9. Roy M, Balaratnasingam S. {{Missed diagnosis of autism in an Australian Indigenous psychiatric population}}. {Australas Psychiatry};2010 (Dec);18(6):534-537.
Objective: The aim of this paper is to review the diagnosis among adult Indigenous patients from the Kimberley region of Western Australia who had an existing diagnosis of schizophrenia. A visit from a psychiatrist specializing in intellectual disability provided the opportunity for conducting psychiatric assessments from a developmental perspective. Method: Selected patients with schizophrenia were assessed from an intellectual disability perspective from an active case load of 215 patients. Result: Thirteen out of 14 selected patients were considered to have a diagnosis of autism when a developmental history was undertaken. Case studies are presented to illustrate the overlap in symptoms and potential for the diagnosis of autism to be missed. Conclusions: Autism spectrum disorders may be missed in Indigenous population groups. This has implications for treatment and service provision. Clinicians need to be mindful of the diagnostic possibility that an autism spectrum disorder might be masquerading as schizophrenia in the context of intellectual disability and atypical presentation.
