1. Balemans MC, Huibers MM, Eikelenboom NW, Kuipers AJ, van Summeren RC, Pijpers MM, Tachibana M, Shinkai Y, van Bokhoven H, Van der Zee CE. {{Reduced exploration, increased anxiety, and altered social behavior: Autistic-like features of euchromatin histone methyltransferase 1 heterozygous knockout mice}}. {Behav Brain Res} (Mar 17);208(1):47-55.
The 9q34.3 subtelomeric deletion syndrome is a newly defined mental retardation syndrome, caused by haplo-insufficiency of the euchromatin histone methyltransferase 1 (EHMT1) gene. Patients also have childhood hypotonia, facial dysmorphisms, delay in reaching developmental milestones, and behavioral problems like aggressive outbursts, hypoactivity, or autistic-like features. Male and female heterozygous Ehmt1 knockout mice (Ehmt1(+/-), aged 1-20 months, kept on a C57BL/6J background), were used to investigate whether they mimic the patients behavioral characteristics by comparing their behavior to wildtype littermates. The Ehmt1(+/-) mice revealed reduced activity and exploration, with increased anxiety compared to wildtype mice when exposed to novel environments in the open field, object exploration, marble burying, light-dark box, mirrored chamber and T-maze tests. They also demonstrated diminished social play when encountering a mouse from a different litter, and a delayed or absent response to social novelty when exposed to a stranger mouse. However, no differences in phenotyper home cage locomotor activity or rotarod motor function were observed between Ehmt1(+/-) and wildtype mice. Together, these results indicate that the hypoactivity and the autistic-like features of 9q34.3 subtelomeric deletion syndrome patients are recapitulated in this Ehmt1(+/-) mouse model, and that the hypoactivity is apparently not caused by any motor dysfunction. Together, these observations make it plausible that the Ehmt1(+/-) mouse is a faithful mammalian model for the autistic-like behavioral features of patients with the 9q34.3 subtelomeric deletion syndrome.
2. Glaze DG, Percy AK, Skinner S, Motil KJ, Neul JL, Barrish JO, Lane JB, Geerts SP, Annese F, Graham J, McNair L, Lee HS. {{Epilepsy and the natural history of Rett syndrome}}. {Neurology} (Mar 16);74(11):909-912.
BACKGROUND: Rett syndrome (RTT) is a neurodevelopmental disorder primarily seen in females, most with a mutation in MECP2. Epilepsy has been reported in 50%-80%. Previous reports were based on small sample sizes or parent-completed questionnaires, or failed to consider the impact of specific MECP2 mutations. METHODS: The Rare Disease Consortium Research Network for RTT is an NIH-funded project to characterize the clinical spectrum and natural history of RTT in advance of clinical trials. Evaluations include clinical status (classic vs atypical RTT), MECP2 mutations, clinical severity, and presence, frequency, and treatment of seizures. RESULTS: Enrollment as of June 2008 is 602; 528 (88%) meet clinical criteria for classic RTT. Of these, 493 (93%) have MECP2 mutations. Age range was 8 months to 64 years. A total of 360 (60%) were reported to have seizures, including 315 (60%) classic and 45 (61%) atypical RTT. Physician assessment of the 602 indicated that 48% had seizures. There was no significant difference in seizure occurrence by race/ethnicity. A significant age impact for seizures was seen and seizures were infrequent before age 2 years. MECP2 mutations most frequently associated with epilepsy were T158M (74%) and R106W (78%), and less frequently R255X and R306C (both 49%). Individuals with seizures had greater overall clinical severity, and greater impairment of ambulation, hand use, and communication. Discussion: Seizures are common in Rett syndrome, have an age-related onset and occurrence, vary by mutation, and are associated with greater clinical severity. This information represents a key consideration for designing clinical trials.
3. Lopata C, Thomeer ML, Volker MA, Toomey JA, Nida RE, Lee GK, Smerbeck AM, Rodgers JD. {{RCT of a Manualized Social Treatment for High-Functioning Autism Spectrum Disorders}}. {J Autism Dev Disord} (Mar 16)
This RCT examined the efficacy of a manualized social intervention for children with HFASDs. Participants were randomly assigned to treatment or wait-list conditions. Treatment included instruction and therapeutic activities targeting social skills, face-emotion recognition, interest expansion, and interpretation of non-literal language. A response-cost program was applied to reduce problem behaviors and foster skills acquisition. Significant treatment effects were found for five of seven primary outcome measures (parent ratings and direct child measures). Secondary measures based on staff ratings (treatment group only) corroborated gains reported by parents. High levels of parent, child and staff satisfaction were reported, along with high levels of treatment fidelity. Standardized effect size estimates were primarily in the medium and large ranges and favored the treatment group.
4. Shen Y, Dies KA, Holm IA, Bridgemohan C, Sobeih MM, Caronna EB, Miller KJ, Frazier JA, Silverstein I, Picker J, Weissman L, Raffalli P, Jeste S, Demmer LA, Peters HK, Brewster SJ, Kowalczyk SJ, Rosen-Sheidley B, McGowan C, Duda AW, 3rd, Lincoln SA, Lowe KR, Schonwald A, Robbins M, Hisama F, Wolff R, Becker R, Nasir R, Urion DK, Milunsky JM, Rappaport L, Gusella JF, Walsh CA, Wu BL, Miller DT. {{Clinical Genetic Testing for Patients With Autism Spectrum Disorders}}. {Pediatrics} (Mar 15)
Background: Multiple lines of evidence indicate a strong genetic contribution to autism spectrum disorders (ASDs). Current guidelines for clinical genetic testing recommend a G-banded karyotype to detect chromosomal abnormalities and fragile X DNA testing, but guidelines for chromosomal microarray analysis have not been established. Patients and Methods: A cohort of 933 patients received clinical genetic testing for a diagnosis of ASD between January 2006 and December 2008. Clinical genetic testing included G-banded karyotype, fragile X testing, and chromosomal microarray (CMA) to test for submicroscopic genomic deletions and duplications. Diagnostic yield of clinically significant genetic changes was compared. Results: Karyotype yielded abnormal results in 19 of 852 patients (2.23% [95% confidence interval (CI): 1.73%-2.73%]), fragile X testing was abnormal in 4 of 861 (0.46% [95% CI: 0.36%-0.56%]), and CMA identified deletions or duplications in 154 of 848 patients (18.2% [95% CI: 14.76%-21.64%]). CMA results for 59 of 848 patients (7.0% [95% CI: 5.5%-8.5%]) were considered abnormal, which includes variants associated with known genomic disorders or variants of possible significance. CMA results were normal in 10 of 852 patients (1.2%) with abnormal karyotype due to balanced rearrangements or unidentified marker chromosome. CMA with whole-genome coverage and CMA with targeted genomic regions detected clinically relevant copy-number changes in 7.3% (51 of 697) and 5.3% (8 of 151) of patients, respectively, both higher than karyotype. With the exception of recurrent deletion and duplication of chromosome 16p11.2 and 15q13.2q13.3, most copy-number changes were unique or identified in only a small subset of patients. Conclusions: CMA had the highest detection rate among clinically available genetic tests for patients with ASD. Interpretation of microarray data is complicated by the presence of both novel and recurrent copy-number variants of unknown significance. Despite these limitations, CMA should be considered as part of the initial diagnostic evaluation of patients with ASD.
5. Smith MJ, Montagne B, Perrett DI, Gill M, Gallagher L. {{Detecting subtle facial emotion recognition deficits in high-functioning Autism using dynamic stimuli of varying intensities}}. {Neuropsychologia} (Mar 11)
Autism Spectrum Disorders (ASD) are characterised by social and communication impairment, yet evidence for deficits in the ability to recognise facial expressions of basic emotions is conflicting. Many studies reporting no deficits have used stimuli that may be too simple (with associated ceiling effects), for example, 100% ‘full-blown’ expressions. In order to investigate subtle deficits in facial emotion recognition, twenty one adolescent males with high-functioning Austism Spectrum Disorders (ASD) and sixteen age and IQ matched typically developing control males completed a new sensitive test of facial emotion recognition which uses dynamic stimuli of varying intensities of expressions of the six basic emotions (Emotion Recognition Test; Montagne et al. 2007). Participants with ASD were found to be less accurate at processing the basic emotional expressions of disgust, anger and surprise; disgust recognition was most impaired-at 100% intensity and lower levels, whereas recognition of surprise and anger were intact at 100% but impaired at lower levels of intensity.
