A protocol for evaluation of Rett Syndrome symptom improvement by metabolic modulators in Mecp2-mutant mice

Mouse models recapitulate many symptoms of Rett Syndrome, an X-linked disorder caused by mutations in methyl-CpG-binding protein 2 (MECP2). The study of Mecp2-null male mice has provided insight into pathogenesis of the disorder; most recently, dysregulation of cholesterol and lipid metabolism. Perisymptomatic treatment with statin drugs successfully mitigates the effects of this metabolic syndrome, increases longevity and improves motor function. Described here is a metabolic drug screening protocol and timeline for symptom evaluation in Mecp2-mutant mice. Specifically, mice are treated twice weekly with a compound of interest alongside subjective health assessments, bi-weekly body composition measurements and blood chemistries. Throughout treatment, behavioral phenotyping tests are carried out at specific time points. This protocol is highly adaptable to other neurological diseases; however, the time for completion depends on the specific mutant model under study. The protocol highlights the use of several different CPMo protocols to carry out testing in a preclinical model.

Keywords: Behavioral Assessment; Cholesterol; Drug Treatment; Lipid; Metabolism; Neurodevelopmental Disorders; Rett Syndrome.

Objective: The DSM-IV-TR specifies 12 behavioral features that can occur in hundreds of possible combinations to meet diagnostic criteria for autism spectrum disorder (ASD). This paper describes the frequency and variability with which the 12 behavioral features are documented in a population-based cohort of 8-year-old children under surveillance for ASD, and examines whether documentation of certain features, alone or in combination with other features, is associated with earlier age of community identification of ASD.

Method: Statistical analysis of behavioral features documented for a population-based sample of 2,757 children, 8 years old, with ASD in 11 geographically-defined areas in the US participating in the Autism and Developmental Disabilities Monitoring Network in 2006.

Results: The median age at ASD identification was inversely associated with the number of documented behavioral features, decreasing from 8.2 years for children with only seven behavioral features to 3.8 years for children with all 12. Documented impairments in nonverbal communication, pretend play, inflexible routines, and repetitive motor behaviors were associated with earlier identification, whereas impairments in peer relations, conversational ability, and idiosyncratic speech were associated with later identification.

Conclusions: The age dependence of some of the behavioral features leading to an autism diagnosis, as well as the inverse association between age at identification and number of behavioral features documented, have implications for efforts to improve early identification. Progress in achieving early identification and provision of services for children with autism may be limited for those with fewer ASD behavioral features, as well as features likely to be detected at later ages

Importance: The DSM-5 contains revised diagnostic criteria for autism spectrum disorder (ASD) from the DSM-IV-TR. Potential impacts of the new criteria on ASD prevalence are unclear.

Objective: To assess potential effects of the DSM-5 ASD criteria on ASD prevalence estimation by retrospectively applying the new criteria to population-based surveillance data collected for previous ASD prevalence estimation.

Design, setting, and participants: Cross-sectional, population-based ASD surveillance based on clinician review of coded behaviors documented in children’s medical and educational evaluations from 14 geographically defined areas in the United States participating in the Autism and Developmental Disabilities Monitoring (ADDM) Network in 2006 and 2008. This study included 8-year-old children living in ADDM Network study areas in 2006 or 2008, including 644 883 children under surveillance, of whom 6577 met surveillance ASD case status based on the DSM-IV-TR.

Main outcomes and measures: Proportion of children meeting ADDM Network ASD criteria based on the DSM-IV-TR who also met DSM-5 criteria; overall prevalence of ASD using DSM-5 criteria.

Results: Among the 6577 children classified by the ADDM Network as having ASD based on the DSM-IV-TR, 5339 (81.2%) met DSM-5 ASD criteria. This percentage was similar for boys and girls but higher for those with than without intellectual disability (86.6% and 72.5%, respectively; P < .001). A total of 304 children met DSM-5 ASD criteria but not current ADDM Network ASD case status. Based on these findings, ASD prevalence per 1000 for 2008 would have been 10.0 (95% CI, 9.6-10.3) using DSM-5 criteria compared with the reported prevalence based on DSM-IV-TR criteria of 11.3 (95% CI, 11.0-11.7).

Conclusions and relevance: Autism spectrum disorder prevalence estimates will likely be lower under DSM-5 than under DSM-IV-TR diagnostic criteria, although this effect could be tempered by future adaptation of diagnostic practices and documentation of behaviors to fit the new criteria.

Although social impairments are considered the hallmark deficit of autism, many behavioral intervention studies rely on cognitive functioning as a primary outcome. Fewer studies have examined whether changes in cognition are associated with changes in social functioning. This study examined whether cognitive gains among 192 students from 47 kindergarten-through-second-grade autism support classrooms participating in a year-long behavioral intervention study were associated with gains in social functioning. Children’s gains in cognitive ability were modestly associated with independent assessors’ and teachers’ evaluations of social functioning but were not associated with changes in parent ratings. Observed social gains were not commensurate with gains in cognition, suggesting the need both for interventions that directly target social functioning and relevant field measures of social functioning.

Keywords: autism spectrum disorder; intervention; social deficits.