Repetitive behavior profiles: Consistency across autism spectrum disorder cohorts and divergence from Prader-Willi syndrome.

Restricted and repetitive behavior (RRB) is a group of heterogeneous maladaptive behaviors. RRB is one of the key diagnostic features of autism spectrum disorders (ASDs) and also commonly observed in Prader-Willi syndrome (PWS). In this study, we assessed RRB using the Repetitive Behavior Scale-Revised (RBS-R) in two ASD samples (University of Illinois at Chicago [UIC] and University of Florida [UF]) and one PWS sample. We compared the RBS-R item endorsements across three ASD cohorts (UIC, UF and an ASD sample from Lam, The Repetitive Behavior Scale-Revised: independent validation and the effect of subject variables, PhD thesis, 2004), and a PWS sample. We also compared the mean RBS-R subscale/sum scores across the UIC, UF and PWS samples; across the combined ASD (UIC + UF), PWS-deletion and PWS-disomy groups; and across the combined ASD sample, PWS subgroup with a Social Communication Questionnaire (SCQ) score ≥15, and PWS subgroup with a SCQ score <15. Despite the highly heterogeneous nature, the three ASD samples (UIC, UF and Lam's) showed a similar pattern of the RBS-R endorsements, and the mean RBS-R scores were not different between the UIC and UF samples. However, higher RRB was noted in the ASD sample compared with the PWS sample, as well as in the PWS subgroup with a SCQ score ≥15 compared with the PWS subgroup with a SCQ score <15. Study limitations include a small sample size, a wide age range of our participants, and not controlling for potential covariates. A future replication study using a larger sample and further investigation into the genetic bases of overlapping ASD and RRB phenomenology are needed, given the higher RRB in the PWS subgroup with a SCQ score ≥15.

A quantitative association study of SLC25A12 and restricted repetitive behavior traits in autism spectrum disorders.

BACKGROUND: SLC25A12 was previously identified by a linkage-directed association analysis in autism. In this study, we investigated the relationship between three SLC25A12 single nucleotide polymorphisms (SNPs) (rs2056202, rs908670 and rs2292813) and restricted repetitive behavior (RRB) traits in autism spectrum disorders (ASDs), based on a positive correlation between the G allele of rs2056202 and an RRB subdomain score on the Autism Diagnostic Interview-Revised (ADI-R). METHODS: We used the Repetitive Behavior Scale-Revised (RBS-R) as a quantitative RRB measure, and conducted linear regression analyses for individual SNPs and a previously identified haplotype (rs2056202-rs2292813). We examined associations in our University of Illinois at Chicago-University of Florida (UIC-UF) sample (179 unrelated individuals with an ASD), and then attempted to replicate our findings in the Simons Simplex Collection (SSC) sample (720 ASD families). RESULTS: In the UIC-UF sample, three RBS-R scores (ritualistic, sameness, sum) had positive associations with the A allele of rs2292813 (p = 0.006-0.012) and with the rs2056202-rs2292813 haplotype (omnibus test, p = 0.025-0.040). The SSC sample had positive associations between the A allele of rs2056202 and four RBS-R scores (stereotyped, sameness, restricted, sum) (p = 0.006-0.010), between the A allele of rs908670 and three RBS-R scores (stereotyped, self-injurious, sum) (p = 0.003-0.015), and between the rs2056202-rs2292813 haplotype and six RBS-R scores (stereotyped, self-injurious, compulsive, sameness, restricted, sum)(omnibus test, p = 0.002-0.028). Taken together, the A alleles of rs2056202 and rs2292813 were consistently and positively associated with RRB traits in both the UIC-UF and SSC samples, but the most significant SNP with phenotype association varied in each dataset. CONCLUSIONS: This study confirmed an association between SLC25A12 and RRB traits in ASDs, but the direction of the association was different from that in the initial study. This could be due to the examined SLC25A12 SNPs being in linkage disequilibrium with another risk allele, and/or genetic/phenotypic heterogeneity of the ASD samples across studies.

Persistent adeno-associated virus 2 and parvovirus B19 sequences in post-mortem human cerebellum.

We previously reported in a large cohort (N = 104) of post-mortem tissues the detection of both the non-pathogenic adeno-associated virus (AAV2) in approximately 13% and the pathogenic human parvovirus B19 (B19) in approximately 42% of human brains, particularly the dorsolateral prefrontal cortex. Multiple animal parvoviruses target the developing cerebellum (CBLM) resulting in hypoplasia and ataxia, but very little is known about the human parvoviruses and their ability to infect or cause disease in the CBLM. We have now confirmed in the above cohort the presence of AAV2 and B19 sequences in the CBLM. Our results show that approximately 27% and approximately 70% of human CBLM are positive by nested polymerase chain reaction for AAV2 and B19 sequences, respectively. We also document in a second cohort (N = 10) the presence of AAV2 (50%) and B19 (100%) sequences in the CBLM and correlate our results for B19 with studies from matched sera. Eighty percent (80%) of this cohort was positive for anti-B19 IgG, while none were IgM+, suggesting that most individuals had been previously infected with B19 but none acutely. To our knowledge, this study is the first to demonstrate that both AAV2 and B19 sequences are present at relatively high frequencies in the CBLM and are likely due to persistent rather than acute infection. Further studies will lead to insights into AAV2- and/or B19-CBLM interactions including mechanisms of infection, persistence, and possibly neuropathology, including cerebellar hypoplasia and ataxia.

Relationship of movements and behaviors to Group A Streptococcus infections in elementary school children.

BACKGROUND: Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcus (PANDAS) research is based on the hypothesis that infections trigger changes in behavior and movement in children. METHODS: We enrolled 693 children (ages 3 to 12 years) into a systematic, longitudinal study. Data were collected monthly for 8 months (October-May) to determine point prevalence of Group A Streptococcal (GAS) infections, tics, behavior, and choreiform movements. Simultaneous throat cultures were obtained, and relational analyses were made between GAS and movement/observation ratings. RESULTS: Combined behavior/GAS associations (concurrent with or 3 subsequent months to GAS) revealed a strong relationship, relative risk (RR) of 1.71 (p < .0001). Detailed analysis revealed that balance/swaying and non-tic grimacing were responsible for a significant proportion of this association (RR = 2.92, p < .0001). A strong seasonal pattern was found, with fall being more significant for GAS infections and observation ratings (p < .0001) compared with winter/spring. Children with repeated streptococcus (n = 64) showed higher rates of behavior and distal choreiform observations (p = .005). CONCLUSIONS: Motor/behavior changes were noted to occur in relationship to positive GAS culture with support that repeated GAS increases risk.