1. Budimirovic DB, Schlageter A, Filipovic-Sadic S, Protic DD, Bram E, Mahone EM, Nicholson K, Culp K, Javanmardi K, Kemppainen J, Hadd A, Sharp K, Adayev T, LaFauci G, Dobkin C, Zhou L, Brown WT, Berry-Kravis E, Kaufmann WE, Latham GJ. {{A Genotype-Phenotype Study of High-Resolution FMR1 Nucleic Acid and Protein Analyses in Fragile X Patients with Neurobehavioral Assessments}}. {Brain Sci};2020 (Sep 30);10(10)
Fragile X syndrome (FXS) is caused by silencing of the FMR1 gene, which encodes a protein with a critical role in synaptic plasticity. The molecular abnormality underlying FMR1 silencing, CGG repeat expansion, is well characterized; however, delineation of the pathway from DNA to RNA to protein using biosamples from well characterized patients with FXS is limited. Since FXS is a common and prototypical genetic disorder associated with intellectual disability (ID) and autism spectrum disorder (ASD), a comprehensive assessment of the FMR1 DNA-RNA-protein pathway and its correlations with the neurobehavioral phenotype is a priority. We applied nine sensitive and quantitative assays evaluating FMR1 DNA, RNA, and FMRP parameters to a reference set of cell lines representing the range of FMR1 expansions. We then used the most informative of these assays on blood and buccal specimens from cohorts of patients with different FMR1 expansions, with emphasis on those with FXS (N = 42 total, N = 31 with FMRP measurements). The group with FMRP data was also evaluated comprehensively in terms of its neurobehavioral profile, which allowed molecular-neurobehavioral correlations. FMR1 CGG repeat expansions, methylation levels, and FMRP levels, in both cell lines and blood samples, were consistent with findings of previous FMR1 genomic and protein studies. They also demonstrated a high level of agreement between blood and buccal specimens. These assays further corroborated previous reports of the relatively high prevalence of methylation mosaicism (slightly over 50% of the samples). Molecular-neurobehavioral correlations confirmed the inverse relationship between overall severity of the FXS phenotype and decrease in FMRP levels (N = 26 males, mean 4.2 ± 3.3 pg FMRP/ng genomic DNA). Other intriguing findings included a significant relationship between the diagnosis of FXS with ASD and two-fold lower levels of FMRP (mean 2.8 ± 1.3 pg FMRP/ng genomic DNA, p = 0.04), in particular observed in younger age- and IQ-adjusted males (mean age 6.9 ± 0.9 years with mean 3.2 ± 1.2 pg FMRP/ng genomic DNA, 57% with severe ASD), compared to FXS without ASD. Those with severe ID had even lower FMRP levels independent of ASD status in the male-only subset. The results underscore the link between FMR1 expansion, gene methylation, and FMRP deficit. The association between FMRP deficiency and overall severity of the neurobehavioral phenotype invites follow up studies in larger patient cohorts. They would be valuable to confirm and potentially extend our initial findings of the relationship between ASD and other neurobehavioral features and the magnitude of FMRP deficit. Molecular profiling of individuals with FXS may have important implications in research and clinical practice.
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2. Bussu G, Llera A, Jones EJH, Tye C, Charman T, Johnson MH, Beckmann CF, Buitelaar JK. {{Uncovering neurodevelopmental paths to autism spectrum disorder through an integrated analysis of developmental measures and neural sensitivity to faces}}. {J Psychiatry Neurosci};2020 (Sep 24);45(6):190148.
BACKGROUND: Autism spectrum disorder (ASD) is highly heterogeneous in its etiology and manifestation. The neurobiological processes underlying ASD development are reflected in multiple features, from behaviour and cognition to brain functioning. An integrated analysis of these features may optimize the identification of these processes. METHODS: We examined cognitive and adaptive functioning and ASD symptoms between 8 and 36 months in 161 infants at familial high risk for ASD and 71 low-risk controls; we also examined neural sensitivity to eye gaze at 8 months in a subsample of 140 high-risk and 61 low-risk infants. We used linked independent component analysis to extract patterns of variation across domains and development, and we selected the patterns significantly associated with clinical classification at 36 months. RESULTS: An early process at 8 months, indicating high levels of functioning and low levels of symptoms linked to higher attention to gaze shifts, was reduced in infants who developed ASD. A longitudinal process of increasing functioning and low levels of symptoms was reduced in infants who developed ASD, and another process suggesting a stagnation in cognitive functioning at 24 months was increased in infants who developed ASD. LIMITATIONS: Although the results showed a clear significant trend relating to clinical classification, we found substantial overlap between groups. CONCLUSION: We uncovered underlying processes that acted together early in development and were associated with clinical outcomes. Our results highlighted the complexity of emerging ASD, which goes beyond the borders of clinical categories. Future work should integrate genetic data to investigate the specific genetic risks linked to these processes.
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3. Gold NB, Li D, Chassevent A, Kaiser FJ, Parenti I, Strom TM, Ramos FJ, Puisac B, Pié J, McWalter K, Guillen Sacoto MJ, Cui H, Saadeh-Haddad R, Smith-Hicks C, Rodan L, Blair E, Bhoj E. {{Heterozygous de novo variants in CSNK1G1 are associated with syndromic developmental delay and autism spectrum disorder}}. {Clin Genet};2020 (Oct 3)
The gamma-1 isoform of casein kinase 1, the protein encoded by CSNK1G1, is involved in the growth and morphogenesis of cells. This protein is expressed ubiquitously among many tissue types, including the brain, where it regulates the phosphorylation of NMDA receptors and plays a role in synaptic transmission. One prior individual with a de novo variant in CSNK1G presenting with severe developmental delay and early-onset epilepsy has been reported. Here we report an updated clinical history of this previously published case, as well as four additional individuals with de novo variants in CSNK1G1 identified via microarray-based comparative genomic hybridization, exome or genome sequencing. All individuals (n = 5) had developmental delay. At least three individuals had diagnoses of autism spectrum disorder. All participants were noted to have dysmorphic facial features, although the reported findings varied widely and therefore may not clearly be recognizable. None of the participants had additional major malformations. Taken together, our data suggest that CSNK1G1 may be a cause of syndromic developmental delay and possibly autism spectrum disorder.
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4. Habayeb S, Tsang T, Saulnier C, Klaiman C, Jones W, Klin A, Edwards LA. {{Visual Traces of Language Acquisition in Toddlers with Autism Spectrum Disorder During the Second Year of Life}}. {J Autism Dev Disord};2020 (Oct 3)
Infants show shifting patterns of visual engagement to faces over the first years of life. To explore the adaptive implications of this engagement, we collected eye-tracking measures on cross-sectional samples of 10-25-month-old typically developing toddlers (TD;N = 28) and those with autism spectrum disorder (ASD;N = 54). Concurrent language assessments were conducted and relationships between visual engagement and expressive and receptive language were analyzed between groups, and within ASD subgroups. TD and ASD toddlers exhibited greater mouth- than eye-looking, with TD exhibiting higher levels of mouth-looking than ASD. Mouth-looking was positively associated with expressive language in TD toddlers, and in ASD toddlers who had acquired first words. Mouth-looking was unrelated to expressive language in ASD toddlers who had not yet acquired first words.
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5. Lee J, Son MJ, Son CY, Jeong GH, Lee KH, Lee KS, Ko Y, Kim JY, Lee JY, Radua J, Eisenhut M, Gressier F, Koyanagi A, Stubbs B, Solmi M, Rais TB, Kronbichler A, Dragioti E, Vasconcelos DFP, Silva F, Tizaoui K, Brunoni AR, Carvalho AF, Cargnin S, Terrazzino S, Stickley A, Smith L, Thompson T, Shin JI, Fusar-Poli P. {{Genetic Variation and Autism: A Field Synopsis and Systematic Meta-Analysis}}. {Brain Sci};2020 (Sep 30);10(10)
This study aimed to verify noteworthy findings between genetic risk factors and autism spectrum disorder (ASD) by employing the false positive report probability (FPRP) and the Bayesian false-discovery probability (BFDP). PubMed and the Genome-Wide Association Studies (GWAS) catalog were searched from inception to 1 August, 2019. We included meta-analyses on genetic factors of ASD of any study design. Overall, twenty-seven meta-analyses articles from literature searches, and four manually added articles from the GWAS catalog were re-analyzed. This showed that five of 31 comparisons for meta-analyses of observational studies, 40 out of 203 comparisons for the GWAS meta-analyses, and 18 out of 20 comparisons for the GWAS catalog, respectively, had noteworthy estimations under both Bayesian approaches. In this study, we found noteworthy genetic comparisons highly related to an increased risk of ASD. Multiple genetic comparisons were shown to be associated with ASD risk; however, genuine associations should be carefully verified and understood.
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6. Ruigrok ANV, Lai MC. {{Sex/gender differences in neurology and psychiatry: Autism}}. {Handb Clin Neurol};2020;175:283-297.
Autism is a heterogenous set of early-onset neurodevelopmental conditions that are more prevalent in males than in females. Due to the high phenotypic, neurobiological, developmental, and etiological heterogeneity in the autism spectrum, recent research programs are increasingly exploring whether sex- and gender-related factors could be helpful markers to clarify the heterogeneity in autism and work toward a personalized approach to intervention and support. In this chapter, we summarize recent clinical and neuroscientific research addressing sex/gender influences in autism and explore how sex/gender-based investigations shed light on similar or different underlying neurodevelopmental mechanisms of autism by sex/gender. We review evidence that may help to explain some of the underlying sex-related biological mechanisms associated with autism, including genetics and the effects of sex steroid hormones in the prenatal environment. We conclude that current research points toward coexisting quantitative and, perhaps more evidently, qualitative sex/gender-modulation effects in autism across multiple neurobiological aspects. However, converging findings of specific neurobiological presentations and sex/gender-informed mechanisms cutting across the many subgroups within the autism spectrum are still lacking. Future research should use big data approaches and new stratification methods to decompose sex/gender-related heterogeneity in autism and work toward personalized, sex/gender-informed intervention and support for autistic people.
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7. Vigli D, Cosentino L, Pellas M, De Filippis B. {{Chronic treatment with cannabidiolic acid (CBDA) reduces thermal pain sensitivity in male mice and rescues the hyperalgesia in a mouse model of Rett syndrome}}. {Neuroscience};2020 (Sep 30)
Rett syndrome (RTT) is a rare neurologic disorder, characterized by severe behavioural and physiological symptoms. RTT is caused by mutations in the MECP2 gene in about 95% of cases and to date no cure is available. Recent evidence suggests that non-euphoric phytocannabinoids (pCBs) extracted from Cannabis sativa may represent innovative therapeutic molecules for RTT, with the cannabinoid cannabidivarin having beneficial effects on behavioural and brain molecular alterations in RTT mouse models. The present study evaluated the potential therapeutic efficacy for RTT of cannabidiolic acid (CBDA; 0.2, 2, 20 mg/kg through intraperitoneal injections for 14 days), a pCB that has proved to be effective for the treatment of nausea and anxiety in rodents. This study demonstrates that systemic treatment with the low dose of CBDA has anti-nociceptive effects and reduces the thermal hyperalgesia in 8-month old MeCP2-308 male mice, a validated RTT mouse model. CBDA did not affect other behavioural or molecular parameters. These results provide support to the antinociceptive effects of CBDA and stress the need for further studies aimed at clarifying the mechanisms underlying the abnormal pain perception in RTT.
