Nearly all children with Down syndrome (DS) are born with hypotonia which later improves with age. We present a case of a 32-month-old female with DS who has persistent hypotonia and ligamentous hyperlaxity. She was subsequently diagnosed with Ehlers-Danlos Syndrome-Hypermobility type (EDS-HMT) based on family history, which resulted in the significant global developmental delay compared to age-matched peers with DS. Further clinical investigation is recommended in individuals with DS who appear to have developmental profiles significantly below what would be expected due to typical Trisomy 21 so that additional diagnostic testing and appropriate interventional therapy may be provided. Specifically, timely diagnosis of inherited disorders such as EDS-HMT is important in identifying other family members with the condition.
by
Jannet Kocerha;
Yuhong Liu;
David Willoughby;
Kumaravel Chidamparam;
Joseph Benito;
Kate Nelson;
Yan Xu;
Tim Chi;
Heidi Engelhardt;
Sean Moran;
Shang-Hsun Yang;
Shi Hua Li;
Xiao-Jiang Li;
Katherine Larkin;
Adam Neumann;
Heather Banta;
Jin Jing Yang;
Anthony Chan
Background: Huntington's Disease (HD) is a progressive neurodegenerative disorder caused by an expansion in the polyglutamine (polyQ) region of the Huntingtin (HTT) gene. The clinical features of HD are characterized by cognitive, psychological, and motor deficits. Molecular instability, a core component in neurological disease progression, can be comprehensively evaluated through longitudinal transcriptomic profiling. Development of animal models amenable to longitudinal examination enables distinct disease-associated mechanisms to be identified.
Results: Here we report the first longitudinal study of transgenic monkeys with genomic integration of various lengths of the human HTT gene and a range of polyQ repeats. With this unique group of transgenic HD nonhuman primates (HD monkeys), we profiled over 47,000 transcripts from peripheral blood collected over a 2 year timespan from HD monkeys and age-matched wild-type control monkeys.
Conclusions: Messenger RNAs with expression patterns which diverged with disease progression in the HD monkeys considerably facilitated our search for transcripts with diagnostic or therapeutic potential in the blood of human HD patients, opening up a new avenue for clinical investigation.
Memory deficits in Drosophila nalyot mutants suggest that the Myb family transcription factor Adf-1 is an important regulator of developmental plasticity in the brain. However, the cellular functions for this transcription factor in neurons or molecular mechanisms by which it regulates plasticity remain unknown. Here, we use in vivo 3D reconstruction of identifiable larval motor neuron dendrites to show that Adf-1 is required cell autonomously for dendritic development and activity-dependent plasticity of motor neurons downstream of CaMKII. Adf-1 inhibition reduces dendrite growth and neuronal excitability, and results in motor deficits and altered transcriptional profiles. Surprisingly, analysis by comparative chromatin immunoprecipitation followed by sequencing (ChIP-Seq) of Adf-1, RNA Polymerase II (Pol II), and histone modifications in Kc cells shows that Adf-1 binding correlates positively with high Pol II-pausing indices and negatively with active chromatin marks such as H3K4me3 and H3K27ac. Consistently, the expression of Adf-1 targets Staufen and Fasciclin II (FasII), identified through larval brain ChIP-Seq for Adf-1, is negatively regulated by Adf-1, and manipulations of these genes predictably modify dendrite growth. Our results imply mechanistic interactions between transcriptional and local translational machinery in neurons as well as conserved neuronal growth mechanisms mediated by cell adhesion molecules, and suggest that CaMKII, Adf-1, FasII, and Staufen influence crucial aspects of dendrite development and plasticity with potential implications for memory formation. Further, our experiments reveal molecular details underlying transcriptional regulation by Adf-1, and indicate active interaction between Adf-1 and epigenetic regulators of gene expression during activity-dependent neuronal plasticity.
Background
Down syndrome (DS, OMIM #190685) is the most commonly identified genetic form of intellectual disability with congenital heart defect (CHD) occurring in 50% of cases. With advances in surgical techniques and an increasing lifespan, this has necessitated a greater understanding of the neurodevelopmental consequences of CHDs. Herein, we explore the impact of CHD on language development in children with DS.
Methods
Twenty-nine children with DS were observed systematically in parent–child interactions using the Communication Play Protocol to evaluate their language use; they also completed the Mullen Scales of Early Learning and MacArthur Communication Development Inventory. Mean ages were 31.2 months for children with DS and CHD (DS + CHD, n = 12) and 32.1 months for children with DS and a structurally normal heart (DS − CHD, n = 17).
Results
Compared with the DS − CHD controls, the DS + CHD group revealed lower scores in multiple areas, including fine motor skills and expressive and receptive vocabulary. Whereas most differences were not statistically significant, the Communication Development Inventory word count and symbol-infused joint engagement differed significantly (P < 0.01) and marginally (P = 0.09) between groups.
Conclusions
Finding that CHDs may account for part of the variation in language delay allows us to consider the specific mechanisms underlying the impact of CHDs on language acquisition in children with DS. Conclusions from this first study on early language outcomes of children with DS + CHD may be useful for clinicians in providing developmental surveillance and early intervention programmes with specific emphasis on language therapy as part of long-term follow-up for children with DS + CHD.
The human gut harbors a complex community of microbes that profoundly influence many aspects of growth and development, including development of the nervous system. Advances in high-throughput DNA sequencing methods have led to rapidly expanding knowledge about this gut microbiome. Here, we review fundamental emerging data on the human gut microbiome, with a focus on potential interactions between the microbiome and autism spectrum disorders (ASD) and consider research on atypical patterns of feeding and nutrition in ASD and how they might interact with the microbiome. Finally we selectively survey results from studies in rodents on the impact of the microbiome on neurobehavioral development. The evidence reviewed here suggests that a deeper understanding of the gut microbiome could open up new avenues of research on ASD, including potential novel treatment strategies.
Objectives
Children with rheumatoid-factor or anti-citrullinated peptide antibody positive juvenile idiopathic arthritis represent the childhood onset of RA (CORA). To test the hypothesis that adult-onset RA-associated variants are also associated with CORA, we investigated RA-associated variants at five loci in our CORA cohort. We also assessed the cumulative association of these variants in the susceptibility to CORA using a weighted genetic risk score (wGRS).
Methods
155 children with CORA and 684 healthy controls were genotyped for five variants in PTPN22, TRAF1/C5, STAT4, and TNFAIP3 loci. High-resolution HLA-DRB1 genotypes were available for 149 cases and 373 controls. We tested each locus for association with CORA via logistic regression. We also computed a wGRS for each subject, with weights based on the natural log of the published odds ratios for the alleles investigated, and used logistic regression to test the wGRS for association with CORA.
Results
CORA was associated with TNFAIP3-rs10499194 [OR 0.60 (95%CI 0.44–0.83)], PTPN22-rs2476601 [OR 1.61 (1.11–2.31)], and STAT4-rs7574865 [OR 1.41 (1.06–1.87)] variants. The wGRS was significantly different between cases and controls (P<2×10−16). Individuals in the third to fifth quintiles of wGRS had a significantly increased disease risk compared to the baseline. Higher wGRS associated with increased risk of CORA, especially among males.
Conclusions
TNFAIP3, STAT4 and PTPN22 variants are associated with CORA in a similar magnitude and direction as in RA, suggesting that adult-onset RA and CORA share common genetic risk factors. Utilizing a wGRS, we have demonstrated the cumulative association of RA-associated variants in the susceptibility to CORA.