Browsing by Subject "trisomy 21"

Now showing 1 - 6 of 6
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    Abnormal mineralization of the Ts65Dn Down syndrome mouse appendicular skeleton begins during embryonic development in a Dyrk1a-independent manner
    (Elsevier, 2015-05) Blazek, Joshua D.; Malik, Ahmed M.; Tischbein, Maeve; Arbones, Maria L.; Moore, Clara S.; Roper, Randall J.; Biology, School of Science
    The relationship between gene dosage imbalance and phenotypes associated with Trisomy 21, including the etiology of abnormal bone phenotypes linked to Down syndrome (DS), is not well understood. The Ts65Dn mouse model for DS exhibits appendicular skeletal defects during adolescence and adulthood but the developmental and genetic origin of these phenotypes remains unclear. It is hypothesized that the postnatal Ts65Dn skeletal phenotype originates during embryonic development and results from an increased Dyrk1a gene copy number, a gene hypothesized to play a critical role in many DS phenotypes. Ts65Dn embryos exhibit a lower percent bone volume in the E17.5 femur when compared to euploid embryos. Concomitant with gene copy number, qPCR analysis revealed a  ~1.5 fold increase in Dyrk1a transcript levels in the Ts65Dn E17.5 embryonic femur as compared to euploid. Returning Dyrk1a copy number to euploid levels in Ts65Dn, Dyrk1a+/− embryos did not correct the trisomic skeletal phenotype but did return Dyrk1a gene transcript levels to normal. The size and protein expression patterns of the cartilage template during embryonic bone development appear to be unaffected at E14.5 and E17.5 in trisomic embryos. Taken together, these data suggest that the dosage imbalance of genes other than Dyrk1a is involved in the development of the prenatal bone phenotype in Ts65Dn embryos.
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    ANALYSIS OF CO-OCCURRING PHENOTYPES IN INFANTS WITH DOWN SYNDROME WITH CARDIAC DEFECTS
    (Office of the Vice Chancellor for Research, 2011-04-08) Shepherd, Nicole; Duvall, Nichole; Stone, Sandra B.; Davis, Charlene; Stanley, Maria; Roper, Randall J.
    Down syndrome (DS), caused by a trisomy 21, is the most common chromosomal aneuploidy occurring in approximately 1 of 750 live births. Individuals with DS exhibit craniofacial dysmorphology, cardiac defects, gastrointestinal problems, and cognitive impairment, although these phenotypes vary in incidence and severity. Common cardiac defects are usually recognized in young infants with DS and include atrial septal anomalies, ventricular septal abnormalities, atrioventricular canal defects, and patent ductus arteriosus. Additional abnormalities may also affect infants with DS, but not be identified until later in life. Since multiple phenotypes are found in these individuals, we hypothesize that children with a severe congenital heart defect may be at increased risk for additional medical issues. To investigate this hypothesis, we performed a retrospective chart review of 170 infants with DS between birth and 6 months of age who were referred to the Down Syndrome Program at Riley Hospital for Children from August 2005 to July 2010. We analyzed comorbidity in infants with upper airway obstruction (UAO) or a feeding problem with and without a severe congenital heart defect. Our data show that 33% of infants without a cardiac defect have identified UAO while 44% with a severe cardiac defect have identified UAO. Additionally, 59% of infants without a cardiac defect compared to 49% with a severe cardiac defect have a feeding problem. With the knowledge of these comorbid clinical features in DS, healthcare providers may be able to identify potential complications affecting infants with DS earlier in life.
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    Low dose EGCG treatment beginning in adolescence does not improve cognitive impairment in a Down syndrome mouse model
    (Elsevier, 2015-11) Stringer, Megan; Abeysekera, Irushi; Dria, Karl J.; Roper, Randall J.; Goodlett, Charles R.; Biology, School of Science
    Down syndrome (DS) or Trisomy 21 causes intellectual disabilities in humans and the Ts65Dn DS mouse model is deficient in learning and memory tasks. DYRK1A is triplicated in DS and Ts65Dn mice. Ts65Dn mice were given up to ~ 20 mg/kg/day epigallocatechin-3-gallate (EGCG), a Dyrk1a inhibitor, or water beginning on postnatal day 24 and continuing for three or seven weeks, and were tested on a series of behavioral and learning tasks, including a novel balance beam test. Ts65Dn as compared to control mice exhibited higher locomotor activity, impaired novel object recognition, impaired balance beam and decreased spatial learning and memory. Neither EGCG treatment improved performance of the Ts65Dn mice on these tasks. Ts65Dn mice had a non-significant increase in Dyrk1a activity in the hippocampus and cerebellum. Given the translational value of the Ts65Dn mouse model, further studies will be needed to identify the EGCG doses (and mechanisms) that may improve cognitive function.
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    Morphological Integration of Soft-Tissue Facial Morphology in Down Syndrome and Siblings
    (2011-12) Starbuck, John M; Reeves, Roger H; Richtsmeier, Joan
    Down syndrome (DS), resulting from trisomy of chromosome 21, is the most common live-born human aneuploidy. The phenotypic expression of trisomy 21 produces variable, though characteristic, facial morphology. Although certain facial features have been documented quantitatively and qualitatively as characteristic of DS (e.g., epicanthic folds, macroglossia, and hypertelorism), all of these traits occur in other craniofacial conditions with an underlying genetic cause. We hypothesize that the typical DS face is integrated differently than the face of non-DS siblings, and that the pattern of morphological integration unique to individuals with DS will yield information about underlying developmental associations between facial regions. We statistically compared morphological integration patterns of immature DS faces (N = 53) with those of non-DS siblings (N = 54), aged 6–12 years using 31 distances estimated from 3D coordinate data representing 17 anthropometric landmarks recorded on 3D digital photographic images. Facial features are affected differentially in DS, as evidenced by statistically significant differences in integration both within and between facial regions. Our results suggest a differential affect of trisomy on facial prominences during craniofacial development.
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    Rescue of the abnormal skeletal phenotype in Ts65Dn Down syndrome mice using genetic and therapeutic modulation of trisomic Dyrk1a
    (Oxford, 2015) Blazek, Joshua D.; Abeysekera, Irushi; Li, Jiliang; Roper, Randall J.; Biology, School of Science
    Trisomy 21 causes skeletal alterations in individuals with Down syndrome (DS), but the causative trisomic gene and a therapeutic approach to rescue these abnormalities are unknown. Individuals with DS display skeletal alterations including reduced bone mineral density, modified bone structure and distinctive facial features. Due to peripheral skeletal anomalies and extended longevity, individuals with DS are increasingly more susceptible to bone fractures. Understanding the genetic and developmental origin of DS skeletal abnormalities would facilitate the development of therapies to rescue these and other deficiencies associated with DS. DYRK1A is found in three copies in individuals with DS and Ts65Dn DS mice and has been hypothesized to be involved in many Trisomy 21 phenotypes including skeletal abnormalities. Return of Dyrk1a copy number to normal levels in Ts65Dn mice rescued the appendicular bone abnormalities, suggesting that appropriate levels of DYRK1A expression are critical for the development and maintenance of the DS appendicular skeleton. Therapy using the DYRK1A inhibitor epigallocatechin-3-gallate improved Ts65Dn skeletal phenotypes. These outcomes suggest that the osteopenic phenotype associated with DS may be rescued postnatally by targeting trisomic Dyrk1a.
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    Usage of and attitudes about green tea extract and Epigallocathechin-3-gallate (EGCG) as a therapy in individuals with Down syndrome
    (Elsevier, 2019-08) Long, Rachel; Drawbaugh, Montana L.; Davis, Charlene M.; Goodlett, Charles R.; Williams, Jane R.; Roper, Randall J.; Biology, School of Science
    Objective Usage of and views concerning alternative therapies in the DS community are not well documented. Some positive effects of green tea extracts (GTE) containing Epigallocathechin-3-gallate (EGCG) have been reported in individuals with DS and DS mouse models, but minimal improvements or detrimental effects of pure EGCG treatment have been reported in DS mouse models. Given the uncertainty about the effectiveness of these supplements, the goal of this study was to determine the relative prevalence of and attitudes about GTE/EGCG treatments among DS caregivers. Methods An anonymous survey about attitudes and usage of GTE/EGCG in individuals with DS was completed by caregivers of these individuals. Results GTE/EGCG treatment was provided by 18% of responding caregivers who were mostly younger, highly educated, and utilized scientific sources and other parents to influence their decision to use GTE/EGCG. Individuals with DS who received GTE/EGCG were characterized as less severely disabled. Most caregivers who did not give GTE/EGCG reported concerns about potential side effects and lack of effectiveness. Few caregivers consulted with medical providers about GTE/EGCG usage. Conclusions These results demonstrate a need for communication between caregivers, medical providers, and scientists about potential benefits and risks for adverse effects of GTE, EGCG, and other nutritional supplements in individuals with DS.