Physiological Abnormalities Associated With Down Syndrome

Study Overview
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Brief Summary
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The overall goal of this study is to evaluate biomarkers of oxidative stress, mitochondrial function, and DNA methylation (epigenetics) in order to determine the extent to which these biomarkers are related to cognitive, behavioral and adaptive function in Down Syndrome. The inter-relationship between measurable biomarkers and functional/cognitive abilities will move beyond genetics to provide unprecedented new knowledge and a broader understanding of the underlying pathophysiology and abnormal gene expression induced by trisomy 21.

Detailed Description
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The Investigators preliminary evidence indicates that people with DS have metabolic biomarkers associated with oxidative stress (GSH/GSSG) and reduced methylation capacity (SAM/SAH) as well as abnormal DNA methylation (epigenetics). The investigative team hypothesize that these abnormal metabolic processes contribute to abnormalities in behavior and development associated with trisomy 21; this connection has never been investigated. Confirming and expanding on the preliminary data would provide new understanding of the biological and functional etiology of the behavioral and developmental delays associated with Trisomy 21. Further, establishing the underlying relationship between metabolic abnormalities and behavioral/cognitive function over the age spectrum can provide strong support for the design of future treatments of individuals with DS aimed at improving their behavior and development. In addition, these biomarkers may also prove to be predictive biomarkers for the risk of developing ASD like behaviors or Alzheimer's disease in this population. Finally, examining the modulating role of diet in the severity of biological abnormalities will provide new information for lifestyle guidance to improve biomarkers and potentially minimize the medical co-morbidities associated with trisomy 21.

Official Title
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Physiologic Biomarkers Within the Functional Spectrum of Down Syndrome

Conditions
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Down Syndrome

Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 1. Participant or guardian ability to consent/assent and willing to comply with protocol requirements Exclusion Criteria: Trisomy translocation or mosaics. Untreated hypothyroidism Known history of liver disease, renal disease, Hepatitis B or C or HIV Recent infection with fever or requiring hospitalization within past 30 days. Any medical condition, use of medications, nutrient or herbal supplements that would interfere with the study results as determined by the PI Chemotherapy Recent surgery (within 2 months) Untreated Epilepsy Any chronic medical/behavioral condition and/or treatments that may interfere with study related outcomes, as determined by PI Dementia History of a significant adverse reaction to a prior blood draw Any other historical event/information that may, in the opinion of the PI, be a reason to exclude the child from participation.

Ages Eligible for Study
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Minimum Age: 3 Years
Maximum Age: 50 Years

Sexes Eligible for Study
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All

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Down Syndrome (DS)<br>120 clinically confirmed full trisomy 21, age 3-50 years of both sexes will be recruited as the target study population. Half of the individuals (n=60) will be children (3-17 years of age) while half (n=60) will be adults (18-50 years of age) | |
| Typically Developing Controls<br>60 typically developing individuals age 3-50, age and gender matched to at least one participant with DS. Half of the controls (n=30) will be age and gender match to children with DS and half (n=30) will be age and gender matched to adults with DS. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Microbiome Analysis | Stool will be collected for Microbiome Analysis on cases and controls | 2 years | 
| Mitochondrial Function Analysis | The Seahorse XR extracellular flux analyzer will be used to measure mitochondrial function in cases and controls | 2 years | 
| Oxidative Stress Analysis | Thiol measurements will be collected and analyzed between cases and controls | 2 years | 
| Immune Function | Salivary measurements of cytokines will be collected on cases and controls | 2 years | 
| Metabolomics | Urine will be collected for metabolomics analysis on cases and controls | 2 years | 
| Epigenetics | Epigenetics will be evaluated on cases and controls | 2 years | 
| Folate Receptor Alpha Autoantibody (FRAA) | Serum will be collected for FRAA analysis on cases and controls | 2 years | 
| Thyroid Function | Thyroid measures of Thyroid Stimulating Hormone (TSH), T3, Reverse T3 and free and total T4 will be evaluated on cases and controls | 2 years | 
| Diet | Examine the modulating role of diet in the severity of biological abnormalities will provide new information for lifestyle guidance to improve biomarkers and potentially minimize the medical co-morbidities associated with trisomy 21. Dietary contributions will be evaluated on cases and controls | 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Down Syndrome, Typically Developing Participants, Children, Adolescents, Adults