David H. Swenson, Ph.D. H. H. Dow Professor of Chemistry
Saginaw Valley State University
University Center, MI 48710
Trisomy 21 Research Conference
September 13-14, 2003. New Orleans, LA
  Permission granted by the author (revised 2006).

Our Research Questions Begin With a Survey of a Genetic Condition: Down Syndrome

  1. Gene overdose, but which?
  2. What are expected metabolic responses to gene dosage?
  3. What are predicted responses to gene dosage, and how can it be demonstrated?
  4. Is intervention possible?

DS Phenotypic Map

DS Phenotypic Map

Three Gene Systems of Interest on 21

Gene Reason for Interest
GART Purine Synthesis
SOD Superoxide Dismutase
CBS Folate and SAM Limitation MORE?

Let's Talk About GART

Gart is a gene system with 3 enzyme activities that make AMP (adenosine monophosphate) and GMP guanosine monophosphate).
AMP and GMP are two components of the genetic code, and are used elsewhere.
AMP and GMP are made in the body and excesses are broken down to uric acid (urate).
Children with DS typically have high urate levels in the blood.

What's Wrong With Urate?

Unresolved Questions About GART

Let's Talk About SOD

First step in conversion of metabolically generated superoxide to water.
Normal Oxygen Metabolism in Mitochondrion     right arrow     Superoxide
Uric Acid Production
Superoxide Dismutase is 50% Overexpressed in DS
GS Px and Catalase Are Not Overexpressed, So Peroxide May Build Up
O2·- H2O2 H2O
Superoxide   Hydrogen

What's So Bad About Hydrogen Peroxide?

Good Antibacterial Agent
From a bottle at 3% or
Produced by white blood cells via SO/SOD
Breaks Down, Especially in Presence of Iron, to Hydroxyl Radical: HO·
Attacks Cell Membranes
Attacks DNA
Initiates Lipid Peroxidation
Alzheimer's Disease Link?
Aging Link?
Retardation Link?

Let's Talk About CBS (Cystathionine Beta Synthase)

  1. Critical enzyme in synthesis of cysteine at expense of methionine
  2. Overexpressed 50% in DS
  3. In DS Critical Region
  4. Current research has focused on disruption of folate metabolism
  5. Overexpression may overproduce cysteine and collapse SAM cycle

Key Folate/SAM Issues in DS

Key Folate/SAM Issues in DS
The overexpression of CBS resulting in the trapping of folate and loss of adenosine from the SAM cycle as the cause of oxidative damage in Down Syndrome seems dubious.
SAM cycle is mighty but small. Is there enough adenosine is in the cycle to account for the high levels of uric acid found in the blood, without total obliteration of the cycle?
If cysteine levels are high, glutathione and its peroxidase should be able to handle oxidative damage loads.

How about another look at CBS?

Current Research Project on LK in DS

A philosophical note on oxidative damage by a single component of the human body:

Many of our studies evaluate the impact of a gene variance on a system-wide basis, yet, it may be responses in compartmentalized systems, such as neutrophils, that turn out to be the cause of the urate and oxidative damage. Hence, in most organ systems or cells of the body, elevated capacity for purine synthesis may be irrelevant because of feedback control. However, in a system that is depleting purines in its functions, this elevated capacity for purine production may serve as a larger input pipeline for output of SO and urate.

Our research is supported by grants from:

The Allen Foundation of Midland, MI, which funds research in nutrition and human health.

The Zdanowicz Family Foundation of Crown Point, IN, which funds research in Down Syndrome amelioration.

Early CBS studies were generously supported by FRIENDS of TRI, which is supporting portions of the proposed studies.

I thank my research colleagues, Dr. Vince Wilson of LSU, Dr. Jill James of the Arkansas Childrens Hospital, Dr. Sally Decker, Dr. Frank Dane, and Dr. David Stanton of SVSU, and Dr. Susan Daley of Children's Memorial Hospital. This research was carried out primarily by student workers including Joel Boehm, Jon Markey, Ron Nowak, Greg Spagnuolo and Olaf Rudnik. Early work on CBS inhibitors was carried out by Kevin Wiese.