3.21 Three two one  
3.21 A newsletter that examines the medical aspects of Down syndrome
Vol. 1, No. 2, April 1998
  Reprinted with the permission of Karalee Wetzel

Being Politically Correct(ed)
The last edition of 3.21 contained language that was not "People First". People First language puts the noun (child) before the adjective (Down syndrome). I honestly did not know what People First language was until some of the readers let me know.
While this type of discussion was what I was trying to stay away from (and concentrate on the medical/therapy aspect), I do not want to offend or keep parents from reading this info. I will edit for People First language, and will do my best to catch deviations.

A Really Good Book
There is not much in the literature about learning styles or reading strategies for kids with DS. Many of the "experts" believe, however, that they use more visual than auditory cues because they have less auditory memory. Phonics, for example, would be less effective for those with auditory deficiencies.
Teaching Reading to Children with Down Syndrome was written by Patricia Logan Oelwein (Woodbine House, 1995). Oelwein believes that nearly all children with DS can learn to read, and that reading will significantly increase their verbal language skills.
There are tons of hints in this book along with step-by-step instructions that make sense. Here is the first step. Take tagboard/cardboard and cut into card-sized rectangles. Glue on pictures of family members and print their names below on the card. Then make smaller cards with the names printed on them so that the child can try to match the name card to the card with the picture and the name.
Even if your child is not ready for the word matching part, other skills may be developed from these exercises. I made cards with each family member, plus a few extra. Jen (almost age 5) loves them, but is not yet interested in matching. However, she did take the puppy card (with Dalmatians stickers on it) to our mutt, showed the card to the very confused dog, and tried to explain to him in her gibberish that he, too, was a puppy. She also called her brother Tanner (instead of Baby) for the first time ever when she handed him his photo. We have been trying to get her to do that forever.

This Issue
SOD-1 and its connection to free radical damage, biochemistry 101 looks at fats and cell membranes, a girl with DS and no signs, and treatment of aggressive adults with DS.

Next Issue
Obesity in DS, metabolism + other good stuff

Her blood said DS, but no other sign
A young girl had full trisomy 21 in her skin cells and lymphocytes. The placenta was mosaic (73%) for trisomy 21, meaning 73% of the placenta cells were DS, while 27% were normal.
What is fascinating is the girl shows no physical signs of DS. The physicians used a checklist called "the Jackson checklist" which lists 25 signs of DS.
What is probably going on is that certain of her cell lines have DS, while others (e.g. brain) do not. It will be interesting to watch her progress.

     Avrampoolos, et al. (1997) A case of apparent trisomy 21 without the Down's syndrome phenotype. J-Med-Genet. 34(7), 597-600

Free Radical Damage
Free Radicals. Antioxidants. The stuff vitamin commercials are made of. But there is more to this than clever marketing.
The quick and dirty explanation is that free radicals hurt cells and antioxidants protect them.
The more detailed explanation goes like this. Free radical agents are missing an electron. They are attracted to chemicals and cells that have lots of electrons. They are especially attracted to brain cells that have lots of electrons around the cell membrane.
If given a chance, a free radical will steal an electron from the cell membrane. As electrons are stolen the charge around the membrane changes. Lots of stolen electrons, and the charge is affected enough to disrupt what goes in and out of the cell. Eventually, the cell may enter "apoptosis". Apoptosis, otherwise known as programmed cell death, is when a cell will "commit suicide" so the organism does not waste precious resources on a damaged cell. Apoptosis is normally protective to the organism. However, brain cells do not reproduce, so once a brain cell is gone, it is never replaced.
Free radical damage occurs naturally and it occurs all of the time. There are numerous sources of free radicals. Oxygen is reactive enough to produce the energy needed to do the amazing things our bodies need, but also reactive enough to cause free radical damage to our bodies. Oxygen can also become dangerous when reperfussion injuries occur. (Reperfussion injuries occur when a part of the body is cut off from oxygen. The oxygen is only "partially processed", and when the area starts to function again, the "partially processed" oxygen molecules are radicals.) Other sources are environmental toxins and imbalances of purines (parts of DNA.).
So what's the deal with free rads in DS???
Clearly the connection is unproven. We know there is more lipid peroxidation (lipids that have had an electron stolen) in DS, and we know that SOD-1, an enzyme that protects against radicals is overproduced in DS. But is it overproduced because there are three instead of two copies of the enzyme, or is it overproduced to protect the cell?

The SOD-1 reaction.
  1. O* SOD-1 H2O2 (hydrogen peroxide)
    Here, SOD-1 takes an oxygen radical to hydrogen peroxide

  2. H2O2 GPX (glutathione perroxidase) H2O + H (or catalase)
    Now, glutathione peroxidase converts the hydrogen peroxide to water

  3. H2O2 + Fe (iron) OH-+OH* (hydroxyl radicals)
    or if iron is nearby and unattached, hydrogen peroxide will be converted to very toxic substances

The above reaction shows one theory of how an overproduction of SOD-1 could have harmful affects on the cell. Here SOD-1 takes oxygen radicals and converts them to hydrogen peroxide(H2O2). While most would think H2O2 is harmless, it is actually quite reactive in the body. The enzyme, gluthathione peroxidase (GPX) takes hydrogen peroxidase to water. This is normal and protective. However, if there is iron in the body that is not bound to anything, it may react with H2O2 to create hydroxyl radicals which are extremely toxic. This is called the Fenton Reaction. The problem with this theory is that iron is nearly all bound, so the iron would not react.
Another theory is the extra SOD-1 would "push" the reaction, and produce too much H2O2 for GPX or catalase to keep up with. Finally, SOD-1 may be increased because in response to an increase in free radicals and not because it has three copies which would mean it could be protective.
Without knowing if SOD-1 overproduction in itself is harmful, it is difficult to know if a goal is to turn that enzyme down.
There are hundreds of journal articles about SOD-1 in DS and in Alzheimer's as well. The following are short discussions about the ones that seemed most interesting and revealing.

The affects of above normal SOD-1 levels/activities
Most of what is known about SOD-1 in DS has been discovered by using transgenic mice. Transgenic mice are genetically altered. A mouse has been engineered that will overproduce SOD-1, and the findings about these mice are interesting.
In these mice, the parts of the brain that most overexpressed SOD-1 were the areas related to Alzheimer's disease and Parkinson's disease. These mice also have neuropathology's in their tongues. They include destruction of axons, development of small terminals, and other differences. These abnormalities are similar to those seen in aging mice, rats, and in patients with DS(Groner, et al, 1994).
Probably the most fascinating finding is that the SOD-1 overavtivity is not 50% higher in all cells as most believe. In fact, the level of activity that is above normal for that cell type varies significantly. While the red blood cells of the transgenic mice have SOD-1 activity only 1.09 times higher than normal, the brain cells have activity levels 1.93 times higher. Some other cells tested (with the increase over normal) include the kidney (1.18 times), heart (1.69 times) shin (1.73 times) and the thymus (1.49 times) . Also of interest is that while the brain cells(with a high level of SOD-1 activity) showed increased lipid peroxidation, liver cells (with nearly normal levels) did not.(Ceballos-Picot, et al., 1991).
Finally, these mice show signs of "premature thymic involution", which would decrease one's immune response because the immune cells are being kicked out of the thymus before they are fully mature. If you remember the last issue of 3.21, that was also a problem with zinc deficiency. The zinc is most likely the key to the thymic problems. Since SOD-1 is dependant on zinc, it binds it, and an overproduction of SOD-1 would tie up zinc, creating a shortage of free zinc.(Nabarra, et al., 1996)

SOD-1 in people with DS
One research study looked at the cerebral cortexes of fetuses with DS. While the SOD-1 activity was not as high as the transgenic mice brain cells, it was still 60% (± 5%) higher than normal. Lipid persoxidation was increased 36% (± 4%) over normal. In addition, there was evidence for differences in composition of phospholipids(an ingredient in the cell membrane) as compared to normals (Brooksbank, 1984)
Patients with DS (along with transgenic mice overexpressing SOD-1) had a significant reduction in the production of the prostaglandin PGE2.(Minc-Golomb et al, 1991). PGE2 is involved in clotting blood, and the decrease found in DS may explain the one health benefit they get; very clean vessels and generally no athlerosclerosis

The connection to Gluthathione Peroxidase (GPX)
In the late 70's, Jerome Lejeune (who discovered DS was caused by an extra #21 chromosome) along with his team, looked at the GPX activity levels in children with DS and plotted them against their IQs. They found a significant correlation (.58) showing that those who had more GPX had a higher IQ. (Sinet, 1979), An Australian team looked at 2 cell lines; one had an increase in only SOD-1, not in GPX or Catalase. Those cells had an increase in H2O2 production and cell death. The other line had an increase in SOD-1 along with an increase in GPX and catalase. These cells had no increase in H2O2 production or cell death. This would support the theory that SOD-1 overproduction is alright if GPX is increased to keep up. (deHaan, et al. 1996).

Can GPX be increased?
Treating cells with eicosapentaenoic acid (EPA), which is an n-3 fatty acid, increased both the membrane phospholipid concentration and the activity of GPX. Fish enriched diets (which have large amounts of n-3 fatty acids) have had similar effects. (Joulain, et al., 1994)

What can Antioxidants do to help?
If free radicals are being overproduced, either from an unknown source or an overproduction of SOD-1, antioxidants can partially protect cells. Researchers at Harvard Medical School looked at brain cells from fetuses with DS and compared them to normals. In cultures, the DS cells had a 3 to 4 increase in oxygen radicals and died much faster then the normal brain cells. They repeated the culture, but this time pretreated the cells with different antioxidants. Some of the antioxidants were able to significantly increase the number of viable cells compared to no antioxidants. Some of the most effective were vitamin E, N-acetyl-cysteine, and Catalase (an enzyme that works similarly to GPX, but in a different part of the cell) (Busciglio & Yanker, 1995). While antioxidants may seem like the solution, there are many questions remaining. Can the antioxidants get to the brain cells in concentrations high enough to offer protection is just one. What is the amount needed in DS?

A study that argues all of this
One study looked at the frontal cortex of deceased adults with DS. Activity levels of SOD-1 and GPX were similar to controls (deceased normals) as was lipid peroxidation. They did find, however, that there was a significant decrease in a neurotransmitter named Chat (Hayn, et al, 1996). This was the only study I could find that suggested that SOD-1 is NOT a key to the problems associated with DS. How exactly the pieces fit together will take much more research.

     Booksbank, B. & Balazs, R. (1984) Superoxide dimutase, glutathione peroxidase and lipoperoxidation in Down's syndrome fetal brain. Brain-Res., 318(1), 377-44.
     Busciglio, J. & Yanker, B. (1995) Apoptosis and increased reactive oxygen in Down's syndrome neurons in vitro. Nature. 378, 776-778.
     Ceballos-Picot, I., (1993) Transgenic mice overexpressing copper-zinc superoxide dimutase: a model for the study of radical mechanisms and aging. C-R-Seance-Soc-Biol-Fil. 187(3), 308-323.
     Ceballos-Picot, I., et al. (1991) Neuronal specific expression of human copper-zinc superoxide dimutase gene in transgenic mice: animal model of gene dosage effects in Down's syndrome. Brain-Res. 552. 198-213.
     Groner, Y., et al. (1994) Cell damage by excess CuZnSOD and Down's syndrome. Biomed-Pharmother. 48(5-6), 231-240.
     de Haan, J., et al. (1996) Elevation in the ratio of Cu/Zn-superoxide dismutase to glutathione peroxidase activity induces features of cellular senescence and thie effect is mediated by hydrogen peroxide. Hum-Mol-Genet. 5(2) 283-292.
     Hayn, et al. (1996) Evidence against the involvement of reactive oxyfgen species in the pathology of neuronal death in Down's syndrome and Alzheimer's disease. Life Science. 59(7) 537-544.
     Joulain, C., et al. (1994) Increased glutathione peroxidase activity in human blood mononuclear cells upon in vitro incubation with n-3 fatty acid. Biochem-Pharmrol. 47(8), 1315-1323.
     Minc-Golomb, et al. (1991) Gene doseage of CuZnSOD and Down's syndrome; diminished prosteglandin synthesis in human trisomy 21, transfected cells and transgenic mice. Embo-J. 10(8), 2119-2124.
     Nabarra, B. (1996) Transgenic mice overexpressing the human Cu/Zn-SOD gene: Ultrastructural studies of a premature thumic involution model of Down's syndrome (Trisomy 21). Lab-Invest. 74(3), 617-624.
     Sinet, P., Lejeune, J. & Jerome, H. (1979) Trisomy 21 (Down's syndrome) glutathione peroxidase, hexose monophosphate shunt and IQ. Life Science. 24, 29-34.

Serotonin drug decreases aggression in adults with DS
Aggression is common in adults with DS and difficult to control. An anti-depressant (trazodone), along with a diet that enhanced seretonin (a neurotransmitter) decreased aggression by 96%. Those with DS maybe low in seretonin, and this may lead to research for others DS problems.

     Gedye, A., (1991) Serotonic treatment for aggression in a DS adult showing signs of AD. J-Ment-Def-Res, 35, 247-58.

To subscribe to 3.21 for 5 issues, send $18 in US/$22 outside for family, $25 in US/$29 outside for organizations to:
Karalee Wetzel, RR2 Box 79P, Grand Forks, ND 58203

This newsletter is not associated with any organizations.
The information in 3.21 is not intended as medical advice. Discuss any treatments with your physician.

National Down Syndrome Congress is having their annual conference Aug 7-9 in Dallas. Call the Congress for more info.

Looking for Moms with more than one DS birth
Jill James from the FDA is doing a study looking for a gene defect in moms (that topic in a future edition) that may increase the risk of having a child with DS. She would like to get a blood sample (she covers the cost) from any mom who has delivered more than one child with DS. If you know of someone who is willing, please send me a note or email Karalee.A.Wetzel@dmu.edu.

There is a new organization set up to fund research regarding DS. PLEASE send donations to:
DS-FIRST, 3880 Johns Lane, Midland, MI 48642

Biochem 101. Lipids, cell membranes and other cool stuff

a group of substances found in the body that are not soluble in water. They include triglycerides, cholesterols, fatty acids, and others.
3 carbons with a fatty acid sting hanging off of each. Triglycerols are how fat is stored in the body.
water hating/non-polar. In the body, hydrophobic items clump together or fold in a water environment
water loving/polar
3 phosphates, each with a lipid chain hanging off it. Are often in cell membranes, where one lipid chain will be polar (hydrophilic), so it is the "head" facing the water environment, and the other 2 chains are the non-polar, hydrophobic tails hiding between the heads. (The "head" is always shown as circular in text books so I'm guessing the chain comes back towards the tails and actually is round looking.)
cell membrane
what surrounds the cell is called a "lipid bilayer" or 2 layers of lipids. Imagine the below figure stretches around a cell. The "polar", water-loving heads face the outside and inside of the cell (both have lots of water), while the hydrophobic tails are safe from water in-between the heads.
What's that big protein thing? That could be a receptor that tells the cell what is going on, a channel for items to move in and out, or many other things made of protein that get stuck in the membrane.

Fat and calories Many believe that, other than the effects on vessels, ingesting 2000 calories of fat means the same as 2000 calories of carbs or protein. Energy is energy, right? What the calories give you is potential energy. What it does not tell you is digesting/processing differences. Fat takes nearly no energy to digest/transport/store, so 2,000 calories of fat would mean about 2000 calories of useable energy (or thigh glob). Carbs and proteins take more energy in digesting (around 20%), so eating 2000 of those calories means about 1600 calories of useable energy.

  Revised: July 2, 1999.