3.21 Three two one  
3.21 A newsletter that examines the medical aspects of Down syndrome
Vol. 3, No. 1, June 2000
  Reprinted with the permission of Karalee Wetzel

Due to time limits, 321 will become a free, twice-a-year newsletter. Those who subscribed for the year got their checks returned, and will continue to receive the newsletter.

This issue: MTHFR and risk of DS, more on Alzheimer's, fertility, eye problems and more.

Medical Problems
Doctors in the opthamology department at Brown University Medical School looked at visual acuity in 68 children with DS. Of those examined, 22% had amblyopia, which is a visual defect in one eye, while 24% had bilateral vision tests of worse than 20/50. The authors stated these results of visual problems running about 50% in the DS population is higher than previously thought, and suggested (guess what) frequent screening. (The next article shows vision problems even higher)

Tsiaras, W. et al (1999) Amblyopia and visual acuity in children with Down's syndrome. Br-J-Ophthalmology. 83(10)1112-4.

What medical problems are kids with DS most likely to have and who will they see regarding those problems? That is what researchers in Australia set out to find. They contacted families of school aged children with DS. Less than half of the children had cardiac problems. More than half of the kids had ear problems, and the kids with DS were 17 times more likely than normal kids to require tubes in their ears. Three quarters had visual problems of some type, and these kids were 5 times more likely than normal to wear glasses. The most common specialist the kids were seen by was the ENT (ears/nose/throat).

Menopause in DS
While the age of menopause is around 53 in the normal US population, women with DS go through it about a decade earlier at age 42. That age is correlated with the onset of dementia in those with DS.
It is known that decreased levels of estrogen can increase the risk of dementia in women, and that estrogen replacement can decrease those risks in postmenopausal women. Estrogen replacement therapy should be considered as well in postmenopausal women with DS. (Progesterone needs to be added for women who still have a uterus to avoid endometrial cancer.)
Estrogen replacement may also decrease osteoporosis, incontinence and heart disease.

     Cosgrave, M. et al. (1999). J-Int-Disab-Res. Age of onset of dementia and age of menopause in women with DS 43:461-5.

Maternal gene defect and risk of having a child with DS
Hard work and persistence paid off for Dr. Jill James. Her research regarding the MTFHR gene defect was published in the January edition of the Journal of Clinical Nutrition.
Jill found moms that had a child with DS, and asked them to recruit a friend who was similar in age but who did not have a child with DS to use as a control. Blood was drawn to look for the MTHFR mutation. MTHFR is a gene needed to "activate" folate, which is required for proper cell division. MTHFR is mutated in more than 30% of the normal population, and most people will have no signs or symptoms.
Diet questionnaires were analyzed, along with questions regarding the pregnancy and issues such as alcohol consumption.The results were as followed:

It would be wonderful if one could say that supplementing with folic acid is the entire answer. Unfortunately, the puzzle is not completely solved. That is because 26% of the DS moms studied had no MTHFR defect. In addition, 28% of the DS moms were taking vitamins with folic acid prior to conception.
However, Jill's findings do show that having the MTHFR gene defect does increase the risk of having a child with DS by 2.6 times.
I discussed this research with my nutrition professor, who then discussed it with my class for about 20 minutes the following day. The following is a mix of what he said and what I have learned.
The implications of this research is that women of childbearing years need to supplement their diets with folic acid. Since the defect in DS occurs in most pregnancies just prior to ovulation, and most pregnancies in the US are unplanned "surprises", this is something that women need to do everyday. It is not enough to take prenatal vitamins after it is known that one is pregnant. That is too late to prevent DS, and it is also too late to prevent neural tube defects, the other birth defect that is higher in women carrying the MTHFR defect. In addition, even if one ate the suggested 5-6 servings of fruit and veggies per day, it would not give a woman enough folic acid to prevent these problems. One needs to take a multivitamin that contains 400 micrograms of folic acid.
If one is known to be at risk, they should add at least another 400 mcg, although the jury is still out on exactly how much is needed. Taking a standard multivitamin can't hurt, and if you have this defect (and much of the population does), it may decrease your risk of vascular disease. One interesting thing about folic acid is it is absorbed better in the supplemented form that the natural form.
Please encourage women you know take a regular multivitamin.

     James, SJ, et al (1999) Am-J-Clin-Nut. Abnormal folate metabolism and mutation in the MTHFR gene may be maternal risk factor for DS. 70:495-501

The 21st chromosome has been completely mapped. Analysis revealed 127 known genes, 98 predicted genes, and 59 pseudogenes (whatever they are).
Since chromosome 21 is not only important in DS, but in Alzheimers and ALS, this is very promising for many diseases. If you are interested in the genes they know, many websites have them listed.
While I was in the middle of writing this newsletter, news came out that the entire genome has been mapped, so I guess the news about chromosome 21 is not as exciting to the world, but it still is for most of us.

Screening pregnant women for DS
The triple marker prenatal test screens women for a variety of birth defects in their unborn children. It looks at levels of estrogen, hcg, and alpha-fetal protein. Depending on the cut off levels of those hormones used, sensitivity (did the test catch what it was supposed to) ranged from 75-92% for catching DS, but it was less sensitive for other trisomies. Unfortunately, sensitive tests often have many false-positive results, so decisions about treatment or the pregnancy should never be made based on one test.
We learned in class that the triple marker is very sensitive for women +35 years old, but will only catch about 50% of the defects in younger women. Both age groups had about a 5% false-positive rate, so 1/20 women who were told their child may have serious problems had a perfectly normal baby.
While prenatal testing is thought by many to be used as only an abortion test, that is not true any more. Over 100 diseases can be treated or managed in-utero. In addition, if surgery is required immediately after delivery, mom can deliver at a bigger hospital with the appropriate resources and trained surgeons.

     Huderer, D. et al (2000). The triple marker test in predicting fetal aneaplody. Eur-J-Obgyn. 88(1) 49-55.

AD and DS
Two genes have been implicated in increasing the risk of developing Alzheimer's Disease (AD). Those two genes are Presenilin-1 (PS-1) and alpha-1-antichymotrypsin (ACT). Levels of PS-1 and ACT were measured in adults with DS and compared to adults without DS. Those with DS had no more defects in those 2 genes than those without DS. Also, the adults with DS and dementia had no correlation to those genes being defected. While those 2 genes maybe correlated with dementia in normals, they do not seem to be connected to DS dementia.

     Tyrrell, J et al. (1999) Presenile 1 ans alpha 1 antichymotrypsin polymorphisms in DS 88(6) 616-20

S-100 protein and DS/Alzheimer's
S-100 is a protein on chromosome 21. It has been implicated in causing some of the mental retardation in DS, and has also been implicated in Alzheimer's Disease (AD). Brains of those with DS aged 17 weeks gestations to age 68 years old were analyzed. It was found the level of S-100 was 2 times higher than normal. While none of the young brains had signs of AD, there were neurofibril tangles in the older brains. In addition, the number of S-100 astrocytes correlated with the number of neurons overproducing beta-APP (a precursor to AD).
Some researchers believe that S-100 may dysregulate the cell cycle, leading to either cell death, or causing the cell to make the defective brain proteins associated with AD.
Another study seemed to support the S-100 connection. Patients with DS aged 13-65 years old were examined. There was a significant correlation between S-100 levels and patient's age (the older the patient, the more S-100), and there was also a connection between the S-100 level and the number of beta-amyloid plaques.      Griffin, WST. et al (1998) Life long expression of S100 in DS. Neurobiol-of-Aging. 19(5), 401-5
     Royston, MC et al (1999) Overexpression of S100 beta in DS. Neuropathol-Appl-Neurobiol. 25(5) 387-93.

Gonadal Function in Young Women with DS
Thirteen women with DS in their early 20's were examined by ultrasound and also had blood analyzed to predict fertility. Ultrasound showed normal uterine and ovarian sizes. All of the ovaries contained follicles.
Some of the blood hormone levels were off average slightly, but all were within normal limits.
Women with DS in this study seem quite fertile. On a sidenote, it seems that Norplant and Depro shots have become the most popular birth control methods in women with special needs.

     Angilopoulon, N (1999) et al Gonadal function in young women with DS. Int-J-Gynaecol-Obstet. 67(1) 15-21

"DS Mice" have abnormal stomach innervation
Trisomy 16 mice (the mouse model for DS) were studied to find out if the nervous system in the stomach was normal. It was found that compared to normal mice, trisomy 16 mice had stomach neurons that were immature and appeared later.

     Li, J (1999) abstract (article in Chinese)

Update on Autism
The debate regarding vaccines and autism was recently played out in front of congress. The House of Representatives held hearings and heard testimony both suggesting vaccines causing autism and those against that theory. The most interesting testimony came from a GI researcher named Wakefield. He presented his findings that kids with autism have colons that resemble Ulcerative Collitis. In addition, he discussed papers by O'Leary and Kawashima in which measles virus was found in the guts of those with autism but not in the guts of normal children. The virus was identified as the one used in vaccines and not what could have been "caught". While that alone does not prove a connection between autism and vaccines, it is very interesting.
If you are interested in reading the testimony, go to the House of Representative's website and you should be able to locate it.

Health concerns of adults with DS
As our kids with DS get older, different health concerns pop up than what we worry about when they are young. This study looked at two groups of adults with DS. One group was less then 50 years old and the other was more than 50.
The results of the combined group showed the following problems:

The authors concluded that many of these problems are treatable and preventable with routine health care. Preventing these health problems would lead to an increased quality of life for those with DS.

     vanAllen, M (1999) Healthcare concerns and guidelines for adults with DS. AM-J-Genetics 89(2), 100-1

Please send any ideas, good websites or articles of interest to me at my email or regular address.

This newsletter is not associated with any organization.
The information provided in 3.21 is not intended as medical advice. Please discuss all treatments with your physician.

For those of you intending to travel to Disney or any major amusement parks, they have passes for children with special needs so that you can go to the front of the line.

Karalee Wetzel
675 35th St
Des Moines IA 50312

Revised: July 28, 2000.