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These neural tube defects (NTDs) exact a huge emotional and economic toll on families and medical services. The tragedy is that women could prevent this trauma simply by taking folic acid supplement in the two months before they become pregnant.
Traditionally known as "the curse of celts", NTDs are at least twice as common in people of celtic ancestry. So it is fitting that this "curse" shoul now be lifted by Irish scientists at Trinity College Dublin and The Health Reserach Board, in cooperation with National Institute of Child Health and Human Development in Washington DC, which has granted the Irish scientist 600.000 UD in the past three years.
And it is also fitting that many Irish women have contributed to the discovery by giving blood samples early in pregnancy. Some 50.000 of the samples are still in freezers at Trinity´s labs, taken from pregnant women at the Coombe, the Rotunda and the National Maternity Hospital, Holles Street.
Those samples were invaluable to Trinity team, led by Prof. John Scott, of the department of Biochemistry, and Dr. Peader Kirke, of the health Research Board, as they put together the complex genetic puzzle which explains the cause of three-quarters of NTDs.
They found the first piece of the jigsaw when they learned that the risk to foetus of developing NTD varies eightfold, in per 1000 of having a baby with NTD. But reduce the status to 150 microgram - still within normal range - and her risk will magnify to 6.0 per 1000.
Diet was clearly significant, but folate level alone did not explain the whole story. There had to be a genetic link, especially considering that NTDs are more common in some gene pools than others, regardless of folic acid levels.
The next piece of the jigsaw was the discovery that Irish women who subsequently gave birth to children with NTDs had abnormally high levels of homocystein, a metabolite.
This implicated anyone of three possible enzymes one of which was 5,10 methylenetetrahydrofolate reductase. When Prof. Steve Whitehead did a genetic analysis for reductase in people with spina bifida and compared them with a control-group, he found that abnormal reductase accounts for 13% of spina bifida.
The links is so convincing that mutations concerning this enzyme or one of the other two identified are almost certain to be responsible for another 60% of cases, in all accounting for three quarters of NTDs, says Prof. Scott.
The significance to the developing embryo of the discovery of role of reductase is this: the enzyme needs folic acid to make DNA, and if the embryo cannot make DNA rapidly enough, it cannot divide cells fast enough.
The genetic mutation in the enzymes prevents the embryo from metabolising folic acid normally, giving them a higher-than-normal requirement for folic acid in order to mantain adequate levels of cell division.
If the foetus which inherit this defects get a massiv injection of folic acid from its mother´s blood stream, it will probly be normal, but if does not, it is likely to have a neural tube defect.
The antonishing rapidity with which this cell division happens is crucial to the story. It takes the neural tube only four days to close, and without sufficient folate, the cells cannot divide rapidly enough and the neural tube remains open.
The extent of opening can vary from slight and insignificant to profound and fatal.
Some people with NTDs are not diagnosed until they receive spinal x-rays in adulthood, while others are so badly affected that they die soon afther birth.
This information is critical for any woman who is thinking about becoming pregnant, because NTDs occur during a critical window of development between the 24th and 28th day of gestation - before many women even know that they are conceived.
Six percent of people inherit the genetic mutation which prevents them from metabolising folic acid properly and therefore puts them at the risk of NTDs. So why are most of these not born with NTDs?
A foetus which has this problem metabolising folic acid will be able to close its spinal column during the crucial four-day opportunity to do so if it gets huge boosts of the micronutrient from its mother´s blood-stream.
This is where supplementation comes in. While screening for the genetic defect is a possibility, it may be more pratical simply to fortify all womens diet with folic acid, not just those at risk.
Prof. Scott predicts that governments, including the Irish, will decide to fortify flour and bread with folic acid in an effort to prevent NTDs. Breakfast cereals are already fortified and some milks are as well.
The best advice for any woman, who could become pregnant - whether she is planning to or not - to take 400 micrograms of folic acid per day throughout her child-bearing years, either as a supplement or in fortified foods.
Another significant finding of the research is that fathers are almost as important as mothers in NTDs. In order to inherit a strong risk of spina bifida, the foetus must have two parents with genetic defect. In everybody´s genes there are two copies of a piece of genetic information. Those two bits are read off and give a message to make protein, which is an enzyme - in this case reductase.
If you are normal, you have two normal copies. If you are heterozygote, you have one abnormal and one normal copy, and if yoy are homozygot you have two abnormal copies of the enzyme.
In order to inherit the defect, the foetus needs to be homozygot - in other words it needs two copies of the faulty message, one from the mother and one from the father.
The Trinity team´s breakthrough will eventually result in identification of the other genes involved in the so-called folate-responsive NTDs, says Prof. Scott. Since these account for 75% of all cases, most NTDs will soon be avoided.
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