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ScienceWeek
MEDICAL BIOLOGY: ON FOLATE AND AUTOANTIBODIES IN PREGNANCY
The following points are made by S.P. Rothenberg et al (New Engl. J. Med. 2004 350:134):
1) Neural-tube defects, which include spina bifida, anencephaly, craniorachischisis, and encephalocele, occur in approximately 1 per 1000 births in the US, and women who have one fetus with this complication are at increased risk in subsequent pregnancies.(1) Although periconceptional folic acid supplementation reduces the occurrence and recurrence of neural-tube defects by approximately 70 percent,(2,3) most women who are pregnant with a fetus with this complication do not have clinical folate deficiency.(4)
2) Though some polymorphisms for folate-pathway enzymes have been identified,(5) they cannot account for the 70 percent decrease in the incidence of this birth defect with folate supplementation. Studies in animals have suggested the importance of folate receptors in embryogenesis. Inactivation of both alleles encoding the mouse homologue of the human folate receptor alpha gene was uniformly fatal in embryos with neural-tube defects. Folinic acid given to the pregnant dams resulted in normal development in 80 percent of the embryos that lacked the folate receptor alpha gene in both alleles. Despite considerable research, no specific polymorphisms or mutations of the human folate receptor gene have been identified that might explain the reduction in the incidence of neural-tube defects with folic acid supplementation.
3) The authors have previously observed that the administration of an antiserum to folate receptors to pregnant rats resulted in the resorption of or multiple developmental abnormalities in embryos, and this prompted the authors to speculate that an autoantibody against folate receptors in women could induce similar embryonic and fetal abnormalities. Therefore, the authors developed an assay to measure these autoantibodies in the serum of women with a current or prior pregnancy complicated by a neural-tube defect and that of women without such a history.
4) The authors conclude: "Serum from women with a pregnancy complicated by a neural-tube defect contains autoantibodies that bind to folate receptors and can block the cellular uptake of folate. Further study is warranted to assess whether the observed association between maternal autoantibodies against folate receptors and neural-tube defects reflects a causal relation."
References (abridged):
1. Cragan JD, Roberts HE, Edmonds LD, et al. Surveillance for anencephaly and spina bifida and the impact of prenatal diagnosis -- United States, 1985-1994. Mor Mortal Wkly Rep CDC Surveill Summ 1995;44:1-13
2. Czeizel AE, Dudás I. Prevention of the first occurrence of neural-tube defects by periconceptional vitamin supplementation. N Engl J Med 1992;327:1832-1835
3. MRC Vitamin Study Research Group. Prevention of neural tube defects: results of the Medical Research Council Vitamin Study. Lancet 1991;338:131-137
4. Giles C. An account of 335 cases of megaloblastic anaemia of pregnancy and the puerperium. J Clin Pathol 1966;19:1-11
5. Christensen B, Arbour L, Tran P, et al. Genetic polymorphisms in methylenetetrahydrofolate reductase and methionine synthase, folate levels in red blood cells, and risk of neural tube defects. Am J Med Genet 1999;84:151-157
New Engl. J. Med. http://www.nejm.org
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ON NEURAL-TUBE DEFECTS AND FOLIC ACID
The elaborate architecture of the adult human brain is the final product of genetic programming, cellular interactions, and the interplay between the newborn and developing child and the external world. The early development of the nervous system is dominated by events that occur prior to the formation of connections between nerve cells, and these events are therefore not dependent on such connections or on interneuronal activity. These early events include the establishment of the primordial nervous system in the early embryo, the initial generation of neurons from undifferentiated precursor cells, the formation of the major brain regions, and the migration of neurons from their sites of generation to their final positions. When any of these processes go awry, because of genetic mutation, disease, exposure to drugs or chemicals, or the absence of essential biological nutrients, the consequences can be disastrous. Indeed, most congenital brain defects (defects apparent at birth and acquired during gestation in the uterus) result from interference with the normal programs of activity-independent neuronal development.
The term "neural tube" refers to the early embryonic structure (an actual hollow tube of cells formed by the infolding and closing of a long sheet of cells) that subsequently gives rise to the entire brain and spinal cord, and the term "neural-tube defects" refers to a group of congenital brain and spinal cord malformations resulting from errors in neural tube development. In general, neural-tube defects have serious viability consequences, and such defects are important factors in fetal and infant mortality. Each year in the US, approximately 4000 fetuses are affected, at least one-third of which are lost as a result of spontaneous or elective abortion.
Folic acids (pteroylglutamic acids; folacin; vitamin B(sub9; folate = the anion of folic acid) are widely distributed members of the vitamin B complex, particularly abundant in green leafy vegetables, liver, and yeast. Folates are essential for the synthesis of purines and pyrimidines, and a deficiency in humans results in *megaloblastic anemia and various birth defects in children born to folate-deficient mothers.
The following points are made by L.D. Botto et al (New England J. Med. 1999 341:1509):
1) The authors point out that each year *spina bifida and *anencephaly, the two most common forms of neural-tube defects, occur in 1 in 1000 pregnancies in the US and in an estimated 300,000 newborns worldwide. Although these severe conditions have been recognized since antiquity, it is only recently that substantial progress has been made in understanding the defects and in the area of prevention of these defects. The results of randomized trials now indicate that at least half the cases of neural-tube defects could be prevented if women consumed sufficient amounts of the B vitamin folic acid before conception and during early pregnancy.
2) Unfortunately, the full potential of folic acid to prevent neural-tube defects has not been realized, despite fortification of cereal products with folic acid in the US, and despite recommendations by various health agencies that women who could become pregnant should consume 400 micrograms of folic acid daily. Preventable disabilities continue to occur, and the underlying cause of neural-tube defects still remains unknown in most cases. Chromosomal abnormalities, single-gene mutations, and *teratogenic causes are identified in less than 10 percent of infants with neural-tube defects.
3) The clinical spectrum of neural-tube defects, in addition to spina bifida and anencephaly, also includes *encephalocele, *craniorachischisis, and *iniencephaly. The latter two are rare, but they tend to occur with disproportionate frequency in geographical regions with a high rate of neural-tube defects. In northern China, for example, the proportion of infants with neural-tube defects who have craniorachischisis or iniencephaly is 10 times as high as that in the US.
4) The authors point out that the development and closure of the neural tube is normally completed within 28 days after conception, before many women are aware that they are pregnant. It is generally accepted that neural-tube defects are caused by the failure of the neural tube to close, although it has also been suggested that a closed tube may reopen in some cases. The embryologic basis of the clinical variation in neural-tube defects is poorly understood. It has been proposed that in humans, as in mice, closure of the neural tube occurs at several sites, and that the clinical types of neural-tube defects differ depending on the site at which closure fails. Variations in the cellular mechanisms of closure at various sites may also underlie the clinical variation in neural-tube defects, as could differences in site sensitivity to type and time of exposure to teratogenic agents. At the present time, the genetic controls of the cellular mechanisms of closure have yet to be determined, although several possible associated genes have been identified in animal models.
5) There is considerable variability in the worldwide geographic incidence of the neural-tube defects spina bifida and anencephaly. North China, for example, has an incidence of these defects 6 times greater than south China, with north China having the largest recorded incidence in the world. Second highest is Mexico, third highest is Venezuela. The country with the lowest incidence of these defects is Switzerland, next lowest Denmark and The Netherlands. The incidence in Australia is significantly greater than the incidence in the US and the UK. The incidence in Argentina is approximately twice that in Uruguay. The following countries have an incidence of neural-tube defects less than the incidence in the US: Czech Republic, Belgium, Italy, The Netherlands, Denmark, Switzerland, Japan.
6) Concerning the biochemistry of folic acid, after entering the cell, folic acid, possibly with the aid of folate receptors, is involved in the transfer of carbon atoms that are used to synthesize nucleotides or that are involved in the methylation of a variety of substrates. These processes are regulated by numerous molecules, including enzymes and vitamins other than folic acid.
7) The authors conclude: "The urgent challenge facing medical and public health professionals with respect to neural-tube defects is how to translate our knowledge about primary prevention into practice. Every day, affected infants are born, and women with affected fetuses electively terminate their pregnancies. In the US, options for prevention include increasing the level of fortification of grains, increasing the consumption of foods now fortified with folic acid, and increasing the consumption of vitamin supplements containing folic acid. Improving the knowledge and changing the habits of women and medical professionals will be critical in efforts to realize the full preventive potential of folic acid. The global health community must make a concerted effort to meet the challenge."
New Engl. J. Med. http://www.nejm.org
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Notes:
megaloblastic anemia: A "megaloblast" is an abnormally large and immature red blood cell that does not function. Megaloblastic anemia is a dangerous blood disorder characterized by the production and dissemination of megaloblasts instead of normal red blood cells.
spina bifida: A congenital nerve-tube defect manifested at birth as a gap in the bone that surrounds the spinal cord.
anencephaly: A birth defect in which there is no brain, the skull does not close, and the spinal canal remains a groove. Anencephalic fetuses are always stillborn.
teratogenic causes: In general, any drug, agent, or event that results in abnormal fetal development.
encephalocele: (cranium bifidum) A congenital gap in the skull with herniation (extrusion) of brain substance.
craniorachischisis: A severe congenital malformation in which there is incomplete closure of the skull and spinal column.
iniencephaly: A cranial malformation involving exposure of the brain at the back of the head (occiput), often in combination with a severe neck flexure.
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