Prevention and Treatment of Neural Tube Defects.

By: Carole Ludwig Student of Broadview University.

Table of Contents

Common factors involved in Neural Tube Defects

Diabetes Nutritional deficiencies ....................................................................................................... 4 Pathogens.
.................................................................................................................................. 5

Mutagens and other environmental factors

Alcohol mercury Cigarette smoking Radiation pharmaceutical drugs

Treatment of Neural Tube defects ................................... 6

Common factors involved in Neural Tube Defects

Diabetes
Maternal diabetes increases oxidative stress and inhibits actions of embryonic genes, most notably, One called Pax-3, which is required for neural tube closure. Pax3 is also necessary for other parts of development.. (T. I. Chang, 2003) Congenital malformations, including neural tube defects (NTD's), happen more in the children of diabetic mothers. Pax-3, which encodes a transcription factor that regulates neural tube development, and that reduced expression of Pax-3 leads to neuroepithelial apoptosis. In study, NTDs were significantly increased in pregnancies when blood glucose levels were >250 mg/dl (P < 0.002) but not in moderately hyperglycemic pregnancies (150-250 mg/dl, P = 0.37).,. congenital malformations associated with diabetic pregnancy are caused by disruption of regulatory gene expression in the embryo in response to elevated glucose. Maternal diabetes increases the risk for neural tube, and other, structural defects. The mother may have either type 1 or type 2 diabetes, but the diabetes must be existing at the earliest stages of pregnancy, during which organogenesis occurs. Abnormally high glucose levels in maternal blood, which leads to increased glucose transport to the embryo, is responsible for the birth defect causing effects of maternal diabetes and expression of genes that control essential developmental processes is disturbed rigorous glycemic control during The birth of Organs can reduce the risk for congenital malformations, but that aggressive control should be initiated prior to conception. birth defects, particularly those affecting the neural tube and the heart, are significantly increased (up to 5-fold) in diabetic pregnancies. Pre-pregnancy counseling on the importance of glycemic control, and compliance with intensive insulin therapy, should be improved. However, another consideration is that altered production of hormones that regulate glucose homeostasis upon pregnancy necessitates modification of insulin administration, diet, and exercise in order to maintain appropriate glycemic control. It should also be recognized that even intensive insulin therapy does not bring the rate of any diabetic complication to the normal rate, and so it may be necessary to develop additional interventions, or perhaps, more physiologic methods of controlling diabetes, before congenital malformations in diabetic pregnancy are no greater than in nondiabetic pregnancy. Excess glucose transported to the embryo is responsible for the adverse effects of maternal diabetes to cause malformations. excess glucose, even episodic and transient, can cause birth defects., May explain the increase in malformations, especially NTDs, in pregnancies of obese women. Obese individuals may be insulin resistant, and so, circulating glucose concentrations may fluctuate above those of non-diabetic, insulin sensitive individuals, or such individuals may have undiagnosed type 2 diabetes.

The most frequently observed in clinical studies related to Diabetes are generally closure defects type of NTDs, Such as spina bifida, although non-closure defects, such as holoprosencephaly which is what my son has are also observed. The distinct anatomical and developmental characteristics of the early post-implantation embryo confer particular vulnerability to oxidative stress. First of all, at this stage of development, embryos express a high blood sugar transporter which may not be of consequence during non-diabetic pregnancy, Thus, glucose flow into the embryo could be 23 times greater than during non-diabetic pregnancy. In humans, there is evidence that genetics, backgrounds and race influence susceptibility to diabetic complications such as nephropathy and cardiovascular disease, independent of glycemic levels. Summarizing the factors contributing to NTD risk in Diabetics.

1. Maternal diabetes increases glucose concentrations in maternal circulation, including in the uterine artery. 2. Glucose, originating from the maternal circulation, is freely transported to the embryo and transported into embryo cells. 3. Increased glucose taken up by embryo cells, through a combination of increased oxidative metabolism at a stage of development in which free radical scavenging is immature, causes oxidative stress in the embryo. 4. Oxidative stress leads to decreased expression of Pax3, a gene required for neuroepithelial and neural crest development. Expression of other genes that participate in the formation of the neural tube, or other organs, may also be affected however reducing the expression of Pax3 below a critical threshold at vulnerable stages in neural tube formation may be sufficient to induce a NTD. 5. As a result of decreased production of Pax3, synthesis or stability of p53 protein increases, and this activates cell death, which stops the process of neural tube closure.

It should be noted that deficient Pax3 expression can be involved in NTD resulting from causes other than diabetic pregnancy. As quality of diabetic treatments have improved, the incidence of congenital malformations has been reduced. (Diabetes Magazine, 2000) (T. I. Chang, 2003)

Nutritional deficiencies
Folic acid taken around the time of conception can prevent many neural-tube defects. some studies suggest that women with below-normal vitamin B12 values may also be at increased risk. It has been considered That the effected homocysteine metabolism , which requires both folate and B12 when it is unable to function properly due to

deficiency is most likely, the Main cause of folate-related neural tube defects Mothers of children with neural-tube defects had significantly higher homocysteine values (862 [SD 28] mol/L) than did B12-matched controls (796 [25] mol/L, P=003). The difference was significant (p=0004) in the lower half of the B12 distribution after adjusting for plasma folate. Our study shows that an abnormality in homocysteine metabolism, , is present in many women who give birth to children with neural-tube defects. that the most effective Pre pregnancy planning to prevent neural-tube defects may require B12 as well as folic acid. (Dr James L Mills, 1995) There is excellent evidence that folic acid given before and during the first 4 wk of pregnancy can prevent many of neural tube defects;. and that to increase folic-acid intake-makes good sense. Fortification at 350 gg/100 g food would be ideal, but fortification at 140 ,ug/100 g would be acceptable. Implementation of food fortification with folic acid was slow because folic acid can mask the hematologic manifestations of pernicious anemia due to vitamin B12 deficiency while, because of this the addition of 1 mg of vitamin B12 to all vitamin supplements containing 400 gg folic acid would almost surely prevent such potential problems. The folic acid/homocysteine relationship emerges as a key example of nutritions relationship with genetics and points to a time when a specific genetic profile may be created as a basis to optimal diet creation for the prevention of disease. References (Motulsky, 1996) Clinical trials suggest that up to 70% of neural tube defects (NTDs) can be prevented by folic acid supplementation in early pregnancy, Some Neural Tube defects cannot be prevented with adequate Folic acid alone. It has been shown. that a second vitamin like substance, myo-inositol, is capable of significantly reducing the incidence of spinal NTDs It is suggested that the combined treatment with folate and inositol would be more effective than folic acid supplementation alone.. (Copp, 1997) Maternal diabetesinduced oxidative stress was blocked with f-tocopherol (vitamin E)in one study I read., Vitamin E succinate prevented the increase in malondialdehyde (a marker of lipid peroxidation), used as an indicator of oxidative stress) caused by maternal diabetes, without affecting blood glucose concentrations; vitamin E prevented the approximately 8-fold decrease in Pax3 mRNA in embryos of diabetic mice, as well as the significant increase in NTD (Diabetes Magazine, 2000) In other words the risk of Diabetic triggered birth Defects was greatly reduced through Vitamin E supplementation. it Should also be noted that excess consumption of Vitamin A is related to birth defects see section called Mutagens and other environmental factors.

Pathogens.
Infection is an important cause of some birth defects worldwide. The most common pathogens include rubella virus, cytomegalovirus, urea plasma urealyticum, (Institute of Population Research/WHO Collaborating Center on Reproductive Health and Population Science, 2004) AIDS, smallpox, chicken pox, mumps and herpes.

(Repacholi, 2010)pathogens' infections may influence the microenvironment of placenta, including levels of enzymes and cytokines, and affect The parts of the Chromosome that start the Process of a birth defect. (Institute of Population Research/WHO Collaborating Center on Reproductive Health and Population Science, 2004) Bacterial agents are also known to be accountable for birth defects, These bacterial infections include syphilis, pneumonia, tuberculosis, typhoid and bacterial vaginosis. Teratogenic viral agents include German measles, For these reasons, prenatal screening of women is advocated to ascertain her immunity against chicken pox and German measles. The effects of in-utero contamination of German measles upon the fetus are well documented medically, with the teratogenic effects including, microcephaly (small brain) and spina bifida (exposed spinal cord). The teratogenic effects are potentiated with exposure in the 3rd to 12th week of pregnancy another common Pathogen contributing to birth defects is Toxoplasma gondii, once an obscure protozoan parasite, has recently become the focus of intense research, both as a serious pathogen in its own right and as a model member of the phylum Apicomplexa. This parasite causes congenital birth defects, (James W. Ajioka, 2007)I have heard this is commonly carried by cats.

Mutagens and other environmental factors

Known environmental causes of birth defects include alcohol, pharmaceutical and non pharmaceutical drugs, cigarette smoking, bacterial and viral pathogens, heavy metals, radiation and altitude

Alcohol
is the most common cause of preventable mental retardation in children globally. Alcohol can freely cross the placental barrier and consumption during the early months when the fetal detoxification systems are still developing places the child at a much heightened risk of congenital birth defects

Mercury
contamination is commonly caused through the consumption of large fish, which store a greater amount of mercury in their systems (compared to smaller sea creatures). This causative relationship was clearly seen in Japan, in the Bay of Minamata in 1960 where 121 cases of mercury poisoning were confirmed. amongst those children whose mothers who had consumed seafood regularly from the bay; There were more Birth defects documented including an array of neurological symptoms including blindness, deafness, lack of coordination, and intellectual impairment

Cigarette smoking is also a common cause of birth defects

Radiation
is contraindicated in pregnancy due to both teratogenic and mutagenic effects; these effects are seen with strong radiation doses, whereas there is no evidence that diagnostic levels of radiation cause congenital abnormalities

Pharmaceutical drugs
are capable of inducing birth defects. Drugs known to have teratogenic effects include anticoagulants such as Warfarin, anticonvulsants, cancer drugs, accutane (Vitamin A derived), propylthiouracil, tetracycline and thalidomide (Porth, 2005, p. 147). It is well known that there are a number of factors that determine the defect causing effects of the drug which include the amount of the drug taken, the duration of ingestion, the stage in fetal development when it was taken, the stage of placental development, the lipid solubility of the drug (and ease to cross the placental barrier) and the molecular weight of the drug (and ease to cross the placental barrier) (Porth, 2005, p. 147). The drug thalidomide is one of the most widely known teratogenic drugs,` (Repacholi, 2010)

Weight and NTDs

Obese mothers are about 50 percent more likely to give birth to babies with neural tube defects. The report also stated that the risk of cardiovascular abnormalities increased by 30 percent and hydrocephaly risk increased by 60 percent. Other academic literature suggests that infants born to obese mothers have an increased risk of other defects. Regardless of these statistics, obese women, who become pregnant, should not restrict calories or engage in a weight-loss program. Doing so could further raise the risk of birth defects by causing a deficiency in nutrients necessary for proper fetal development. Ideally, obese women, hoping to become pregnant, should undergo weight loss counseling before conceiving Read more: (D., 2011)

Treatment of Neural Tube defects

My son has a neural Tube defect called Lobar holoprosenccephaly Holopresencphaly is when the two hemispheres fail to fully become two and the Corpus Collusum is either fully or partially missing The main area affected is motor skills. It has had many effects on his health and well being he has what is called a Baclofen pump which places an

antispasmodic Medication directly into his spinal fluid. he sees Physical, Occupational, and Speech Therapists Regularly He has had trouble with Severe muscle Spasms n the past now they are mild and well managed with medications. He wears a orthotic device That helps him to stand better than he would without it though he does not stand without support of some kind he is learning to use a walker again after he had hip surgery to correct Hip dysplasia caused by Muscle Spasticity, and The muscle spasms that he had for awhile made his recover much more difficult than it would have been otherwise. He also Suffers from constipation which according to the Rehab Physician that my son see Most children with muscle dystonia hyper and hypotonias have constipation which must be managed. My child sometimes has mood swings which are sudden and intense but often pass very quickly He also takes much longer to learn things than other children do He is at higher risk for Pediatric stroke due to the fact that he has Malformed Arteries in his Brain. He used to get Botox injections in his most spastic muscles, until the pump was placed and it allows for less medication to do a better job than giving him the medication Orally. He must be stretched regularly . We see several Specialists an Endocrine Specialist as he is at high risk for several endocrine disorders the most likely one for him to develop is Diabetes Insipidus, We see a primary Care Physician for many things as well he used to get sick really easily but I have worked hard to build his immune system and as he has gotten more mobile through time his vulnerability to lung infections has been reduced a lot. In many ways my sons symptoms are much like those of Cerebral Palsy ( which Ironically all that the word Cerebral Palsy means is that the palsy is originating in the brain. And so technically he has Cerebral Palsy his life expectancy is less than a normal Healthy child but as of yet no one has a real idea of what that life expectancy is though many children with more severe forms of Do not live long. As a caretaker I have to be careful both how I lift him and how often as it can Cause some health issues for me such as hernia Damage to the weight bearing joints, exhaustion The ability to take a time out and recoup is vital for the caretakers of any child with a health condition, and his is no exception to this. The effects of his Defect are far less than some families deal with There are more severe cases for more information please see. http://www.holoprosencephaly.net and http://hpe.stanford.edu/about/ these are sources I have used to find out more about what I might expect as time goes one for my son.

Works Cited
: Seminars in Medical Genetics. (2005). American Journal of Medical Genetics , 77-87.

Copp, N. D. (1997). Inositol prevents folate-resistant neural tube defects in the mouse. Retrieved February 2011, from Nature Medicine: http://www.connotea.org/add?uri=http://www.nature.com/nm/journal/v3/n1/abs/nm0197-60.html D., J. R. (2011, an 25,). Maternal Obesity and Birth Defects. Retrieved March 1, 2011, from Journal of the American Medical Association: http://www.articlesbase.com/womens-health-articles/maternal-obesityand-birth-defects-4108773.html#ixzz1FObLJwpb Diabetes Magazine. (2000). Evidence that elevated glucose causes altered gene expression, apoptosis, and neural tube defects in a mouse model of diabetic pregnancy. Retrieved from Diabetes. Dr James L Mills. (1995, January 21). Retrieved February 2011, from The Lancet: http://www.sciencedirect.com/science?_ob=PublicationURL&_tockey=%23TOC%234886%231995%239 96541056%23453105%23FLP%23&_cdi=4886&_pubType=J&view=c&_auth=y&_acct=C000050221&_ver sion=1&_urlVersion=0&_userid=10&md5=15445a04ae31afe27cc52d7fe70cf1ec Institute of Population Research/WHO Collaborating Center on Reproductive Health and Population Science. (2004, Dec 17). Intrauterine infections and birth defects. Bio med , pp. Periodical 17(4):476-91. James W. Ajioka, D. (2007). Toxoplasma. In D. James W. Ajioka, Toxoplasma: Molecular and Cellular Biology (p. abstract.). Horizon Bioscience. Motulsky, A. G. (1996). INVITED EDITORIAL. American. Journal of. Human. Genetics. , p. 3 of 4. Repacholi, J. (2010, October 1). Understanding the environmental causes of birth defects in a modern world . Retrieved March 2011, from One Stop health: http://www.onestophealth.com.au/spip.php?page=jquery.js T. I. Chang, M. H. (2003, March 26). diabetolgia. Retrieved February 2011, from SpringerLink: http://www.springerlink.com/content/0012-186x/