lundi 13 décembre 2010

Genetic link for folic acid supplementation: Study

Genetic link for folic acid supplementation: Study: "A link between changes in the DNA of newborn babies, folic acid supplementation during pregnancy, and birth weight, has been identified for the first time, researchers claim."

lundi 6 décembre 2010

Use of clomiphene citrate and birth defects, National Birth Defects Prevention Study, 1997–2005

Clomiphene citrate (CC) is the first line drug for subfertility treatment. Studies assessing the association between CC and birth defects have been inconclusive.

We used data from the National Birth Defects Prevention Study, a population-based, multi-site case–control study of major birth defects. Women from 10 US regions with deliveries affected by at least one of >30 birth defects (cases) and mothers of live born infants without a major birth defect (controls) who delivered October 1997–December 2005 were interviewed. The exposure of interest was reported CC use in the period from 2 months before conception through the first month of pregnancy. Women who conceived using assisted reproductive technology were excluded. Thirty-six birth defect categories with at least three exposed cases were studied. Multiple logistic regression was used to control for potential confounders.

CC use was reported by 1.4% of control mothers (94/6500). Among 36 case-groups assessed, increased adjusted odds ratios (aOR) were found [all: aOR, 95% confidence interval (CI)] for anencephaly (2.3, 1.1–4.7), Dandy–Walker malformation (4.4, 1.7–11.6), septal heart defects (1.6, 1.1–2.2), muscular ventricular septal defect (4.9, 1.4–16.8), coarctation of aorta (1.8, 1.1–3.0), esophageal atresia (2.3, 1.3–4.0), cloacal exstrophy (5.4, 1.6–19.3), craniosynostosis (1.9, 1.2–3.0) and omphalocele (2.2, 1.1–4.5).

Several associations between CC use and birth defects were observed. However, because of the small number of cases, inconsistency of some findings with previous reports, and the fact that we cannot assess the CC effect separately from that of the subfertility, these associations should be interpreted cautiously.

Journal Reference:
J. Reefhuis, M.A. Honein, L.A. Schieve, S.A. Rasmussen, and the National Birth Defects Prevention Study
Use of clomiphene citrate and birth defects, National Birth Defects Prevention Study, 1997–2005
Hum. Reprod. 2010 : deq313v1-deq313.

mardi 26 octobre 2010

Maternal fumonisin exposure and risk for neural tube defects: Mechanisms in an in vivo mouse model

Fumonisin B1 (FB1) is a mycotoxin produced by the fungus Fusarium verticillioides, a common contaminant of corn worldwide. FB1 disrupts sphingolipid biosynthesis by inhibiting the enzyme ceramide synthase, resulting in an elevation of free sphingoid bases and depletion of downstream glycosphingolipids. A relationship between maternal ingestion of FB1-contaminated corn during early pregnancy and increased risk for neural tube defects (NTDs) has recently been proposed in human populations around the world where corn is a dietary staple. The current studies provide an in vivo mouse model of FB1 teratogenicity.

Pregnant LM/Bc mice were injected with increasing doses of FB1 on GD 7.5 and 8.5, and exposed fetuses were examined for malformations. Sphingolipid profiles and 3H-folate concentrations were measured in maternal and fetal tissues. Immunohistochemical expression of the GPI-anchored folate receptor (Folbp1) and its association with the lipid raft component, ganglioside GM1, were characterized. Rescue experiments were performed with maternal folate supplementation or administration of gangliosides.

Maternal FB1 administration (20 mg/kg of body weight) during early gestation resulted in 79% NTDs in exposed fetuses. Sphingolipid profiles were significantly altered in maternal and embryonic tissues following exposure, and 3H-folate levels and immunohistochemical expression of Folbp1 were reduced. Maternal folate supplementation partially rescued the NTD phenotype, whereas GM1 significantly restored folate concentrations and afforded almost complete protection against FB1-induced NTDs.

Maternal FB1 exposure altered sphingolipid metabolism and folate concentrations in LM/Bc mice, resulting in a dose-dependent increase in NTDs that could be prevented when adequate folate levels were maintained.

Journal Reference:
Gelineau-van Waes, J., Starr, L., Maddox, J., Aleman, F., Voss, K. A., Wilberding, J. and Riley, R. T. (2005), Maternal fumonisin exposure and risk for neural tube defects: Mechanisms in an in vivo mouse model. Birth Defects Research Part A: Clinical and Molecular Teratology, 73: 487–497. doi: 10.1002/bdra.20148

Study Looks At Suspected Link Between Corn Mycotoxin And Birth Defects

A Creighton University School of Medicine researcher has been awarded a $2.7 million grant by the National Institutes of Health (NIH) to investigate a possible link between the ingestion of tortillas and corn-based food products contaminated with a fungal toxin and increased risk for birth defects.

The three-year award is a collaborative effort among investigators at Creighton, the U.S. Department of Agriculture-Agricultural Research Service (USDA-ARS) in Athens, Georgia; Duke University Medical Center in Durham, N.C., and Centro de Investigaciones en Nutricion y Salud (CIENSA) in Guatemala.

Janee Gelineau-van Waes, D.V.M., Ph.D., principal investigator and associate professor in Creighton's Department of Pharmacology, will use the grant to continue her research studying a potential connection between exposure to fumonisin during early pregnancy and an increased risk for having a baby with a neural tube defect (NTD).

NTDs are one of the most common congenital malformations (one per 1,000 births) and include defects such as anencephaly and spina bifida. NTDs occur when the embryonic neural tube, which forms the brain and spinal cord, fails to close properly during the first few weeks of pregnancy.

Fumonisin is a mycotoxin produced by a common fungal contaminant of corn worldwide.

In animals, the toxin disrupts sphingolipid metabolism, causing diseases such as leukoencephalomalacia in horses, pulmonary edema in pigs and cancer in laboratory rodents. In humans, ingestion of fumonisin-contaminated corn is associated with increased risk for esophageal cancer and having a baby with a NTD.

An unusually high incidence of NTDs (six to 10 cases per 1,000 births) has been observed in regions of Guatemala, China, and South Africa where corn is a dietary staple and fumonisin contamination is frequent.

Gelineau-van Waes and USDA scientists have shown that early gestational exposure to the toxin disrupts sphingolipid metabolism and induces NTDs in mice.

In the new study, preliminary data obtained from mice will be used to validate biomarkers of exposure in blood and urine samples collected from women in Guatemala. The human samples, collected by CIENSA scientists, will be analyzed by the USDA-ARS Mycotoxin Research Unit.

Creighton researchers will use mouse models to investigate underlying signaling mechanisms that result in failure of neural tube closure after fumonisin exposure, and collaborative studies with Duke University will focus on identifying genetic mutations that increase susceptibility.

Gelineau-van Waes' research program is supported by the Nebraska Tobacco Settlement Biomedical Research Program (LB-692). Her current NIH grant was awarded under the American Recovery and Reinvestment Act of 2009, in response to the NIH Director's Opportunity for Research on Global Health.

Background on fumonisin:

-- Fumonisin contamination of corn is periodically a problem in the U.S. In 1990, a cluster of babies born with NTDs was reported among Hispanic women living along the south Texas border. The incident occurred a year after very high levels of fumonisin were reported in the corn crop used to make tortillas, prompting scientists at the Texas Department of Health to suspect a possible connection.

-- In 2001, the U.S. Food and Drug Administration (FDA) established industry guidelines containing recommended maximum levels for fumonisin in corn used to prepare human and animal foods. However, the FDA guidelines do not contain enforceable regulatory limits.

-- In 2002, the World Health Organization (WHO) released provisional maximum tolerable daily intake (PMTDI) for fumonisins and suggested that further research was needed to examine the potential for this compound to cause birth defects.

-- In areas where corn is consumed in large quantities, such as Mexico and Guatemala, a significant percentage of the population exceeds (by more than 20 times) the WHO daily intake limit for fumonisin. In the U.S., a recent analysis of corn tortilla and masa flour samples from various retail sources in southern California indicates that fumonisin contamination of corn-based foods is common, and, depending on the amount an individual consumes, it is possible to exceed the WHO recommended daily limit.

Source: Creighton University

lundi 25 octobre 2010

Further evidence for a maternal genetic effect and a sex-influenced effect contributing to risk for human neural tube defects

Neural tube defects (NTDs), including spina bifida and anencephaly, are the second most common birth defect with an incidence of 1/1000. Genetic factors are believed to contribute to NTD risk and family-based studies can be useful for identifying such risk factors.

We ascertained 1066 NTD families (1467 affected patients), including 307 multiplex NTD families. We performed pedigree analysis to describe the inheritance patterns, pregnancy outcomes, and recurrence risks to relatives of various types.

Myelomeningocele or spina bifida (66.9%) and cranial defects (17.7%) were the most common NTD subtypes observed. The overall male:female ratio for affected individuals was 0.82, and there were even fewer males among individuals with an upper level NTD (0.62). Among twins, 2 of the 5 monozygotic twins and only 3 of 35 dizygotic twins were concordant, while 27% of the same sex twins were concordant, but none of the different sex twins. The estimated 6.3% recurrence risk to siblings (CI 0.04–0.08) is consistent with previous reports. Families with two or more affected individuals show a higher proportion of female transmitters (p = 0.0002). Additionally, the number of affected relatives in maternal compared to paternal lineages was more than double (p = 0.006). There were significantly more miscarriages, infant deaths, and stillborn pregnancies of the maternal aunts and uncles (p < 0.0001) and of first cousins (p = 0.04).

Our data provide several lines of evidence consistent with a maternal effect, as well as a sex-influenced effect, in the etiology of NTDs.

Journal Reference:
Deak, K. L., Siegel, D. G., George, T. M., Gregory, S., Ashley-Koch, A. and Speer, M. C. (2008), Further evidence for a maternal genetic effect and a sex-influenced effect contributing to risk for human neural tube defects. Birth Defects Research Part A: Clinical and Molecular Teratology, 82: 662–669. doi: 10.1002/bdra.20511

lundi 11 octobre 2010

Loss of Nutrients Following Gastric Bypass Surgery in Adolescent Girls Increases Risk for Neural Tube Defects

SAN FRANCISCO – An increasing number of obese adolescents, particularly females, are undergoing gastric bypass surgery. Yet a case study presented Sunday, Oct. 3, at the American Academy of Pediatrics (AAP) National Conference and Exhibition in San Francisco, highlights the possible link between gastric bypass surgery in adolescent girls and an increased risk for neural tube defects, which can lead to varying degrees of disability such as paralysis and mental retardation due to damage to the nervous system, in their future children.

Neural tube defects in the brain and spinal cord can be due to nutritional deficiencies. The report, “Neural Tube Defects: An Unforseen Consequence of Gastric Bypass Surgery in Young Female Patients?” reviewed the case of a young patient who had undergone gastric bypass surgery prior to becoming pregnant. She presented to the Fetal Treatment Center at UCSF Benioff Children’s Hospital to discuss the possibility of fetal surgery as her fetus had spina bifida. A literature review found six additional documented cases of children born with neural tube defects thought to be due to maternal nutritional deficiencies, particularly malabsorption (when the body cannot absorb nutrients), following bypass surgery.

It is well documented that gastric bypass surgery leads to malabsorption causing multiple nutritional deficiencies, including folate (folic acid), which is a key element in the prevention of neural tube defects. Although daily folate replacement can reverse this deficiency, adolescents often don’t comply with medication regimens.

This situation is especially critical because adolescents who have undergone gastric bypass surgery are at an increased risk of unintended pregnancies.

“We postulate that the malabsorption of folate, poor compliance with nutritional supplements and a higher risk of unintended pregnancies places young women at an increased risk for pregnancies complicated with neural tube defects,” said senior study author Diana L. Farmer, MD.

“Although obesity is epidemic in this country, we believe non-reversible gastric bypass surgery should be avoided in adolescent women given the potential increased risk of fetal neural tube defects,” Farmer said. “If gastric bypass is performed on an adolescent female, great efforts must be made to minimize the risks of both
unintended pregnancies and nutritional deficiencies. This should include extensive pre-surgery counseling and frequent post-operative follow-up, as well as consideration of highly efficacious contraceptives such as an intrauterine device.”


lundi 14 juin 2010

Valproic Acid Monotherapy in Pregnancy and Major Congenital Malformations


The use of valproic acid in the first trimester of pregnancy is associated with an increased risk of spina bifida, but data on the risks of other congenital malformations are limited.

We first combined data from eight published cohort studies (1565 pregnancies in which the women were exposed to valproic acid, among which 118 major malformations were observed) and identified 14 malformations that were significantly more common among the offspring of women who had received valproic acid during the first trimester. We then assessed the associations between use of valproic acid during the first trimester and these 14 malformations by performing a case–control study with the use of the European Surveillance of Congenital Anomalies (EUROCAT) antiepileptic-study database, which is derived from population-based congenital-anomaly registries. Registrations (i.e., pregnancy outcomes with malformations included in EUROCAT) with any of these 14 malformations were compared with two control groups, one consisting of infants with malformations not previously linked to valproic acid use (control group 1), and one consisting of infants with chromosomal abnormalities (control group 2). The data set included 98,075 live births, stillbirths, or terminations with malformations among 3.8 million births in 14 European countries from 1995 through 2005.

Exposure to valproic acid monotherapy was recorded for a total of 180 registrations, with 122 registrations in the case group, 45 in control group 1, and 13 in control group 2. As compared with no use of an antiepileptic drug during the first trimester (control group 1), use of valproic acid monotherapy was associated with significantly increased risks for 6 of the 14 malformations under consideration; the adjusted odds ratios were as follows: spina bifida, 12.7 (95% confidence interval [CI], 7.7 to 20.7); atrial septal defect, 2.5 (95% CI, 1.4 to 4.4); cleft palate, 5.2 (95% CI, 2.8 to 9.9); hypospadias, 4.8 (95% CI, 2.9 to 8.1); polydactyly, 2.2 (95% CI, 1.0 to 4.5); and craniosynostosis, 6.8 (95% CI, 1.8 to 18.8). Results for exposure to valproic acid were similar to results for exposure to other antiepileptic drugs.

The use of valproic acid monotherapy in the first trimester was associated with significantly increased risks of several congenital malformations, as compared with no use of antiepileptic drugs or with use of other antiepileptic drugs.

Journal Reference:
Jentink J. et al. Valproic Acid Monotherapy in Pregnancy and Major Congenital Malformations, NEJM Volume 362:2185-2193 June 10, 2010 Number 23

jeudi 3 juin 2010

The Antifolate Activity of Tea Catechins

A naturally occurring gallated polyphenol isolated from green tea leaves, ( )-epigallocatechin gallate (EGCG), has been shown to be an inhibitor of dihydrofolate reductase (DHFR) activity in vitro at concentrations found in the serum and tissues of green tea drinkers (0.1-1.0 Mmol/L). These data
provide the first evidence that the prophylactic effect of green tea drinking on certain forms of cancer, suggested by epidemiologic studies, is due to the inhibition of DHFR by EGCG and could also explain why tea extracts have been traditionally used in ‘‘alternative medicine’’ as anticarcinogenic/antibiotic agents or in the treatment of conditions such
as psoriasis. EGCG exhibited kinetics characteristic of a slow, tight-binding inhibitor of 7,8-dihydrofolate reduction with bovine liver DHFR (KI = 0.109 Mmol/L), but of a classic, reversible, competitive inhibitor with chicken liver DHFR (KI = 10.3 MAmol/L). Structural modeling showed that EGCG can bind to human DHFR at the same site and in a similar orientation to that observed for some structurally characterized DHFR inhibitor complexes. The responses of lymphoma cells to EGCG and known antifolates were similar, that is, a dose-dependent inhibition of cell growth (IC50 = 20 Mmol/L for EGCG), G0-G1 phase arrest of the cell cycle, and induction of apoptosis. Folate depletion increased the sensitivity of these cell lines to antifolates and EGCG. These effects were attenuated by growing the cells in a medium containing hypoxanthine-thymidine, consistent with DHFR being the site of action for EGCG.

Our data may also explain why neural tube defects such as anencephaly and spina bifida, which are usually associated with folic acid deficiency, have been linked to high levels of maternal green tea consumption during the periconceptional

Journal Reference:
Enma Navarro-Pera´n et al. The Antifolate Activity of Tea Catechins. Cancer Res 2005; 65(6): 2059-64

mardi 13 avril 2010

Documentary: Five Hours With Raja

Five Hours with Raja is an intimate and confronting documentary, which charts the experiences of a young mother carrying her unborn baby to term, despite the diagnosis of anencephaly. The pregnancy and short life of the new baby have a profound impact on the entire extended family: the events affect them in a variety of ways over the following months and years.

Claudia’s and Amit’s journey is documented carefully, and their thoughts and feelings as well as those of their extended family. The resulting documentary film provides the viewer with an intimate “inside view” of one family’s experience, revealing the steps that this group of people have taken to acknowledge and grieve the loss of a child who was very much part of their family.

Raja’s life has had a particularly profound impact on his mother Claudia. She has made a series of “Raja related” choices that have taken her to places she never imagined. This is a about death – but – it is also a love story. It gives us the experience of being in the company of people who love, who know how to love each other, and who are able to handle sorrow, loss and death with love. Director McKessar ‘s surprising and challenging documentary takes us on an extraordinary journey with Claudia, her partner and family, and leaves us enlightened, moved and challenged.

lundi 22 mars 2010

Palliative care for prenatally diagnosed lethal fetal abnormality

Diagnosis of lethal fetal abnormality raises challenging decisions for parents and clinicians. Most parents opt for termination, which may include feticide. Advances in imaging seem unlikely to lead to earlier diagnoses. Perinatal palliative care offers an alternative. Parental decision making and the clinical aspects of perinatal palliative care were studied after a prenatal diagnosis of lethal fetal abnormality in 20 pregnancies.
40% of parents chose to continue the pregnancy and pursue perinatal palliative care. Six of these eight babies were liveborn and lived for between 1,5 h and 3 weeks.

"In our experience, those parents who chose this model of care gave positive feedback about their decision and the care provided."

Free Fulltext

Journal Reference:
A C G Breeze et al. Palliative care for prenatally diagnosed lethal fetal abnormality. Arch. Dis. Child. Fetal Neonatal Ed. 2007;92;56-58; originally published online 16 May 2006;

Full of Grace, Couple grieves loss of their infant daughter

Grace Marion Chapman lived outside her mother’s womb for only 90 minutes.
But her parents — Sherry and Brent Chapman of Erie — will remember her for a lifetime.
“We’re very proud parents,” Sherry said. “We’re not ashamed of our daughter. We’re not ashamed of our situation. We’re certainly not angry or bitter. We’re very proud, and in our story, we’re still parents. Our daughter’s not here now, but we’re still parents.”

Full article

published on 3/21/2010 in the Longmont Times-Call

vendredi 19 mars 2010

Perinatal Hospice: Family-Centered Care of the Fetus with a Lethal Condition

Twenty-eight newborns prenatally diagnosed with lethal anomalies were eligible for a pilot hospice program at Rockford Memorial Hospital (RMH). Comprehensive care in a comforting community setting was provided to the 75% of families who chose this option. No maternal morbidity resulted. In the 76% of infants who were born live, survival ranged from 20 minutes to 256 days. Further study of psychological outcomes is warranted.

"the need for comprehensive, especially psychological, care for families of infants who will die in utero, or live for only a short while after birth, has been underestimated. The family's experience with these pregnancies is analogous to that of families with a terminally ill child. Their needs are best fulfilled with a comprehensive end-of-life approach."

"We recognize that when a prenatal diagnosis portends perinatal death of the family's newest member, hospice care must start at the time of diagnosis."

"To provide adequate understanding, especially while exploring anticipatory
grieving, parents were carefully counseled regarding the fetal diagnosis and probable prognosis. Families were allowed to grieve, explore life issues, and prepare for the precious time they might have to spend with their child. Antepartum consultation with the neonatology service included development of a postnatal plan for the eventuality of a live birth."

"Perinatal hospice care has now been offered on the RMH perinatal service for a number of years. During the pilot program, 75% of patients chose to continue their pregnancies in this environment of care, despite prenatal diagnosis of a lethal condition. The care of this group of patients was accomplished without any notable maternal morbidity."

"Typically, the options presented to the parents at the time a lethal condition is diagnosed include abortion of the pregnancy versus continued pregnancy with routine maternal care, and nonintervention for the neonate at the time of labor and delivery. A bare presentation of these options may leave parents with the perceived choice of futilely watching their
infant die, which they may also interpret as increasing the suffering of their child, versus actively doing something to end this sudden, emotionally wrenching dilemma."

"Parents of infants with external congenital defects are not repulsed by the appearance of their infant, and most emphasize the normal aspects of the child. A major advantage of perinatal hospice is that a significant majority of these infants may be live-born, allowing the parents and family a chance to share precious time with their infant, even if the infant's life is exceedingly brief."

Free Fulltext

Journal Reference:
Calhoun BC, Napolitano P, Terry M, et al. Perinatal hospice. Perinatal Hospice: Family-Centered Care of the Fetus with a Lethal Condition. Journal of American Physicians and Surgeons Volume 11 Number 2 Summer 2006

jeudi 18 mars 2010

Counselling following diagnosis of a fetal abnormality: the differing approaches of obstetricians, clinical geneticists, and genetic nurses

Women receiving a positive diagnosis of an abnormality during pregnancy may be counselled about a termination by one of several types of health professionals including obstetricians, geneticists, and genetic nurses. There is anecdotal evidence to suggest that these groups differ in both
their approaches to counselling and their attitudes towards abnormality. The aim of the current study is to document how genetic nurses, geneticists, and obstetricians describe their own counselling of women following the diagnosis of specific fetal abnormalities. Obstetricians reported counselling in a significantly more directive fashion than
did geneticists, who in turn reported counselling in a more directive way than did genetic nurses. The extent to which the groups differed in their reported approaches varied across conditions. The most marked difference was evident for Down's syndrome: 94% of genetic nurses, 57% of geneticists, and 32% of obstetricians reported counselling non-directively.
Future research needs to focus on what these different groups see as the
objectives of counselling in this situation, how they actually counsel, and with what effects.

So, for example, respondents in all three groups were more likely to report counselling non-directively for sickle cell disease, than they were for cleft lip or anencephaly.
... consensus between all three groups was evident for just two conditions, cleft lip and anencephaly, the majority of respondents reporting counselling parents in the direction of terminating the affected pregnancy for anencephaly.

Free Fulltext

Journal Reference:
T Marteau, H Drake and M Bobrow. Counselling following diagnosis of a fetal abnormality: the differing approaches of obstetricians, clinical geneticists, and genetic nurses. J Med Genet 1994 31: 864-867 doi: 10.1136/jmg.31.11.864

Continuing with pregnancy after a diagnosis of lethal abnormality: experience of five couples and recommendations for management

In the genetics clinic we meet many parents whose pregnancy has been complicated by the unexpected finding of a serious fetal malformation. Many of these couples terminate their pregnancy but some continue and allow nature to take its course. We summarise the experience of five couples and highlight various aspects showing the inappropriateness of routine obstetric care for these women. These were five consecutive couples (see table 1) known to the genetics department who agreed to a semistructured, tape recorded interview at varying intervals (one week to eight months) after their pregnancies.
The decision to continue the pregnancy allowed the parents to avoid some feelings of guilt, regret, and doubt. "We saw him. If I had had a termination we would have had nothing to remember. And I would always have wondered if the scans were wrong. I would have had that termination on my conscience for the rest of my life" (case 4). "I'd 99.9% accepted that the baby wasn't going to live. I was always holding out a little hope. But if the pregnancy had been terminated I would have had guilt. Now I feel no guilt or remorse" (case 5).
Some parents wish to continue a pregnancy given a poor prognosis for the fetus. If counselling was less directive possibly the proportion would be higher. All the parents interviewed found the time to prepare for the death of their child valuable, but many had distressing experiences during that time. These parents need extra support, understanding, and respect for their decision.

Journal Reference:
Chitty Lyn S et al. For Debate: Continuing with pregnancy after a diagnosis of lethal abnormality: experience of five couples and recommendations for management. BMJ 1996;313:478-480 (24 August)

mercredi 17 février 2010

Two Rhombencephalic Anencephalics

One of us systematically examined 78 anencephalics (in the broad sense of the term) in the Central Pathological Laboratory in Rotterdam. On the basis of differences with respect to the closure of the neural tube, the material could be divided into three groups:
(1) In 18 cases there was faulty closure in the rostral portion of the brain;
(2) In 15 cases there was a defect in the caudal portion of the brain and the rostral portion of the spinal cord;
(3) In 45 .cases there was a defect both in the entire brain and in the spinal cord.
In all these cases, the skull and vertebral column participated in the closure-defect.

Localization of Brain Defect Female Male Sex Dominance
Statist. Signific
Rostral brain 6 12 Male +
Caudal brain and rostral spinal cord 14 1 Female +
Total brain and spinal cord 36 9 Female +
56 22

This Table shows that anencephaly clearly preferentially affects the female sex. This was already known, and is confirmed by the Rotterdam material (56 females v. 22 males) but, if we consider the groups of anencephalics separately, then those with a closure defect in the rostral portion of the brain (the so-called hemicephalics or merencephalics) occupy a unique position: here the male sex predominates, in contrast to the other groups, where the caudal part of the CNS is much more extensively involved. This supports the opinion that “hemicephaly" should be considered a special type of anencephaly.

Journal Reference:
V.W.D. Schenk et al. Two Rhombencephalic Anencephalics, BRAIN—VOL. XCI, 497-506

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Polyhydramnios in Anencephaly

In a newborn infant with esophageal stenosis and atresia extending 9 cm, the amniotic fluid volume was found to be normal, yet this infant could not possibly have swallowed. In a case of anencephaly in which the infant had partial esophageal atresia and stenosis extending 1 cm, the infant swallowed sodium diatrizoate (Hypaque Sodium) injected into the amnion, yet the mother had polyhydramnios. Two more cases of anencephaly are presented in which the infants swallowed radiopaque media, yet both mothers had polyhydramnios.
These findings emphasize that polyhydramnios is a complex phenomenon and indicate that "failure to swallow" cannot explain all such cases associated with esophageal atresia and anencephaly.

Journal Reference:
John Nichols, Rosemary Schrepfer. Polyhydramnios in Anencephaly. JAMA, Aug 15, 1966, Vol 197, No 7

Free Fulltext

It is apparent that a delicate homeostatic mechanism exists which balances amniotic fluid formation and résorption to maintain a normal volume of approximately 1,000 ml at term. Polyhydramnios results when the rate of formation at all sites exceeds the rate of résorption.

lundi 1 février 2010

Neurulation in the cranial region – normal and abnormal

Cranial neurulation is the embryonic process responsible for formation of the brain primordium. In the mouse embryo, cranial neurulation is a piecemeal process with several initiation sites and two neuropores. Variation in the pattern of cranial neurulation occurs in different mouse strains, and a simpler version of this morphogenetic scheme has been described in human embryos. Exencephaly is more common in females than in males, an unexplained phenomenon seen in both mice and humans. As the cranial neural tube closes, a critical morphogenetic event is the formation of dorsolateral bending points near the neural fold tips, which enables subsequent midline fusion of the neural folds. Many mutant and gene-targeted mouse strains develop cranial neural tube defects, and analysis of the underlying molecular defects identifies several requirements for normal dorsolateral bending. These include a functional actin cytoskeleton, emigration of the cranial neural crest, spatio-temporally regulated apoptosis, and a balance between cell proliferation and the onset of neuronal differentiation. A small number of mouse mutants exhibit craniorachischisis, a combined brain and spine neurulation defect. Recent studies show that disturbance of a single molecular signalling cascade, the planar cell polarity pathway, is implicated in mutants with
this defect.

Journal Reference:
Copp A.J. Neurulation in the cranial region – normal and abnormal. J. Anat. (2005) 207, pp623–635

Subclassification of Anencephalic Human Fetuses According to Morphology of the Posterior Cranial Fossa

Anencephaly is a designation for congenital absence of the cranial vault with cerebral hemispheres completely missing or decreased to small masses attached to the base of the skull. The etiology is unknown. Whether the bony tissue or soft brain tissue is a primary factor is also unknown. The present study has focused on the posterior cranial fossa in anencephaly. The goal is to determine whether differences in the posterior cranial fossa could provide a basis for subclassification of anencephalic fetal skeletons. Twenty-three human anencephalic fetuses, at gestational ages 13 to 22 weeks, were studied. Radiologic and cephalometric analyses, including measurements of bone sizes and different angles, were performed. Permission for autopsy of the central nervous system was not available. For
comparison of anencephalic findings with normal conditions, standards from a recent publication were used. Foot length served as a parameter for age comparison. The study showed 2 morphologic types of the posterior cranial fossa. One type had a fossa cranial morphology close to normal morphology, whereas the other had a malformed and much smaller posterior cranial fossa. The latter condition was presumed to be due to a primary error in chondral and cranial development. The current skeletal subgrouping might be
essential for clinicians’ or pathologists’ future assessment of the autopsy results. The skeletal subgrouping should, if possible, be associated with karyotyping and analysis of the central nervous system. The goal is to distinguish between congenital conditions resulting in anencephaly and acquired conditions resulting in anencephaly.

Journal Reference:
Lomholt J.F. et al. Subclassification of Anencephalic Human Fetuses According to Morphology of the Posterior Cranial Fossa. Pediatric and Developmental Pathology 7, 601–606, 2004 DOI: 10.1007/s10024-004-9098-z

Teratology of the neural tube: history and paleopathology

A lack of closing of the neural tube extremities between the 23rd and 27th days of embryonic life is responsible of various grades in abnormalities, from spina bifida to complete anencephalo-amyelia. Spina bifida is known in osteo-archaeology, but not anencephaly: that is the reason of our study.
Because it was a long time confused with acephaly, the history of anencephaly is very old, since 426 B.C. (Ctesias, Greek physician of Persian king Cambyse), but the most ancient case is an anencephalus-mummy from Thebes (Egypt), described in 1826 by a French naturalist, Etienne Geoffroy Saint-Hilaire.
We present one case of spina bifida associated with the sacralization of L5, proceeding from a recent digging up by Professor J.-L. Heim in Egypt. Eight skulls originate from the Musee de l’Homme in Paris: two anencephalies, two anencephaloamyelias, and four various degrees of encephalo-meningoceles.
The anencephalies have total lack of cranial vault and conservation of the face, the cranial basis and vertebral channel. In the cases of anencephalo-amyelias the posterior arch of a more or less high number of vertebrae also lacks.
Encephalomeningoceles are characterised by an opening of various size in the cranial vault through which, during life, the brain and meninges made herniation.

Free Fulltext (the text is in French, but there are many interesting illustrations and pictures.

Journal Reference:
Charon, P.,Teratology of the neural tube: history and paleopathology, 2005. Antropo, 10, 83-101.

Tératologie du tube neural: histoire et paléopathologie

Anomalies de sévérité variable, dues à un défaut plus ou moins complet de fermeture du tube neural survenu entre le 23ème et le 27ème jour de la vie embryonnaire, elles peuvent aller de la simple spina bifida à l’anencéphalomyélie (anencéphalo-arachie) complète. Historiquement, le cas le plus ancien observé date de l’antiquité égyptienne: c’est celui d’une momie de foetus atteint d’anencéphalo-myélie, qui fut décrit en 1826 par Etienne Geoffroy Saint-Hilaire. C’est cet auteur qui sépara l’anencéphalie de l’acéphalie avec laquelle elle fut longtemps confondue. Si l’ostéo-archéologie de la spina bifida, consécutive à la mauvaise fermeture du neuropore postérieur, est bien documentée de longue date, ce n’est pas le cas des anencéphalies, anencéphalomyélies et encéphaloméningocèles; toutes liées à un trouble de la fermeture du neuropore antérieur.
C’est pourquoi nous présentons une exceptionnelle collection de huit crânes: quatre encéphalo-méningocèles et quatre anencéphalies ou anencéphalomyélies, provenant du Musée de l’Homme de Paris, avec, pour mémoire, une spina bifida d’origine égyptienne qu’a bien voulu nous confier Monsieur Jean-Louis Heim, Professeur d’anthropologie biologique au Museum national d’histoire naturelle. Deux têtes osseuses (n° 1, collection F. J. Gall , et n° 4) illustrent l’anencéphalie vraie, avec conservation du massif facial, de la base du crâne et du canal rachidien. Deux observations (collection R. Verneau) sont des anencéphalomyélies, associant aux malformations précédentes la fente complète de l’arc vertébral postérieur portant sur les quatre (n° 3) ou huit (n° 2) premières vertèbres. Les quatre encéphaloméningocèles se caractérisent par une ouverture étendue, mais non totale, de la voûte crânienne (par laquelle cerveau et méninges étaient extériorisés du vivant du sujet; certaines formes sont compatibles avec une assez longue survie). L’observation n° 5 (collection F. J. Gall) comporte une grande ouverture postérieure et inférieure de l’occipital; celle des crânes n° 6, 7 et 8 (collection E.T. Hamy) siège entre la partie postérieure des pariétaux pour la n° 7, et dans la partie supérieure de l’écaille occipitale, juste derrière la suture lambdoïde pour la n° 8, tandis que celle de l’observation 6, beaucoup plus vaste, pourrait en imposer pour une anencéphalie, mais les frontaux, pariétaux et la partie supérieure de l’occipital, certes réduits, sont surtout refoulés (la description anatomo-clinique publiée par E.T. Hamy confirme qu’il y avait bien extériorisation de l’encéphale).

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Journal Reference:
Charon, P.,Teratology of the neural tube: history and paleopathology, 2005. Antropo, 10, 83-101.

Neural Tube Defect Rates before and after Food Fortification with Folic Acid

Since 1998, enriched cereal grains sold in the United States have been fortified with folic acid, to reduce the incidence of neural tube defects (NTDs). The Centers for Disease Control and Prevention (CDC) recently reported that NTD rates have decreased 26% since fortification, but that additional effort is needed to achieve the national goal of a 50% reduction. However, accurate determination of NTD rates requires counting antenatally detected cases; the CDC study noted that the number of prenatally diagnosed cases was likely underestimated.

We examined studies from the United States and Canada that compared rates of NTDs before and after very similar fortification programs were instituted in each country. U.S. studies had incomplete ascertainment of prenatally diagnosed NTD cases, and as a result, underreported the number of NTDs prevented. Canadian studies, in which ascertainment was more complete, showed decreases in NTD rates up to 54%.

There is a strong correlation between the completeness of ascertainment and the percentage decrease in NTD rates. Studies that identify cases best show that folic acid fortification is preventing around 50% of NTDs. The percentage of NTDs that are folate-preventable in the United States is uncertain, but is probably 50–60%. Thus, we may be quite close to chieving the optimum level of protection at current fortification levels.

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Journal Reference:
Mills J.L, Signore C. Neural Tube Defect Rates before and after Food Fortification with Folic Acid. Birth Defects Research (Part A) 70:844–845, 2004

vendredi 29 janvier 2010

Minimum effective dose of folic acid for food fortification to prevent neural-tube defects

Although a daily supplement of 400 micrograms folic acid has been shown to prevent neural-tube defects (NTD), most women do not take the recommended supplement. Thus, food fortification is to be introduced in the USA and is being considered in the UK. Because of safety concerns, the USA has chosen a level of fortification that will increase the average woman's intake by only 100 micrograms. Such an increase, although safe, may be ineffective; but a trial to assess its efficacy would be unethical. Because women with red-cell folate concentrations above 400 micrograms/L have a very low risk of NTD, we undertook a randomised trial of several folic acid doses to find out how much is needed to reach this protective concentration.

We screened 323 women. 172 with red-cell folate between 150 micrograms/L and 400 micrograms/L were invited to take part in the trial. 121 women were randomly assigned placebo or 100 micrograms, 200 micrograms, or 400 micrograms daily of additional folic acid. Compliance was monitored by having the women sign a dated sheet when taking the tablet. 95 women completed the 6-month study.

There were significant increases in red-cell folate in all folic acid groups. The placebo group showed no significant change. The median incremental changes and median post-treatment concentrations were 67 micrograms/L (95% CI 43-120) and 375 micrograms/L (354-444) in the 100 micrograms/day group, 130 micrograms/L (108-184) and 475 micrograms/L (432-503) in the 200 micrograms/day group, and 200 micrograms/L (125-312) and 571 micrograms/L (481-654) in the 400 micrograms/day group.

A fortification programme that delivered 400 micrograms folic acid daily to women would protect against NTD, but at the expense of unnecessarily high exposure for many people. Delivery of 200 micrograms daily is also effective against NTD and safer for the general population. Based on projections from the positive folate balance in the group that received 100 micrograms daily, this dose taken continually, as it will be in fortified food, will also produce an important decrease in NTD.

Journal Reference:
Daly S, Mills JL, Molloy AM, Conley M, Lee YJ, Kirke PN, Weir DG, Scott JM. 1997. Minimum effective dose of folic acid for food fortification to prevent neural-tube defects. Lancet 350:1666–1669.

mardi 26 janvier 2010

Pathobiology and genetics of Neural tube defects

Neural tube defects (NTDs), including spina bifida and anencephaly, are common congenital malformations that occur when the neural tube fails to achieve proper closure during early embryogenesis. Based on epidemiological and clinical data obtained over the last few decades, it is apparent that these multifactorial defects have a significant genetic component to theiretiology that interacts with specific environmental risk factors. The purpose of this review article is to synthesize the existing literature on the genetic factors contributing to NTD risk.

To date, there is evidence that closure of the mammalian neural tube initiates and fuses intermittently at four discrete locations. Disruption of this process at any of these four sites may lead to an NTD, possibly arising through closure site-specific genetic mechanisms. Candidate genes involved in neural tube closure include genes of the folate metabolic pathway, as well as those involved in folate transport.

Although extensive efforts have focused on elucidating the genetic risk factors contributing to the etiology of NTDs, the population burden for these malformations remains unknown. One group at high risk for having children with NTDs is epileptic women receiving antiepileptic medications during pregnancy. Efforts to better understand the genetic factors that may contribute to their heightened risk, as well as the pathogenesis of neural tube closure defects, are reviewed herein.

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Journal Reference:
FINNELL Richard H. et al. Pathobiology and genetics of Neural tube defects. Epilepsia 44 (Suppl. 3):14-23, 2003

Prevalence of spina bifida and anencephaly during the transition to mandatory folic acid fortification in the United States

In 1992, the United States Public Health Service recommended that all women of childbearing age consume 400 g of folic acid daily. The Food and Drug Administration authorized the addition of synthetic folic acid to grain products in March 1996 with mandatory compliance by January 1998. The impact of these public health policies on the prevalence of neural tube defects needs to be evaluated. We sought to determine the prevalences of spina bifida and anencephaly during the transition to mandatory folic acid fortification.

Twenty-four population-based surveillance systems were used to identify 5,630 cases of spina bifida and anencephaly from 1995-99. Cases were divided into three temporal categories depending on whether neural tube development occurred before folic acid fortification (January 1995 to December 1996), during optional fortification (January 1997 to September 1998), or during mandatory fortification (October 1998 to December 1999). Prevalences for each defect were calculated for each time period. Data were also stratified by programs that did and did not ascertain prenatally diagnosed cases.

The prevalence of spina bifida decreased 31% (prevalence ratio [PR] = 0.69, 95% confidence interval [CI] = 0.63-0.74) from the pre- to the mandatory fortification period and the prevalence of anencephaly decreased 16% (PR = 0.84, 95% CI = 0.75-0.95). Stratification by prenatal ascertainment did not alter results for spina bifida but did impact anencephaly trends.

The decline in the prevalence of spina bifida was temporally associated with folic acid fortification of US grain supplies. The temporal association between fortification and the prevalence of anencephaly is unclear.

Journal Reference:
L.J. Williams et al. Prevalence of spina bifida and anencephaly during the transition to mandatory folic acid fortification in the United States. Teratology 66:33-39, 2002

It is also possible that because these defects have multiple etiologies, and thus, may follow the multifactorial/threshold model (Fraser, ’98), the combination of factors that results in the development of spina bifida may differ from that for anencephaly. Given differing etiologies, two possible conclusions could be drawn about the relationship between folic acid consumption and these defects. First, the amount of folic acid needed to prevent anencephaly may be higher than the amount needed to prevent spina bifida. The MRC (’91) and Czeizel and Dudas studies (’92) administered 4,000 g and 800 g of folic acid to subjects, respectively. The current level of folic acid fortification mandated by the FDA may not be high enough to prevent cases of anencephaly. Second, there may be a smaller percentage of folic acid-preventable anencephaly cases compared to spina bifida and additional fortification would not contribute to the further prevention of this birth defect.

Anomalous Costochondral Cartilage in Fetal Anencephaly

Anencephaly is a human fetal malformation with absence of brain and calvarium superior to the orbits. The consequent absence of hypothalamus provides a unique model for studying human development, and therefore
skeletal growth, in the absence of hypothalamic hormones and their regulatory functions. To assess the influence of hypothalamic insufficiency on cartilage development, we studied costochondral cartilage sections from eight anencephalic fetuses (18–22 weeks old) and seven controls (16–22 weeks old) with pathologies not directly related to skeletal growth. We found a previously undescribed anomalous organization of the cartilage in the anencephalic. The proliferative chondrocytes showed a disordered appearance with an increased proliferative zonal length (156 6 28 mm in anencephalic fetuses vs. 103 6 14 mm in controls, p 5 0.006) and a concomitant decrease in the maturing portion, where
cells form ordered isogenic groups (58 6 13 mm in anencephalic fetuses vs. 93 6 19 mm in controls, p 5 0.003).
In addition, cell density was significantly decreased in the proliferating and maturing zones in the anencephalic cases (84 6 21 vs. 130 6 21 cells/40 mm2 in proliferating zone; 53 6 8 vs. 94 6 8 in maturing portion,
p , 0.005). These alterations in the developing cartilage of the anencephalic may contribute to the observed growth retardation in these fetuses and reflect modifications in pituitary hormones and growth factors resulting from reduction in hypothalamopituitary function.

Journal Reference:
Garcia-Ramirez M, Toran N, Carrascosa A, Audi L. Anomalous Costochondral Cartilage in Fetal Anencephaly. Pediatr Dev Pathol. 2000 May-Jun;3(3):256-63.

Epidemiology of Neural Tube Defects

Neural tube defects (NTDs)—malformations secondary to abnormal neural tube closure between the third and fourth weeks of gestational age—have a complex and imperfectly understood etiology in which both genetic and environmental factors appear to be involved. A number of specific chromosomal or single-gene disorders, presumably not affected by environmental influences, are associated with the development of NTDs, but such syndromal cases account for a small proportion of NTDs in live-born infants. Analysis of recurrence patterns within families and of twin-concordance data provides evidence of a genetic influence in nonsyndromal cases, but factors such as socioeconomic status and geographic area (independent of race or ethnicity) are also associated with variations in the incidence of NTDs. The prevalence at birth of both anencephaly and spina bifida has decreased, but the advent of antenatal diagnosis and elective termination of affected pregnancies has undermined the reliability of birth prevalence rate as an estimate of incidence. Some occupational and other exposures, including maternal use of antiepileptic drugs (AEDs), are associated with increased risk for NTDs. Among women who have had an NTD-affected pregnancy, recurrence risk is markedly higher than the risk for a first NTD-affected pregnancy in the general population. There is strong evidence, overall, for a protective effect of adequate folate consumption. In some high-risk groups, however, such as women taking AEDs, folate supplementation has not been proven to reduce NTD risk.

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Journal Reference:
Frey, Lauren; Hauser, W. Allen. Epidemiology of Neural Tube Defects. Epilepsia, Volume 44, Supplement 3, June 2003 , pp. 4-13(10)

lundi 25 janvier 2010

Impact of Prenatal Diagnosis and Elective Termination on the Prevalence of Selected Birth Defects in Hawaii

This study examined the effect of prenatal diagnosis and elective termination on the prevalence of neural tube defects, oral clefts, abdominal wall defects, and chromosomal anomalies in Hawaii by using actively ascertained surveillance data collected between 1987 and 1996 by the Hawaii Birth Defects Program. Because the Program has nearly universal access to prenatal diagnostic information and to follow-up data on elective terminations, Hawaii is an ideal setting in which to study their effects on prevalence rates of birth defects.
Except for oral clefts, a large proportion of the defects studied were prenatally diagnosed: anencephaly (87%), spina bifida (62%), encephalocele (83%), cleft palate (0%), cleft lip with or without cleft palate (14%), omphalocele (60%), gastroschisis (76%), Down syndrome (43%), trisomy 18 (61%), and trisomy 13 (40%). The effect of elective terminations on the birth prevalence rates for most of these birth defects was significant. Including electively terminated cases in the calculations of birth prevalence rates increased the rates by more than 50% for five of the 10 birth defects studied.

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Journal Reference:
Forrester M.B. Impact of Prenatal Diagnosis and Elective Termination on the Prevalence of Selected Birth Defects in Hawaii. Am J Epidemiol Vol. 148, No. 12, 1998

Conflits d'intérêts entre jumeaux = Discordant anomaly in twin pregnancy

Le risque de perte fœtale spontanée est multiplié par 4 pour la grossesse monochoriale par rapport à la grossesse bichoriale. L'incidence du RCIU sélectif (sRCIU) varie de 12,5 à 25 % selon la définition du retard de croissance. Cette variation s'explique par le mélange entre des syndromes transfuseur-transfusé (STT) purs et des grossesses sans STT avec un sRCIU pur. La pertinence du diagnostic anténatal de sRCIU est faible, la VPP n'étant que de 37 % (NP4). Le Doppler ombilical avec flux diastolique nul (type II) ou avec flux intermittent (type III) est un facteur pronostique de risque de mortalité du fœtus hypotrophe et de lésions cérébrales du fœtus le plus gros (NP3). L'incidence observée des malformations des jumeaux est de 4,05 % versus 2,38 % pour les singletons (RR = 1,7 [IC 95 % 1,47-1,97]). De la même manière, le taux de malformations est supérieur dans les grossesses monochoriales par comparaison aux grossesses bichoriales, 6,33 % versus 3,43 % (RR = 1,8 [IC 95 % 1,3-2,5]) (NP3). Dans la majorité des cas, la malformation ne concerne que l'un des fœtus. Les malformations les plus fréquentes sont celles du système nerveux central (par comparaison aux singletons), du tractus urinaire et les malformations cardiaques (NP3). Les grossesses monozygotes ne sont pas nécessairement phénotypiquement et génétiquement identiques. Il faut proposer un prélèvement du fœtus porteur de la malformation, et secondairement du fœtus apparemment sain en cas d'anomalie chromosomique. Il faut discuter la recherche d'une disomie uniparentale en cas de discordance chromosomique (NP3). Dans le cadre du fœtus acardiaque, un suivi intensif de la taille du fœtus acardiaque, des Doppler et des signes d'insuffisance cardiaque du fœtus « pompe » est indispensable (avis d'expert). Lorsque la malformation met en péril la grossesse, pour les grossesses bichoriales avec anencéphalie de l'un des fœtus, un fœticide sélectif permet d'augmenter l'âge gestationnel à la naissance, au prix d'un taux de fausse couche de 8 % et d'un risque de prématurité de 12 %. Aussi pourrait-il être justifié d'attendre l'évolutivité ou le troisième trimestre pour la réalisation de ce geste (NP3). Dans la grossesse monochoriale, il faut privilégier l'occlusion funiculaire par coagulation à la pince bipolaire et attendre l'âge gestationnel d'au moins 18 semaines (NP4). Le principal risque est la rupture prématurée des membranes de 20 %. L'analyse actuelle de la littérature ne permet pas de dégager des indications formelles de geste fœticide hormis les rares situations de fœtus acardiaque avec décompensation du fœtus sain. La situation très particulière du sRCIU fait l'objet d'un essai randomisé. La participation active des patientes au choix thérapeutiques est indispensable (avis d'expert).

Source: Cat.Inist

Journal Reference:
FAVRE R. Conflits d'intérêts entre jumeaux. Journal de gynécologie obstétrique et biologie de la reproduction. 2009, vol. 38, no8, SUP, [Note(s): S90-S99] (51 ref.)

vendredi 22 janvier 2010

Zoonotic Ljungan Virus Associated with Central Nervous System Malformations in Terminated Pregnancy

The Ljungan virus (LV) has been shown to cause central nervous system malformations in laboratory mouse models. The LV has also been associated with intrauterine fetal death in humans. We investigated the presence of LV in a series of human hydrocephaly and anencephaly cases from elective abortions.

A series of elective abortions owing to hydrocephaly, anencephaly, and similarly aged trisomy 21 elective abortions as controls were examined for LV by immunohistochemistry and real time RTPCR. A second experiment involved newborn mice exposed to LV. RESULTS: LV was diagnosed in 9 of 10 cases with hydrocephalus and in 1 of 18 trisomy 21 controls by immunohistochemistry. Five of nine cases with anencephaly had a positive PCR result, whereas none of the 12 trisomy 21 available for PCR testing had a positive result. The 47 newborn mice exposed to LV all developed encephalitis, with eight having hydrocephalus. None of the 52 control animals had encephalitis or hydrocephalus.

The association between LV both hydrocephaly and anencephaly suggests that LV may be playing an important role in AQ3 central nervous system malformations in humans.

"The finding that LV causes anencephaly and hydrocephaly in infected laboratory mice stimulated our interest in studying possible associations between LV and CMS in humans (Samsioe et al., 2006). This small pilot study indicates that LV is associated with a substantial proportion of CMS. The present study demonstrated LV in the majority of hydrocephaly cases and in more than half of the anencephaly cases from elective abortions."

Journal Reference:
Bo Niklasson, et al. Zoonotic Ljungan Virus Associated with Central Nervous System Malformations in Terminated Pregnancy. Birth Defects Research (Part A) 00:000–000, 2009. 2009 Wiley-Liss, Inc.

Mutations in VANGL1 Associated with Neural-Tube Defects

Neural-tube defects such as anencephaly and spina bifida constitute a group of common congenital malformations caused by complex genetic and environmental factors. We have identified three mutations in the VANGL1 gene in patients with familial types (V239I and R274Q) and a sporadic type (M328T) of the disease, including a spontaneous mutation (V239I) appearing in a familial setting. In a protein–protein interaction assay V239I abolished interaction of VANGL1 protein with its binding partners, disheveled-1, -2, and -3. These findings implicate VANGL1 as a risk factor in human neural-tube defects.

Journal Reference:
Kibar Z. et al. Mutations in VANGL1 Associated with Neural-Tube Defects. N Engl J Med 2007;356:1432-7.

Toward understanding the genetic basis of NTDs

Neural tube defects (NTDs) represent a common group of severe congenital malformations that result from failure of neural tube closure during early development. Their etiology is quite complex involving environmental and genetic factors and their underlying molecular and cellular pathogenic mechanisms remain poorly understood. Animal studies have recently demonstrated an essential role for the planar cell polarity pathway (PCP) in mediating a morphogenetic process called convergent extension during neural tube formation. Alterations in members of this pathway lead to NTDs in vertebrate models, representing novel and exciting candidates for human NTDs. Genetic studies in NTDs have focused mainly on folate-related genes based on the finding that perinatal folic acid supplementation reduces the risk of NTDs by 60–70%. A few variants in these genes have been found to be significantly associated with an increased risk for NTDs. The candidate gene approach investigating genes involved in neurulation has failed to identify major causative genes in the etiology of NTDs. Despite this history of generally negative findings, we are achieving a rapid and impressive progress in understanding the genetic basis of NTDs, based mainly on the powerful tool of animal models.

Journal Reference:
Kibar Z, Capra V, Gros P. Toward understanding the genetic basis of neural tube defects. Clin Genet 2007: 71: 295–310.

Impact of Prenatal Diagnosis on the Birth Prevalence of NTDs

To determine the impact of prenatal diagnosis on the birth prevalence of neural tube defects (NTDs) in Atlanta during 1990 through 1991.
Methods. Live-born and stillborn infants with NTDs who were at least 20 weeks’ gestation were ascertained by the Metropolitan Atlanta Congenital Defects Program (MACDP), a population-based birth defects registry. Prenatally diagnosed NTh-affected pregnancies were ascertamed from the four perinatal centers and the three genetic laboratories operating in Atlanta during 1990 through 1991. Fetal death certificates were also reviewed for potential cases.

During 1990 through 1991, MACDP ascertamed 59 NTh cases, for a birth prevalence of 0.77/1000 live births. During this period, an additional 28 NTDaffected pregnancies were detected prenatally and terminated before 20 weeks’ gestation. The adjusted NTh rate
during 1990 through 1991, which includes prenatally diagnosed cases, was 1.13/1000 live births.

Prenatal diagnosis is making a substantial impact on the birth prevalence of NTDs in Atlanta.
However, since NTD rates in Atlanta were 2 to 2.5 per 1000 live births in 1970, prenatal diagnosis and termination of pregnancy does not completely account for the declining rate of NTDs.

Impact of Prenatal Diagnosis on the Birth Prevalence of Neural Tube Defects, Atlanta, 1990-4991. Helen E. Roberts et al. Pediatrics 1995;96:880-883;

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Children with anencephaly and their families

The project “Children with anencephaly” is leaded by Prof. Dr. Harald Goll, of the Division on Intellectual and Developmental Disabilities of the University of Erfurt / Germany. Since 2003 there has been an ongoing research cooperation with the professorship of theological ethics at the Theological Faculty of the University of Erfurt (Prof. Dr. Josef Römelt) and the integration of parents as experts. Several international conferences on the situation of children with anencephaly and their parents have been held. An interdisciplinary “anencephaly network” with participants from the fields of medicine, philosophy, psychology and law emerged from this activities.
One of the first results of the project was the publication of a book in Spring 2009. “Children with anencephaly and their families” has been published in German and contains articles from participants of the network from different disciplines.

Kinder mit Anenzephalie und ihre Familien

Anenzephalie bedeutet das Fehlen des Großhirns. Es gibt keine Heilung. Die Überlebensdauer der betroffenen Kinder beträgt nur wenige Tage. Die Diagnose wird meist pränatal gestellt. Zunehmend entscheiden sich Eltern, die Schwangerschaft fortsetzen. Sie wollen das Zusammensein mit ihrem Kind bereits vor der Geburt bewusst erleben und in Ruhe Abschied nehmen können. Angesichts der massiven Schädigung des Gehirns und der kurzen Lebenserwartung stellen sich anthropologisch-ethische Grundfragen des Menschseins sowie Fragen nach den Voraussetzungen für Bewusstsein, Wahrnehmung und Empfindung. Hinzu kommt die Entwicklung angemessener Angebote zur Begleitung von Eltern und Kind.

Seit vielen Jahren besteht eine Forschungskooperation der Herausgeber. Daraus entstand ein internationales „Netzwerk Anenzephalie“. Der kulturwissenschaftliche Zugang, die interdisziplinäre Zusammensetzung und die Einbindung betroffener Eltern als Experten in eigener Sache bilden ein zentrales Charakteristikum dieses Forschungsverbundes. Dies dürfte weltweit einzigartig sein.

Daher bietet das Buch Beiträge aus dem Bereich der Medizin, der Sonderpädagogik, der Psychologie sowie der philosophischen und theologischen Ethik. Und es bemüht sich um die Verknüpfung der wissenschaftlichen Diskussion mit den Erfahrungen von Eltern, die ein Kind mit Anenzephalie geboren haben.

Kinder mit Anenzephalie und ihre Familien
Harald Goll / Monika Jaquier / Josef Römelt (Hrsg.)
Bad Heilbrunn, Klinkhardt Verlag, Juli 2009
ISBN-13: 978-3-7815-1663-2

Neogenin and RGMa Control Neural Tube Closure and Neuroepithelial Morphology by Regulating Cell Polarity

In humans, neural tube closure defects occur in 1:1000 pregnancies. The design of new strategies for the prevention of such common defects would benefit from an improved understanding of the molecular events underlying neurulation. Neural fold elevation is a key morphological process that acts during neurulation to drive neural tube closure. However, to date, the molecular pathways underpinning neural fold elevation have not been elucidated. Here, we use morpholino knock-down technology to demonstrate that Repulsive Guidance Molecule (RGMa)-Neogenin interactions are essential for effective neural fold elevation during Xenopus neurulation and that loss of these molecules results in disrupted neural tube closure. We demonstrate that Neogenin and RGMa are required for establishing the morphology of deep layer cells in the neural plate throughout neurulation. We also show that loss of Neogenin severely disrupts the microtubule network within the deep layer cells suggesting that Neogenin-dependent microtubule organization within the deep cells is essential for radial intercalation with the overlying superficial cell layer, thereby driving neural fold elevation. In addition, we show that sustained Neogenin activity is also necessary for the establishment of the apicobasally polarized pseudostratified neuroepithelium of the neural tube. Therefore, our study identifies a novel

Journal Reference:
Nigel Kee et al. Neogenin and RGMa Control Neural Tube Closure and Neuroepithelial Morphology by Regulating Cell Polarity. The Journal of Neuroscience, November 26, 2008 • 28(48):12643–12653

Spontaneous pregnancy outcome after prenatal

Parents are usually told that many anencephalic offspring die in utero or soon after delivery, and many obstetricians offer electivetermination of the pregnancy. Following the personal experience of the first author, a personal website was created with the intentionof providing information and exchanging views with other parents confronted with a prenatal diagnosis of anencephaly. Data werecollected from 211 pregnancies where the parents opted not to terminate pregnancy.

These data revealed that polyhydramnios was a feature in 56 (26%) pregnancies, death in utero in 15 (7%) pregnancies, 72 (34%) babies were born prematurely (<37 weeksof gestation), 113 (53%) at term and 21 (10%) after 42 weeks. Stillbirth, presumably resulting from intrapartum death, occurred in 43 (20%) deliveries. One hundred and fifty-three (72%) ofanencephalic offspring were liveborn, of those, 103 (67%) died within 24 hours but 6/211 survived 6 or more days (maximum28 days). Continuation of pregnancy after a diagnosis of anencephaly is medically safe and should be considered as anoption. Free Fulltext

Journal Reference:
Jaquier M, Klein A, Boltshauser E., Spontaneous pregnancy outcome after prenatal diagnosis of anencephaly, BJOG 2006; 113:951-953

Consciousness without a cerebral cortex: A challenge for neuroscience and medicine

A broad range of evidence regarding the functional organization of the vertebrate brain – spanning from comparative neurology to experimental psychology and neurophysiology to clinical data – is reviewed for its bearing on conceptions of the neural organization of consciousness. A novel principle relating target selection, action selection, and motivation to one another, as a means to optimize integration for action in real time, is introduced. With its help, the principal macrosystems of the vertebrate brain can be seen to form a centralized functional design in which an upper brain stem system organized for conscious function performs a penultimate step in action control. This upper brain stem system retained a key role throughout the evolutionary process by which an expanding forebrain – culminating in the cerebral cortex of mammals – came to serve as a medium for the elaboration of conscious contents. This highly conserved upper brainstem system, which extends from the roof of the midbrain to the basal diencephalon, integrates the massively parallel and distributed information capacity of the cerebral hemispheres into the limited-capacity, sequential mode of operation required for coherent behavior. It maintains special connective relations with cortical territories implicated in attentional and conscious functions, but is not rendered nonfunctional in the absence of cortical input. This helps explain the purposive, goal-directed behavior exhibited by mammals after experimental decortication, as well as the evidence that children born without a cortex are conscious. Taken together these circumstances suggest that brainstem mechanisms are integral to the constitution of the conscious state, and that an adequate account of neural mechanisms of conscious function cannot be confined to the thalamocortical complex alone.

Journal Reference:
Bjorn Merker. Consciousness without a cerebral cortex: A challenge for neuroscience and medicine. BEHAVIORAL AND BRAIN SCIENCES (2007) 30, 63–134 DOI: 10.1017/S0140525X07000891

Proteins called protease-activated receptors (PARs) are required for neural tube closure

During normal embryonic development, a flat sheet of cells that is destined to give rise to the brain and spinal cord thickens and forms a groove with raised sides. Eventually, the sides of the groove fuse, almost like zipping a zipper, to form a hollow structure called the neural tube. If the neural tube does not "zip up" completely, it causes the brain and spinal cord to develop abnormally, resulting in defects that that range in severity from partial paralysis to death. These neural tube defects are relatively common, representing serious problems for 1/1000 live human births.

Details about what drives formation of the neural tube have remained elusive. But now, a study led by Drs. Eric Camerer and Shaun R. Coughlin from the Cardiovascular Research Institute at the University of California, San Francisco has shown that proteins called protease-activated receptors (PARs), which are best known for their role in tissue response to injury in adults, are required for neural tube closure. The researchers found that mice lacking specific PARs exhibited neural tube defects.

Interestingly, specific PARs and the protein that controls them were only active along the edges of the groove where and when the edges of the neural tube fused. These observations led the researchers to hypothesize that this PAR signaling system might sense the integrity of the tissue, as it does in the case of injuries, to regulate the closure of the tube. "Our discovery of molecular events that contribute to neural tube closure in mice might lead to insights into the complex mechanisms underlying human neural tube defects," concludes Dr. Coughlin.

Story Source: Science Daily

Journal Reference:
1.Camerer et al. Local Protease Signaling Contributes to Neural Tube Closure in the Mouse Embryo. Developmental Cell, 2010; 18 (1): 25-38 DOI: 10.1016/j.devcel.2009.11.014