Papers from the Ninth International Conference on Neural Tube Defects.

Abstract

Neural tube defects (NTDs) are the second most prevalent structural birth defect affecting approximately 324,000 births worldwide (Christianson et al., 2006), including 3000 pregnancies in the United States (Mersereau et al., 2004) annually. NTDs result from abnormalities in the development of the spinal cord and brain as well as the tissues that surround these structures such as the bones of the skull and vertebrae. The most common NTDs are anencephaly and myelomeningocele (commonly referred to as spina bifida). Anencephaly results from abnormal development of the portion of the neural tube that will develop into the brain, is uniformly lethal in the pre- or early postnatal period, and has a prevalence of ∼2.6/10,000 births in the United States (Canfield et al., 2006). Spina bifida results from abnormal development of the portion of the neural tube that will develop into the spinal cord, is associated with increased mortality and significant morbidity through the lifespan of survivors (Ouyang et al., 2007), and has a prevalence of ∼3.7/10,000 births in the United States (Canfield et al., 2006). The basis of NTDs in humans (in particular anencephaly and spina bifida) has been extensively studied yet the definitive causes are identified in only a few instances. A small proportion of NTDs occurs as part of chromosomal, single-gene, or teratogenic syndromes. Similarly, NTDs segregate in a Mendelian manner in only a minority of families. The majorities of NTDs are not associated with syndromes and have complex etiologies involving the combinatorial effects of multiple genetic and environmental factors. For instance, both maternal obesity and inadequate maternal folate status/intake of folic acid are associated with an increased risk of nonsyndromic NTDs (Waller et al., 2007; Correa et al., 2008). However, these and other known risk factors only account for a small proportion of NTDs, providing limited avenues for prevention. For instance, implementation of mandatory folic acid fortification of the food supply in the United States was followed by only a 24% reduction in the incidence of spina bifida (Canfield et al., 2006). Thus, additional efforts to understand the underlying genetic and environmental factors contributing to NTDs is imperative to achieve further reductions in the incidence of this birth defect. To accelerate discoveries in NTD research, the International Neural Tube Defects Conference was initiated in 1999 to bring together researchers from a wide variety of disciplines with the common goal of understanding the causes and ultimately preventing NTDs. The Ninth International Neural Tube Defects Conference was held October 26 to 29, 2015, at the AT&T Executive Conference Center in Austin, Texas. The conference was organized by Richard Finnell, Laura Mitchell, Philip Lupo, and John Wallingford and was supported by generous contributions from the National Institutes of Health (NICHD, NINDS, NIEHS); the School of Human Ecology, The University of Texas at Austin; Fibich, Leebron, Copeland, Briggs & Josephson; Rosenblum, Ronan, Kessler & Sarachan; and Blizzard & Nabers. Over 80 attendees from 15 countries throughout the world gathered to discuss recent advances in the field. Since its inception, the NTD Conference has provided a forum for the exchange of information across disparate disciplines of clinical medicine, public health, and the basic sciences. Following in this tradition, the Ninth International NTD Conference included oral and poster presentations covering a diverse spectrum of investigation, from clinical, epidemiological, computational toxicology, developmental biology, and genomics. This special issue of Birth Defects Research highlights a sampling of the interdisciplinary research presented at the Ninth International conference on NTD as well as providing a glimpse of the broad spectrum of research conducted by the vigorous NTD research community. Dr. Edward R.B. McCabe from the March of Dimes Foundation and Dr. Sergiu P. Pasca of Department of Psychiatry at Stanford University (Stanford, CA) gave keynote presentations. Dr. McCabe provided an update on folic acid fortification and a discussion of March of Dimes funding opportunities for research related to NTDs. Dr. Pasca presented his work on the development of novel three-dimensional culture systems to differentiate human induced pluripotent stem cells (IPSCs) into laminated cerebral cortical-like structures for the interrogation of cortical development and disease. The potential for these technologies to be used in NTD research to examine cell polarity and fate in IPSCs from NTD patients was discussed. Because folic acid supplementation does not prevent all NTDs, there are significant efforts in the field to identify additional preventative treatments. One new and exciting approach originates from studies in model systems where it was found that supplementation with inositol prevents NTDs in mouse models. This and other findings prompted initiation of clinical trials to determine if combined inositol and folate supplementation would prevent NTDs in subjects with previous NTD affected pregnancies despite having taken folate supplements. Nicholas Greene (University College London, UK) presented an update on the PONTI (Prevention of Neural Tube Defects by Inositol) study. Their promising results support the efficacy and safety of combined inositol and folate supplementation for the prevention of NTDs in high-risk populations. Furthermore, their study provides strong support for the feasibility of a large double blind clinical trial. Another nutrient of interest for prevention of NTDs is iron, and Irene Zohn (Children's National Medical Center, Washington, DC) presented work demonstrating that iron and folate supplementation prevented NTDs in a mouse model with severe iron deficiency. Unexpectedly, high levels of iron supplementation reduced folate levels in both pregnant dams and embryos, suggesting that high levels of iron supplementation might be counterproductive during pregnancy. Other presentations emphasized the need to carefully consider the role of environmental factors and gene–environment interactions in human studies. As summarized in this issue, Maitreyi Mazumdar (Harvard University, Cambridge, MA) presented findings from a new case-control study of NTDs in Bangladesh. This study explored how arsenic might influence NTD risk through disruption of maternal glucose and folate metabolism. Margaret Nguyen (The University of Texas Health Science Center at Houston, Texas) examined the role of maternal gene–micronutrient interactions on the risk of myelomeningocele among offspring using a case–parent trio approach. While they found no significant interactions, it is apparent that future studies should not only account for gene–environment interactions, but also account for maternal genotypes. Studies in mouse models paralleled this human work. Stephen Gross (Weill Medical College of Cornell University, New York, NY) presented results from a collaborative study with Richard Finnell (The University of Texas at Austin, Austin, TX) and Margaret Ross (Weill Medical College of Cornell University, New York, NY) using a novel metabolite profiling technique to define the metabolic perturbations that occur in both pregnant dams and their offspring in response to valproate exposure, a known teratogen that increases NTD risk. Several presentations focused on the identification of inherited genetic risk factors that increase susceptibility to NTDs. Included in this issue is an extensive review by Margaret Ross (Weill Medical College of Cornell University, New York, NY) that documents the various genomic approaches used in evaluating the risk of spina bifida in humans. This important review reminds us that the goal of human genomic studies is to find strategies for optimizing conditions to promote healthy birth outcomes. Furthermore, compared with other relatively common structural birth defects, large-scale genome-wide studies to identify the genes responsible for NTDs are currently missing from the literature. Animal model systems provide an essential complement to human genomic studies by identifying novel candidate genes and pathways required for neural tube closure. Several presentations on the genes and pathways involved in NTDs in these model systems were given. The plethora of genes discussed illustrates the diverse cellular functions required to generate the mechanical forces and tissue movements that drive neural tube closure. As an example, in this issue an extensive review by Saikat Mukhopadhyay (University of Texas Southwestern Medical Center, Dallas, TX) summarizes our current knowledge of the involvement of G-protein coupled receptor signaling and neural tube closure. The complex genetic landscape underlying NTDs is also echoed in mouse genetic studies. Dr. Heather McDermid (University of Alberta, Canada) presented an update on the analysis of genetic modifiers present in various inbred mouse strains and the opportunity the identification of these modifiers presents toward providing a greater understanding the complex genetics of NTDs. One of the goals of the conference is to provide opportunities for trainees to learn about the opportunities in the field of NTD research and present their research. At each meeting, the Marcy Speer Memorial Awards are bestowed to the predoctoral and postdoctoral level trainees judged to have given the most meritorious platform presentations. This award is in honor of Marcy Speer (1959–2007), one of the initial founders of the International NTD Conference. The awardees for 2015 were Deepthi Vijayraghavan (predoctoral) and Youssef Kousa (postdoctoral). Deepthi Vijayraghavan is a graduate student at the University of Pittsburgh, Pittsburgh, PA (mentor Dr. Lance Davidson). Ms. Vijayraghavan presented her research on the physical mechanics that shape, fold, and form the neural tube. Dr. Youssef Kousa is currently a Medical Resident (Children's National Medical Center in Washington DC) and presented research from his Ph.D. thesis with Brian Schutte (Michigan State University, Lansing, MI) on shared pathways in orofacial and neural tube development. At the conclusion of the meeting, the possibility that the NTD community might contribute to a white paper representing interests of the greater birth defects research community was discussed. This white paper calls for strategies and investments to tackle significant challenge involved in the study of birth defects with the goal of understanding the genetic basis of these complex disorders. The product of these discussions titled “White paper on the study of birth defects” is published in this special issue of Birth Defects Research. This white paper is authored by Mustafa Khokha (Yale University School of Medicine, New Haven, CN), Laura Mitchell (University of Texas Health Science Center at Houston, Houston, TX), and John Wallingford (University of Texas at Austin, Austin, TX) and signed by representatives of multiple scientific societies with vested interests in understanding and preventing birth defects. The International Conference on NTDs provides an interdisciplinary forum for sharing current research on the causes of NTDs. This meeting helps to foster existing and new collaborations as well as providing opportunities in career development for trainees. The breadth of subjects covered by the papers in this issue illustrates the complexities faced by researchers in understanding the underlying factors that contribute to NTDs and the challenges in developing new strategies to prevent their occurrence. More information about this and future international conferences on NTDs can be found at http://ntdconference.com Philip J. Lupo1 Irene Zohn2 1Department of Pediatrics, Section of Hematology--Oncology, Baylor College of Medicine, Houston, Texas 2Neuroscience Research, Children's National Medical Center, Washington, DC