[Music] it is a multifactorial problem it's a problem it's fundamentally a genetic problem but there are clearly genetic and environmental or so-called epigenetic factors that can impact neural tube closure okay and and many many of these involve the folate pathway right now folate is the building block of purines and pyrimidines which of course are the backbone of them of the uh nucleotides right it provides the key element of folate is is that it provides methyl groups for other men for other macromolecules so the methylation of genomic dna appears increasingly implicated in the epigenetic regulation of the crucial gene expression fundamental to the expression of these neural tube defects and the pathway that seems to be most focused upon by the by the basic investigators um sort of trailblazing in this area are is a pathway in mice called the planar cell polarity pathway and basically it's not a big surprise but guess what this has to do with folic acid metabolism it's a transmembrane cytosolic protein and it has to do with um cytosolic proteins that enable folic acid metabolism to occur normally okay so the critical event is depicted uh in the lower uh right little cartoon here i think everybody's familiar with it i know it's been reviewed in your other lectures and shown quite nicely some of the embryology so i skipped over that but the fundamental issue in uh neural tube defect formation is the failure of dissociation between neuroectoderm and cutaneous ectoderm so that failure of primary neurolation occurring about the 25th or 26th day is under regulation of these various pathways and that failure draws the neural elements to the surface enables the spinal fluid to be trapped beneath them and fundamentally changes the the landscape of the way um of the way uh these uh the the of of the of the expression of these disorders i'm gonna skip that for a moment all right so this is a very important paper because again it takes us back to what is the root cause of a lot of these problems and this is a paper that many people um kind of skip over but i think it's i think it's absolutely central it's by an a very talented young woman epidemiologist at cdc whose name is krista kreider and i've met dr kreider she's wonderful person um very engaging person to talk to about neural tube defects because she has brought something to the table that's very important and that is the concept of dose dependency and if you want to prove something in pharmacology you have to establish dose dependency and what she did was that she directly correlated in large epidemiologic studies as i said she's an epidemiologist who's worked at cdc she used large populations in in actually in upper asia china and in fact part of the mongolian plateau and what she showed was that there's a dose-dependent relationship between between maternal red blood cell folate and the inherent prevalence of neural tube defects so she fundamentally established that you can draw a linear correlation between what the what the average woman of child bearing age what the uh folic acid levels are on the red blood cells and her and the uh the direct incidence of neural tube defects hey everyone ryan rad here from neurosurgery training.org if you like that video subscribe and donate to keep our content available for medical students across the world