User:Etchevers/Notebook/Conference notes/2009/09/13: Difference between revisions
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Cf [http://www.amazon.com/gp/product/0195166035 book] review [http://books.google.com/books?id=lkhw5eDA9mIC&pg=PA188&lpg=PA188&dq=autosomal+dominant+neural+tube+defects+rasmussen&source=bl&ots=YgPin3RZp8&sig=zutrpS-2ZLE69NfFYw2_XGdZ60g&hl=en&ei=dwytSrCpFNTolAfUgLXHBg&sa=X&oi=book_result&ct=result&resnum=1#v=onepage&q=autosomal%20dominant%20neural%20tube%20defects%20rasmussen&f=false chapter] by Rasmussen SA and Frias JI in 2006: AD and AR conditions with syndromic NTD. | Cf [http://www.amazon.com/gp/product/0195166035 book] review [http://books.google.com/books?id=lkhw5eDA9mIC&pg=PA188&lpg=PA188&dq=autosomal+dominant+neural+tube+defects+rasmussen&source=bl&ots=YgPin3RZp8&sig=zutrpS-2ZLE69NfFYw2_XGdZ60g&hl=en&ei=dwytSrCpFNTolAfUgLXHBg&sa=X&oi=book_result&ct=result&resnum=1#v=onepage&q=autosomal%20dominant%20neural%20tube%20defects%20rasmussen&f=false chapter] by Rasmussen SA and Frias JI in 2006: AD and AR conditions with syndromic NTD. | ||
In selected populations, association between consanguinity and NTD risk. Chromosomal anomalies cf articles by Hume 1996, Kennedy 1998, Babcook 1995. Recent study using CGH microarray showing region on 13q including ZIC2 and ZIC5 among others (Kirchoff 2009 Am J Med Genet 149A:894). | |||
Teratogenic exposure - metabolic pbs (maternal diabetes, Zn deficiency - interesting in light of previous talk on Zn overdose, hyperthermia including fever from viral infections) and drugs of various sorts. | |||
Assess NTD recurrence including homocysteinemia or folatemia, venous blood glucose concentration, Hb1Ac. | |||
Questions: | |||
RJ - what about advanced paternal age? (Cited literature, nothing more to add). | |||
Hb1ac only informative early in pregnancy, as when additional blood produced will be diluted down. Reponse can be indicator of glycaemic control rather than oxygen transport - they seemed to be talking at cross-purposes. | |||
=== Janee Gelineau-van Waes === | === Janee Gelineau-van Waes === | ||
Revision as of 09:42, 13 September 2009
 Conference and seminar notes
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Second day of 6th Intl Neural Tube Defects conferenceDania Pastora, NTDs in Nicaragua 2007-8NTD most common CM in Nicaragua, registry started in 2007. NW Ncaragua - Leon and Chinandega For 20K newborns in two years, 800 stillborn, 495 CM's (2.5%) and 43 NTD. No sex bias. NTDs in stillborn = 9/800 (112/10K) and others = 34/19200 (18/10000). SB most frequent, more in males (9 vs 1 for meningocoele (half dead but from another cause - premature for 3 or respiratory distress); 8 vs 11 for myelomeningocoele (4 dead from surgical complications); 2 cases of encephalocoele and 19 anencephales - where the last have no sex bias). 14% mothers took folic acid and only in 2nd trimester. Supplementation not regulated by health authorities. Damn - my battery did not recharge overnight for some reason!! Will take notes on paper and recopy later.
Suzan Carmichael - nutrient intake and risks of NTDs in CaliforniaMosley 2009 - births after folic acid supplementation only study actually found increase in anencephaly. Contribute data to Mosley study also the CA cohort (part of national birth defect study). Oxidative stress nutrients and anencephaly Lutein (caratenoid?) - odds ratio 1 = no association for first quartile (low intake) and last quartile (high) Vit C - low intake OR = 3.2, high intake protective (-0.6) restricted to women w/o supplements - trend was significant. Vit E OR = 1.4, protective 0.5 with wide CI but trend was significant. b-carotene, low intake slightly protective, high intake v protective (0.2) and for iron - high intake increased risk to 2.5 (as a pro-oxidant... but in light of I Zohn's talk wonders what to think now). One-carbon nutrients and anencephaly Methioninem choline, betaine no differences, folate expected and riboflavin low intake increased risk but high intake brought back to normal. This was exaggerated for spina bifida except unexpected methionine. Thiamin and zinc were opposite - esp high zinc intake OR up to 4 for anencephaly, not very significant trends for spina bifida. Glycemic index - higher index expected increased risk but not found, not for other simple sugars - fructose, glucose or sucrose. Is there a ceiling effect of supplementation? *Supplements are weakly if at all protective.* The folate-sensitive NTDs are now being protected in the US at least. Other nutrients in supplements can be helpful in theory but have not seen a stronger association. For example, subsequent to fortification, NTDs did not go down in the CA Central valley region. Question: from Hank: Low choline risk in another study - in blood the levels are related to those of folate. Also, wonder about serine and something else I didn't catch. Comment about higher iron, higher risk.... re Irene's talk? And comment that the protective effect of folates in supplements may be offset by the not-protective effect of additional zinc in those same supplements. Wonder if can check supplement vs non-supplemented mothers particularly wrt iron status as hard to measure. Main sources of iron and zinc coming from meat, wondering about other nutrients eg in animal fats?
Madeleine Brouns on Grlh genesFrom Amsterdam. Not finding most of the 200 NTD mouse genes (usually upon KO) to be defective in humans. Ideal model should be variable phenotypic expn, not lethal, not syndromic. Curly-tail (1950's) and axial defects (1990's) models. Hypomorph of Grhl3 = curly-tail, whereas, Axd not yet cloned? defect at E9-10, curled tail htz in 60% so slightly dominant? and all hmz have E13 SB but only 1/2 at birth. Intrauterine repair? or just reabsorption of some? Possible methionine rescue in diet. Did a tour de genome with 105 markers - look at Chr 15 between CA15-16 to CA15-05 (37.5) containing 6 genes and marker D15MIT250 to discriminate the genetic backgrounds - in 86 embryos from htz crosses, get 100% linkage so confirms region. Genes are Ankrd46, Zfp706 and Grhl2 gene (most likely candidate!!), Ncald, couple others. No mutations in any, check by qPCR but Grhl2 get temporary upregulation between 25-40 somites development in the SB embryos. Grhl3 is reduced expression to get defect. Looking at conserved non-coding sequences. LOD1229, LOD1404, LOD1549 potential regulatory sequences, still are looking for molecular defect. (me: Are there molecular segments aside from Hox genes explaining predilection to NTD at certain sites rather than the older model discussion curvature and mechanical forces, or closure sequence?) For curly-tail, look at Gustavsson BDRA 2008 for criteria - less prolif in hindgut and ntd, too much ventral curvature caudally, inhibits posterior neuropore closure leading to delay = curly tail or failure = SB. Measured ventral curvature of neuropore region from Brook et al Development 1991 to measure an angle between penultimate somite and some other tail feature. Nick Greene has examined ISH expression. Cross between curly-tail and axd do not interact genetically. Expression in hindgut seen by gene trap. Cross of gene trap and axd underway to see if rescue. Grhl3 expression in Axd/Curly-tail, by qRT-PCR no change Up front, Muriel bets that nature may be a retroviral transposable element close to gene - can check by long-range PCR. Pietro Cavalli - clinical approach to assessing NTD recurrence riskdiagnosis + etiology to appropriate risk assessment. Cf book review chapter by Rasmussen SA and Frias JI in 2006: AD and AR conditions with syndromic NTD. In selected populations, association between consanguinity and NTD risk. Chromosomal anomalies cf articles by Hume 1996, Kennedy 1998, Babcook 1995. Recent study using CGH microarray showing region on 13q including ZIC2 and ZIC5 among others (Kirchoff 2009 Am J Med Genet 149A:894). Teratogenic exposure - metabolic pbs (maternal diabetes, Zn deficiency - interesting in light of previous talk on Zn overdose, hyperthermia including fever from viral infections) and drugs of various sorts. Assess NTD recurrence including homocysteinemia or folatemia, venous blood glucose concentration, Hb1Ac. Questions: RJ - what about advanced paternal age? (Cited literature, nothing more to add). Hb1ac only informative early in pregnancy, as when additional blood produced will be diluted down. Reponse can be indicator of glycaemic control rather than oxygen transport - they seemed to be talking at cross-purposes. Janee Gelineau-van WaesWilliam Klitz
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