Ybot-Gonzalez P, Gaston-Massuet C, Girdler G, Klingensmith J, Arkell R, Greene ND, Copp AJ. Neural plate morphogenesis during mouse neurulation is regulated by antagonism of Bmp signalling. Development. 2007 Sep;134(17):3203-11.
Dorsolateral bending of the neural plate, an undifferentiated pseudostratified epithelium, is essential for neural tube closure in the mouse spinal region. If dorsolateral bending fails, spina bifida results. In the present study, we investigated the molecular signals that regulate the formation of dorsolateral hinge points (DLHPs). We show that Bmp2 expression correlates with upper spinal neurulation (in which DLHPs are absent); that Bmp2-null embryos exhibit premature, exaggerated DLHPs; and that the local release of Bmp2 inhibits neural fold bending. Therefore, Bmp signalling is necessary and sufficient to inhibit DLHPs. By contrast, the Bmp antagonist noggin is expressed dorsally in neural folds containing DLHPs, noggin-null embryos show markedly reduced dorsolateral bending and local release of noggin stimulates bending. Hence, Bmp antagonism is both necessary and sufficient to induce dorsolateral bending. The local release of Shh suppresses dorsal noggin expression, explaining the absence of DLHPs at high spinal levels, where notochordal expression of Shh is strong. DLHPs ;break through' at low spinal levels, where Shh expression is weaker. Zic2 mutant embryos fail to express Bmp antagonists dorsally and lack DLHPs, developing severe spina bifida. Our findings reveal a molecular mechanism based on antagonism of Bmp signalling that underlies the regulation of DLHP formation during mouse spinal neural tube closure.
PMID: 17693602
Monday, August 20, 2007
Risk of recurrence in major central nervous system malformations between 1976 and 2005
Joo JG, Beke A, Papp Z, Csaba A, Rab A, Papp C. Risk of recurrence in major central nervous system malformations between 1976 and 2005. Prenatal Diagnosis. 2007 Aug 13; [Epub ahead of print]
OBJECTIVE: The goal of the current publication is to review isolated central nervous system malformations (CSMs) using a database in excess of 75 000 cases, with special regard to the risk of recurrence of these malformations alone or in combination.
METHODS: In the period between 1 January 1976 and 31 December 2005, among the 75 320 documented cases, consultations were requested due to earlier isolated CSMs in the patients' histories in 3030 cases (4.2%). Processing the data we only considered disorders of genetic origin, and that was why we excluded the cases due to intrauterine infection. Monogenically inherited malformations were also excluded from the analysis. The diagnosis of the malformations was based on the prenatal diagnosis of ultrasonography as well as the findings of the foetopathological examination.
RESULTS: In 65% of the cases, the couples sought counselling because of malformation in a previous pregnancy. In these cases, the risk of recurrence was thought to be 5.2%, while in the case of two affected children this figure stood at 21.9%. Analysing the values for the risk of recurrence in 5-year periods, neural tube defects (NTDs) (particularly anencephaly and spina bifida) showed a detectable decrease, which could be attributed to a growing use of folic acid supplementation around the time of conception and during pregnancy.
CONCLUSION: There is a clear decrease of risk of recurrence of NTDs, while in the case of the other CSMs in this study, there is no noteworthy chronological change in their risk of recurrence. Copyright (c) 2007 John Wiley & Sons, Ltd.
PMID: 17694579
OBJECTIVE: The goal of the current publication is to review isolated central nervous system malformations (CSMs) using a database in excess of 75 000 cases, with special regard to the risk of recurrence of these malformations alone or in combination.
METHODS: In the period between 1 January 1976 and 31 December 2005, among the 75 320 documented cases, consultations were requested due to earlier isolated CSMs in the patients' histories in 3030 cases (4.2%). Processing the data we only considered disorders of genetic origin, and that was why we excluded the cases due to intrauterine infection. Monogenically inherited malformations were also excluded from the analysis. The diagnosis of the malformations was based on the prenatal diagnosis of ultrasonography as well as the findings of the foetopathological examination.
RESULTS: In 65% of the cases, the couples sought counselling because of malformation in a previous pregnancy. In these cases, the risk of recurrence was thought to be 5.2%, while in the case of two affected children this figure stood at 21.9%. Analysing the values for the risk of recurrence in 5-year periods, neural tube defects (NTDs) (particularly anencephaly and spina bifida) showed a detectable decrease, which could be attributed to a growing use of folic acid supplementation around the time of conception and during pregnancy.
CONCLUSION: There is a clear decrease of risk of recurrence of NTDs, while in the case of the other CSMs in this study, there is no noteworthy chronological change in their risk of recurrence. Copyright (c) 2007 John Wiley & Sons, Ltd.
PMID: 17694579
A model of comprehension in spina bifida meningomyelocele: Meaning activation, integration, and revision
Barnes MA, Huber J, Johnston AM, Dennis M. A model of comprehension in spina bifida meningomyelocele: Meaning activation, integration, and revision. Journal of the International Neuropsychological Society 2007 Sep;13(5):854-64.
Spina bifida meningomyelocele (SBM) is a neurodevelopmental disorder associated with adequate development of word reading and single word comprehension, but deficient text and discourse comprehension. Studies of comprehension in children with SBM are reviewed in relation to a comprehension model in which meanings are either activated from the surface code or constructed through resource-intensive integration and revision processes to form representations of the text base and models of the situation described by the text. Two new studies probed the construction of situation models in SBM. Experiment 1 tested the ability to build spatial and affective situation models from single sentences in 86 children with SBM (8 to 18 years of age) and 37 control children (8 to 16 years of age). Experiment 2 tested the ability to integrate across sentences to build spatial situation models in 15 children with SBM and 15 age-matched controls. Compared to age peers, children with SBM did not construct situation models that required integration of information across sentences, even though they could construct such models from single sentences. The data bear on the distinctive SBM neurocognitive profile, and more generally, on the significance of integration processes for the constructive aspects of language comprehension. (JINS, 2007, 13, 854-864.).
PMID: 17697417
Spina bifida meningomyelocele (SBM) is a neurodevelopmental disorder associated with adequate development of word reading and single word comprehension, but deficient text and discourse comprehension. Studies of comprehension in children with SBM are reviewed in relation to a comprehension model in which meanings are either activated from the surface code or constructed through resource-intensive integration and revision processes to form representations of the text base and models of the situation described by the text. Two new studies probed the construction of situation models in SBM. Experiment 1 tested the ability to build spatial and affective situation models from single sentences in 86 children with SBM (8 to 18 years of age) and 37 control children (8 to 16 years of age). Experiment 2 tested the ability to integrate across sentences to build spatial situation models in 15 children with SBM and 15 age-matched controls. Compared to age peers, children with SBM did not construct situation models that required integration of information across sentences, even though they could construct such models from single sentences. The data bear on the distinctive SBM neurocognitive profile, and more generally, on the significance of integration processes for the constructive aspects of language comprehension. (JINS, 2007, 13, 854-864.).
PMID: 17697417
Monday, August 13, 2007
Lessons learned from stomal complications in children with cutaneous catheterizable continent stomas
Barqawi A, de Valdenebro M, Furness PD 3rd, Koyle MA. Lessons learned from stomal complications in children with cutaneous catheterizable continent stomas.
BJU International. 2004 Dec;94(9):1344-7.
OBJECTIVE: To evaluate the impact of various factors that might ultimately influence the stoma complication rate associated with the construction of a continent catheterizable urinary (CCU) and Malone antegrade colonic enema (MACE) stoma in children.
PATIENTS AND METHODS: Retrospectively, we reviewed our experience in patients who had a CCU and/or MACE stoma reconstructed at our institution from 1992 to 2003. Diagnosis, type of stoma constructed (CCU vs MACE), single vs dual stomas, stomal site, conduit material (appendix, split appendix, Monti-Yang or ureter), sex, age, patient mobility and body mass index, race and concomitant surgery (e.g. bladder augmentation with or without bladder neck reconstruction) were evaluated for stoma-related complications. In all, 109 patients (64 males and 45 female), with a mean (sd, range) age of 8.6 (5.7, 2-37) years, had 151 stomas constructed during the period of analysis, comprising 56 CCU only, 11 MACE only and 42 (84 stomas) both simultaneously.
RESULTS: The mean (range) follow-up was 48 (6-144) months. The primary diagnoses were neurogenic bladder in 60 (55%), bladder exstrophy/epispadias in 17 (16%) and posterior urethral valves in 11 (9%) patients. The umbilicus was the primary site for the CCU stoma in 88 of 98 (90%) cases, while the right lower quadrant was the primary site for MACE in 46 of 53 (87%). After surgery complete stomal continence was provided in 95 of 98 (97%) CCU stoma, whereas the MACE was successful in 52 of 53 (99%). The stoma-related complications included stenosis in 27, leakage in eight, false passage in four, atrophy in two, keloid in one, and breakdown of the stoma in two. Individually, only greater age and a primary diagnosis of neurogenic bladder were independent risk factors associated with an increased rate of stomal complications and higher incidence of revision (P < 0.05).
CONCLUSION: Stomal complications are extremely common whether CCU or MACE stomas are constructed individually or together. Nevertheless, despite the need for revision, the high stoma continence rate supports their use. Greater age at surgery and a primary diagnosis of neurogenic bladder were associated with a significant increase in the stoma-related complications and the need for revision.
PMID: 15610118
BJU International. 2004 Dec;94(9):1344-7.
OBJECTIVE: To evaluate the impact of various factors that might ultimately influence the stoma complication rate associated with the construction of a continent catheterizable urinary (CCU) and Malone antegrade colonic enema (MACE) stoma in children.
PATIENTS AND METHODS: Retrospectively, we reviewed our experience in patients who had a CCU and/or MACE stoma reconstructed at our institution from 1992 to 2003. Diagnosis, type of stoma constructed (CCU vs MACE), single vs dual stomas, stomal site, conduit material (appendix, split appendix, Monti-Yang or ureter), sex, age, patient mobility and body mass index, race and concomitant surgery (e.g. bladder augmentation with or without bladder neck reconstruction) were evaluated for stoma-related complications. In all, 109 patients (64 males and 45 female), with a mean (sd, range) age of 8.6 (5.7, 2-37) years, had 151 stomas constructed during the period of analysis, comprising 56 CCU only, 11 MACE only and 42 (84 stomas) both simultaneously.
RESULTS: The mean (range) follow-up was 48 (6-144) months. The primary diagnoses were neurogenic bladder in 60 (55%), bladder exstrophy/epispadias in 17 (16%) and posterior urethral valves in 11 (9%) patients. The umbilicus was the primary site for the CCU stoma in 88 of 98 (90%) cases, while the right lower quadrant was the primary site for MACE in 46 of 53 (87%). After surgery complete stomal continence was provided in 95 of 98 (97%) CCU stoma, whereas the MACE was successful in 52 of 53 (99%). The stoma-related complications included stenosis in 27, leakage in eight, false passage in four, atrophy in two, keloid in one, and breakdown of the stoma in two. Individually, only greater age and a primary diagnosis of neurogenic bladder were independent risk factors associated with an increased rate of stomal complications and higher incidence of revision (P < 0.05).
CONCLUSION: Stomal complications are extremely common whether CCU or MACE stomas are constructed individually or together. Nevertheless, despite the need for revision, the high stoma continence rate supports their use. Greater age at surgery and a primary diagnosis of neurogenic bladder were associated with a significant increase in the stoma-related complications and the need for revision.
PMID: 15610118
Continent catheterizable channels and the timing of their complications
Thomas JC, Dietrich MS, Trusler L, DeMarco RT, Pope JC 4th, Brock JW 3rd, Adams MC. Continent catheterizable channels and the timing of their complications. Journal of Urology. 2006 Oct;176(4 Pt 2):1816-20; discussion 1820.
PURPOSE: We reviewed our experience with continent catheterizable channels with interest in the timing of conduit related complications.
MATERIALS AND METHODS: A retrospective review was performed of the outcome of continent catheterizable channels in all patients between 1998 and 2003 who had undergone construction of an antegrade continence enema and/or a Mitrofanoff procedure using appendix, small bowel or continent cutaneous vesicostomy. We performed a total of 117 such stomas in 37 male and 41 female patients 2.5 to 20 years old (mean age 8.9). For the antegrade continence enema we used appendix in 92% of cases, an ileal Yang-Monti tube in 6% and a cecal tube in 2%. For the continent catheterizable channel we used appendix in 43% of cases, a Yang-Monti tube in 38% and continent cutaneous vesicostomy in 19%.
RESULTS: Continence was achieved in 98% of patients. Followup was 6 to 71 months (mean 28.4). There were 27 channel related complications (23%). Stomal stenosis occurred in 7 antegrade continence enema procedures (14%) within 1 to 10 months (mean 6.2) and in 9 continent bladder channels (13%), including 5 continent cutaneous vesicostomies, within 1 to 24 months (mean 9.4) after surgery. False passages occurred in 5 antegrade continence enema procedures (10%) within 1 to 13 months (mean 3.6) and in 4 continent catheterizable channels (6%) within 1 to 13 months (mean 6.5) after surgery. Of patients with stomal stenosis 50% were treated with surgical revision, while the remainder was successfully treated with dilation. Most false passages were managed by catheter drainage alone. Reasons for revision were contained perforation, colovesical fistula and inability to catheterize. Patient noncompliance appeared to have a role in stomal stenosis.
CONCLUSIONS: Continent catheterizable stomas help patients achieve bowel and bladder continence. Stomal incontinence after reconstruction is rare. In our experience most stoma related complications occurred in the first year after reconstruction. Experience with more patients and longer followup will help determine whether such problems continue to accumulate with time or whether continent stomas function well with time, particularly after the initial period of healing.
PMID: 16945657
PURPOSE: We reviewed our experience with continent catheterizable channels with interest in the timing of conduit related complications.
MATERIALS AND METHODS: A retrospective review was performed of the outcome of continent catheterizable channels in all patients between 1998 and 2003 who had undergone construction of an antegrade continence enema and/or a Mitrofanoff procedure using appendix, small bowel or continent cutaneous vesicostomy. We performed a total of 117 such stomas in 37 male and 41 female patients 2.5 to 20 years old (mean age 8.9). For the antegrade continence enema we used appendix in 92% of cases, an ileal Yang-Monti tube in 6% and a cecal tube in 2%. For the continent catheterizable channel we used appendix in 43% of cases, a Yang-Monti tube in 38% and continent cutaneous vesicostomy in 19%.
RESULTS: Continence was achieved in 98% of patients. Followup was 6 to 71 months (mean 28.4). There were 27 channel related complications (23%). Stomal stenosis occurred in 7 antegrade continence enema procedures (14%) within 1 to 10 months (mean 6.2) and in 9 continent bladder channels (13%), including 5 continent cutaneous vesicostomies, within 1 to 24 months (mean 9.4) after surgery. False passages occurred in 5 antegrade continence enema procedures (10%) within 1 to 13 months (mean 3.6) and in 4 continent catheterizable channels (6%) within 1 to 13 months (mean 6.5) after surgery. Of patients with stomal stenosis 50% were treated with surgical revision, while the remainder was successfully treated with dilation. Most false passages were managed by catheter drainage alone. Reasons for revision were contained perforation, colovesical fistula and inability to catheterize. Patient noncompliance appeared to have a role in stomal stenosis.
CONCLUSIONS: Continent catheterizable stomas help patients achieve bowel and bladder continence. Stomal incontinence after reconstruction is rare. In our experience most stoma related complications occurred in the first year after reconstruction. Experience with more patients and longer followup will help determine whether such problems continue to accumulate with time or whether continent stomas function well with time, particularly after the initial period of healing.
PMID: 16945657
Factors that influence outcomes of the Mitrofanoff and Malone antegrade continence enema reconstructive procedures in children
Clark T, Pope JC 4th, Adams C, Wells N, Brock JW 3rd. Factors that influence outcomes of the Mitrofanoff and Malone antegrade continence enema reconstructive procedures in children. Journal of Urology. 2002 Oct;168(4 Pt 1):1537-40; discussion 1540.
PURPOSE: Surgical techniques that provide adequate urinary and fecal continence in children with neurogenic bladder and bowel dysfunction are becoming increasingly used. We reviewed our experience and discuss factors that influence outcome.
MATERIALS AND METHODS: Between 1994 and 2000, 65 stomal procedures were performed in 47 patients. For the urinary continent catheterizable channel we used appendix in 60% of cases, a continent bladder tube in 20%, a Yang-Monti tube in 16% and ureter in 4%. For the antegrade continence enema continent catheterizable channel we used appendix in 85% of cases, a Yang-Monti tube in 5% and a cecal tube in 10%. In the 19 patients who underwent simultaneous Mitrofanoff and antegrade continence enema procedures the urinary continent catheterizable channel was appendix in 21%, a Yang-Monti tube in 32% and continent vesicostomy in 47%. Patients were divided into 2 groups based on compliance status. In addition, percentile body weight for age was evaluated.
RESULTS: Stomal continence was achieved in 63 of the 65 cases (97%). Of the patients who underwent the antegrade continence enema procedure 95% achieved continence via the rectum. Except for ureter stenosis rates according to continent catheterizable channel type did not differ greatly, namely 19% for appendix, 11% for the Yang-Monti tube, 22% for the bladder tube, 50% for ureter and 0% for the cecal tube. Infectious complications developed in 16 patients and 4 had stones. The rates of infection (p = 0.004), stomal stenosis (p = 0.001) and revision (p = 0.004) were statistically lower in the compliant group and the stone formation rate showed a trend favoring the compliant group (p = 0.11). No significant difference was noted for incontinence. Percentile weight predicted a higher rate of stomal stenosis with the highest rate of stomal stenosis overall in the greater than 100th percentile group.
CONCLUSIONS: The Mitrofanoff and antegrade continence enema procedures are reliable and effective. Proper patient selection and surgical technique with a tension-free anastomosis are essential. The choice of tissue for constructing the continent catheterizable channel is not as important as patient compliance, age and possibly body habitus. This report reinforces the importance of careful screening, and rigorous preoperative and postoperative teaching to achieve overall patient success.
PMID: 12352454
PURPOSE: Surgical techniques that provide adequate urinary and fecal continence in children with neurogenic bladder and bowel dysfunction are becoming increasingly used. We reviewed our experience and discuss factors that influence outcome.
MATERIALS AND METHODS: Between 1994 and 2000, 65 stomal procedures were performed in 47 patients. For the urinary continent catheterizable channel we used appendix in 60% of cases, a continent bladder tube in 20%, a Yang-Monti tube in 16% and ureter in 4%. For the antegrade continence enema continent catheterizable channel we used appendix in 85% of cases, a Yang-Monti tube in 5% and a cecal tube in 10%. In the 19 patients who underwent simultaneous Mitrofanoff and antegrade continence enema procedures the urinary continent catheterizable channel was appendix in 21%, a Yang-Monti tube in 32% and continent vesicostomy in 47%. Patients were divided into 2 groups based on compliance status. In addition, percentile body weight for age was evaluated.
RESULTS: Stomal continence was achieved in 63 of the 65 cases (97%). Of the patients who underwent the antegrade continence enema procedure 95% achieved continence via the rectum. Except for ureter stenosis rates according to continent catheterizable channel type did not differ greatly, namely 19% for appendix, 11% for the Yang-Monti tube, 22% for the bladder tube, 50% for ureter and 0% for the cecal tube. Infectious complications developed in 16 patients and 4 had stones. The rates of infection (p = 0.004), stomal stenosis (p = 0.001) and revision (p = 0.004) were statistically lower in the compliant group and the stone formation rate showed a trend favoring the compliant group (p = 0.11). No significant difference was noted for incontinence. Percentile weight predicted a higher rate of stomal stenosis with the highest rate of stomal stenosis overall in the greater than 100th percentile group.
CONCLUSIONS: The Mitrofanoff and antegrade continence enema procedures are reliable and effective. Proper patient selection and surgical technique with a tension-free anastomosis are essential. The choice of tissue for constructing the continent catheterizable channel is not as important as patient compliance, age and possibly body habitus. This report reinforces the importance of careful screening, and rigorous preoperative and postoperative teaching to achieve overall patient success.
PMID: 12352454
Appendiceal versus ileal segment for antegrade continence enema.
Tackett LD, Minevich E, Benedict JF, Wacksman J, Sheldon CA. Appendiceal versus ileal segment for antegrade continence enema. Journal of Urology. 2002 Feb;167(2 Pt 1):683-6.
PURPOSE: To assess outcomes after the antegrade continence enema procedure, we present our results with an ileal segment or the appendix in children with severe bowel dysfunction.
MATERIALS AND METHODS: A retrospective review of 45 children who had undergone the creation of a continent cecostomy for severe chronic constipation and fecal incontinence was performed.
RESULTS: The appendix was used to create the continent cecostomy in 28 patients (group 1) and ileum 17 (group 2). Of 16 patients who underwent simultaneous construction of appendiceal Mitrofanoff neourethra, including continent catheterizable stoma, the appendix was split and used for the cecostomy and neourethra in 11. Overall, acceptable continence was achieved in 39 (87%) patients and total continence 31 (69%). No significant difference was noted in the rate of continence between groups 1 and 2. Nonstomal postoperative complications occurred in 5 patients in group 1 and 3 group 2. Complications that required reoperation related to the continent cecostomy occurred in 10 patients, including stomal stenosis in 8, with 6 group 1 and 2 group 2 (p >0.05), and stricture in 2, with 1 group 1 and 1 group 2. There were 2 patients who had previously undergone colostomy for intractable constipation who were undiverted at the time of the creation of continent cecostomy. Both were continent postoperatively. There were 3 patients, including those 2 who presented with chronic severe constipation of unclear etiology, who underwent colostomy for unrecoverable colonic dys-motility, of whom 1 subsequently required total colectomy.
CONCLUSIONS: The creation of a continent cecostomy for antegrade continence enema is a successful management option in children with debilitating fecal incontinence, and may enable undiversion of an existing colostomy. The appendix and ileal segment are viable options for the procedure, with no significant difference noted in continence or complication rates.
PMID: 11792954
PURPOSE: To assess outcomes after the antegrade continence enema procedure, we present our results with an ileal segment or the appendix in children with severe bowel dysfunction.
MATERIALS AND METHODS: A retrospective review of 45 children who had undergone the creation of a continent cecostomy for severe chronic constipation and fecal incontinence was performed.
RESULTS: The appendix was used to create the continent cecostomy in 28 patients (group 1) and ileum 17 (group 2). Of 16 patients who underwent simultaneous construction of appendiceal Mitrofanoff neourethra, including continent catheterizable stoma, the appendix was split and used for the cecostomy and neourethra in 11. Overall, acceptable continence was achieved in 39 (87%) patients and total continence 31 (69%). No significant difference was noted in the rate of continence between groups 1 and 2. Nonstomal postoperative complications occurred in 5 patients in group 1 and 3 group 2. Complications that required reoperation related to the continent cecostomy occurred in 10 patients, including stomal stenosis in 8, with 6 group 1 and 2 group 2 (p >0.05), and stricture in 2, with 1 group 1 and 1 group 2. There were 2 patients who had previously undergone colostomy for intractable constipation who were undiverted at the time of the creation of continent cecostomy. Both were continent postoperatively. There were 3 patients, including those 2 who presented with chronic severe constipation of unclear etiology, who underwent colostomy for unrecoverable colonic dys-motility, of whom 1 subsequently required total colectomy.
CONCLUSIONS: The creation of a continent cecostomy for antegrade continence enema is a successful management option in children with debilitating fecal incontinence, and may enable undiversion of an existing colostomy. The appendix and ileal segment are viable options for the procedure, with no significant difference noted in continence or complication rates.
PMID: 11792954
Cecostomy in children with defecation disorders
Mousa HM, van den Berg MM, Caniano DA, Hogan M, Di Lorenzo C, Hayes J. Cecostomy in children with defecation disorders. Digestive Diseases and Sciences. 2006 Jan;51(1):154-60.
Administration of antegrade enemas through a cecostomy is a therapeutic option for children with severe defecation disorders. The purpose of this study is to report our 4-year experience with the cecostomy procedure in 31 children with functional constipation (n = 9), Hirschsprung's disease (n = 2), imperforate anus (n = 5), spinal abnormalities (n = 8), and imperforate anus in combination with tethered spinal cord (n = 7). Data regarding complications, antegrade enemas used, symptoms, and quality of life were retrospectively obtained. Placement of cecostomy tubes was successful in 30 of 31 patients. Soiling episodes decreased significantly in children with functional constipation (P = 0.01), imperforate anus (P < 0.01), and spinal abnormalities (P = 0.04). Quality of life improved in patients with functional constipation and imperforate anus. No difference in complications was found between percutaneous and surgical placement. Use of antegrade enemas via cecostomy improved symptoms and quality of life in children with a variety of defecation disorders.
PMID: 16416229
Administration of antegrade enemas through a cecostomy is a therapeutic option for children with severe defecation disorders. The purpose of this study is to report our 4-year experience with the cecostomy procedure in 31 children with functional constipation (n = 9), Hirschsprung's disease (n = 2), imperforate anus (n = 5), spinal abnormalities (n = 8), and imperforate anus in combination with tethered spinal cord (n = 7). Data regarding complications, antegrade enemas used, symptoms, and quality of life were retrospectively obtained. Placement of cecostomy tubes was successful in 30 of 31 patients. Soiling episodes decreased significantly in children with functional constipation (P = 0.01), imperforate anus (P < 0.01), and spinal abnormalities (P = 0.04). Quality of life improved in patients with functional constipation and imperforate anus. No difference in complications was found between percutaneous and surgical placement. Use of antegrade enemas via cecostomy improved symptoms and quality of life in children with a variety of defecation disorders.
PMID: 16416229
Percutaneous cecostomy for management of fecal incontinence in pediatric patients.
Sierre S, Lipsich J, Questa H, Bailez M, Solana J. Percutaneous cecostomy for management of fecal incontinence in pediatric patients. Journal of Vascular and Interventional Radiology. 2007 Aug;18(8):982-5.
Purpose To report the authors' experience with percutaneous cecostomy and demonstrate its effectiveness in the management of pediatric patients with fecal incontinence. Materials and Methods Between March 2002 and November 2006, 21 percutaneous cecostomy procedures were performed in 20 patients in whom classical therapeutic approaches for the management of fecal incontinence had failed. Eighteen patients had anorectal malformations, one had myelomeningocele, and one had chronic constipation. All procedures were performed under general anesthesia and fluoroscopic guidance. In all cases, an 8.5-F Dawson-Mueller catheter was placed in the cecum and exchanged after 45 days with a cecostomy button (ie, Trapdoor catheter). Data regarding complications, effectiveness of treatment, satisfaction, and quality of life were obtained by interviewing the patients' parents at follow-up consultation. Results Nineteen of 20 procedures were technically successful. There were no major complications. All patients' symptoms of incontinence improved. Ninety percent of patients in our series (n = 18) reported satisfaction with the procedure, mainly related to their independence and quality of life. Conclusions Percutaneous cecostomy is a safe and effective procedure for the management of pediatric patients with fecal incontinence. Percutaneous cecostomy allows antegrade and more physiologic colon irrigation, avoiding the need for multiple retrograde enemas, achieving more patient independence, and improving quality of life.
PMID: 17675615
Purpose To report the authors' experience with percutaneous cecostomy and demonstrate its effectiveness in the management of pediatric patients with fecal incontinence. Materials and Methods Between March 2002 and November 2006, 21 percutaneous cecostomy procedures were performed in 20 patients in whom classical therapeutic approaches for the management of fecal incontinence had failed. Eighteen patients had anorectal malformations, one had myelomeningocele, and one had chronic constipation. All procedures were performed under general anesthesia and fluoroscopic guidance. In all cases, an 8.5-F Dawson-Mueller catheter was placed in the cecum and exchanged after 45 days with a cecostomy button (ie, Trapdoor catheter). Data regarding complications, effectiveness of treatment, satisfaction, and quality of life were obtained by interviewing the patients' parents at follow-up consultation. Results Nineteen of 20 procedures were technically successful. There were no major complications. All patients' symptoms of incontinence improved. Ninety percent of patients in our series (n = 18) reported satisfaction with the procedure, mainly related to their independence and quality of life. Conclusions Percutaneous cecostomy is a safe and effective procedure for the management of pediatric patients with fecal incontinence. Percutaneous cecostomy allows antegrade and more physiologic colon irrigation, avoiding the need for multiple retrograde enemas, achieving more patient independence, and improving quality of life.
PMID: 17675615
Saturday, August 11, 2007
Neurobiology of perceptual and motor timing in children with spina bifida in relation to cerebellar volume
Dennis M, Edelstein K, Hetherington R, Copeland K, Frederick J, Blaser SE, Kramer LA, Drake JM, Brandt M, Fletcher JM. Neurobiology of perceptual and motor timing in children with spina bifida in relation to cerebellar volume. Brain. 2004 Jun;127(Pt 6):1292-301. Epub 2004 Apr 6.
The cerebellum is important for perceptual and motor timing in the mature brain, but the timing function of the cerebellum in the immature brain is less well understood. We investigated timing in children with spina bifida meningomyelocele (SB), a neural tube defect that involves cerebellar dysgenesis, and in age-matched controls. Specifically, we studied perceptual timing (judgements of 400 ms duration) and motor timing (isochronous motor tapping); measured cerebellar volumes; and related perceptual and motor timing to each other and to cerebellar volume measurements. Children with SB had impairments in the perception of duration (around 400 ms) but not frequency (around 3000 Hz), showing that their perceptual timing deficit was not a generalized auditory impairment. Children with SB had motor timing deficits on unpaced but not paced isochronous tapping, and their unpaced timing performance was associated with clock variance rather than with motor implementation. Perceptual and motor timing were correlated, suggesting that children with SB have impairments in a central timing mechanism. Children with SB, especially those with upper spinal cord lesions, had significant cerebellar volume reductions in grey and white matter, as well as different regional patterns of grey matter, white matter and CSF. Duration perception was correlated with cerebellar volumes, and the number of valid tapping trials was correlated with cerebellar volumes in the SB group, which data demonstrate structure-function relations between timing and cerebellar volumes.
PMID: 15069019
Full Text Online
The cerebellum is important for perceptual and motor timing in the mature brain, but the timing function of the cerebellum in the immature brain is less well understood. We investigated timing in children with spina bifida meningomyelocele (SB), a neural tube defect that involves cerebellar dysgenesis, and in age-matched controls. Specifically, we studied perceptual timing (judgements of 400 ms duration) and motor timing (isochronous motor tapping); measured cerebellar volumes; and related perceptual and motor timing to each other and to cerebellar volume measurements. Children with SB had impairments in the perception of duration (around 400 ms) but not frequency (around 3000 Hz), showing that their perceptual timing deficit was not a generalized auditory impairment. Children with SB had motor timing deficits on unpaced but not paced isochronous tapping, and their unpaced timing performance was associated with clock variance rather than with motor implementation. Perceptual and motor timing were correlated, suggesting that children with SB have impairments in a central timing mechanism. Children with SB, especially those with upper spinal cord lesions, had significant cerebellar volume reductions in grey and white matter, as well as different regional patterns of grey matter, white matter and CSF. Duration perception was correlated with cerebellar volumes, and the number of valid tapping trials was correlated with cerebellar volumes in the SB group, which data demonstrate structure-function relations between timing and cerebellar volumes.
PMID: 15069019
Full Text Online
Covert orienting to exogenous and endogenous cues in children with spina bifida
Dennis M, Edelstein K, Copeland K, Frederick J, Francis DJ, Hetherington R, Blaser SE, Kramer LA, Drake JM, Brandt ME, Fletcher JM. Covert orienting to exogenous and endogenous cues in children with spina bifida. Neuropsychologia. 2005;43(6):976-87. Epub 2004 Dec 8.
Children with spina bifida meningomyelocele and hydrocephalus (SBM) have congenital dysmorphology of the midbrain and thinning of the posterior cortex, brain regions associated with the control of covert orienting. We studied cued covert orienting in 92 children with SBM, and 40 age-matched typically developing controls. Cues were of three types: exogenous (luminance change in a peripheral box either valid or invalid for upcoming target location), endogenous arrow (a central arrow either valid or invalid for upcoming target location), or endogenous word (a central word either valid or invalid for upcoming target location). Compared to controls, children with SBM showed slowed covert orienting to both exogenous and endogenous cues and a higher cost of attentional disengagement (e.g., a greater cue-validity effect) for exogenous although not for endogenous cues. Covert orienting deficits were associated with midbrain dysmorphology in the form of beaking of the tectum, and with right posterior brain volume loss.
PMID: 15716168
Children with spina bifida meningomyelocele and hydrocephalus (SBM) have congenital dysmorphology of the midbrain and thinning of the posterior cortex, brain regions associated with the control of covert orienting. We studied cued covert orienting in 92 children with SBM, and 40 age-matched typically developing controls. Cues were of three types: exogenous (luminance change in a peripheral box either valid or invalid for upcoming target location), endogenous arrow (a central arrow either valid or invalid for upcoming target location), or endogenous word (a central word either valid or invalid for upcoming target location). Compared to controls, children with SBM showed slowed covert orienting to both exogenous and endogenous cues and a higher cost of attentional disengagement (e.g., a greater cue-validity effect) for exogenous although not for endogenous cues. Covert orienting deficits were associated with midbrain dysmorphology in the form of beaking of the tectum, and with right posterior brain volume loss.
PMID: 15716168
Testing for genetic associations with the PAX gene family in a spina bifida population
Volcik KA, Blanton SH, Kruzel MC, Townsend IT, Tyerman GH, Mier RJ, Northrup H. Testing for genetic associations with the PAX gene family in a spina bifida population. American Journal of Medical Genetics. 2002 Jul 1;110(3):195-202.
Neural tube defects (NTDs) are among the most common severely disabling birth defects in the United States, affecting approximately 1-2 of every 1,000 live births. The etiology of NTDs is multifactorial, involving the combined action of both genetic and environmental factors. A nonparametric linkage method, the transmission disequilibrium test (TDT), was utilized to determine if the genes in the PAX family play a role in the formation of NTDs. DNA from 459 spina bifida (SB) patients and their parents (430 mothers and 239 fathers, for a total population of 1,128 subjects) was tested for linkage and association utilizing polymorphic markers from within or very close to the PAX genes of interest. Significant findings were obtained for the following markers: marker locus D20S101 flanking the PAX1 gene (P = 0.019), marker locus D1S228 within the PAX7 gene (P = 0.011), and marker locus D2S110 within the PAX8 gene (P = 0.013). Even though our findings are only mildly significant, given the known expression patterns of the PAX genes in development and the availability of their sequences, we elected to follow up these results by testing these genes directly for mutations utilizing single-strand conformational analysis (SSCA) and direct sequencing. Multiple variations were detected in each of the PAX genes with significant TDT results; however, these variations were not passed from parent to child in phase with the positively transmitted allele. Therefore, it is unlikely that these variations contribute to susceptibility for SB, but rather are previously unreported polymorphisms.
PMID: 12116225
Neural tube defects (NTDs) are among the most common severely disabling birth defects in the United States, affecting approximately 1-2 of every 1,000 live births. The etiology of NTDs is multifactorial, involving the combined action of both genetic and environmental factors. A nonparametric linkage method, the transmission disequilibrium test (TDT), was utilized to determine if the genes in the PAX family play a role in the formation of NTDs. DNA from 459 spina bifida (SB) patients and their parents (430 mothers and 239 fathers, for a total population of 1,128 subjects) was tested for linkage and association utilizing polymorphic markers from within or very close to the PAX genes of interest. Significant findings were obtained for the following markers: marker locus D20S101 flanking the PAX1 gene (P = 0.019), marker locus D1S228 within the PAX7 gene (P = 0.011), and marker locus D2S110 within the PAX8 gene (P = 0.013). Even though our findings are only mildly significant, given the known expression patterns of the PAX genes in development and the availability of their sequences, we elected to follow up these results by testing these genes directly for mutations utilizing single-strand conformational analysis (SSCA) and direct sequencing. Multiple variations were detected in each of the PAX genes with significant TDT results; however, these variations were not passed from parent to child in phase with the positively transmitted allele. Therefore, it is unlikely that these variations contribute to susceptibility for SB, but rather are previously unreported polymorphisms.
PMID: 12116225
The human T locus and spina bifida risk
Jensen LE, Barbaux S, Hoess K, Fraterman S, Whitehead AS, Mitchell LE. The human T locus and spina bifida risk. Human Genetics. 2004 Nov;115(6):475-82. Epub 2004 Sep 24.
The transcription factor T is essential for mesoderm formation and axial development during embryogenesis. Embryonic genotype for a single-nucleotide polymorphism in intron 7 of T ( TIVS7 T/C) has been associated with the risk of spina bifida in some but not all studies. We developed a novel genotyping assay for the TIVS7 polymorphism using heteroduplex generator methodology. This assay was used to genotype spina bifida case-parent trios and the resulting data were analyzed using the transmission disequilibrium test and log-linear analyses. Analyses of these data demonstrated that heterozygous parents transmit the TIVS7-C allele to their offspring with spina bifida significantly more frequently than expected under the assumption of Mendelian inheritance (63 vs 50%, P=0.02). Moreover, these analyses suggest that the TIVS7-C allele acts in a dominant fashion, such that individuals carrying one or more copies of this allele have a 1.6-fold increased risk of spina bifida compared with individuals with zero copies. In silico analysis of the sequence surrounding this polymorphism revealed a potential target site for olfactory neuron-specific factor-1, a transcription factor expressed in the neural tube during development, spanning the polymorphic site. Several other putative, developmentally important and/or environmentally responsive transcription factor-binding sites were also identified close to the TIVS7 polymorphism. The TIVS7 polymorphism or a variant that is in linkage disequilibrium with the TIVS7 polymorphism may, therefore, play a role in T gene expression and influence the risk of spina bifida.
PMID: 15449172
The transcription factor T is essential for mesoderm formation and axial development during embryogenesis. Embryonic genotype for a single-nucleotide polymorphism in intron 7 of T ( TIVS7 T/C) has been associated with the risk of spina bifida in some but not all studies. We developed a novel genotyping assay for the TIVS7 polymorphism using heteroduplex generator methodology. This assay was used to genotype spina bifida case-parent trios and the resulting data were analyzed using the transmission disequilibrium test and log-linear analyses. Analyses of these data demonstrated that heterozygous parents transmit the TIVS7-C allele to their offspring with spina bifida significantly more frequently than expected under the assumption of Mendelian inheritance (63 vs 50%, P=0.02). Moreover, these analyses suggest that the TIVS7-C allele acts in a dominant fashion, such that individuals carrying one or more copies of this allele have a 1.6-fold increased risk of spina bifida compared with individuals with zero copies. In silico analysis of the sequence surrounding this polymorphism revealed a potential target site for olfactory neuron-specific factor-1, a transcription factor expressed in the neural tube during development, spanning the polymorphic site. Several other putative, developmentally important and/or environmentally responsive transcription factor-binding sites were also identified close to the TIVS7 polymorphism. The TIVS7 polymorphism or a variant that is in linkage disequilibrium with the TIVS7 polymorphism may, therefore, play a role in T gene expression and influence the risk of spina bifida.
PMID: 15449172
Loss of function polymorphisms in NAT1 protect against spina bifida.
Jensen LE, Hoess K, Mitchell LE, Whitehead AS. Loss of function polymorphisms in NAT1 protect against spina bifida. Human Genetics. 2006 Aug;120(1):52-7. Epub 2006 May 6.
Periconceptional folic acid supplementation reduces the risk of having a child with spina bifida. N-acetyltransferase 1 (NAT1) participates in the catabolism of folates and the acetylation of aromatic and heterocyclic amines. Hence, functional polymorphisms in NAT1, the gene encoding NAT1, could influence the risk of spina bifida via either folate catabolism or acetylation of exogenous agents. Individuals with spina bifida and their parents were genotyped for six NAT1 single nucleotide polymorphisms (SNPs) for which the less common allele is associated with reduced or absent enzyme activity (i.e. 97C>T, 190C>T, 559C>T/560G>A, 640T>G and 752A>T). In addition, a "composite" NAT1 genotype was defined as a function of the genotyped SNPs. Descriptive analyses of the SNPs and of the composite genotype indicated that heterozygous parents were more likely to transmit the common allele than the rare allele to their affected offspring. Furthermore, matings of mothers homozygous for the common allele and heterozygous fathers were more common than the reciprocal matings. Log-linear analyses confirmed that both the maternal (P = 0.008) and offspring (P = 0.003) composite NAT1 genotypes were significantly related to the risk of spina bifida. NAT1 variants that reduce or abolish enzyme activity appear to protect against spina bifida, and to exert their influence via both the maternal and the offspring genotypes. These associations may be attributable to a decrease in either folate catabolism or the conversion of exogenous agents to teratogenic derivatives in women and/or developing embryos with a NAT1 genotype that includes a loss of function allele relative to those who do not.
PMID: 16680433
Periconceptional folic acid supplementation reduces the risk of having a child with spina bifida. N-acetyltransferase 1 (NAT1) participates in the catabolism of folates and the acetylation of aromatic and heterocyclic amines. Hence, functional polymorphisms in NAT1, the gene encoding NAT1, could influence the risk of spina bifida via either folate catabolism or acetylation of exogenous agents. Individuals with spina bifida and their parents were genotyped for six NAT1 single nucleotide polymorphisms (SNPs) for which the less common allele is associated with reduced or absent enzyme activity (i.e. 97C>T, 190C>T, 559C>T/560G>A, 640T>G and 752A>T). In addition, a "composite" NAT1 genotype was defined as a function of the genotyped SNPs. Descriptive analyses of the SNPs and of the composite genotype indicated that heterozygous parents were more likely to transmit the common allele than the rare allele to their affected offspring. Furthermore, matings of mothers homozygous for the common allele and heterozygous fathers were more common than the reciprocal matings. Log-linear analyses confirmed that both the maternal (P = 0.008) and offspring (P = 0.003) composite NAT1 genotypes were significantly related to the risk of spina bifida. NAT1 variants that reduce or abolish enzyme activity appear to protect against spina bifida, and to exert their influence via both the maternal and the offspring genotypes. These associations may be attributable to a decrease in either folate catabolism or the conversion of exogenous agents to teratogenic derivatives in women and/or developing embryos with a NAT1 genotype that includes a loss of function allele relative to those who do not.
PMID: 16680433
Prepregnancy obesity as a risk factor for structural birth defects
Waller DK, Shaw GM, Rasmussen SA, Hobbs CA, Canfield MA, Siega-Riz AM, Gallaway MS, Correa A; National Birth Defects Prevention Study. Prepregnancy obesity as a risk factor for structural birth defects. Archives of Pediatric and Adolescent Medicine. 2007 Aug;161(8):745-50.
OBJECTIVE: To describe the relation between maternal obesity, overweight and underweight status, and 16 categories of structural birth defects.
DESIGN: An ongoing multisite, case-control study. Clinical geneticists reviewed all of the cases, excluding those that had or were strongly suspected to have a single-gene disorder or chromosomal abnormality. Mothers with preexisting diabetes were also excluded. Body mass index was based on maternal report of height and weight prior to pregnancy.
SETTING: Eight participating states in the United States.
PARTICIPANTS: Mothers enrolled in the National Birth Defects Prevention Study who had index pregnancies between October 1, 1997, and December 31, 2002.
MAIN EXPOSURE: Maternal obesity.
MAIN OUTCOME MEASURES: Crude and adjusted odds ratios.
RESULTS: Mothers of offspring with spina bifida, heart defects, anorectal atresia, hypospadias, limb reduction defects, diaphragmatic hernia, and omphalocele were significantly more likely to be obese than mothers of controls, with odds ratios ranging between 1.33 and 2.10. Mothers of offspring with gastroschisis were significantly less likely to be obese than mothers of controls.
CONCLUSIONS: To our knowledge, this is the first population-based study of its scale to examine prepregnancy obesity and a range of structural birth defects. These results suggest a weak to moderate positive association of maternal obesity with 7 of 16 categories of birth defects and a strong inverse association with gastroschisis. The mechanisms underlying these associations are not yet understood but may be related to undiagnosed diabetes.
PMID: 17679655
Full Text Online
OBJECTIVE: To describe the relation between maternal obesity, overweight and underweight status, and 16 categories of structural birth defects.
DESIGN: An ongoing multisite, case-control study. Clinical geneticists reviewed all of the cases, excluding those that had or were strongly suspected to have a single-gene disorder or chromosomal abnormality. Mothers with preexisting diabetes were also excluded. Body mass index was based on maternal report of height and weight prior to pregnancy.
SETTING: Eight participating states in the United States.
PARTICIPANTS: Mothers enrolled in the National Birth Defects Prevention Study who had index pregnancies between October 1, 1997, and December 31, 2002.
MAIN EXPOSURE: Maternal obesity.
MAIN OUTCOME MEASURES: Crude and adjusted odds ratios.
RESULTS: Mothers of offspring with spina bifida, heart defects, anorectal atresia, hypospadias, limb reduction defects, diaphragmatic hernia, and omphalocele were significantly more likely to be obese than mothers of controls, with odds ratios ranging between 1.33 and 2.10. Mothers of offspring with gastroschisis were significantly less likely to be obese than mothers of controls.
CONCLUSIONS: To our knowledge, this is the first population-based study of its scale to examine prepregnancy obesity and a range of structural birth defects. These results suggest a weak to moderate positive association of maternal obesity with 7 of 16 categories of birth defects and a strong inverse association with gastroschisis. The mechanisms underlying these associations are not yet understood but may be related to undiagnosed diabetes.
PMID: 17679655
Full Text Online
Tuesday, August 7, 2007
Space-based inhibition of return in children with spina bifida
Dennis M, Edelstein K, Copeland K, Frederick JA, Francis DJ, Hetherington R, Blaser SE, Kramer LA, Drake JM, Brandt ME, Fletcher JM. Space-based inhibition of return in children with spina bifida. Neuropsychology. 2005 Jul;19(4):456-65.
Inhibition of return (IOR) refers to an increase in time to react to a target in a previously attended location. Children with spina bifida meningomyelocele (SBM) and hydrocephalus have congenital dysmorphology of the midbrain, a brain region associated with the control of covert orienting in general and with IOR in particular. The authors studied exogenously cued covert orienting in 8- to 19-year-old children and adolescents (84 with SBM and 37 age-matched, typically developing controls). The exogenous cue was a luminance change in a peripheral box that was 50% valid for the upcoming target location. Compared with controls, children with SBM showed attenuated IOR in the vertical plane, a deficit that was associated with midbrain dysmorphology in the form of tectal beaking but not with posterior brain volume loss. The data add to the emerging evidence for SBM deficits in attentional orienting to salient information. (c) 2005 APA, all rights reserved.
PMID: 16060820
Inhibition of return (IOR) refers to an increase in time to react to a target in a previously attended location. Children with spina bifida meningomyelocele (SBM) and hydrocephalus have congenital dysmorphology of the midbrain, a brain region associated with the control of covert orienting in general and with IOR in particular. The authors studied exogenously cued covert orienting in 8- to 19-year-old children and adolescents (84 with SBM and 37 age-matched, typically developing controls). The exogenous cue was a luminance change in a peripheral box that was 50% valid for the upcoming target location. Compared with controls, children with SBM showed attenuated IOR in the vertical plane, a deficit that was associated with midbrain dysmorphology in the form of tectal beaking but not with posterior brain volume loss. The data add to the emerging evidence for SBM deficits in attentional orienting to salient information. (c) 2005 APA, all rights reserved.
PMID: 16060820
What do we really know about the transition to adult-centered health care?
Binks JA, Barden WS, Burke TA, Young NL. What do we really know about the transition to adult-centered health care? A focus on cerebral palsy and spina bifida. Archives of Physical Medicine & Rehabilitation 2007 Aug;88(8):1064-73.
OBJECTIVES: To address the lack of synthesis regarding the factors, processes, and outcomes specific to the transition from child-centered to adult-centered health care for people with cerebral palsy (CP) and spina bifida (SB); more specifically, to identify barriers, to outline key elements, to review empirical studies, and to make clinical and research recommendations.
DATA SOURCES: We searched Medline and CINAHL databases from 1990 to 2006 using the key words: transition, health care transition, pediatric health care, adult health care, health care access, health care use, chronic illness, special health care needs, and physical disability. The resulting studies were reviewed with a specific focus on clinical transition for persons with CP and SB, and were supplemented with key information from other diagnostic groups.
STUDY SELECTION: All studies meeting the inclusion criteria were included.
DATA EXTRACTION: Each article classified according to 5 criteria: methodology, diagnostic group, country of study, age group, and sample size.
DATA SYNTHESIS: We identified 149 articles: 54 discussion, 21 case series, 28 database or register, 25 qualitative, and 34 survey articles (some included multiple methods). We identified 5 key elements that support a positive transition to adult-centered health care: preparation, flexible timing, care coordination, transition clinic visits, and interested adult-centered health care providers. There was, however, limited empirical evidence to support the impact of these elements.
CONCLUSIONS: This review summarizes key factors that must be considered to support this critical clinical transition and sets the foundation for future research. It is time to apply prospective study designs to evaluate transition interventions and determine long-term health outcomes.
PMID: 17678671
OBJECTIVES: To address the lack of synthesis regarding the factors, processes, and outcomes specific to the transition from child-centered to adult-centered health care for people with cerebral palsy (CP) and spina bifida (SB); more specifically, to identify barriers, to outline key elements, to review empirical studies, and to make clinical and research recommendations.
DATA SOURCES: We searched Medline and CINAHL databases from 1990 to 2006 using the key words: transition, health care transition, pediatric health care, adult health care, health care access, health care use, chronic illness, special health care needs, and physical disability. The resulting studies were reviewed with a specific focus on clinical transition for persons with CP and SB, and were supplemented with key information from other diagnostic groups.
STUDY SELECTION: All studies meeting the inclusion criteria were included.
DATA EXTRACTION: Each article classified according to 5 criteria: methodology, diagnostic group, country of study, age group, and sample size.
DATA SYNTHESIS: We identified 149 articles: 54 discussion, 21 case series, 28 database or register, 25 qualitative, and 34 survey articles (some included multiple methods). We identified 5 key elements that support a positive transition to adult-centered health care: preparation, flexible timing, care coordination, transition clinic visits, and interested adult-centered health care providers. There was, however, limited empirical evidence to support the impact of these elements.
CONCLUSIONS: This review summarizes key factors that must be considered to support this critical clinical transition and sets the foundation for future research. It is time to apply prospective study designs to evaluate transition interventions and determine long-term health outcomes.
PMID: 17678671
Friday, August 3, 2007
The Chiari II malformation: cause and impact
McLone DG, Dias MS. The Chiari II malformation: cause and impact. Child's Nervous System. 2003 Aug;19(7-8):540-50. Epub 2003 Aug 12.
INTRODUCTION: It is the Chiari II malformation and its effects that determine the quality of life of the individual born with spina bifida.
DISCUSSION: The cause of this malformation has been a source of debate for many years. Understanding the cause enables strategies for the management of problems created by this malformation to be developed. An open neural tube defect allows fluid to escape from the cranial vesicles, altering the intracranial environment and leads to all of the brain changes seen in the Chiari II malformation. Decompression of the intracranial vesicles causes overcrowding, decrease in the size of the third ventricle, and changes in the fetal skull. It also permanently links the intracranial ventricular system to the spinal cord central canal.
PMID: 12920543
INTRODUCTION: It is the Chiari II malformation and its effects that determine the quality of life of the individual born with spina bifida.
DISCUSSION: The cause of this malformation has been a source of debate for many years. Understanding the cause enables strategies for the management of problems created by this malformation to be developed. An open neural tube defect allows fluid to escape from the cranial vesicles, altering the intracranial environment and leads to all of the brain changes seen in the Chiari II malformation. Decompression of the intracranial vesicles causes overcrowding, decrease in the size of the third ventricle, and changes in the fetal skull. It also permanently links the intracranial ventricular system to the spinal cord central canal.
PMID: 12920543
The etiology of neural tube defects: the role of folic acid
McLone DG. The etiology of neural tube defects: the role of folic acid.
Child's Nervous System. 2003 Aug;19(7-8):537-9. Epub 2003 Aug 12.
DISCUSSION: While the cause of neural tube defects in humans is considered to be multifactorial, it is apparent that folic acid can prevent 70% of open neural tube defects. Even in laboratory animals with known genetic defects, folic acid can prevent the genetic expression.
CONCLUSION: While some of the metabolic pathways for folic acid are known, the true effects of folic acid on closure of the neural tube have yet to be discovered.
PMID: 12920544
Child's Nervous System. 2003 Aug;19(7-8):537-9. Epub 2003 Aug 12.
DISCUSSION: While the cause of neural tube defects in humans is considered to be multifactorial, it is apparent that folic acid can prevent 70% of open neural tube defects. Even in laboratory animals with known genetic defects, folic acid can prevent the genetic expression.
CONCLUSION: While some of the metabolic pathways for folic acid are known, the true effects of folic acid on closure of the neural tube have yet to be discovered.
PMID: 12920544
Wednesday, August 1, 2007
Candidate gene analysis in human neural tube defects
Boyles AL, Hammock P, Speer MC. Candidate gene analysis in human neural tube defects. American Journal of Medical Genetics 2005 May 15;135(1):9-23. Review.
Biochemical and developmental pathways, mouse models, and positional evidence have provided numerous candidate genes for the study of human neural tube defects. In a survey of 80 studies on 38 candidate genes, few found significant results in human populations through case-control or family-based association studies. While the folate pathway has been explored extensively, only the MTHFR 677C > T polymorphism was significant, and only in an Irish population. Developmental pathways such as the Wnt signaling pathway and Hox genes have also been explored without positive results. More than 90 mouse candidates have been identified through spontaneous and knockout mutations, but only the T locus (mouse Brachyury gene) showed association in an initial study that was not confirmed on follow-up. Positional candidates have been derived from cytogenetic evidence, but preliminary genomic screens have limited power due to small sample sizes. Future studies would increase their power to detect association by using more samples. In addition a clarification of the phenotype would be beneficial as many studies used different inclusion criteria. Incorporating several types of data could highlight better candidates, as would looking beyond the traditional sources for candidate genes. Recent studies of an energy metabolism gene (UCP2) and vitamin B metabolism (Transcoalbumin) have produced promising results. Utilizing other model organisms may also be beneficial, as in a recent study from a chick model of NTDs in NCAM1. New approaches combined with traditional methods and increased sample sizes will help prioritize human NTD candidate genes and clarify the complex etiology of this condition.
PMID: 15816061
Biochemical and developmental pathways, mouse models, and positional evidence have provided numerous candidate genes for the study of human neural tube defects. In a survey of 80 studies on 38 candidate genes, few found significant results in human populations through case-control or family-based association studies. While the folate pathway has been explored extensively, only the MTHFR 677C > T polymorphism was significant, and only in an Irish population. Developmental pathways such as the Wnt signaling pathway and Hox genes have also been explored without positive results. More than 90 mouse candidates have been identified through spontaneous and knockout mutations, but only the T locus (mouse Brachyury gene) showed association in an initial study that was not confirmed on follow-up. Positional candidates have been derived from cytogenetic evidence, but preliminary genomic screens have limited power due to small sample sizes. Future studies would increase their power to detect association by using more samples. In addition a clarification of the phenotype would be beneficial as many studies used different inclusion criteria. Incorporating several types of data could highlight better candidates, as would looking beyond the traditional sources for candidate genes. Recent studies of an energy metabolism gene (UCP2) and vitamin B metabolism (Transcoalbumin) have produced promising results. Utilizing other model organisms may also be beneficial, as in a recent study from a chick model of NTDs in NCAM1. New approaches combined with traditional methods and increased sample sizes will help prioritize human NTD candidate genes and clarify the complex etiology of this condition.
PMID: 15816061
High-density single nucleotide polymorphism screen in a large multiplex neural tube defect family
Stamm DS, Rampersaud E, Slifer SH, Mehltretter L, Siegel DG, Xie J, Hu-Lince D, Craig DW, Stephan DA, George TM, Gilbert JR, Speer MC; NTD Collaborative Group.
High-density single nucleotide polymorphism screen in a large multiplex neural tube defect family refines linkage to loci at 7p21.1-pter and 2q33.1-q35.
Birth Defects Research; Clinical & Molecular Teratology. 2006 Jun;76(6):499-505.
BACKGROUND: Neural tube defects (NTDs) are considered complex, with both genetic and environmental factors implicated. To date, no major causative genes have been identified in humans despite several investigations. The first genomewide screen in NTDs demonstrated evidence of linkage to chromosomes 7 and 10. This screen included 44 multiplex families and consisted of 402 microsatellite markers spaced approximately 10 cM apart. Further investigation of the genomic screen data identified a single large multiplex family, pedigree 8776, as primarily driving the linkage results on chromosome 7.
METHODS: To investigate this family more thoroughly, a high-density single nucleotide polymorphism (SNP) screen was performed. Two-point and multipoint linkage analyses were performed using both parametric and nonparametric methods.
RESULTS: For both the microsatellite and SNP markers, linkage analysis suggested the involvement of a locus or loci proximal to the telomeric regions of chromosomes 2q and 7p, with both regions generating a LOD* score of 3.0 using a nonparametric identity by descent relative sharing method.
CONCLUSIONS: The regions with the strongest evidence for linkage map proximal to the telomeres on these two chromosomes. In addition to mutations and/or variants in a major gene, these loci may harbor a microdeletion and/or translocation; potentially, polygenic factors may also be involved. This single family may be promising for narrowing the search for NTD susceptibility genes. (c) 2006 Wiley-Liss, Inc.
PMID: 16933213
High-density single nucleotide polymorphism screen in a large multiplex neural tube defect family refines linkage to loci at 7p21.1-pter and 2q33.1-q35.
Birth Defects Research; Clinical & Molecular Teratology. 2006 Jun;76(6):499-505.
BACKGROUND: Neural tube defects (NTDs) are considered complex, with both genetic and environmental factors implicated. To date, no major causative genes have been identified in humans despite several investigations. The first genomewide screen in NTDs demonstrated evidence of linkage to chromosomes 7 and 10. This screen included 44 multiplex families and consisted of 402 microsatellite markers spaced approximately 10 cM apart. Further investigation of the genomic screen data identified a single large multiplex family, pedigree 8776, as primarily driving the linkage results on chromosome 7.
METHODS: To investigate this family more thoroughly, a high-density single nucleotide polymorphism (SNP) screen was performed. Two-point and multipoint linkage analyses were performed using both parametric and nonparametric methods.
RESULTS: For both the microsatellite and SNP markers, linkage analysis suggested the involvement of a locus or loci proximal to the telomeric regions of chromosomes 2q and 7p, with both regions generating a LOD* score of 3.0 using a nonparametric identity by descent relative sharing method.
CONCLUSIONS: The regions with the strongest evidence for linkage map proximal to the telomeres on these two chromosomes. In addition to mutations and/or variants in a major gene, these loci may harbor a microdeletion and/or translocation; potentially, polygenic factors may also be involved. This single family may be promising for narrowing the search for NTD susceptibility genes. (c) 2006 Wiley-Liss, Inc.
PMID: 16933213
Neural tube defects and folate pathway genes: family-based association tests of gene-gene and gene-environment interactions
Boyles AL, Billups AV, Deak KL, Siegel DG, Mehltretter L, Slifer SH, Bassuk AG, Kessler JA, Reed MC, Nijhout HF, George TM, Enterline DS, Gilbert JR, Speer MC; Neural tube defects and folate pathway genes: family-based association tests of gene-gene and gene-environment interactions. Environmental Health Perspectives. 2006 Oct;114(10):1547-52.
BACKGROUND: Folate metabolism pathway genes have been examined for association with neural tube defects (NTDs) because folic acid supplementation reduces the risk of this debilitating birth defect. Most studies addressed these genes individually, often with different populations providing conflicting results.
OBJECTIVES: Our study evaluates several folate pathway genes for association with human NTDs, incorporating an environmental cofactor: maternal folate supplementation.
METHODS: In 304 Caucasian American NTD families with myelomeningocele or anencephaly, we examined 28 polymorphisms in 11 genes: folate receptor 1, folate receptor 2, solute carrier family 19 member 1, transcobalamin II, methylenetetrahydrofolate dehydrogenase 1, serine hydroxymethyl-transferase 1, 5,10-methylenetetrahydrofolate reductase (MTHFR), 5-methyltetrahydrofolate-homo-cysteine methyltransferase, 5-methyltetrahydrofolate-homocysteine methyltransferase reductase, betaine-homocysteine methyltransferase (BHMT), and cystathionine-beta-synthase.
RESULTS: Only single nucleotide polymorphisms (SNPs) in BHMT were significantly associated in the overall data set; this significance was strongest when mothers took folate-containing nutritional supplements before conception. The BHMT SNP rs3733890 was more significant when the data were stratified by preferential transmission of the MTHFR rs1801133 thermolabile T allele from parent to offspring. Other SNPs in folate pathway genes were marginally significant in some analyses when stratified by maternal supplementation, MTHFR, or BHMT allele transmission.
CONCLUSIONS: BHMT rs3733890 is significantly associated in our data set, whereas MTHFR rs1801133 is not a major risk factor. Further investigation of folate and methionine cycle genes will require extensive SNP genotyping and/or resequencing to identify novel variants, inclusion of environmental factors, and investigation of gene-gene interactions in large data sets.
PMID: 17035141
Full Text Online
BACKGROUND: Folate metabolism pathway genes have been examined for association with neural tube defects (NTDs) because folic acid supplementation reduces the risk of this debilitating birth defect. Most studies addressed these genes individually, often with different populations providing conflicting results.
OBJECTIVES: Our study evaluates several folate pathway genes for association with human NTDs, incorporating an environmental cofactor: maternal folate supplementation.
METHODS: In 304 Caucasian American NTD families with myelomeningocele or anencephaly, we examined 28 polymorphisms in 11 genes: folate receptor 1, folate receptor 2, solute carrier family 19 member 1, transcobalamin II, methylenetetrahydrofolate dehydrogenase 1, serine hydroxymethyl-transferase 1, 5,10-methylenetetrahydrofolate reductase (MTHFR), 5-methyltetrahydrofolate-homo-cysteine methyltransferase, 5-methyltetrahydrofolate-homocysteine methyltransferase reductase, betaine-homocysteine methyltransferase (BHMT), and cystathionine-beta-synthase.
RESULTS: Only single nucleotide polymorphisms (SNPs) in BHMT were significantly associated in the overall data set; this significance was strongest when mothers took folate-containing nutritional supplements before conception. The BHMT SNP rs3733890 was more significant when the data were stratified by preferential transmission of the MTHFR rs1801133 thermolabile T allele from parent to offspring. Other SNPs in folate pathway genes were marginally significant in some analyses when stratified by maternal supplementation, MTHFR, or BHMT allele transmission.
CONCLUSIONS: BHMT rs3733890 is significantly associated in our data set, whereas MTHFR rs1801133 is not a major risk factor. Further investigation of folate and methionine cycle genes will require extensive SNP genotyping and/or resequencing to identify novel variants, inclusion of environmental factors, and investigation of gene-gene interactions in large data sets.
PMID: 17035141
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Human neural tube defects: developmental biology, epidemiology, and genetics
Detrait ER, George TM, Etchevers HC, Gilbert JR, Vekemans M, Speer MC. Human neural tube defects: developmental biology, epidemiology, and genetics.
Neurotoxicology & Teratology. 2005 May-Jun;27(3):515-24. Epub 2005 Mar 5. Review.
Birth defects (congenital anomalies) are the leading cause of death in babies under 1 year of age. Neural tube defects (NTD), with a birth incidence of approximately 1/1000 in American Caucasians, are the second most common type of birth defect after congenital heart defects. The most common presentations of NTD are spina bifida and anencephaly. The etiologies of NTDs are complex, with both genetic and environmental factors implicated. In this manuscript, we review the evidence for genetic etiology and for environmental influences, and we present current views on the developmental processes involved in human neural tube closure.
PMID: 15939212
Neurotoxicology & Teratology. 2005 May-Jun;27(3):515-24. Epub 2005 Mar 5. Review.
Birth defects (congenital anomalies) are the leading cause of death in babies under 1 year of age. Neural tube defects (NTD), with a birth incidence of approximately 1/1000 in American Caucasians, are the second most common type of birth defect after congenital heart defects. The most common presentations of NTD are spina bifida and anencephaly. The etiologies of NTDs are complex, with both genetic and environmental factors implicated. In this manuscript, we review the evidence for genetic etiology and for environmental influences, and we present current views on the developmental processes involved in human neural tube closure.
PMID: 15939212
Reduced folate carrier polymorphism (80A-->G) and neural tube defects
De Marco P, Calevo MG, Moroni A, Merello E, Raso A, Finnell RH, Zhu H, Andreussi L, Cama A, Capra V. Reduced folate carrier polymorphism (80A-->G) and neural tube defects. European Jounral of Human Genetics. 2003 Mar;11(3):245-52.
Transport of folates in mammalian cells occurs by a carrier-mediated mechanism. The human folate carrier (RFC-1) gene has been isolated and characterized. Within this gene, a common polymorphism, 80A-->G, changing a histidine to an arginine in exon 2 (H27R), was recently identified. Defects in folate metabolism, such as defective carrier molecules, could be implicated in the etiology of neural tube defects (NTDs). In the present case-control study, we recruited 174 Italian probands with nonsyndromic NTD, 43 mothers, 53 fathers and 156 control individuals and evaluated the impact of RFC-1 variant on NTD risk. A statistically significant risk was calculated for the 80GG genotype of the NTD cases (OR=2.35; 95% CI 1.21-4.58) and mothers (OR=2.74; 95% CI 0.92-8.38). On the contrary, the heterozygous genotype of the mothers and both heterozygous and homozygous genotypes of the fathers did not seem to be significant NTD risk factors. Furthemore, according to the multifactorial inheritance of NTDs, we demonstrated that the combined genotypes for MTHFR 1298A-->C and RFC-1 80A-->G polymorphisms of cases resulted in greater NTD risk than heterozygosity or homozygosity for RFC-1 80A-->G variant alone. Conversely, our data provide no evidence for an association between NTD phenotype and combined MTHFR C677T/RFC-1 A80G genotypes. Moreover, here we describe the combinations of the two MTHFR polymorphic sites (677CT and 1298AC) with RFC-1 genotypes. We found that both patients and controls could have at most quadruple-mutation combinations. Interestingly, 27% (7/26) of the mothers and 18.75% (30/160) of the cases genotyped presented four mutant alleles in comparison with 8.5% (11/129) of the controls. Finally, the frequency of NTD cases and mothers carrying combined heterozygosity for the two MTHFR polymorphisms and RFC-1 80GG homozygosity (677CT/1298AC/80GG) (cases=11.3%; mothers 11.5%) was increased compared with controls (1.6%). Altogether, our findings support the hypothesis that RFC-1 A80G variant may contribute to NTD susceptibility in the Italian population.
PMID: 12673279
Full Text Online
Transport of folates in mammalian cells occurs by a carrier-mediated mechanism. The human folate carrier (RFC-1) gene has been isolated and characterized. Within this gene, a common polymorphism, 80A-->G, changing a histidine to an arginine in exon 2 (H27R), was recently identified. Defects in folate metabolism, such as defective carrier molecules, could be implicated in the etiology of neural tube defects (NTDs). In the present case-control study, we recruited 174 Italian probands with nonsyndromic NTD, 43 mothers, 53 fathers and 156 control individuals and evaluated the impact of RFC-1 variant on NTD risk. A statistically significant risk was calculated for the 80GG genotype of the NTD cases (OR=2.35; 95% CI 1.21-4.58) and mothers (OR=2.74; 95% CI 0.92-8.38). On the contrary, the heterozygous genotype of the mothers and both heterozygous and homozygous genotypes of the fathers did not seem to be significant NTD risk factors. Furthemore, according to the multifactorial inheritance of NTDs, we demonstrated that the combined genotypes for MTHFR 1298A-->C and RFC-1 80A-->G polymorphisms of cases resulted in greater NTD risk than heterozygosity or homozygosity for RFC-1 80A-->G variant alone. Conversely, our data provide no evidence for an association between NTD phenotype and combined MTHFR C677T/RFC-1 A80G genotypes. Moreover, here we describe the combinations of the two MTHFR polymorphic sites (677CT and 1298AC) with RFC-1 genotypes. We found that both patients and controls could have at most quadruple-mutation combinations. Interestingly, 27% (7/26) of the mothers and 18.75% (30/160) of the cases genotyped presented four mutant alleles in comparison with 8.5% (11/129) of the controls. Finally, the frequency of NTD cases and mothers carrying combined heterozygosity for the two MTHFR polymorphisms and RFC-1 80GG homozygosity (677CT/1298AC/80GG) (cases=11.3%; mothers 11.5%) was increased compared with controls (1.6%). Altogether, our findings support the hypothesis that RFC-1 A80G variant may contribute to NTD susceptibility in the Italian population.
PMID: 12673279
Full Text Online
Evaluation of genetic variants in the reduced folate carrier and in glutamate carboxypeptidase II for spina bifida risk
Morin I, Devlin AM, Leclerc D, Sabbaghian N, Halsted CH, Finnell R, Rozen R. Evaluation of genetic variants in the reduced folate carrier and in glutamate carboxypeptidase II for spina bifida risk. Molecular Genetics & Metabolism 2003 Jul;79(3):197-200.
Genetic variants in folate metabolism have been reported to increase risk for neural tube defects (NTD). The first such sequence change was the 677C-->T substitution in methylenetetrahydrofolate reductase (MTHFR), but additional sequence changes have been identified in enzymes or transporters for folates. Two recently identified variants are the 1561C-->T (H475Y) mutation in glutamate carboxypeptidase II (GCPII) and the 80A-->G (H27R) change in the reduced folate carrier RFC-1. We examined a group of mothers of spina bifida offspring, and a group of control women, for the above polymorphisms to assess their impact on NTD risk as well as on homocysteine and nutrient (RBC folate, serum folate, and serum cobalamin) levels. The GCPII variant (in the heterozygous state) did not influence NTD risk or metabolite levels; homozygous mutant (YY) women were not observed in our study group. The homozygous mutant (RR) genotype for the RFC-1 gene was not associated with a significant difference in NTD risk (OR=1.39, 95% CI=0.55-3.54), but there was a borderline significant (p=0.065) decrease in RBC folate levels, compared with the HH genotype. However, the combination of the RR genotype for RFC-1 and low RBC folate was associated with a significant 4.6-fold increase in NTD risk (OR=4.6, 95% CI=1.47-14.37). Since this small study is the first to demonstrate increased risk for women with the RFC-1 variant for having a child with a NTD, additional larger studies are required to confirm this change as another potential genetic modifier for spina bifida risk.
PMID: 12855225
Genetic variants in folate metabolism have been reported to increase risk for neural tube defects (NTD). The first such sequence change was the 677C-->T substitution in methylenetetrahydrofolate reductase (MTHFR), but additional sequence changes have been identified in enzymes or transporters for folates. Two recently identified variants are the 1561C-->T (H475Y) mutation in glutamate carboxypeptidase II (GCPII) and the 80A-->G (H27R) change in the reduced folate carrier RFC-1. We examined a group of mothers of spina bifida offspring, and a group of control women, for the above polymorphisms to assess their impact on NTD risk as well as on homocysteine and nutrient (RBC folate, serum folate, and serum cobalamin) levels. The GCPII variant (in the heterozygous state) did not influence NTD risk or metabolite levels; homozygous mutant (YY) women were not observed in our study group. The homozygous mutant (RR) genotype for the RFC-1 gene was not associated with a significant difference in NTD risk (OR=1.39, 95% CI=0.55-3.54), but there was a borderline significant (p=0.065) decrease in RBC folate levels, compared with the HH genotype. However, the combination of the RR genotype for RFC-1 and low RBC folate was associated with a significant 4.6-fold increase in NTD risk (OR=4.6, 95% CI=1.47-14.37). Since this small study is the first to demonstrate increased risk for women with the RFC-1 variant for having a child with a NTD, additional larger studies are required to confirm this change as another potential genetic modifier for spina bifida risk.
PMID: 12855225
Genetic susceptibility to neural tube defect pregnancy varies with offspring phenotype
Relton CL, Wilding CS, Jonas PA, Lynch SA, Tawn EJ, Burn J. Genetic susceptibility to neural tube defect pregnancy varies with offspring phenotype.
Clinical Genetics. 2003 Nov;64(5):424-8.
Neural tube defects (NTDs) have a well-established genetic basis, although no single genetic factor has been identified as a major risk factor in NTD susceptibility. A large number of association studies have been conducted to investigate the possibility that NTD susceptibility is linked to polymorphic variation in genes involved in early embryonic development or in the absorption or metabolism of folate, a nutrient that has been clearly associated with a reduction in the risk of NTD pregnancy. A study of three candidate gene polymorphisms at loci implicated in folate absorption and metabolism has been conducted on a population of 211 mothers of a heterogeneous mix of NTD phenotypes: 59% spina bifida aperta (SBA), 20.3% spina bifida occulta (SBO), 17% anencephaly, and 3.7% other NTD. Allele and genotype frequencies were stratified according to offspring NTD phenotype, and variation in the level of NTD risk was associated with different phenotypes. All the three variants (MTHFR 677C > T, GCPII 1561C > T, and RFC-1 80G > A) were shown to significantly influence the risk of anencephalic pregnancy. In addition, the MTHFR 677C > T variant conferred a modest protective effect in SBO mothers and the total NTD mother group, but not in SBA mothers. The RFC-1 80G > A variant elevated the risk of SBO and anencephalic pregnancy. The findings of this study suggest that NTD phenotypic heterogeneity may help explain the mixed findings of previous association studies and that different polymorphisms may hold differing degrees of significance for the various NTD phenotypes.
PMID: 14616766
Clinical Genetics. 2003 Nov;64(5):424-8.
Neural tube defects (NTDs) have a well-established genetic basis, although no single genetic factor has been identified as a major risk factor in NTD susceptibility. A large number of association studies have been conducted to investigate the possibility that NTD susceptibility is linked to polymorphic variation in genes involved in early embryonic development or in the absorption or metabolism of folate, a nutrient that has been clearly associated with a reduction in the risk of NTD pregnancy. A study of three candidate gene polymorphisms at loci implicated in folate absorption and metabolism has been conducted on a population of 211 mothers of a heterogeneous mix of NTD phenotypes: 59% spina bifida aperta (SBA), 20.3% spina bifida occulta (SBO), 17% anencephaly, and 3.7% other NTD. Allele and genotype frequencies were stratified according to offspring NTD phenotype, and variation in the level of NTD risk was associated with different phenotypes. All the three variants (MTHFR 677C > T, GCPII 1561C > T, and RFC-1 80G > A) were shown to significantly influence the risk of anencephalic pregnancy. In addition, the MTHFR 677C > T variant conferred a modest protective effect in SBO mothers and the total NTD mother group, but not in SBA mothers. The RFC-1 80G > A variant elevated the risk of SBO and anencephalic pregnancy. The findings of this study suggest that NTD phenotypic heterogeneity may help explain the mixed findings of previous association studies and that different polymorphisms may hold differing degrees of significance for the various NTD phenotypes.
PMID: 14616766
Gene-gene interaction in folate-related genes and risk of neural tube defects in a UK population.
Relton CL, Wilding CS, Pearce MS, Laffling AJ, Jonas PA, Lynch SA, Tawn EJ, Burn J. Gene-gene interaction in folate-related genes and risk of neural tube defects in a UK population. Journal of Medical Genetics. 2004 Apr;41(4):256-60.
OBJECTIVE: To investigate the contribution of polymorphic variation in genes involved in the folate-dependent homocysteine pathway in the aetiology of neural tube defects (NTD).
DESIGN: Case-control association study.
SUBJECTS: A total of 530 individuals from families affected by NTD, 645 maternal controls, and 602 healthy newborn controls from the northern UK.
MAIN OUTCOME MEASURES: Seven polymorphisms in six genes coding for proteins in the folate-dependent homocysteine pathway (MTHFR 677C-->T, MTHFR 1298A-->C, MTRR 66A-->G, SHMT 1420C-->T, CbetaS 844ins68, GCPII 1561C-->T, RFC-1 80G-->A). The impact of each polymorphism and the effect of gene-gene interactions (epistasis) upon risk of NTD were assessed using logistic regression analysis.
RESULTS: The MTHFR 677C-->T polymorphism was shown to represent a risk factor in NTD cases (CC v CT+TT odds ratio (OR) 2.03 [95% confidence interval (CI) 1.09, 3.79] p = 0.025) and the MTRR 66A-->G polymorphism was shown to exert a protective effect in NTD cases (AA v AG+GG OR 0.31 [95% CI 0.10, 0.94] p = 0.04). When statistical tests for interaction were conducted, three genotype combinations in cases (MTRR/GCPII; MTHFR 677/CbetaS; MTHFR 677/MTRR) and one combination in case mothers (CbetaS/RFC-1) were shown to elevate NTD risk. Maternal-fetal interaction was also detected when offspring carried the MTHFR 677C-->T variant and mothers carried the MTRR 66A-->G variant, resulting in a significantly elevated risk of NTD.
CONCLUSION: Both independent genetic effects and gene-gene interaction were observed in relation to NTD risk. Multi-locus rather than single locus analysis might be preferable to gain an accurate assessment of genetic susceptibility to NTD.
PMID: 15060097
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OBJECTIVE: To investigate the contribution of polymorphic variation in genes involved in the folate-dependent homocysteine pathway in the aetiology of neural tube defects (NTD).
DESIGN: Case-control association study.
SUBJECTS: A total of 530 individuals from families affected by NTD, 645 maternal controls, and 602 healthy newborn controls from the northern UK.
MAIN OUTCOME MEASURES: Seven polymorphisms in six genes coding for proteins in the folate-dependent homocysteine pathway (MTHFR 677C-->T, MTHFR 1298A-->C, MTRR 66A-->G, SHMT 1420C-->T, CbetaS 844ins68, GCPII 1561C-->T, RFC-1 80G-->A). The impact of each polymorphism and the effect of gene-gene interactions (epistasis) upon risk of NTD were assessed using logistic regression analysis.
RESULTS: The MTHFR 677C-->T polymorphism was shown to represent a risk factor in NTD cases (CC v CT+TT odds ratio (OR) 2.03 [95% confidence interval (CI) 1.09, 3.79] p = 0.025) and the MTRR 66A-->G polymorphism was shown to exert a protective effect in NTD cases (AA v AG+GG OR 0.31 [95% CI 0.10, 0.94] p = 0.04). When statistical tests for interaction were conducted, three genotype combinations in cases (MTRR/GCPII; MTHFR 677/CbetaS; MTHFR 677/MTRR) and one combination in case mothers (CbetaS/RFC-1) were shown to elevate NTD risk. Maternal-fetal interaction was also detected when offspring carried the MTHFR 677C-->T variant and mothers carried the MTRR 66A-->G variant, resulting in a significantly elevated risk of NTD.
CONCLUSION: Both independent genetic effects and gene-gene interaction were observed in relation to NTD risk. Multi-locus rather than single locus analysis might be preferable to gain an accurate assessment of genetic susceptibility to NTD.
PMID: 15060097
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Investigation of folate pathway gene polymorphisms and the incidence of neural tube defects in a Texas hispanic population
Barber R, Shalat S, Hendricks K, Joggerst B, Larsen R, Suarez L, Finnell R. Investigation of folate pathway gene polymorphisms and the incidence of neural tube defects in a Texas hispanic population. Molecular Genetics & Metabolism. 2000 May;70(1):45-52.
Neural tube defects (NTDs) are multifactorial in their etiology, having both genetic and environmental factors contributing to their development. Recent evidence demonstrates that periconceptional supplementation of the maternal diet with a multivitamin containing folic acid significantly reduces the occurrence and recurrence risk for having a pregnancy complicated by NTDs. Unfortunately, the mechanism underlying the beneficial effects of folic acid remains unknown. NTD surveillance data from the Texas-Mexico border show that the high NTD rate (28/10,000 live births) noted during the 1990-1991 Cameron county NTD cluster was superimposed on a background Cameron county NTD rate (16/10,000 live births) which is considerably higher than that generally noted in the United States (8-10/10,000 live births). These data suggest that genetic factors as well as transient environmental factors may contribute to the etiology of the NTDs. Furthermore, clinical and experimental evidence imply that allelic forms of genes involved with folate metabolism and/or transport may explain some of the observed variation in the NTD rates found across different populations. Two folate pathway genes were selected for evaluation in this study. The loci investigated included two known alleles of the 5, 10-methylenetetrahydrofolate reductase (MTHFR) gene, as well as the promoter region of the folate receptor-alpha (FR-alpha) gene. Odds ratios (ORs) for the C677T polymorphism in the MTHFR gene were 1.8 (CI 0.47-6.8) for heterozygosity and 1.8 (CI 0.35-9.4) for homozygosity for the mutant 677T allele, relative to wildtype homozygotes. The odds ratio for the heterozygosity for the A1298C polymorphism in the same gene was 1.1 (CI 0.09-14). No individuals homozygous for the 1298C allele were observed. The OR for heterozygosity of FR-alpha gene polymorphisms detected at nucleotide 762 and at nucleotides 610/631 was 1.4 and 0.7, respectively. Neither of the FR-alpha polymorphisms was observed in the homozygous condition. No statistically significant associations were observed for any of the polymorphisms examined, as the 95% confidence intervals for all of the ORs included one. However, the frequency of the MTHFR 677T allele in the largely Hispanic control group from Texas was significantly different from other populations (P < 0.005), and among the highest reported for any control populations examined. Copyright 2000 Academic Press.
PMID: 10833330
Neural tube defects (NTDs) are multifactorial in their etiology, having both genetic and environmental factors contributing to their development. Recent evidence demonstrates that periconceptional supplementation of the maternal diet with a multivitamin containing folic acid significantly reduces the occurrence and recurrence risk for having a pregnancy complicated by NTDs. Unfortunately, the mechanism underlying the beneficial effects of folic acid remains unknown. NTD surveillance data from the Texas-Mexico border show that the high NTD rate (28/10,000 live births) noted during the 1990-1991 Cameron county NTD cluster was superimposed on a background Cameron county NTD rate (16/10,000 live births) which is considerably higher than that generally noted in the United States (8-10/10,000 live births). These data suggest that genetic factors as well as transient environmental factors may contribute to the etiology of the NTDs. Furthermore, clinical and experimental evidence imply that allelic forms of genes involved with folate metabolism and/or transport may explain some of the observed variation in the NTD rates found across different populations. Two folate pathway genes were selected for evaluation in this study. The loci investigated included two known alleles of the 5, 10-methylenetetrahydrofolate reductase (MTHFR) gene, as well as the promoter region of the folate receptor-alpha (FR-alpha) gene. Odds ratios (ORs) for the C677T polymorphism in the MTHFR gene were 1.8 (CI 0.47-6.8) for heterozygosity and 1.8 (CI 0.35-9.4) for homozygosity for the mutant 677T allele, relative to wildtype homozygotes. The odds ratio for the heterozygosity for the A1298C polymorphism in the same gene was 1.1 (CI 0.09-14). No individuals homozygous for the 1298C allele were observed. The OR for heterozygosity of FR-alpha gene polymorphisms detected at nucleotide 762 and at nucleotides 610/631 was 1.4 and 0.7, respectively. Neither of the FR-alpha polymorphisms was observed in the homozygous condition. No statistically significant associations were observed for any of the polymorphisms examined, as the 95% confidence intervals for all of the ORs included one. However, the frequency of the MTHFR 677T allele in the largely Hispanic control group from Texas was significantly different from other populations (P < 0.005), and among the highest reported for any control populations examined. Copyright 2000 Academic Press.
PMID: 10833330
Polymorphisms in genes involved in folate metabolism as risk factors for NTDs.
De Marco P, Calevo MG, Moroni A, Arata L, Merello E, Cama A, Finnell RH, Andreussi L, Capra V. Polymorphisms in genes involved in folate metabolism as risk factors for NTDs. European Journal of Pediatric Surgery. 2001 Dec;11 Suppl 1:S14-7.
Moderate hyperhomocysteinemia in pregnant women has been associated with an increased risk of neural tube defects (NTDs). Periconceptional supplementation with multi-vitamins containing folic acid may normalize homocysteine metabolism and decrease the NTD risk. The C677 T variant of the MTHFR gene coding for a thermolabile enzyme has been described as the first genetic risk factor that accounts for a group of NTDs characterized by low maternal folate status and high homocysteine concentrations. Another common mutation of the same MTHFR gene, A1298 C, has also been described as an NTD risk factor. In addition to abnormal folate metabolism, anything that compromises the internalization of folate into the cell may be involved in the pathogenesis of NTDs. For this reason, a common polymorphism in the RFC-1 gene encoding the reduced folate carrier protein (A80 G) could also be an additional NTD risk factor. In the present study we examined the genotypic distributions and the allele frequencies of MTHFR A1298 C and RFC-1 A80 G polymorphisms in DNA samples from healthy Italian individuals and compared them to the frequencies observed in NTD cases and their parents. By means of restriction enzymatic analysis, we determined that the frequency of the mutated C allele of the A1298 C mutation was 0.25 among control individuals, which is in the range of that recently reported in other ethnic groups. However, we report that the mutant C allele frequencies are significantly higher among NTD cases and case mothers than among controls (0.39, 0.44, 0.25). Furthermore, for the RFC-1 A80 G mutation, we found that the frequency of the G allele of the RFC-1 mutation was 0.46 in the control population, suggesting that this is a common polymorphism in the Italian population. In spite of the high prevalence of the 80 G/G genotype among healthy subjects, we observed an increased frequency of the G allele in NTD-affected children, and their mothers and fathers. These preliminary results indicate that both the MTHFR and RFC-1 polymorphisms may play a role in NTD risk, at least in the Italian population. Further studies should be directed toward the evaluation of the level of risk conferred by the mutant MTHFR and RFC-1 genotypes, as well as the interaction between these genetic determinants and other nutritional and environmental factors.
PMID: 11813127
Moderate hyperhomocysteinemia in pregnant women has been associated with an increased risk of neural tube defects (NTDs). Periconceptional supplementation with multi-vitamins containing folic acid may normalize homocysteine metabolism and decrease the NTD risk. The C677 T variant of the MTHFR gene coding for a thermolabile enzyme has been described as the first genetic risk factor that accounts for a group of NTDs characterized by low maternal folate status and high homocysteine concentrations. Another common mutation of the same MTHFR gene, A1298 C, has also been described as an NTD risk factor. In addition to abnormal folate metabolism, anything that compromises the internalization of folate into the cell may be involved in the pathogenesis of NTDs. For this reason, a common polymorphism in the RFC-1 gene encoding the reduced folate carrier protein (A80 G) could also be an additional NTD risk factor. In the present study we examined the genotypic distributions and the allele frequencies of MTHFR A1298 C and RFC-1 A80 G polymorphisms in DNA samples from healthy Italian individuals and compared them to the frequencies observed in NTD cases and their parents. By means of restriction enzymatic analysis, we determined that the frequency of the mutated C allele of the A1298 C mutation was 0.25 among control individuals, which is in the range of that recently reported in other ethnic groups. However, we report that the mutant C allele frequencies are significantly higher among NTD cases and case mothers than among controls (0.39, 0.44, 0.25). Furthermore, for the RFC-1 A80 G mutation, we found that the frequency of the G allele of the RFC-1 mutation was 0.46 in the control population, suggesting that this is a common polymorphism in the Italian population. In spite of the high prevalence of the 80 G/G genotype among healthy subjects, we observed an increased frequency of the G allele in NTD-affected children, and their mothers and fathers. These preliminary results indicate that both the MTHFR and RFC-1 polymorphisms may play a role in NTD risk, at least in the Italian population. Further studies should be directed toward the evaluation of the level of risk conferred by the mutant MTHFR and RFC-1 genotypes, as well as the interaction between these genetic determinants and other nutritional and environmental factors.
PMID: 11813127
Abnormal folate metabolism in foetuses affected by neural tube defects
Dunlevy LP, Chitty LS, Burren KA, Doudney K, Stojilkovic-Mikic T, Stanier P, Scott R, Copp AJ, Greene ND. Abnormal folate metabolism in foetuses affected by neural tube defects. Brain: A Journal of Neurology. 2007 Apr;130(Pt 4):1043-9.
Folic acid supplementation can prevent many cases of neural tube defects (NTDs), whereas suboptimal maternal folate status is a risk factor, suggesting that folate metabolism is a key determinant of susceptibility to NTDs. Despite extensive genetic analysis of folate cycle enzymes, and quantification of metabolites in maternal blood, neither the protective mechanism nor the relationship between maternal folate status and susceptibility are understood in most cases. In order to investigate potential abnormalities in folate metabolism in the embryo itself, we derived primary fibroblastic cell lines from foetuses affected by NTDs and subjected them to the dU suppression test, a sensitive metabolic test of folate metabolism. Significantly, a subset of NTD cases exhibited low scores in this test, indicative of abnormalities in folate cycling that may be causally linked to the defect. Susceptibility to NTDs may be increased by suppression of the methylation cycle, which is interlinked with the folate cycle. However, reduced efficacy in the dU suppression test was not associated with altered abundance of the methylation cycle intermediates, s-adenosylmethionine and s-adenosylhomocysteine, suggesting that a methylation cycle defect is unlikely to be responsible for the observed abnormality of folate metabolism. Genotyping of samples for known polymorphisms in genes encoding folate-associated enzymes did not reveal any correlation between specific genotypes and the observed abnormalities in folate metabolism. These data suggest that as yet unrecognized genetic variants result in embryonic abnormalities of folate cycling that may be causally related to NTDs.
PMID: 17438019
Folic acid supplementation can prevent many cases of neural tube defects (NTDs), whereas suboptimal maternal folate status is a risk factor, suggesting that folate metabolism is a key determinant of susceptibility to NTDs. Despite extensive genetic analysis of folate cycle enzymes, and quantification of metabolites in maternal blood, neither the protective mechanism nor the relationship between maternal folate status and susceptibility are understood in most cases. In order to investigate potential abnormalities in folate metabolism in the embryo itself, we derived primary fibroblastic cell lines from foetuses affected by NTDs and subjected them to the dU suppression test, a sensitive metabolic test of folate metabolism. Significantly, a subset of NTD cases exhibited low scores in this test, indicative of abnormalities in folate cycling that may be causally linked to the defect. Susceptibility to NTDs may be increased by suppression of the methylation cycle, which is interlinked with the folate cycle. However, reduced efficacy in the dU suppression test was not associated with altered abundance of the methylation cycle intermediates, s-adenosylmethionine and s-adenosylhomocysteine, suggesting that a methylation cycle defect is unlikely to be responsible for the observed abnormality of folate metabolism. Genotyping of samples for known polymorphisms in genes encoding folate-associated enzymes did not reveal any correlation between specific genotypes and the observed abnormalities in folate metabolism. These data suggest that as yet unrecognized genetic variants result in embryonic abnormalities of folate cycling that may be causally related to NTDs.
PMID: 17438019
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