Timothy Brei

Neural tube defects and folate pathway genes : Family-based association tests of gene-gene and gene-environment interactions

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.

The Malone antegrade continence enema procedure: quality of life and family perspective.

PURPOSE Since introducing the Malone antegrade continence enema (MACE) procedure into our practice, it has been our bias that social confidence and independence are significantly improved and satisfaction is overwhelmingly high. We objectively determine outcomes after the MACE to refine patient selection, and maximize the quality of perioperative counseling and teaching. MATERIALS AND METHODS An anonymous questionnaire was mailed to all patients who had undergone the MACE procedure within the last 4 years. Patient/parent satisfaction, impact on quality of life and clinical outcome were assessed with Likert scales. Demographic information, MACE specifics, preoperative expectations, and unanticipated benefits and problems were also recorded. RESULTS A total of 65 questionnaires were returned from our first 92 patients (71%). Myelodysplasia was the primary diagnosis in 88% of patients. Complete or near complete fecal continence was achieved in 77% of patients and all others had improved incontinence. The highest level of satisfaction was reported by 89% of patients. Social confidence and hygiene were significantly improved. Daily time commitment, pain/cramping, intermittent constipation and time for fine-tuning the regimen were cited as unanticipated issues. CONCLUSIONS The MACE procedure has received high praise from patients and families after years of battling constipation and fecal incontinence. Significant improvement rather than perfection is the realistic expectation. Objective feedback from patients and families will continue to improve patient selection and education.

Adolescents with myelomeningocele: activities, beliefs, expectations, and perceptions

The Carnegie Council on Adolescent Development, USA has identified activities, beliefs, and perceptions critical for healthy development. The aim of this study was to measure the activities, beliefs and expectations, and perceived outcomes of adolescents with myelomeningocele. In this descriptive study, 66 adolescents with myelomeningocele, aged 12 to 21 years and functioning at grade level, completed a structured interview. Thirty-eight (58%) of the participants were female. The level of lesion was distributed as follows: 30% had thoracic level lesions, 32% had lumbar level lesions, 15% had lumbosacral level lesions, and 23% of the sample had sacral level lesions. Instruments used had both established reliability and validity (WeeFIM, Harters Self-Perception Profile, Austins Child Attitude Toward Illness Scale, and Snyders Hope Scale, Adolescent Decision-Making Inventory, Adolescent Coping Scale) or were scales developed for this study (Adolescent Activities Inventory, Future Expectations Scale, Communication Efficacy, and Adolescent Self-Management and Independence Scale). Scale reliabilities ranged from 0.70 to 0.88. These participants, though hopeful and positive in their attitudes toward myelomeningocele and generally able to perform activities of daily living independently, are not engaging in the full range of adolescent activities (decision making, friendship activities, and household responsibilities) and achieving positive outcomes (self-management and job) necessary to make a successful transition to adulthood. This might explain why so many individuals with myelomeningocele are underemployed and are not living independently as young adults.

Genetic studies in neural tube defects

Neural tube defects (NTD) are one of the most common birth defects and are caused by both environmental and genetic factors. The approach to identifying the genes predisposing to NTD, through linkage analysis and candidate gene analysis, is reviewed along with characteristics of a large, nationally ascertained cohort of families. Results from specific assessments of p53, PAX3 and MTHFR failed to suggest that these genes play a major role in NTD development in these families. Advances in genetic laboratory and statistical techniques have made this a prime opportunity for investigation into the causes of complex disorders, such as NTD. However, traditional approaches may prove to be challenging due to the difficulty of ascertaining samplable multiplex families.

Introduction: Spina bifida--a multidisciplinary perspective.

Spina bifida is the most common birth defect affecting the central nervous system (CNS) and is often characterized as the most complex birth defect compatible with survival [Liptak and El Samra, 2010]. Because of its complexity, the diagnosis and treatment of infants born with spina bifida begins before birth and through adulthood, involving multiple disciplines. Not surprisingly, research has flourished across several domains over the past decade. The purpose of this special issue of Developmental Disabilities Research Reviews is to systematically review research on spina bifida within different domains in an effort to promote integration and awareness of this research across disciplines involved directly with spina bifida. In addition, we hope to increase the awareness of contemporary research and treatment strategies for researchers and practitioners involved with other developmental disabilities. Although some aspects of spina bifida have been reviewed as part of previous issues, this is the first issue of the journal specifically devoted to spina bifida since an issue on neural tube defects edited by Sells [1998].

Possible interaction of genotypes at cystathionine β‐synthase and methylenetetrahydrofolate reductase (MTHFR) in neural tube defects

Neural tube defects are a common, complex disorder with genetic and environmental components to risk. We investigated the previously reported interaction between homozygosity for the thermolabile variant at the methylenetetrahydrofolate reductase and heterozygosity for the 844ins68 allele at the cystathionine β‐synthase loci in cases with lumbosacral myelomeningocele and their parents. Using control allele frequencies from our sample pooled with those published in the literature, we confirm a marginally significant interaction at these two loci. This finding suggests that additional, larger studies are warranted to investigate this possible interaction in more detail.

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

BACKGROUND Neural tube defects (NTDs), including spina bifida and anencephaly, are the second most common birth defect with an incidence of 1/1000. Genetic factors are believed to contribute to NTD risk and family-based studies can be useful for identifying such risk factors. METHODS We ascertained 1066 NTD families (1467 affected patients), including 307 multiplex NTD families. We performed pedigree analysis to describe the inheritance patterns, pregnancy outcomes, and recurrence risks to relatives of various types. RESULTS Myelomeningocele or spina bifida (66.9%) and cranial defects (17.7%) were the most common NTD subtypes observed. The overall male:female ratio for affected individuals was 0.82, and there were even fewer males among individuals with an upper level NTD (0.62). Among twins, 2 of the 5 monozygotic twins and only 3 of 35 dizygotic twins were concordant, while 27% of the same sex twins were concordant, but none of the different sex twins. The estimated 6.3% recurrence risk to siblings (CI 0.04-0.08) is consistent with previous reports. Families with two or more affected individuals show a higher proportion of female transmitters (p = 0.0002). Additionally, the number of affected relatives in maternal compared to paternal lineages was more than double (p = 0.006). There were significantly more miscarriages, infant deaths, and stillborn pregnancies of the maternal aunts and uncles (p < 0.0001) and of first cousins (p = 0.04). CONCLUSIONS Our data provide several lines of evidence consistent with a maternal effect, as well as a sex-influenced effect, in the etiology of NTDs.

Updated investigations of the role of methylenetetrahydrofolate reductase in human neural tube defects

Folate supplementation appears to reduce the risk for neural tube defects (NTDs). Methylenetetrahydrofolate reductase (MTHFR) is a candidate gene in the folate metabolism pathway that has been extensively studied in different human populations. We examined the risk associated with having the thermolabile variant (TT) of MTHFR in a study of 175 American Caucasians with NTDs and their families. We found a significant association in patients compared with 195 unrelated controls [odds ratio (OR) = 2.13, 95% confidence interval (95% CI) = 1.11–4.09)], but not in mothers (OR = 1.29, 95% CI = 0.622–2.67) or in fathers (OR = 1.45, 95% CI = 0.681–3.09). We found no evidence for unequal transmission from parents to an affected child (p > 0.10). We failed to find a previously reported association for a combined haplotype for MTHFR and cystathionine β‐synthase, except in subjects with NTDs compared with 559 pooled controls (OR = 2.87, 95% CI = 1.03–8.03). We found no evidence for an association for a novel CA‐repeat polymorphism identified in a gene closely linked to MTHFR (p > 0.10). Our studies continue to suggest that additional candidate genes other than MTHFR may be responsible for an increased risk to NTD in some American Caucasian families. 

Whole genomewide linkage screen for neural tube defects reveals regions of interest on chromosomes 7 and 10

Neural tube defects (NTDs) are the second most common birth defects (1 in 1000 live births) in the world. Periconceptional maternal folate supplementation reduces NTD risk by 50–70%; however, studies of folate related and other developmental genes in humans have failed to definitively identify a major causal gene for NTD. The aetiology of NTDs remains unknown and both genetic and environmental factors are implicated. We present findings from a microsatellite based screen of 44 multiplex pedigrees ascertained through the NTD Collaborative Group. For the linkage analysis, we defined our phenotype narrowly by considering individuals with a lumbosacral level myelomeningocele as affected, then we expanded the phenotype to include all types of NTDs. Two point parametric analyses were performed using VITESSE and HOMOG. Multipoint parametric and nonparametric analyses were performed using ALLEGRO. Initial results identified chromosomes 7 and 10, both with maximum parametric multipoint lod scores (Mlod) >2.0. Chromosome 7 produced the highest score in the 24 cM interval between D7S3056 and D7S3051 (parametric Mlod 2.45; nonparametric Mlod 1.89). Further investigation demonstrated that results on chromosome 7 were being primarily driven by a single large pedigree (parametric Mlod 2.40). When this family was removed from analysis, chromosome 10 was the most interesting region, with a peak Mlod of 2.25 at D10S1731. Based on mouse human synteny, two candidate genes (Meox2, Twist1) were identified on chromosome 7. A review of public databases revealed three biologically plausible candidates (FGFR2, GFRA1, Pax2) on chromosome 10. The results from this screen provide valuable positional data for prioritisation of candidate gene assessment in future studies of NTDs.

The Experience of Self-Management in Adolescent Women with Spina Bifida

&NA; It is essential for youth with chronic health conditions like spina bifida (SB) to develop self‐management skills to combat vulnerability, achieve self‐sufficiency, and transition to adulthood. The purpose of this qualitative study was to describe the experience of self‐management in 31 adolescent women with SB. Three themes emerged from this study: (1) opportunities to engage in self‐management activities—knowledge, skills, and aspirations; (2) dance of individuation—parental impact on self‐management; and (3) advocacy within self‐management—confronting discrimination and stigma. The findings indicate that assessment and interventions to enhance self‐management in adolescent women with SB are critical for supporting the range of condition‐related and life skills needed for a transition to adulthood and independent living.