Hydrocephalus and school-age neurodevelopmental outcomes in the management of myelomeningocele prenatal surgery trial: a secondary analysis.

OBJECTIVE: The purpose of this secondary analysis was to assess the role of hydrocephalus on neurodevelopmental outcomes in a cohort of school-age children enrolled in the Management of Myelomeningocele Study (MOMS) clinical trial. METHODS: The sample analyzed in this report consisted of 150 of 183 children aged 5-10 years (mean ± SD 7 years 8 months ± 1.2) who were randomly assigned between 20 and 26 weeks of gestational age to undergo either prenatal or postnatal surgery and were enrolled in the school-age follow-up study of MOMS. These 150 children (76 prenatal and 74 postnatal) were placed into three groups: no hydrocephalus (n = 22), unshunted hydrocephalus (n = 31), and shunted hydrocephalus (n = 97). Comparisons were made on the basis of measures of adaptive behavior, intelligence, reading and math skills, verbal and nonverbal memory, fine motor dexterity, and sensorimotor skills. Parent ratings of executive functions, inattention, and hyperactivity-impulsivity were also compared. RESULTS: There were no statistically significant differences in neurodevelopmental outcomes between the groups with no hydrocephalus and unshunted hydrocephalus, or between the prenatal and postnatal groups with shunted hydrocephalus, so these groups were combined (no/unshunted vs shunted hydrocephalus). The no/unshunted group showed significantly better performance (p < 0.05) than the shunted group in terms of adaptive behavior, intelligence, verbal and nonverbal memory, reading skills (but not math), fine motor dexterity, sensorimotor skills (but not visual-motor integration), and inattention (but not hyperactivity-impulsivity or executive function ratings). An assessment of the prenatal surgery group showed that the combined no/unshunted group performed better than the shunted group in terms of adaptive behavior and verbal memory skills. Both the prenatal and postnatal surgery subgroups with unshunted hydrocephalus performed as well as the group with no hydrocephalus despite significantly enlarged ventricles. CONCLUSIONS: Although the primary assessment of school-age outcomes in the MOMS clinical trial did not show better adaptive behavior and cognitive skills in the prenatal group, hydrocephalus and shunting were associated with poorer neurodevelopmental outcomes (both prenatal and postnatal groups). Disease severity and dynamic changes in hydrocephalus status may be the primary factors in the need for shunting and a major determinant of adaptive behavior and cognitive outcomes after prenatal surgery.

Prenatal Repair of Myelomeningocele and School-age Functional Outcomes.

BACKGROUND AND OBJECTIVES: The Management of Myelomeningocele Study (MOMS), a randomized trial of prenatal versus postnatal repair for myelomeningocele, found that prenatal surgery resulted in reduced hindbrain herniation and need for shunt diversion at 12 months of age and better motor function at 30 months. In this study, we compared adaptive behavior and other outcomes at school age (5.9-10.3 years) between prenatal versus postnatal surgery groups. METHODS: Follow-up cohort study of 161 children enrolled in MOMS. Assessments included neuropsychological and physical evaluations. Children were evaluated at a MOMS center or at a home visit by trained blinded examiners. RESULTS: The Vineland composite score was not different between surgery groups (89.0 ± 9.6 in the prenatal group versus 87.5 ± 12.0 in the postnatal group; P = .35). Children in the prenatal group walked without orthotics or assistive devices more often (29% vs 11%; P = .06), had higher mean percentage scores on the Functional Rehabilitation Evaluation of Sensori-Neurologic Outcomes (92 ± 9 vs 85 ± 18; P < .001), lower rates of hindbrain herniation (60% vs 87%; P < .001), had fewer shunts placed for hydrocephalus (49% vs 85%; P < .001) and, among those with shunts, fewer shunt revisions (47% vs 70%; P = .02) than those in the postnatal group. Parents of children repaired prenatally reported higher mean quality of life z scores (0.15 ± 0.67 vs 0.11 ± 0.73; P = .008) and lower mean family impact scores (32.5 ± 7.8 vs 37.0 ± 8.9; P = .002). CONCLUSIONS: There was no significant difference between surgery groups in overall adaptive behavior. Long-term benefits of prenatal surgery included improved mobility and independent functioning and fewer surgeries for shunt placement and revision, with no strong evidence of improved cognitive functioning.

Long-Term Intellectual and Fine Motor Outcomes in Spina Bifida Are Related to Myelomeningocele Repair and Shunt Intervention History.

OBJECTIVE: Lifespan outcomes of simultaneous versus sequential myelomeningocele repair and shunt placement or effects of repeated shunt revisions on specific domains of IQ or fine motor dexterity are largely unknown. The current study addressed these gaps in a large cohort of children and adults with spina bifida myelomeningocele (SBM). METHODS: Participants between 7 and 44 years of age with SBM and shunted hydrocephalus were recruited from international clinics at two time points. Each participant completed a standardized neuropsychological evaluation that included estimates of IQ and fine motor dexterity. Simultaneous versus sequential surgical repair and number of shunt revisions were examined in relation to long-term IQ and fine motor scores. RESULTS: Simultaneous myelomeningocele repair and shunting were associated with more frequent shunt revisions, as well as to lower Full Scale and verbal IQ scores, controlling for number of shunt revisions. More shunt revisions across study time points were associated with higher nonverbal IQ (NVIQ) scores. No effects were observed on fine motor dexterity. CONCLUSIONS: Findings indicate generally greater influence of surgery type over shunt revision history on outcomes in well-managed hydrocephalus. Findings supported apparent, domain-specific benefits of sequential compared to simultaneous surgery across the lifespan in SBM. Higher NVIQ scores with greater number of additional shunt revisions across surgery type supported positive outcomes with effective surgical management for hydrocephalus.

Are primary and secondary types of brain anomalies exclusive factors affecting the attention networks in individuals with spina bifida?

OBJECTIVE: Individuals with spina bifida myelomeningocele (SBM) frequently exhibit cognitive impairments on tasks mediated by brain regions involved in the posterior attention network. Although such deficits have been historically assumed to result from primary and secondary brain insults, there is a dearth of literature regarding whether sequential versus simultaneous surgical closure of neural folds and surgical shunt placement affect neuropsychological function and brain structure of attention networks that have been widely studied in individuals with SBM. The current study addressed these gaps in a large cohort of children and adults with SBM. METHOD: White matter pathways and regional brain volumes of anterior and posterior attention networks were quantified through probabilistic tractography and automated segmentation, respectively. The Child Attention Network Test measured behavioral components of posterior and anterior attention networks. RESULTS: Sequential operations were associated with reduced orienting accuracy and smaller left superior parietal and dorsolateral prefrontal cortex volumes compared to simultaneous operations, controlling for a number of shunt revisions and age. Greater number of shunt revisions was associated with higher radial diffusivity values in the parietal tectocortical pathway. Older participants had greater accuracy and faster conflict resolution performance compared to younger participants, across operation type and number of shunt revisions. CONCLUSIONS: Shunt treatment and revision history related to brain structure and functions associated with the posterior attention network. Neurosurgical history also differentiated the harmful effects of early hydrocephalus on brain structure of the posterior from the anterior attention networks in SBM. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Interactions between visual working memory and visual attention among survivors of pediatric acute lymphoblastic leukemia (ALL) and their healthy peers.

Introduction: There is increasing concern for adverse cognitive late effects among survivors of pediatric acute lymphoblastic leukemia (ALL) given the widespread impact they have on academic achievement, particularly working memory and attention. We assessed performance among survivors and their healthy peers on a dual task paradigm measuring visual working memory (VWM) and visual attention independently and the dynamic relationship between the two. Assessing specific subsets within cognitive domains allows for understanding the distinct nature of cognitive impairments. Method: Participants were 34 survivors of ALL who have been off-treatment and disease free for 7.5 years; and 20 healthy controls, all between the ages of 10 and 18 years. We utilized behavioral single- and dual-task paradigms. In the dual tasks, participants maintained several items in VWM while performing a visual attention task (Eriksen Flanker Task) that required processing of a target stimulus while inhibiting the processing of distractor stimuli. The single tasks involved performing only the VWM task or only the visual attention task. Results: Results revealed survivors of ALL performed significantly worse than their healthy peers on the single visual attention task but not the single VWM task. Of particular interest, group differences were obtained on the dual VWM and visual attention tasks, such that the VWM and attention tasks reciprocally interfered with each other only among survivors and not their healthy peers. Conclusions: Our results highlight a core deficit in visual attention that is exacerbated by VWM demands among survivors of ALL. The implementation of tasks from cognitive neuroscience paradigms may be sensitive to cognitive impairments experienced by cancer survivors. Assessment and intervention practices among survivors of pediatric ALL are discussed.

Typical and Aberrant Functional Brain Flexibility: Lifespan Development and Aberrant Organization in Traumatic Brain Injury and Dyslexia.

Intrinsic functional connectivity networks derived from different neuroimaging methods and connectivity estimators have revealed robust developmental trends linked to behavioural and cognitive maturation. The present study employed a dynamic functional connectivity approach to determine dominant intrinsic coupling modes in resting-state neuromagnetic data from 178 healthy participants aged 8-60 years. Results revealed significant developmental trends in three types of dominant intra- and inter-hemispheric neuronal population interactions (amplitude envelope, phase coupling, and phase-amplitude synchronization) involving frontal, temporal, and parieto-occipital regions. Multi-class support vector machines achieved 89% correct classification of participants according to their chronological age using dynamic functional connectivity indices. Moreover, systematic temporal variability in functional connectivity profiles, which was used to empirically derive a composite flexibility index, displayed an inverse U-shaped curve among healthy participants. Lower flexibility values were found among age-matched children with reading disability and adults who had suffered mild traumatic brain injury. The importance of these results for normal and abnormal brain development are discussed in light of the recently proposed role of cross-frequency interactions in the fine-grained coordination of neuronal population activity.

Aberrant resting-state functional brain networks in dyslexia: Symbolic mutual information analysis of neuromagnetic signals.

Neuroimaging studies have identified a variety of structural and functional connectivity abnormalities in students experiencing reading difficulties. The present study adopted a novel approach to assess the dynamics of resting-state neuromagnetic recordings in the form of symbolic sequences (i.e., repeated patterns of neuromagnetic fluctuations within and/or between sensors). Participants were 25 students experiencing severe reading difficulties (RD) and 27 age-matched non-impaired readers (NI) aged 7-14 years. Sensor-level data were first represented as symbolic sequences in eight conventional frequency bands. Next, dominant types of sensor-to-sensor interactions in the form of intra and cross-frequency coupling were computed and subjected to graph modeling to assess group differences in global network characteristics. As a group RD students displayed predominantly within-frequency interactions between neighboring sensors which may reflect reduced overall global network efficiency and cost-efficiency of information transfer. In contrast, sensor networks among NI students featured a higher proportion of cross-frequency interactions. Brain-reading achievement associations highlighted the role of left hemisphere temporo-parietal functional networks, at rest, for reading acquisition and ability.

Data-Driven Topological Filtering Based on Orthogonal Minimal Spanning Trees: Application to Multigroup Magnetoencephalography Resting-State Connectivity.

In the present study, a novel data-driven topological filtering technique is introduced to derive the backbone of functional brain networks relying on orthogonal minimal spanning trees (OMSTs). The method aims to identify the essential functional connections to ensure optimal information flow via the objective criterion of global efficiency minus the cost of surviving connections. The OMST technique was applied to multichannel, resting-state neuromagnetic recordings from four groups of participants: healthy adults (n = 50), adults who have suffered mild traumatic brain injury (n = 30), typically developing children (n = 27), and reading-disabled children (n = 25). Weighted interactions between network nodes (sensors) were computed using an integrated approach of dominant intrinsic coupling modes based on two alternative metrics (symbolic mutual information and phase lag index), resulting in excellent discrimination of individual cases according to their group membership. Classification results using OMST-derived functional networks were clearly superior to results using either relative power spectrum features or functional networks derived through the conventional minimal spanning tree algorithm.

Measurement of neurodevelopmental changes in children treated with radiation for brain tumors: what is a true 'baseline?'

OBJECTIVE: To review the various ways in which baseline neuropsychological functioning is measured in the extant literature on pediatric brain tumors, describe the pros and cons of each approach, and increase the awareness of researchers as to the implications of each. METHOD: We reviewed the literature from 1993 to 2013, and classified studies by baseline approach and explicitness of selection of approach. RESULTS: There are multiple approaches to operationalizing baseline levels of ability and to assess change from baseline. Each approach has strengths and weaknesses, and selection may depend on the question under investigation. Approaches to baseline estimation varied widely with a trend over time toward reliance on statistical modeling. Researchers were often insufficiently explicit about the reasons for adopting a particular approach. The common use of standardized scores requires caution as they obscure critical inferential limitations about change and magnitude of change. Some viable approaches were infrequently used, such as actuarial prediction formulas. Multiple simultaneous methods akin to theory testing and formal methods of construct validation could enhance scientific yield since all approaches are fallible. CONCLUSIONS: Estimating baseline neuropsychological functioning is very challenging, particularly when it concerns children in the preschool years. Nevertheless, it is a crucial methodological decision with important implications for the interpretation of research findings that needs to be dealt with explicitly.

Are Shunt Revisions Associated with IQ in Congenital Hydrocephalus? A Meta -Analysis.

Although it is generally acknowledged that shunt revisions are associated with reductions in cognitive functions in individuals with congenital hydrocephalus, the literature yields mixed results and is inconclusive. The current study used meta-analytic methods to empirically synthesize studies addressing the association of shunt revisions and IQ in individuals with congenital hydrocephalus. Six studies and three in-house datasets yielded 11 independent samples for meta-analysis. Groups representing lower and higher numbers of shunt revisions were coded to generate effect sizes for differences in IQ scores. Mean effect size across studies was statistically significant, but small (Hedges' g = 0.25, p < 0.001, 95 % CI [0.08, 0.43]) with more shunt revisions associated with lower IQ scores. Results show an association of lower IQ and more shunt revisions of about 3 IQ points, a small effect, but within the error of measurement associated with IQ tests. Although clinical significance of this effect is not clear, results suggest that repeated shunt revisions because of shunt failure is associated with a reduction in cognitive functions.

Greater Repertoire and Temporal Variability of Cross-Frequency Coupling (CFC) Modes in Resting-State Neuromagnetic Recordings among Children with Reading Difficulties.

Cross-frequency, phase-to-amplitude coupling (PAC) between neuronal oscillations at rest may serve as the substrate that supports information exchange between functionally specialized neuronal populations both within and between cortical regions. The study utilizes novel algorithms to identify prominent instantaneous modes of cross-frequency coupling and their temporal stability in resting state magnetoencephalography (MEG) data from 25 students experiencing severe reading difficulties (RD) and 27 age-matched non-impaired readers (NI). Phase coherence estimates were computed in order to identify the prominent mode of PAC interaction for each sensor, sensor pair, and pair of frequency bands (from δ to γ) at successive time windows of the continuous MEG record. The degree of variability in the characteristic frequency-pair PAC(f1-f2) modes over time was also estimated. Results revealed a wider repertoire of prominent PAC interactions in RD as compared to NI students, suggesting an altered functional substrate for information exchange between neuronal assemblies in the former group. Moreover, RD students showed significant variability in PAC modes over time. This temporal instability of PAC values was particularly prominent: (a) within and between right hemisphere temporo-parietal and occipito-temporal sensors and, (b) between left hemisphere frontal, temporal, and occipito-temporal sensors and corresponding right hemisphere sites. Altered modes of neuronal population coupling may help account for extant data revealing reduced, task-related neurophysiological and hemodynamic activation in left hemisphere regions involved in the reading network in RD. Moreover, the spatial distribution of pronounced instability of cross-frequency coupling modes in this group may provide an explanation for previous reports suggesting the presence of inefficient compensatory mechanisms to support reading.

Covert orienting in three etiologies of congenital hydrocephalus: the effect of midbrain and posterior fossa dysmorphology.

Covert orienting is related to the integrity of the midbrain, but the specificity of the relation is unclear. We compared covert orienting in three etiologies of congenital hydrocephalus (aqueductal stenosis [AS], Dandy-Walker malformation [DWM], and spina bifida myelomeningocele [SBM]--with and without tectal beaking) to explore the effects of midbrain and posterior fossa malformations. We hypothesized a stepwise order of group performance reflecting the degree of midbrain tectum dysmorphology. Performance on an exogenously cued covert orienting task was compared using repeated measures analysis of covariance, controlling for age. Individuals with SBM and tectal beaking demonstrated the greatest disengagement cost in the vertical plane, whereas individuals with AS performed as well as a typically developing (TD) group. Individuals with SBM but no tectal beaking and individuals with DWM showed greater disengagement costs in the vertical plane relative to the TD group, but better performance relative to the group with SBM and tectal beaking. Individuals with AS, DWM, and SBM and tectal beaking demonstrated poorer inhibition of return than TD individuals. Impairments in attentional disengagement in SBM are not attributable to the general effects of hydrocephalus, but are instead associated with specific midbrain anomalies that are part of the Chiari II malformation.

Alternative approaches to outcomes assessment: beyond psychometric tests.

Outcomes assessments in clinical trials involving cognition and behavior rely upon IQ and neuropsychological assessments. These procedures provide limited evaluations of everyday functions. Some participants cannot perform cognitive tasks because they are low functioning or may represent missing data because of inability to travel. Interview-based assessments of adaptive behavior yield results that reflect everyday functions and can be done by telephone regardless of level of cognitive functioning. The design of the neurobehavioral component of the follow-up study for the management of myelomeningocele fetal surgery trial is as an example of a clinical trial that incorporates these alternatives.

Selection of patients and results of 25 years of topical anesthesia and adjustable suture surgery.

BACKGROUND AND PURPOSE: The author has used adjustable suture techniques either in the operating room with topical anesthesia or at a later time after retrobulbar or general anesthesia for over 25 years. Careful selection of patients is essential to the success of this technique. It is the purpose of this paper to report the selection criteria used and to compare the results of the two methods utilized. PATIENTS AND METHODS: One hundred eighty-three patients were included in this study: 123 were operated upon with topical anesthesia. For comparison, sixty patients were included who had adjustment later in the day or the next day after having retrobulbar or general anesthesia. Both horizontal and vertical strabismus cases were included. RESULTS: Adjustable techniques done in the operating room or at a later time have both shown significant improvement in the strabismus angle following one operation in 86% of the cases. Diplopia was eliminated in 63% of patients with this complaint. (63% and 64.5% in the two groups, respectively). Seventeen of 123 patients having topical anesthesia (13.8%) required a second operation, and 8 of 60 (13.3%) of those having a later adjustment needed further surgery. CONCLUSION: Careful selection of patients undergoing strabismus surgery allows successful topical muscle adjustment in the operating room with results similar to adjustments done following retrobulbar or general anesthesia at a later time.

Time-constrained functional connectivity analysis of cortical networks underlying phonological decoding in typically developing school-aged children: a magnetoencephalography study.

The study investigated functional associations between left hemisphere occipitotemporal, temporoparietal, and inferior frontal regions during oral pseudoword reading in 58 school-aged children with typical reading skills (aged 10.4±1.6, range 7.5-12.5years). Event-related neuromagnetic data were used to compute source-current density waveforms using a minimum norm algorithm. Temporally-constrained contributions were established for four ROIs (STG, SMG, ANG, and IFG) by controlling for the autoregressive effects of activity in each ROI. Unique contributions made by activity in one ROI to subsequent activity in a second ROI were assessed through multiple regression analyses. Forward associations between lateral (LOC) and ventral occipitotemporal cortices (fusiform gyrus) to each of the four main ROIs were also examined. The earliest significant contributions to SMG and ANG activation (at 200-250ms) were made by preceding activity in the fusiform gyrus. The degree of activity in IFG appeared to be determined by earlier activity in ANG and STG.

Factors associated with strabismus in spina bifida myelomeningocele.

PURPOSE: Higher prevalence of strabismus in individuals with spina bifida myelomeningocele (SBM) has previously been attributed to hydrocephalus; however, SBM is associated with many other complications. This study investigates the relation between strabismus and other factors in SBM. METHODS: Children aged 3 to 18 years with SBM (n = 112) received an eye examination including assessment of ocular alignment by cover or Hirschberg test. Gestational age, respiratory distress at birth, birth weight, maternal age at birth, number of shunt revisions, and spinal lesion level were also obtained. The relation between these factors and strabismus was analyzed. RESULTS: Forty-two participants had strabismus. Maternal age (P = .4) and respiratory distress (P = .6) were not significantly related to strabismus. Lower birth weight was suggestive of a relation with strabismus (logistic regression, P = .05) and younger gestational age was related to strabismus (logistic regression, P = .01). Participants who had at least one shunt revision were more likely to have strabismus (Fisher's exact test, P = .038). Spinal lesion level was significantly related to strabismus with increased likelihood of strabismus for spinal lesions closer to the brain (Wald chi-square, 1,100 = 4.29, P = .038). CONCLUSION: These findings indicate that several factors are associated with strabismus in SBM. Some of these factors (lower birth weight and younger gestational age) are associated with strabismus in the general population, whereas the association of strabismus and level of spinal lesion may be unique to SBM and may be related to the more severe brain dysmorphology associated with upper level spinal lesions.

Functional disruption of the brain mechanism for reading: effects of comorbidity and task difficulty among children with developmental learning problems.

OBJECTIVE: The study investigated the relative degree and timing of cortical activation associated with phonological decoding in poor readers. METHOD: Regional brain activity was assessed during performance of a pseudoword reading task and a less demanding, letter-sound naming task by three groups of students: children who experienced reading difficulties without attention problems (N = 50, RD) and nonreading impaired (NI) readers either with (N = 20) or without attention-deficit/hyperactivity disorder (ADHD; N = 50). Recordings were obtained with a whole-head neuromagnetometer, and activation profiles were computed through a minimum norm algorithm. RESULTS: Children with RD showed decreased amplitude of neurophysiological activity in the superior temporal gyrus, bilaterally, and in the left supramarginal and angular gyri during late stages of decoding, compared to typical readers. These effects were restricted to the more demanding pseudoword reading task. No differences were found in degree of activity between NI and ADHD students. Regression analyses provided further support for the crucial role of left hemisphere temporoparietal cortices and the fusiform gyrus for basic reading skills. CONCLUSIONS: Results were in agreement with fMRI findings and replicate previous MEG findings with a larger sample, a higher density neuromagnetometer, an overt pseudoword reading task, and a distributed current source-modeling method.

Association of retinoic acid receptor genes with meningomyelocele.

BACKGROUND: Neural tube defects (NTDs) occur in as many as 0.5-2 per 1000 live births in the United States. One of the most common and severe neural tube defects is meningomyelocele (MM) resulting from failed closure of the caudal end of the neural tube. MM has been induced by retinoic acid teratogenicity in rodent models. We hypothesized that genetic variants influencing retinoic acid (RA) induction via retinoic acid receptors (RARs) may be associated with risk for MM. METHODS: We analyzed 47 single nucleotide polymorphisms (SNPs) that span across the three retinoic acid receptor genes using the SNPlex genotyping platform. Our cohort consisted of 610 MM families. RESULTS: One variant in the RARA gene (rs12051734), three variants in the RARB gene (rs6799734, rs12630816, rs17016462), and a single variant in the RARG gene (rs3741434) were found to be statistically significant at p < 0.05. CONCLUSION: RAR genes were associated with risk for MM. For all associated SNPs, the rare allele conferred a protective effect for MM susceptibility.

Association of folate receptor (FOLR1, FOLR2, FOLR3) and reduced folate carrier (SLC19A1) genes with meningomyelocele.

BACKGROUND: Meningomyelocele (MM) results from lack of closure of the neural tube during embryologic development. Periconceptional folic acid supplementation is a modifier of MM risk in humans, leading toan interest in the folate transport genes as potential candidates for association to MM. METHODS: This study used the SNPlex Genotyping (ABI, Foster City, CA) platform to genotype 20 single polymorphic variants across the folate receptor genes (FOLR1, FOLR2, FOLR3) and the folate carrier gene (SLC19A1) to assess their association to MM. The study population included 329 trio and 281 duo families. Only cases with MM were included. Genetic association was assessed using the transmission disequilibrium test in PLINK. RESULTS: A variant in the FOLR2 gene (rs13908), three linked variants in the FOLR3 gene (rs7925545, rs7926875, rs7926987), and two variants in the SLC19A1 gene (rs1888530 and rs3788200) were statistically significant for association to MM in our population. CONCLUSION: This study involved the analyses of selected single nucleotide polymorphisms across the folate receptor genes and the folate carrier gene in a large population sample. It provided evidence that the rare alleles of specific single nucleotide polymorphisms within these genes appear to be statistically significant for association to MM in the patient population that was tested.

Genetic association study of putative functional single nucleotide polymorphisms of genes in folate metabolism and spina bifida.

OBJECTIVE: We tested putative functional single nucleotide polymorphisms (SNPs) in genes that regulate the folate/homocysteine metabolism pathway for their contribution to spina bifida (SB) susceptibility. STUDY DESIGN: The study consisted of 610 unrelated simplex SB patient families. Genotypes of 46 SNPs located in the coding sequence or promoter region of 11 genes were investigated. Associations between transmission of alleles and SB in the offspring were examined using the reconstruction combined transmission disequilibrium test. RESULTS: Significant association of SNP rs5742905 in cystathionine-beta-synthase, rs1643649 in dihydrofolate reductase, rs2853533 in thymidylate synthetase, and rs3737965 in methylenetetrahydrofolate reductase was found (P = .015, .041, .021, and .007 respectively). CONCLUSION: Transmission disequilibrium of SNP alleles in cystathionine-beta-synthase, dihydrofolate reductase, methylenetetrahydrofolate reductase, and thymidylate synthetase confers an increased susceptibility to SB.