Talk:Neural System - Abnormalities

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Cite this page: Hill, M.A. (2021, April 20) Embryology Neural System - Abnormalities. Retrieved from


J Neurosci Res. 2019 Dec;97(12):1624-1635. doi: 10.1002/jnr.24503. Epub 2019 Jul 28. Developmental origins of cortical hyperexcitability in Huntington's disease: Review and new observations. Cepeda C1, Oikonomou KD1, Cummings D1, Barry J1, Yazon VW1, Chen DT1, Asai J1, Williams CK2,3, Vinters HV2,3. Author information 1 IDDRC, Jane and Terry Semel Institute for Neuroscience and Human Behavior, University of California Los Angeles, Los Angeles, California. 2 Section of Neuropathology, Department of Pathology and Laboratory Medicine, University of California Los Angeles, Los Angeles, California. 3 Department of Neurology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California. Abstract Huntington's disease (HD), an inherited neurodegenerative disorder that principally affects striatum and cerebral cortex, is generally thought to have an adult onset. However, a small percentage of cases develop symptoms before 20 years of age. This juvenile variant suggests that brain development may be altered in HD. Indeed, recent evidence supports an important role of normal huntingtin during embryonic brain development and mutations in this protein cause cortical abnormalities. Functional studies also demonstrated that the cerebral cortex becomes hyperexcitable with disease progression. In this review, we examine clinical and experimental evidence that cortical development is altered in HD. We also provide preliminary evidence that cortical pyramidal neurons from R6/2 mice, a model of juvenile HD, are hyperexcitable and display dysmorphic processes as early as postnatal day 7. Further, some symptomatic mice present with anatomical abnormalities reminiscent of human focal cortical dysplasia, which could explain the occurrence of epileptic seizures in this genetic mouse model and in children with juvenile HD. Finally, we discuss recent treatments aimed at correcting abnormal brain development. © 2019 Wiley Periodicals, Inc. KEYWORDS: Huntington's disease; cortical development; cortical dysplasia; electrophysiology; epilepsy PMID: 31353533 PMCID: PMC6801077 [Available on 2020-06-01] DOI: 10.1002/jnr.24503


Maternal hormonal milieu influence on fetal brain development

Brain Behav. 2018 Jan 24;8(2):e00920. doi: 10.1002/brb3.920. eCollection 2018 Feb.

Miranda A1,2,3, Sousa N1,2,4. Author information Abstract An adverse maternal hormonal environment during pregnancy can be associated with abnormal brain growth. Subtle changes in fetal brain development have been observed even for maternal hormone levels within the currently accepted physiologic ranges. In this review, we provide an update of the research data on maternal hormonal impact on fetal neurodevelopment, giving particular emphasis to thyroid hormones and glucocorticoids. Thyroid hormones are required for normal brain development. Despite serum TSH appearing to be the most accurate indicator of thyroid function in pregnancy, maternal serum free T4 levels in the first trimester of pregnancy are the major determinant of postnatal psychomotor development. Even a transient period of maternal hypothyroxinemia at the beginning of neurogenesis can confer a higher risk of expressive language and nonverbal cognitive delays in offspring. Nevertheless, most recent clinical guidelines advocate for targeted high-risk case finding during first trimester of pregnancy despite universal thyroid function screening. Corticosteroids are determinant in suppressing cell proliferation and stimulating terminal differentiation, a fundamental switch for the maturation of fetal organs. Not surprisingly, intrauterine exposure to stress or high levels of glucocorticoids, endogenous or synthetic, has a molecular and structural impact on brain development and appears to impair cognition and increase anxiety and reactivity to stress. Limbic regions, such as hippocampus and amygdala, are particularly sensitive. Repeated doses of prenatal corticosteroids seem to have short-term benefits of less respiratory distress and fewer serious health problems in offspring. Nevertheless, neurodevelopmental growth in later childhood and adulthood needs further clarification. Future studies should address the relevance of monitoring the level of thyroid hormones and corticosteroids during pregnancy in the risk stratification for impaired postnatal neurodevelopment. KEYWORDS: fetal neurodevelopment; fetal programming; glucocorticoids; maternal hormones; melatonin; oxytocin; sex steroids; thyroid hormones PMID: 29484271 PMCID: PMC5822586 DOI: 10.1002/brb3.920


The Lateral Temporal Lobe in Early Human Life

J Neuropathol Exp Neurol. 2017 Jun 1;76(6):424-438. doi: 10.1093/jnen/nlx026.

Goldstein IS1, Erickson DJ1, Sleeper LA1, Haynes RL1, Kinney HC1.


Abnormalities of lateral temporal lobe development are associated with a spectrum of genetic and environmental pathologic processes, but more normative data are needed for a better understanding of gyrification in this brain region. Here, we begin to establish guidelines for the analysis of the lateral temporal lobe in humans in early life. We present quantitative methods for measuring gyrification at autopsy using photographs of the gross brain and simple computer-based quantitative tools in a cohort of 28 brains ranging in age from 27 to 70 postconceptional weeks (end of infancy). We provide normative ranges for different indices of gyrification and identify a constellation of qualitative features that should also be considered in these analyses. The ratio of the temporal area to the whole brain area increased dramatically in the second half of gestation, but then decelerated after birth before increasing linearly around 50 postconceptional weeks. Tertiary gyrification continued beyond birth in a linear process through infancy with considerable variation in patterns. Analysis of 2 brains with gyral disorders of the lateral temporal lobe demonstrated proof-of-principle that the proposed methods are of diagnostic value. These guidelines are proposed for assessments of temporal lobe pathology in pediatric brains in early life. © 2017 American Association of Neuropathologists, Inc. All rights reserved.

KEYWORDS: Down syndrome; Gyrification; Operculum; Sylvian fissure; Temporal lobe pathology PMID 28498956 DOI: 10.1093/jnen/nlx026

Quantitative Folding Pattern Analysis of Early Primary Sulci in Human Fetuses with Brain Abnormalities

AJNR Am J Neuroradiol. 2017 May 18. doi: 10.3174/ajnr.A5217. [Epub ahead of print]

Im K1, Guimaraes A2, Kim Y2, Cottrill E2, Gagoski B2, Rollins C2, Ortinau C2, Yang E2, Grant PE2.


BACKGROUND AND PURPOSE: Aberrant gyral folding is a key feature in the diagnosis of many cerebral malformations. However, in fetal life, it is particularly challenging to confidently diagnose aberrant folding because of the rapid spatiotemporal changes of gyral development. Currently, there is no resource to measure how an individual fetal brain compares with normal spatiotemporal variations. In this study, we assessed the potential for automatic analysis of early sulcal patterns to detect individual fetal brains with cerebral abnormalities. MATERIALS AND METHODS: Triplane MR images were aligned to create a motion-corrected volume for each individual fetal brain, and cortical plate surfaces were extracted. Sulcal basins were automatically identified on the cortical plate surface and compared with a combined set generated from 9 normal fetal brain templates. Sulcal pattern similarities to the templates were quantified by using multivariate geometric features and intersulcal relationships for 14 normal fetal brains and 5 fetal brains that were proved to be abnormal on postnatal MR imaging. Results were compared with the gyrification index. RESULTS: Significantly reduced sulcal pattern similarities to normal templates were found in all abnormal individual fetuses compared with normal fetuses (mean similarity [normal, abnormal], left: 0.818, 0.752; P < .001; right: 0.810, 0.753; P < .01). Altered location and depth patterns of sulcal basins were the primary distinguishing features. The gyrification index was not significantly different between the normal and abnormal groups. CONCLUSIONS: Automated analysis of interrelated patterning of early primary sulci could outperform the traditional gyrification index and has the potential to quantitatively detect individual fetuses with emerging abnormal sulcal patterns. © 2017 American Society of Neuroradiology.

PMID 28522661 DOI: 10.3174/ajnr.A5217


Cellular Profiles and Molecular Mediators of Lesion Cascades in the Placode in Human Open Spinal Neural Tube Defects

J Neuropathol Exp Neurol. 2016 Sep;75(9):827-42. doi: 10.1093/jnen/nlw057. Epub 2016 Jun 28.

Kowitzke B1, Cohrs G1, Leuschner I1, Koch A1, Synowitz M1, Mehdorn HM1, Held-Feindt J1, Knerlich-Lukoschus F2.


Myelomeningoceles (mmc) are clinically challenging CNS malformations. Although improvement in their management has been achieved with respect to antenatal diagnosis, prevention, and fetal surgery, the cellular mechanisms of damage in the neural placode are poorly understood. We aimed to identify cellular and molecular factors in lesion amplifying cascades in mmc placodes. Seventeen mmc specimens obtained during reconstructive surgery that harbored sufficient neuroepithelial tissue were investigated. Normal adult and stillborn spinal cord tissue served as controls. Placodes exhibited similar cellular profiles with consistent neuronal marker expression, elevated GFAP-/vimentin immunoreactivity in all, and CD3/CD11b/CD68-immunolabeling in some cases. Increased expression of pro-inflammatory (tumor necrosis factor, interleukin-1β [Il-1β]/IL-1 receptor type 1 [IL-R1]) and neuroprotective erythropoietin/erythropoietin receptor (Epo/EpoR) cytokines was detected by immunohistochemistry, double-fluorescence labeling, and real-time RT-PCR. In all cases, there was a multi-cellular induction of IL-1β and IL1-R1. EpoR and Epo immunoreactivity was elevated in some cases with neuronal expression patterns. Epo was further co-expressed with HIF-1/-2α, which paralleled Epo induction in the corresponding placodes. These observations confirm the induction of cellular and molecular alterations in human mmc placodes that resemble the secondary lesion cascades induced by spinal cord injury. The pro-inflammatory and neuroprotective cytokine expression in mmc placodes may represent new targets for the treatment of open neural tube defects. © 2016 American Association of Neuropathologists, Inc. All rights reserved.

KEYWORDS: Cytokines; Erythropoietin; Immunohistochemistry; Inflammation; Myelomeningocele; Real-time RT-PCR. PMID 27354486 DOI: 10.1093/jnen/nlw057


Identification of PCSK9 as a novel serum biomarker for the prenatal diagnosis of neural tube defects using iTRAQ quantitative proteomics

Sci Rep. 2015 Dec 22;5:17559. doi: 10.1038/srep17559.

An D1,2, Wei X1, Li H1, Gu H1, Huang T1, Zhao G1, Liu B1, Wang W3, Chen L1, Ma W1, Zhang H1, Cao S1, Yuan Z1.


To identify candidate serum molecule biomarkers for the non-invasive early prenatal diagnosis of neural tube defects (NTDs), we employed an iTRAQ-based quantitative proteomic approach to analyze the proteomic changes in serum samples from embryonic day (E) 11 and E13 pregnant rats with spina bifida aperta (SBA) induced by all-trans retinoic acid. Among the 390 proteins identified, 40 proteins at E11 and 26 proteins at E13 displayed significant differential expression in the SBA groups. We confirmed 5 candidate proteins by ELISA. We observed the space-time expression changes of proprotein convertase subtilisin/kexin type 9 (PCSK9) at different stages of fetal development, including a marked decrease in the sera of NTD pregnancies and gradual increase in the sera of normal pregnancies with embryonic development. PCSK9 demonstrated the diagnostic efficacy of potential NTD biomarkers [with an area under the receiver operating characteristic curve of 0.763, 95% CI: 065-0.88]. Additionally, PCSK9 expression in the spinal cords and placentas of SBA rat fetuses was markedly decreased. PCSK9 could serve as a novel molecular biomarker for the non-invasive prenatal screening of NTDs and may be involved in the pathogenesis of NTDs at critical periods of fetal development.

PMID 26691006


MicroRNAs function primarily in the pathogenesis of human anencephaly via the mitogen-activated protein kinase signalling pathway

Genet Mol Res. 2014 Feb 20;13(1):1015-29. doi: 10.4238/2014.February.20.3.

Zhang WD1, Yu X1, Fu X1, Huang S1, Jin SJ1, Ning Q2, Luo XP3. Author information


Anencephaly is one of the most serious forms of neural tube defects (NTDs), a group of congenital central nervous system (CNS) malformations. MicroRNAs (miRNAs) are involved in diverse biological processes via the post-transcriptional regulation of target mRNAs. Although miRNAs play important roles in the development of mammalian CNS, their function in human NTDs remains unknown. Using a miRNA microarray, we identified a unique expression profile in fetal anencephalic brain tissues, characterized by 70 upregulated miRNAs (ratio ≥2) and 7 downregulated miRNAs (ratio ≤0.5) compared with healthy human samples. Ten miRNAs with altered expression were selected from the microarray findings for validation with real-time quantitative reverse transcription-polymerase chain reaction. We found that in anencephalic tissues, miR-22, miR-23a, miR-34a, miR-103, miR-125a, miR-132, miR-134, miR-138, and miR-185 were significantly upregulated, while miR-149 was significantly downregulated. Furthermore, 459 potential target genes within the validated miRNAs were revealed using combined four target prediction algorithms in the human genome, and subsequently analyzed with the Molecule Annotation System 3.0. A total of 119 target genes were ultimately identified, including those involved in 22 singular annotations (i.e., transcription, signal transduction, and cell cycle) and 55 functional pathways [i.e., mitogen-activated protein kinase (MAPK) signaling pathway, and actin cytoskeleton regulation]. Six target genes (HNRPU, JAG1, FMR1, EGR3, RUNX1T1, and NDEL1) were chosen as candidate genes and associated with congenital birth abnormalities of the brain structure. Our results, therefore, suggest that miRNA maladjustment mainly contributes to the etiopathogenesis of anencephaly via the MAPK signaling pathway.

PMID 24634123


Selective Roles of Normal and Mutant Huntingtin in Neural Induction and Early Neurogenesis

PLoS One. 2013 May 14;8(5):e64368. Print 2013.

Nguyen GD, Gokhan S, Molero AE, Mehler MF. Source Roslyn and Leslie Goldstein Laboratory for Stem Cell Biology and Regenerative Medicine, Albert Einstein College of Medicine, Bronx, New York, United States of America ; Institute for Brain Disorders and Neural Regeneration, Albert Einstein College of Medicine, Bronx, New York, United States of America ; Department of Neuroscience, Albert Einstein College of Medicine, Bronx, New York, United States of America ; Rose F. Kennedy Center for Research on Intellectual and Developmental Disabilities, Albert Einstein College of Medicine, Bronx, New York, United States of America. Abstract Huntington's disease (HD) is a neurodegenerative disorder caused by abnormal polyglutamine expansion in the amino-terminal end of the huntingtin protein (Htt) and characterized by progressive striatal and cortical pathology. Previous reports have shown that Htt is essential for embryogenesis, and a recent study by our group revealed that the pathogenic form of Htt (mHtt) causes impairments in multiple stages of striatal development. In this study, we have examined whether HD-associated striatal developmental deficits are reflective of earlier maturational alterations occurring at the time of neurulation by assessing differential roles of Htt and mHtt during neural induction and early neurogenesis using an in vitro mouse embryonic stem cell (ESC) clonal assay system. We demonstrated that the loss of Htt in ESCs (KO ESCs) severely disrupts the specification of primitive and definitive neural stem cells (pNSCs, dNSCs, respectively) during the process of neural induction. In addition, clonally derived KO pNSCs and dNSCs displayed impaired proliferative potential, enhanced cell death and altered multi-lineage potential. Conversely, as observed in HD knock-in ESCs (Q111 ESCs), mHtt enhanced the number and size of pNSC clones, which exhibited enhanced proliferative potential and precocious neuronal differentiation. The transition from Q111 pNSCs to fibroblast growth factor 2 (FGF2)-responsive dNSCs was marked by potentiation in the number of dNSCs and altered proliferative potential. The multi-lineage potential of Q111 dNSCs was also enhanced with precocious neurogenesis and oligodendrocyte progenitor elaboration. The generation of Q111 epidermal growth factor (EGF)-responsive dNSCs was also compromised, whereas their multi-lineage potential was unaltered. These abnormalities in neural induction were associated with differential alterations in the expression profiles of Notch, Hes1 and Hes5. These cumulative observations indicate that Htt is required for multiple stages of neural induction, whereas mHtt enhances this process and promotes precocious neurogenesis and oligodendrocyte progenitor cell elaboration.

PMID 23691206

Planar cell polarity genes control the connectivity of enteric neurons

J Clin Invest. 2013 Mar 8. pii: 66759. doi: 10.1172/JCI66759. [Epub ahead of print]

Sasselli V, Boesmans W, Berghe PV, Tissir F, Goffinet AM, Pachnis V. Abstract

A highly complex network of intrinsic enteric neurons is required for the digestive and homeostatic functions of the gut. Nevertheless, the genetic and molecular mechanisms that regulate their assembly into functional neuronal circuits are currently unknown. Here we report that the planar cell polarity (PCP) genes Celsr3 and Fzd3 are required during murine embryogenesis to specifically control the guidance and growth of enteric neuronal projections relative to the longitudinal and radial gut axes. Ablation of these genes disrupts the normal organization of nascent neuronal projections, leading to subtle changes of axonal tract configuration in the mature enteric nervous system (ENS), but profound abnormalities in gastrointestinal motility. Our data argue that PCP-dependent modules of connectivity established at early stages of enteric neurogenesis control gastrointestinal function in adult animals and provide the first evidence that developmental deficits in ENS wiring may contribute to the pathogenesis of idiopathic bowel disorders.

PMID 23478408


Mutations in genes encoding the glycine cleavage system predispose to neural tube defects in mice and humans

Hum Mol Genet. 2012 Apr 1;21(7):1496-503. Epub 2011 Dec 13.

Narisawa A, Komatsuzaki S, Kikuchi A, Niihori T, Aoki Y, Fujiwara K, Tanemura M, Hata A, Suzuki Y, Relton CL, Grinham J, Leung KY, Partridge D, Robinson A, Stone V, Gustavsson P, Stanier P, Copp AJ, Greene ND, Tominaga T, Matsubara Y, Kure S.


Neural tube defects (NTDs), including spina bifida and anencephaly, are common birth defects of the central nervous system. The complex multigenic causation of human NTDs, together with the large number of possible candidate genes, has hampered efforts to delineate their molecular basis. Function of folate one-carbon metabolism (FOCM) has been implicated as a key determinant of susceptibility to NTDs. The glycine cleavage system (GCS) is a multi-enzyme component of mitochondrial folate metabolism, and GCS-encoding genes therefore represent candidates for involvement in NTDs. To investigate this possibility, we sequenced the coding regions of the GCS genes: AMT, GCSH and GLDC in NTD patients and controls. Two unique non-synonymous changes were identified in the AMT gene that were absent from controls. We also identified a splice acceptor site mutation and five different non-synonymous variants in GLDC, which were found to significantly impair enzymatic activity and represent putative causative mutations. In order to functionally test the requirement for GCS activity in neural tube closure, we generated mice that lack GCS activity, through mutation of AMT. Homozygous Amt(-/-) mice developed NTDs at high frequency. Although these NTDs were not preventable by supplemental folic acid, there was a partial rescue by methionine. Overall, our findings suggest that loss-of-function mutations in GCS genes predispose to NTDs in mice and humans. These data highlight the importance of adequate function of mitochondrial folate metabolism in neural tube closure.

PMID 22171071


Early effects of lipopolysaccharide-induced inflammation on foetal brain development in rat

ASN Neuro. 2011 Nov 17;3(4). pii: e00068. doi: 10.1042/AN20110027.

Ghiani CA, Mattan NS, Nobuta H, Malvar JS, Boles J, Ross MG, Waschek JA, Carpenter EM, Fisher RS, de Vellis J. Source Intellectual and Developmental Disability Research Center, Jane and Terry Semel Institute for Neuroscience and Human Behavior, Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine at the University of California at Los Angeles, 90095, USA.


Studies in humans and animal models link maternal infection and imbalanced levels of inflammatory mediators in the foetal brain to the aetiology of neuropsychiatric disorders. In a number of animal models, it was shown that exposure to viral or bacterial agents during a period that corresponds to the second trimester in human gestation triggers brain and behavioural abnormalities in the offspring. However, little is known about the early cellular and molecular events elicited by inflammation in the foetal brain shortly after maternal infection has occurred. In this study, maternal infection was mimicked by two consecutive intraperitoneal injections of 200 μg of LPS (lipopolysaccharide)/kg to timed-pregnant rats at GD15 (gestational day 15) and GD16. Increased thickness of the CP (cortical plate) and hippocampus together with abnormal distribution of immature neuronal markers and decreased expression of markers for neural progenitors were observed in the LPS-exposed foetal forebrains at GD18. Such effects were accompanied by decreased levels of reelin and the radial glial marker GLAST (glial glutamate transporter), and elevated levels of pro-inflammatory cytokines in maternal serum and foetal forebrains. Foetal inflammation elicited by maternal injections of LPS has discrete detrimental effects on brain development. The early biochemical and morphological changes described in this work begin to explain the sequelae of early events that underlie the neurobehavioural deficits reported in humans and animals exposed to prenatal insults.

PMID 22007738 PMCID: PMC3218569

Spinal dysraphism

J Pediatr Neurosci. 2011 Oct;6(Suppl 1):S31-40. doi: 10.4103/1817-1745.85707.

Venkataramana NK. Source Department of Neurosurgery, Advanced Neuroscience Institute, BGS Global Hospital, Bangalore, India.


To review the clinical features and current understanding of spina bifida with an emphasis on the Indian Scenario. Selected articles and current English language texts were reviewed. The authors experience was also reviewed and analysed. Spina bifida is a common congenital anomaly encompassing a wide spectrum of neural tube defects.It is broadly classified as spina bifida aperta and occulta. With the prenatal screening, the incidence of aperta is gradually declining, whereas the detection of occulta has increased with the advent of magnetic resonance imaging. Over the years, the understanding of pathophysiology has made a significant changein the management of these anomalies. Early detection and complete correction can significantly reduce the neurological disability. This article is an overview of spina bifida with a special emphasis on Indian scenario.

PMID 22069428

Congenital hydrocephalus associated with myeloschisis

Childs Nerv Syst. 2011 Oct;27(10):1585-8. Epub 2011 Sep 17.

Jeelani Y, McComb JG. Source Division of Neurosurgery, Children's Hospital Los Angeles, Department of Neurological Surgery, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA. Abstract BACKGROUND: Neural tube defects (NTDs) can be divided into two main groups, one being open NTDs wherein visible neural tissue and cerebrospinal fluid leakage are present and the other, closed NTDs without exposed neural tissue and no drainage of CSF. METHODS: This communication is devoted to open NTDs that can be further subdivided into myelomeningoceles, myeloschisis, and hemimyelomeningoceles. RESULTS: Common to all these is the loss of CSF during fetal development that leads to an extensive malformation of the central nervous system with hydrocephalus being a frequent feature. CONCLUSION: The only known difference between a newborn with myelomeningocele versus a newborn with myeloschisis is the initial presence (myelomeningocele) or absence (myeloschisis) of a cystic component with the overall clinical picture the same for these two forms of open neural tube defects. PMID 21928024

Myelomeningocele (open spina bifida) - surgical management

Adv Tech Stand Neurosurg. 2011;37:113-41. Akalan N. Source Department of Neurosurgery, Hacettepe University School of Medicine, Ankara, Turkey.


Myelomeningocele has been recognized since ancient times although written descriptions began not before the 17th century. Among all serious congenital malformations, myelomeningocele is unique that is has a steady and considerable prevalence while being compatible with life. It has a dismal prognosis when left untreated where virtually all die within the first year while aggressive treatment have a profound effect on survival and quality of life. Effective surgical treatment became possible parallel to the treatment of hydrocephalus in the late 1950s. Advent of the shunt systems undoubtedly changed the morbidity and mortality rates due to associated hydrocephalus. Aggressive and effective treatment improved survival rates but also those suffering physical and mental disabilities have increased as well. Ethical and socioeconomic concerns have led to proposal for selective treatment criteria which have raised arguments on medical and ethico-legal rounds. After the swing of the pendulum between early treatment in all affected children and selective treatment of those who fulfilled the criteria for good prognosis, early myelomeningocele repair is practiced widely unless the infant is critically ill.Incidence of myelomeningocele has been decreasing especially in the Western world, partly due to prenatal diagnosis and elective terminations, dietary folate supplementation. Still, it is the most common central nervous system malformation and one of the leading causes of paraplegia, worldwide. Unfortunately, gains in the management of myelomeningocele have been mainly on antenatal diagnosis and prevention while efforts on understanding its cause, mechanisms involved are still tentative. Concerning the surgical management, no revolutionary modification improving outcome has been introduced unlike other fields of neurosurgery.Medical management of a child with myelomeningocele requires a lifelong effort of several disciplines including urology, orthopedics physical and social therapy besides neurosurgery. The initial and probably the most crucial step begin with proper repair of the lesion. The aim of surgery, with its simplest definition should be towards maintaining the medical condition of the newborn. In other words, consequences of an open spinal cord segment with associated malformations have to be avoided with appropriate measures. Comparable to the surgical treatment of any congenital malformation, myelomeningocele repair consist of reversing the failed steps of normal neural tube closure. This requires a thorough understanding of the normal and abnormal embryological sequence of events in formation of the spinal cord. Although the purpose of this chapter is to describe the basic concepts and technique of myelomeningocele repair, contemporary information and progress on epidemiology, and etiology and embryology is presented with discussion of controversial issues regarding the selection process, optimal time for surgery and technical modifications.

PMID 21997743

A randomized trial of prenatal versus postnatal repair of myelomeningocele

N Engl J Med. 2011 Mar 17;364(11):993-1004. Epub 2011 Feb 9.

Adzick NS, Thom EA, Spong CY, Brock JW 3rd, Burrows PK, Johnson MP, Howell LJ, Farrell JA, Dabrowiak ME, Sutton LN, Gupta N, Tulipan NB, D'Alton ME, Farmer DL; MOMS Investigators. Collaborators (91)

Source Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.


BACKGROUND: Prenatal repair of myelomeningocele, the most common form of spina bifida, may result in better neurologic function than repair deferred until after delivery. We compared outcomes of in utero repair with standard postnatal repair.

METHODS: We randomly assigned eligible women to undergo either prenatal surgery before 26 weeks of gestation or standard postnatal repair. One primary outcome was a composite of fetal or neonatal death or the need for placement of a cerebrospinal fluid shunt by the age of 12 months. Another primary outcome at 30 months was a composite of mental development and motor function.

RESULTS: The trial was stopped for efficacy of prenatal surgery after the recruitment of 183 of a planned 200 patients. This report is based on results in 158 patients whose children were evaluated at 12 months. The first primary outcome occurred in 68% of the infants in the prenatal-surgery group and in 98% of those in the postnatal-surgery group (relative risk, 0.70; 97.7% confidence interval [CI], 0.58 to 0.84; P<0.001). Actual rates of shunt placement were 40% in the prenatal-surgery group and 82% in the postnatal-surgery group (relative risk, 0.48; 97.7% CI, 0.36 to 0.64; P<0.001). Prenatal surgery also resulted in improvement in the composite score for mental development and motor function at 30 months (P=0.007) and in improvement in several secondary outcomes, including hindbrain herniation by 12 months and ambulation by 30 months. However, prenatal surgery was associated with an increased risk of preterm delivery and uterine dehiscence at delivery.

CONCLUSIONS: Prenatal surgery for myelomeningocele reduced the need for shunting and improved motor outcomes at 30 months but was associated with maternal and fetal risks. (Funded by the National Institutes of Health; number, NCT00060606.).

Comment in N Engl J Med. 2011 Jun 30;364(26):2555; author reply 2556. N Engl J Med. 2011 Jun 30;364(26):2554-5; author reply 2556. N Engl J Med. 2011 Jun 30;364(26):2555; author reply 2556. N Engl J Med. 2011 Mar 17;364(11):1076-7.

PMID 21306277


Regulators of the proteasome pathway, Uch37 and Rpn13, play distinct roles in mouse development

PLoS One. 2010 Oct 27;5(10):e13654.

Al-Shami A, Jhaver KG, Vogel P, Wilkins C, Humphries J, Davis JJ, Xu N, Potter DG, Gerhardt B, Mullinax R, Shirley CR, Anderson SJ, Oravecz T.

Lexicon Pharmaceuticals, Inc, The Woodlands, Texas, United States of America.

Abstract Rpn13 is a novel mammalian proteasomal receptor that has recently been identified as an amplification target in ovarian cancer. It can interact with ubiquitin and activate the deubiquitinating enzyme Uch37 at the 26S proteasome. Since neither Rpn13 nor Uch37 is an integral proteasomal subunit, we explored whether either protein is essential for mammalian development and survival. Deletion of Uch37 resulted in prenatal lethality in mice associated with severe defect in embryonic brain development. In contrast, the majority of Rpn13-deficient mice survived to adulthood, although they were smaller at birth and fewer in number than wild-type littermates. Absence of Rpn13 produced tissue-specific effects on proteasomal function: increased proteasome activity in adrenal gland and lymphoid organs, and decreased activity in testes and brain. Adult Rpn13(-/-) mice reached normal body weight but had increased body fat content and were infertile due to defective gametogenesis. Additionally, Rpn13(-/-) mice showed increased T-cell numbers, resembling growth hormone-mediated effects. Indeed, serum growth hormone and follicular stimulating hormone levels were significantly increased in Rpn13(-/-) mice, while growth hormone receptor expression was reduced in the testes. In conclusion, this is the first report characterizing the physiological roles of Uch37 and Rpn13 in murine development and implicating a non-ATPase proteasomal protein, Rpn13, in the process of gametogenesis.

PMID: 21048919


3-D reconstruction of a human fetus with combined holoprosencephaly and cyclopia

Head Face Med. 2009 Jun 29;5:14.

Arnold WH, Meiselbach V. Source Department of Anatomy, Faculty of Dental Medicine, University of Witten/Herdecke, Alfred Herrhausenstrasse 50, 58448 Witten, Germany.

Abstract BACKGROUND: The purpose of this study was to examine a human fetus with combined holoprosencephaly and cyclopia by means of histology and 3-D reconstruction to determine the internal structure and extent of the malformation. METHODS: The head from a human fetus at 20 weeks gestation and a diagnosis of holoprosencephaly and cyclopia was investigated histologically and three-dimensionally reconstructed with CAD techniques. The cranial bones, blood vessels, nerves, eye and brain anlagen were reconstructed. RESULTS: The 3-D reconstruction revealed both severe malformation and absence of the facial midline bones above the maxilla, and a malformation of the maxilla and sphenoid bone. The mandible, posterior cranial bones, cranial nerves and blood vessels were normal. A synophthalmic eye with two lenses was found. The prosencephalon was a single small protrusion above the diencephalon. No nasal cavity was present. Above the single eye a proboscis was found. CONCLUSION: The absence of the facial midline bones above the maxilla and the presence of a proboscis as a nose-like structure above the cyclopic eye both mean that there was a developmental defect in the fronto-nasal facial process of this fetes.

PMID 19563629


Scanning electron microscopy of fetal murine myelomeningocele reveals growth and development of the spinal cord in early gestation and neural tissue destruction around birth

J Pediatr Surg. 2007 Sep;42(9):1561-5.

Stiefel D, Meuli M.

Neural Development Unit, Institute of Child Health, University College London, London, WC1N 1EH United Kingdom. Abstract BACKGROUND: Previous studies demonstrated that the spinal cord within a fetal myelomeningocele (MMC) lesion suffers progressive destruction during gestation. This study aims at elucidating this pathophysiologic feature on a cellular and ultrastructural level in a model of genetically determined MMC.

METHODS: Curly tail/loop tail mouse fetuses at various gestational stages and neonates were analyzed electron-microscopically to document time-point and nature of neural tissue development and pathologic alterations within the MMC.

RESULTS: At embryonic day (E) 8.5 and E9.5, round cells displaying multiple microvilli covered the entire region of interest, and some specimens showed initial stages of neurulation. At E10.5, neurulation was terminated in normal animals, whereas the neural placode remained unfolded in MMC fetuses and became distinguishable from adjacent epidermal layers. At E15.5, an apparently normal differentiation was found. Until this time-point, there was no tissue damage or inflammation. Thereafter, increasingly severe tissue alterations were identified with ongoing gestation leading to almost complete loss of neural tissue at birth.

CONCLUSION: We show here in fetal mice with MMC that, apart from absent neurulation, growth and development of the otherwise perfectly intact exposed spinal cord appear normal in early gestation, whereas later, the unprotected neural tissue is progressively destroyed.

PMID: 17848249

Neonatal Brain US by Erik Beek and Floris Groenendaal

ultrasound scans of head region

Preconceptional Folate Supplementation and the Risk of Spontaneous Preterm Birth: A Cohort Study

"Preconceptional folate supplementation is associated with a 50%–70% reduction in the incidence of early spontaneous preterm birth. The risk of early spontaneous preterm birth is inversely proportional to the duration of preconceptional folate supplementation. Preconceptional folate supplementation was specifically related to early spontaneous preterm birth and not associated with other complications of pregnancy."


An unusual case of duplication of the spinal canal

Rev Med Brux. 2007 Mar-Apr;28(2):119-22.

(Article in French)

Ranguelov N, Sourtzis S, Delpierre I, Christophe C, Louryan S.

Service de Pédiatrie, C.H.U. de Charleroi. Abstract We describe here a very rare congenital malformation, in which the vertebra Th 9 to 11 were divided into independent bodies and neural arches. The vertebral canal contained the spinal cord, whereas the space between bodies and arches was filled by nerve roots and a central remnant cord, not clearly connected to the main spinal cord. This malformation was considered as related to a fetal alcohol syndrome, with craniofacial and genitourinary abnormalities. The authors analyze, moreover the possible role of abnormal Sonic Hedgehog gene patterning in the pathogeny of this complex malformative sequence.

PMID: 17561726

Maternal serum alpha-fetoprotein levels in fetal hydrocephalus: a retrospective population based study