CNS Defects Research Articles

Role of 3D / 4D Ultrasound in Assessment of Fetal CNS Congenital Anomalies

Background: Using contemporary ultrasound equipment, it is possible to diagnose CNS defects in prenatal life. Many CNS defects can be detected by ultrasound in the first and early second trimesters. 4D ultrasonography has a high sensitivity for detecting prenatal CNS abnormalities and is used to detect and diagnose some foetal CNS disorders.

Promising Role of Oral Cavity Mesenchymal Stem Cell-Derived Extracellular Vesicles in Neurodegenerative Diseases.

Mesenchymal stem cells (MSCs) and mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) have been regarded as the beneficial and available tools to treat various hereditary, multifactorial, acute, and chronic diseases. Mesenchymal stem cells can be extracted from numerous sources for clinical purposes while oral cavity-derived mesenchymal stem cells seem to be more effective in neuroregeneration than other sources due to their similar embryonic origins to neuronal tissues. In various studies and different neurodegenerative diseases (NDs), oral cavity mesenchymal stem cells have been applied to prove their promising capacities in disease improvement. Moreover, oral cavity mesenchymal stem cells' secretion is regarded as a novel and practical approach to neuroregeneration; hence, extracellular vesicles (EVs), especially exosomes, may provide promising results to improve CNS defects. This review article focuses on how oral cavity-derived stem cells and their extracellular vesicles can improve neurodegenerative conditions and tries to show which molecules are involved in the recovery process.

Аpproaches to the medical and social rehabilitation for children with organic lesions of the nervous system: history and current trends

Preschool children with organic lesions of the nervous system need a comprehensive approach to medical and social rehabilitation. These pathologies (organic lesions of the organs of hearing, vision, vestibular and speech apparatus) are quite common among children nowadays. The process of speech formation and social behavior of such patients is complex in structural and functional organization. The purpose of the article is to investigate the history and current state of social and medical rehabilitation for sensory and other CNS defects. The novelty of the reserch. The problem of forming life competence in children with special needs from an early age remains undeveloped. Research methods are based on historical and comparative-analytical principles. Conclusions. Thus, considering various aspects of rehabilitation care for early preschool children with CNS defects and speech disorders, it was possible to determine the paramount importance of speech development in rehabilitation work with early preschool children, because successes in learning Ukrainian in this sensitive period, or their absence will significantly affect all aspects of further medical and social rehabilitation.

Deconstructing Sox2 Function in Brain Development and Disease.

SOX2 is a transcription factor conserved throughout vertebrate evolution, whose expression marks the central nervous system from the earliest developmental stages. In humans, SOX2 mutation leads to a spectrum of CNS defects, including vision and hippocampus impairments, intellectual disability, and motor control problems. Here, we review how conditional Sox2 knockout (cKO) in mouse with different Cre recombinases leads to very diverse phenotypes in different regions of the developing and postnatal brain. Surprisingly, despite the widespread expression of Sox2 in neural stem/progenitor cells of the developing neural tube, some regions (hippocampus, ventral forebrain) appear much more vulnerable than others to Sox2 deletion. Furthermore, the stage of Sox2 deletion is also a critical determinant of the resulting defects, pointing to a stage-specificity of SOX2 function. Finally, cKOs illuminate the importance of SOX2 function in different cell types according to the different affected brain regions (neural precursors, GABAergic interneurons, glutamatergic projection neurons, Bergmann glia). We also review human genetics data regarding the brain defects identified in patients carrying mutations within human SOX2 and examine the parallels with mouse mutants. Functional genomics approaches have started to identify SOX2 molecular targets, and their relevance for SOX2 function in brain development and disease will be discussed.

Prevalence and Pattern of Birth Defects in a Tertiary Care Hospital in Bangladesh

Background: Birth Defect is one of the most important causes of neonatal mortality and morbidity worldwide. The pattern and prevalence of Birth Defects may vary overtime or with geographic location. The objective of the study to determine the prevalence and pattern of Birth Defects in live newborn admitted in Hospital.
 Materials & Methods: This cross-sectional descriptive study was carried in Neonatology and OBS-gynae department of Sir Salimullah Medical college Hospital during the period of July 2016 to December 2019. A total 306 babies with Birth Defects were examined and detailed history for any risk factor was taken. A through physical examination was performed. Confirmation of internal defect was done by various imaging modalities; i.e, radiography, ultrasound, echocardiography and CT scan. A detailed history was taken regarding maternal age, gestational age and previous delivery of abnormal baby.
 Results: During this period total 27799 was born alive, of which 306 had Birth Defects, the prevalence of Birth Defects was 1.1%. The predominant system involved was Musculoskeletal system (30%) followed by CNS (19%), oro-facial clefts (13%), GIT, CVS, Ear-nosethroat( 7%) and least involved system was urinary system(4%). Talipes was most common one in musculo-skeletal system defect and Anencephaly in CNS defect.
 Conclusion: Prevalence of Birth Defects is common among newborn admitted in hospital and musculoskeletal system is most commonly affected system. Birth Defects is upcoming issue in current newborn situation which need to be prioritized.
 Sir Salimullah Med Coll J 2022; 30: 23-28

Prenatal alcohol exposure disrupts Sonic hedgehog pathway and primary cilia genes in the mouse neural tube

Neurulation-stage alcohol exposure (NAE; embryonic day [E] 8–10) is associated with midline craniofacial and CNS defects that likely arise from disruption of morphogen pathways, such as Sonic hedgehog (Shh). Notably, midline anomalies are also a hallmark of genetic ciliopathies such as Joubert syndrome. We tested whether NAE alters Shh pathway signaling and the number and function of primary cilia, organelles critical for Shh pathway transduction. Female C57BL/6 J mice were administered two doses of alcohol (2.9 g/kg/dose) or vehicle on E9. Embryos were collected 6, 12, or 24 h later, and changes to Shh, cell cycle genes, and primary cilia were measured in the rostroventral neural tube (RVNT). Within the first 24 h post-NAE, reductions in Shh pathway and cell cycle gene expression and the ratio of Gli3 forms in the full-length activator state were observed. RVNT volume and cell layer width were reduced at 12 h. In addition, altered expression of multiple cilia-related genes was observed at 6 h post-NAE. As a further test of cilia gene-ethanol interaction, mice heterozygous for Kif3a exhibited perturbed behavior during adolescence following NAE compared to vehicle-treated mice, and Kif3a heterozygosity exacerbated the hyperactive effects of NAE on exploratory activity. These data demonstrate that NAE downregulates the Shh pathway in a region of the neural tube that gives rise to alcohol-sensitive brain structures and identifies disruption of primary cilia function, or a “transient ciliopathy”, as a possible cellular mechanism of prenatal alcohol pathogenesis.

Visualization of PS/γ-Secretase Activity in Living Cells.

SummaryA change in Presenilin (PS)/γ-secretase activity is linked to essential biological events as well as to the progression of many diseases. However, not much is known about how PS/γ-secretase activity is spatiotemporally regulated in cells. One of the limitations is lack of tools to directly monitor dynamic behavior of the PS/γ-secretase in intact/live cells. Here we present successful development and validation of the Förster resonance energy transfer (FRET)-based biosensors that enable quantitative monitoring of endogenous PS/γ-secretase activity in live cells longitudinally on a cell-by-cell basis. Using these FRET biosensors, we uncovered that PS/γ-secretase activity is heterogeneously regulated among live neurons.

Gene Therapy for Angelman Syndrome: Contemporary Approaches and Future Endeavors.

Angelman Syndrome (AS) is a congenital non inherited neurodevelopmental disorder. The contemporary AS management is symptomatic and it has been accepted that gene therapy may play a key role in the treatment of AS. The purpose of this study is to summarize existing and suggested gene therapy approaches to Angelman syndrome. This is a literature review. Pubmed and Scopus databases were researched with keywords (gene therapy, Angelman's syndrome, neurological disorders, neonates). Peer-reviewed studies that were closely related to gene therapies in Angelman syndrome and available in English, Greek, Ukrainian or Indonesian were included. Studies that were published before 2000 were excluded and did not align with the aforementioned criteria. UBE3A serves multiple roles in signaling and degradation procedures. Although the restoration of UBE3A expression rather than targeting known activities of the molecule would be the optimal therapeutic goal, it is not possible so far. Reinstatement of paternal UBE3A appears as an adequate alternative. This can be achieved by administering topoisomerase-I inhibitors or reducing UBE3A antisense transcript (UBE3A-ATS), a molecule which silences paternal UBE3A. Understanding UBE3A imprinting unravels the path to an etiologic treatment of AS. Gene therapy models tested on mice appeared less effective than anticipated pointing out that activation of paternal UBE3A cannot counteract the existing CNS defects. On the other hand, targeting abnormal downstream cell signaling pathways has provided promising rescue effects. Perhaps, combined reinstatement of paternal UBE3A expression with abnormal signaling pathways-oriented treatment is expected to provide better therapeutic effects. However, AS gene therapy remains debatable in pharmacoeconomics and ethics context.

TSC patient-derived isogenic neural progenitor cells reveal altered early neurodevelopmental phenotypes and rapamycin-induced MNK-eIF4E signaling

BackgroundTuberous sclerosis complex (TSC) is a neurodevelopmental disorder with frequent occurrence of epilepsy, autism spectrum disorder (ASD), intellectual disability (ID), and tumors in multiple organs. The aberrant activation of mTORC1 in TSC has led to treatment with mTORC1 inhibitor rapamycin as a lifelong therapy for tumors, but TSC-associated neurocognitive manifestations remain unaffected by rapamycin.MethodsHere, we generated patient-specific, induced pluripotent stem cells (iPSCs) from a TSC patient with a heterozygous, germline, nonsense mutation in exon 15 of TSC1 and established an isogenic set of heterozygous (Het), null and corrected wildtype (Corr-WT) iPSCs using CRISPR/Cas9-mediated gene editing. We differentiated these iPSCs into neural progenitor cells (NPCs) and examined neurodevelopmental phenotypes, signaling and changes in gene expression by RNA-seq.ResultsDifferentiated NPCs revealed enlarged cell size in TSC1-Het and Null NPCs, consistent with mTORC1 activation. TSC1-Het and Null NPCs also revealed enhanced proliferation and altered neurite outgrowth in a genotype-dependent manner, which was not reversed by rapamycin. Transcriptome analyses of TSC1-NPCs revealed differentially expressed genes that display a genotype-dependent linear response, i.e., genes upregulated/downregulated in Het were further increased/decreased in Null. In particular, genes linked to ASD, epilepsy, and ID were significantly upregulated or downregulated warranting further investigation. In TSC1-Het and Null NPCs, we also observed basal activation of ERK1/2, which was further activated upon rapamycin treatment. Rapamycin also increased MNK1/2-eIF4E signaling in TSC1-deficient NPCs.ConclusionMEK-ERK and MNK-eIF4E pathways regulate protein translation, and our results suggest that aberrant translation distinct in TSC1/2-deficient NPCs could play a role in neurodevelopmental defects. Our data showing upregulation of these signaling pathways by rapamycin support a strategy to combine a MEK or a MNK inhibitor with rapamycin that may be superior for TSC-associated CNS defects. Importantly, our generation of isogenic sets of NPCs from TSC patients provides a valuable platform for translatome and large-scale drug screening studies. Overall, our studies further support the notion that early developmental events such as NPC proliferation and initial process formation, such as neurite number and length that occur prior to neuronal differentiation, represent primary events in neurogenesis critical to disease pathogenesis of neurodevelopmental disorders such as ASD.

Individual and combined presenilin 1 and 2 knockouts reveal that both have highly overlapping functions in HEK293T cells

Presenilins 1 and 2 (PS1 and 2) are the catalytic subunits of γ-secretase, a multiprotein protease that cleaves amyloid protein precursor and other type I transmembrane proteins. Previous studies with mouse models or cells have indicated differences in PS1 and PS2 functions. We have recently reported that clinical γ-secretase inhibitors (GSIs), initially developed to manage Alzheimer's disease and now being considered for other therapeutic interventions, are both pharmacologically and functionally distinct. Here, using CRISPR/Cas9-based gene editing, we established human HEK 293T cell lines in which endogenous PS1, PS2, or both have been knocked out. Using these knockout lines to examine differences in PS1- and PS2-mediated cleavage events, we confirmed that PS2 generates more intracellular β-amyloid than does PS1. Moreover, we observed subtle differences in PS1- and PS2-mediated cleavages of select substrates. In exploring the question of whether differences in activity among clinical GSIs could be attributed to differential inhibition of PS1 or PS2, we noted that select GSIs inhibit PS1 and PS2 activities on specific substrates with slightly different potencies. We also found that endoproteolysis of select PS1 FAD-linked variants in human cells is more efficient than what has been previously reported for mouse cell lines. Overall, these results obtained with HEK293T cells suggest that selective PS1 or PS2 inhibition by a given GSI does not explain the previously observed differences in functional and pharmacological properties among various GSIs.

A Cellular Atlas of the Developing Meninges Reveals Meningeal Fibroblast Diversity and Function

The meninges, a multilayered structure that encases the CNS, is composed mostly of fibroblasts, along with vascular and immune cells. Meningeal fibroblasts are a vital source of signals that control neuronal migration and neurogenesis yet strikingly little is known about their development. We used single cell RNA sequencing to generate a cellular atlas of embryonic meningeal fibroblasts in control and Foxc1-KO mice in which severe CNS defects arise from failed meningeal fibroblast development. We report unique transcriptional signatures for dura, arachnoid and pial fibroblasts and identify S100a6 as the first unique marker of the pial layer. We describe a new meningeal fibroblast subtype marked by µ-Crystallin expression and show these cell types and markers are conserved in human fetal meninges. Our analysis demonstrates layer specific production of extracellular matrix components, transporter expression, and synthesis of secreted factors. Lastly, the cellular atlas of Foxc1-KO meninges provides insight into their severe phenotype, confirming a massive loss in arachnoid and dura fibroblasts and Foxc1-KO pial fibroblasts are so altered that they cluster as a different cell type based on gene expression. These studies provide an unprecedented view of meningeal fibroblast development, highlighting unexpected fibroblast diversity and function, while providing mechanistic insights into the meninges role in CNS development.

EP05.01: Customised Indian biometry of the length and height of fetal corpus callosum by 2D ultrasound

The aim of this study was to develop customised reference ranges for basic quantitative characteristics of the corpus callosum (CC) between 19 to 32 weeks of gestation for the Indian population from a prospective cross-sectional study. Patient selection was done according to the inclusion and exclusion criteria. Total sample size was 166. Each fetus was examined only once. High resolution two-dimensional images of the mid-sagittal plane of fetal brain were obtained by transvaginal ultrasound. The length of CC was measured from the most anterior aspect of the genu to the most posterior aspect of the splenium, tracing a straight rostrocaudal line. Height (thickness) was measured at the mid-body part of CC. Regression equations for mean and SD values were generated from the dataset. Using mean and SD values for each gestational age, fitted centiles were created for the length as well as the height of CC. The growth rate of the corpus callosal length is almost constant between 19 and 32 weeks, with the mean length doubling from 18mm at 19 weeks to 35.7mm at 28 weeks. The increase in length is almost constant at 2mm per week. The height of the body of CC increased from 1.9mm at 19 weeks to 2.3mm at 32 weeks. The maximum growth was seen between 19-23 weeks, following which it stayed relatively constant at 2.3mm ± 0.1mm in size. As a result of technological advances, the high resolution CNS imaging possible by transvaginal ultrasonography provides an excellent method for direct examination of the CC. With this study, we have generated the reference ranges for the measurement of CC in the Indian population. This data can be used for the assessment of normal brain development, as well as for suspected fetal CNS defects. Furthermore, accurate measurement of the height (thickness) can help in the diagnosis of more subtle anomalies associated with “callosal thinning”. As per our knowledge, ours is the first study to publish population specific reference ranges for the measurement of corpus callosum in the Indian population. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

EP05.09: Customised Indian biometry of the height of fetal cerebellar vermis by 2D ultrasound

The aim of this study was to develop customised reference ranges for the height of the fetal cerebellar vermis between 19 to 32 weeks of gestation for the Indian population from a prospective cross-sectional study. Patient selection was done according to the inclusion and exclusion criteria. Total sample size was 166. Each fetus was examined only once. High resolution two-dimensional images of the mid-sagittal plane of fetal brain were obtained by transvaginal ultrasound. The size of the cerebellar vermis was measured directly from a magnified view using 0.1 mm resolution. The vermis height was defined as the maximum distance between the most cranial portion of the culmen and the most caudal portion of the uvula. Regression equations for mean and SD values were generated from the dataset. Using mean and SD values for each gestational age, fitted centiles were created for height of the vermis. Cerebellar vermis height increases in a linear fashion between 19 and 32 weeks, with the mean length doubling from 9.6mm at 19 weeks to 19mm at 30 weeks. Imaging of the vermis is part of the protocol of the targeted anomaly scan at 20 weeks of gestation. According to convention, if we consider dimensions below 5th centile to be indicative of vermian hypoplasia, our data suggests a cut-off of 8mm at 20 weeks for the vermis to be labelled as hypoplastic. As a result of technological advances, the high resolution CNS imaging possible by transvaginal ultrasonography provides an excellent method for direct examination of the fetal vermis. With this study, we have generated the reference ranges for the measurement of the height of the fetal cerebellar vermis. This data can be used for the assessment of normal brain development, as well as for suspected fetal CNS defects. As per our knowledge, ours is the first study to publish population specific reference ranges for the measurement of the height of fetal cerebellar vermis in the Indian population. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

Constitutive Cyclin O deficiency results in penetrant hydrocephalus, impaired growth and infertility.

Cyclin O (encoded by CCNO) is a member of the cyclin family with regulatory functions in ciliogenesis and apoptosis. Homozygous CCNO mutations have been identified in human patients with Reduced Generation of Multiple Motile Cilia (RGMC) and conditional inactivation of Ccno in the mouse recapitulates some of the pathologies associated with the human disease. These include defects in the development of motile cilia and hydrocephalus. To further investigate the functions of Ccno in vivo, we have generated a new mouse model characterized by the constitutive loss of Ccno in all tissues and followed a cohort during ageing. Ccno-/- mice were growth impaired and developed hydrocephalus with high penetrance. In addition, some Ccno+/- mice also developed hydrocephalus and affected Ccno-/- and Ccno+/- mice exhibited additional CNS defects including cortical thinning and hippocampal abnormalities. In addition to the CNS defects, both male and female Ccno-/- mice were infertile and female mice exhibited few motile cilia in the oviduct. Our results further establish CCNO as an important gene for normal development and suggest that heterozygous CCNO mutations could underlie hydrocephalus or diminished fertility in some human patients.

Serum Prolactin Level in Children with Febrile Seizure and Epileptic Seizure; Comparative Study

Introduction: Transient hyperprolactinaemia has been reported to follow unprovoked seizures, a finding proposed to be useful in the differential diagnosis of epilepsy. On this basis we conducted a study with an objective to compare the postictal serum prolactin level in children with febrile seizures (FS) and epileptic seizures (ES) to evaluate, whether serum prolactin (PL) could be used a predictor in the diagnosis of ES.Material and Methods: This was a prospective comparative study was conducted on 52 children (26 in febrile seizures group and 26 in epileptic seizure group) in the age group of six months to five years. Children with CNS infection, developmental delay, structural CNS defects or neurological abnormality, metabolic disorders and those on drugs, known to have altered serum prolactin level were excluded. Blood for estimation of serum prolactin was collected within 180 minutes of occurrence of seizure. Level of serum prolactin was quantitatively assayed by chemiluminescence method and the levels were considered high, if values were greater than 23 ng/ml, which is the upper limit of normal for all age groups and both sex.Results: The mean serum prolactin level in epileptic seizures group was 25 ng/ml and that of febrile seizures group was 10.72 ng/ml. High level of serum prolactin was noted in 17 children (77.2%) with GTCS and 3 children (75%) with CPS. None of the children with febrile seizures had significant raise in the level of serum prolactin.Conclusion: There is a significant rise in serum prolactin level in children with epileptic seizures compared to febrile seizures, if measured within 3 hours of occurrence of seizures. Thus, the post-ictal serum prolactin level can be used as an additional investigation to diagnose or predict epileptic seizures in children.

Goldenhar syndrome: a rare entity

Goldenhar syndrome was first described by Maurice Goldenhar in 1952 it involves abnormalities in the first and second branchial arches. This syndrome appears to have varying degree of presentation from mild to severe form. Different pathophysiological mechanisms have been proposed .Oculo auriculo vertebral syndrome which includes reduction in blood flow resulting in focal haemorrhage in the first and second branchial arches. In addition there may be cardiac vertebral and CNS defects. A male baby 30-32 wks, preterm SGA was admitted in NICU for evaluation of Congenital Malformations which includes swelling of the anterior border of both eyes with b/l preauricular ear tags, malformed pinna, high arched palate and micrognatia ophthalmology examination revealed b/l limbal dermoid inferotemporal aspect. ECHO done revealed ASD 4mm.CT scan showed obstructive hydrocephalus. Treatment of the condition varies according to the severity. Ophthalmic treatment aimed first because of amblyogenic risk. Craniofacial surgery in view of severe micrognathia systemic treatment may be related to cardiac, renal and CNS malformations. Goldenhar Syndrome is a rare congenital anomaly, with cosmetic defects whose treatment may pose numerous challenges with multidisciplinary approach for optimal management.

Development of New Strategies for Enzyme Replacement Therapy for Lysosomal Storage Disorders

Enzyme replacement therapy (ERT) is a well-established means of treating lysosomal storage disease (LSD). However, classical IV infusion based ERT method produces less than ideal results, especially, CNS defects and quality of life in patients. To improve these main problems of parental IV formulation for LSDs, we investigate modified ERT method and evaluated the efficacy in animal model.

Epidemiology of Congenital Anomalies among the Children born in Different Hospitals under Sylhet Division in Bangladesh- a Retrospective Study

Congenital anomalies play a significant role in perinatal and neonatal mortality. Frequency of these congenital anomalies varies in different populations. Epidemiology is the study of frequency, distribution and determinants of disease in populations. The mission of epidemiology is to contribute to the understanding of etiology and prevention of disease and to improve the health of public through excellence in research. So, this study was conducted to find out proportion, types and immediate outcome of congenital anomalies. In this retrospective and cross-sectional study all patients admitted with congenital anomalies in different hospitals of Sylhet division in Bangladesh from October 2012 to January 2013 (04 months) were included. At first, the patients were examined for major and minor congenital anomalies and recorded properly. Diagnosis of congenital anomalies was based on ultrasonography and clinical evaluation of the fetus/newborn by experienced neonatologist. Major and minor congenital anomalies were categorized depending on their life threatening effects. Various data which were obtained was analyzed by using SPSS 13. Rates and proportions were calculated with 95% confidence interval. The proportions were compared using students T-test. Level of significance was set at P<0.05.The most frequently occurring anomalies involved the central nervous system (28.33%) of which myelomeningocele was the commonest CNS defect (9.09%). According to data, females were more susceptible to myelomeningocele than the male patients. The second frequently occurring congenital anomaly was associated with cardiovascular system (15%). Patients with urogenital anomalies (6.67%) were male, except for one who had ambiguous genitalia. Congenital anomaly associated with gastrointestinal -, respiratory -, musculoskeletal -, chromosomal - and dysmorphism– were noted as 11.67%, 5%, 6.67%, 5% and 3.33%, respectively. About 11% congenital anomalies were found to be linked to other body part system. After analysis of mothers’ lifestyle, it was likely to conclude that more stress and efforts should be given on the role of peri-conceptional vitamin supplementation to the pregnant mother. Folic acid was found to be the primary agent for prevention of congenital defects.Dhaka Univ. J. Pharm. Sci. 14(2): 225-230, 2015 (December)

Decreased nasal nitric oxide in children with isolated midline neuroanatomical defects: a possible indicator of ciliary dysfunction?

Background: Ciliary mutations cause multi-system disorders, often involving the CNS. We set to evaluate the prevalence of ciliary dysfunction in children with isolated neuroanatomical defects, by measuring nasal nitric oxide (nNO), a screening test for Primary Ciliary Dyskinesia (PCD). Study design: We measured nNO levels of 26 children with congenital midline CNS defects. We evaluated the effect of age, gender, and anomaly (brain, spinal cord, or combined) on measurements. We compared our results to the previously established normal range (153.6-509.9 nL/min), and to the cutoff for PCD (77 nL/min). Results: The range for nNO in our cohort was 56.5-334.7 nL/min, with age, gender, and anomaly not having a significant effect. The overall mean, 217.7 nL/min, was significantly lower than that of normal children, 314.51 nL/min (p<0.01). Four subjects (15.4%) had nNO levels below the lower end of normal, with two (7.7%) having values fitting the cutoff for PCD. Conclusions: We report an association between ciliary dysfunction and isolated midline neuroanatomical defects, not in context of any known syndrome. This suggests that genes causing isolated CNS defects, may be implied in the function of cilia. Longitudinal studies are required to investigate whether children with abnormal measurements suffer from any respiratory sequelae.

PP05.2 – 2269: Decreased levels of nasal nitric oxide in children with midline neuroanatomical anomalies: A possible connection between ciliary dysfunction and isolated nervous system defects?

Objectives Given the involvement of cilia in neurodevelopment, we set to determine whether children with midline neuroanatomical defects have increased prevalence of ciliary dysfunction, using nasal nitric oxide measurement, a screening test for Primary Ciliary Dyskinesia. Methods We measured the nasal nitric oxide levels of 26 children ages 6–17, with congenital midline central nervous system defects, who are otherwise healthy. We evaluated the effect of variables including: age, gender, and anomaly (brain, spinal cord, or combined) on our measurements. We compared our results to the previously established normal range (153.6–509.9 nL/min), and to the cutoff for children with Primary Ciliary Dyskinesia (77 nL/min). Results The overall range for nasal nitric oxide in our cohort was 56.5 to 334.7 nL/min, with age, gender, and anomaly not having a significant effect. The overall mean, 217.7 nL/min, was significantly lower than the preestablished mean in normal children, 314.51 nL/min (p Conclusions This is the first study reporting a possible association between ciliary dysfunction and isolated congenital midline neuroanatomical defects, not in the context of any known syndrome. We suggest that genes known to cause isolated CNS defects, may also be implied in the function of cilia. Longitudinal studies are required to investigate whether, in children with abnormal measurements, nasal nitric oxide levels normalize over time, and whether these children suffer from any respiratory sequelae.