Central Nervous System Malformations Research Articles

Identification of Novel Mutations in Amniotic Fluid Derived Stem Cells Collected from the Mothers Having Case of Neural Tube Defects

Neural tube defects (NTDs) are severe congenital malformations of central nervous system that have high prevalence with severe consequences. The etiology of NTDs involves interactions of both genetic and epigenetic factors and their complex interactions with stems cells during organogenesis. Despite of recent advances, there has been limited progress in delineating the molecular basis of NTDs that can pave way for prevention, diagnostics and therapeutics. We have previously identified a role for stem cell markers Oct 4, Sox 2 and Nanog 3 in neural tube defect affected pregnancies. In the present report we identified mutations in stem cell pluripotency markers from amniotic fluid derived stem cells isolated from women with NTD affected pregnancy. Oct 4 and Nanog 3 were studied to find a correlation with the disease and its severity. Interestingly, sequence based DNA analysis revealed two different forms of nucleotide changes that were observed in different clinical conditions of NTDs. The mutation in Oct 4 at position 183 G →T and in the sequence of Nanog 3 at ⁶³CAAAAA ACA⁷² to ³⁸ACAGTCTCT⁴⁷ appears in the cases of anencephaly and meningomyelocele respectively in comparison to control. These findings suggest that these mutational spectra might be responsible for the alterations in the developmental process during embryogenesis leading to NTDs.

Novel VPS33B mutations of G514S gene cause an arthrogryposis, renal dysfunction and cholestasis syndrome

Introduction: Arthrogryposis-renal dysfunctioncholestasis (Arc) syndrome is a rare multisystem disorder first described in 1979 and recently attributed to mutation in VPs33b, whose product acts in intracellular trafficking. It shows wide clinical variability. the characteristic features of Arc core phenotype include arthrogryposis, spillage of various substances in the urine, and conjugated hyperbilirubinemia. In some patients, these features are sometimes accompanied by different manifestations, such as ichthyosis, central nervous system malformation, deafness, and platelet abnormalities. Many patients with different associations of cholestasis, renal tubular acidosis, and dysmorphic morphology may be underdiagnosed. case report: We assessed the clinical characteristics of patients and investigated the VPs33b mutation in the gene G514s in a turkish patient with Arc syndrome. We reported one turkish patient with Arc syndrome, along with the presentations of renal tubular dysfunction, cholestasis, arthrogryposis, VPs33b Mutations in the gene G514s. conclusion: this case shows that the variability of different manifestations of Arc syndrome is well described.

Macrocephaly with cutis marmorata telangiectatica congenita: Appending a case in literaure

Macrocephaly with cutis marmorata telangiectatica congenita (M-CMTC) is a cutaneous disorder often accompanied by additional anomalies, most commonly segmental overgrowth. Recently, a clinically discrete condition has been described comprising CMTC and congenital macrocephaly together with pre- and post-natal macrosomia, segmental overgrowth, central nervous system malformations, connective tissue abnormalities, and intellectual handicap. We describe the natural history of M-CMTC syndrome of an 11-month-old female child first born of nonconsanguinous marraige brought to us with complaints of delayed development, asymmetric swelling over the body, and progressively increasing head size. On examination, we found macrocephaly, frontal bossing, segmental hypertrophy of right side of face, left side of upper limb and right side of lower limb, multiple hemangiomas over philtrum and nape of neck, cutis marmorata over bilateral upper limbs, hypotonia, laryngomalacia, bilateral syndactyly, hyperextensibility of joints, and magnetic resonance imaging showing arrested hydrocephalus; all these features fitting into a rare disorder known as M-CMTC. M-CMTC is a multisystem disorder and a team of specialist pediatrics, dermatology, neurology and radiology is needed to diagnose and treat such patients.

The subclinical epileptiform discharges among nonepileptic cerebral palsy patients

Background Subclinical epileptiform discharges (SEDs) are assumed to play a role in the development of cognitive dysfunction in cerebral palsy (CP) patients. Purpose The aim of this study was to estimate the prevalence of SEDs among nonepileptic CP patients and their cognitive correlates. Patients and methods Fifty-one nonepileptic CP patients were recruited. All patients were subjected to history taking, neurological examination, assessment using Gross Motor Function Classification System for CP, the Stanford–Binet scale (5th edition), encephalography, and MRI of the brain. They were divided into two groups: group 1, which included 19 CP patients without SEDs, and group 2, which included 32 CP patients with SEDs. A comparison between patients’ features studied in groups 1 and 2 was made using independent-samples t-test and the χ2-test. A correlation between SEDs and the studied features was made using Spearman’s rank correlation coefficient (ρ). Results The prevalence of SEDs among nonepileptic CP patients was 62.7%. The presence of MRI abnormality and moderate mental retardation showed a highly significant positive correlation with SEDs. Meanwhile, central nervous system malformation and severe mental retardation showed a significant positive correlation with SEDs. However, normal intelligence showed a highly significant negative correlation with SEDs. Kernicterus and dyskinetic CP showed a significant negative correlation with SEDs. Conclusion SEDs are a common finding among nonepileptic CP children. They are positively correlated to cognitive dysfunction. This finding supports the assumption that SEDs are therapeutic target in mentally subnormal children. Larger studies are needed to confirm our results and to evaluate the clinical benefit of treating SEDs.

Diagnosis of Meckel Gruber Syndrome Ultrasound Scan

Meckel syndrome is a rare lethal ciliopathic genetic disorder, characterized by renal cystic dysplasia, central nervous system malformations, polydactyly, hepatic developmental defects, and pulmonary hypoplasia due to oligohydramnios. 34 years old, neither diabetic nor hypertensive, she is gravida III, para I, came for first ultrasound scan with amenorrhea for four months. The ultrasound scan shows single viable fetus, gestational age was 19 weeks + 5 days, with enlarged highly echogenic kidneys.

A Wide Spectrum of Axial Mesodermal Dysplasia Complex With Rhombencephalic Anomaly: A Case Report.

Axial mesodermal dysplasia complex (AMDC) arises in variable combinations of craniocaudal anomalies such as musculoskeletal deformities, neuroschisis, or rhombencephalic developmental disorders. To the best of our knowledge, the co-existence of AMDC with associated musculoskeletal anomalies, medullary neuroschisis with mirror movements, and cranial nerve anomalies has not yet been reported. Here, we report the case of a 4-year-old boy whose clinical features were suggestive of Goldenhar syndrome and Poland syndrome with Sprengel deformity. Moreover, he showed mirror movements in his hands suspected of rhombencephalic malformation, and infranuclear-type facial nerve palsy of the left side of his face, the opposite side to the facial anomalies of Goldenhar syndrome. After conducting radiological studies, he was diagnosed with medullary neuroschisis without pontine malformations and Klippel-Feil syndrome with rib anomalies. Based on these findings, we propose that clinical AMDC can be accompanied by a wide variety of musculoskeletal defects and variable degrees of central nervous system malformations. Therefore, in addition to detailed physical and neurological examinations, imaging studies should be considered in AMDC.

Zika Virus: The New Rubella Epidemic

The explosive epidemic of Zika virus with resultant central nervous system malformations in children born to infected mothers has now reached epidemic proportions. This disease is reminiscent of our struggle with rubella prior to the development of safe and effective vaccines in the 1960s. Both are benign infections in children and adults, but capable of affecting fetal brain development in pregnant women.

Outcome of Fetuses With Abnormal Cavum Septi Pellucidi: Experience of a Tertiary Center

Background: Cavum septi pellucidi (CSP) is easily evaluated in the second and third trimester of the pregnancy. The structure is an important feature of the standard planes used for routine morphological assessment of fetal head and central nervous system (CNS): trans-thalamic and trans-ventricular plane. The standard description of the CSP is an anechoic rectangular box between two hyperechoic lines represented by the septum pellucidum. The pathological aspects are mainly represented by the absence of its normal appearance, which is associated with severe CNS malformations of the brain midline as corpus callosum agenesis, hydranencephaly, porencephaly, schizencephaly, holoprosencephaly, syntelencephaly or severe chronic hydrocephaly. Other issues such as increased or reduced dimensions of the CSP are not considered significant if found isolated, although the fetal genetic investigation is suggested by some authors. The objective of the study was to evaluate the outcome of fetuses with abnormal CSP detected by sonography in the last 5 years, in the Prenatal Diagnosis Unit (PDU) of our tertiary center. Methods: We performed a retrospective review of the cases with abnormal CSP evaluated in our tertiary unit, diagnosed between January 2012 and November 2016. The fetal anatomy was evaluated in all cases following the recommendations of the international guidelines. In abnormal CSP cases, fetal neurosonogram and an extended fetal anomaly scan were performed and amniocentesis was proposed to identify genetic disorders. Results: A total of 7,520 cases were examined for morphological purposes and abnormal CSP was found in 36 cases. Absent CSP was the initial observation that triggered further investigation and diagnosis in the cases with agenesis of corpus callosum (ACC) (seven cases) and septo-optic dysplasia (two cases). In hydranencephaly or severe hydrocephaly, porencephaly, schizencephaly and holoprosencephaly, the heavily malformed aspect of the brain is obvious, and the absence of CSP is only an observation, with less diagnostic importance and clinical implications. Partial or total ACC was mainly associated to absent CSP, as the development of two structures is merged. Almost half of the total abnormal CSP cases (16/36) were associated with genetic disorders, most of them with abnormal karyotype and all of them were associated with the absence of CSP. The persistent enlargement of CSP (4/36 cases) and the hyperechoic aspect of CSP (1/36) were not associated with other structural or genetic abnormalities and the postnatal neuromotor development was normal. Conclusions: The CSP evaluation is mandatory and normal aspects suggest a normal development of the midbrain. Genetic testing should be offered especially for the cases with absent CSP because of the high incidence of chromosomal disorders. As the absence of CSP is associated with severe structural or genetic disorders, its visualization in the second half of pregnancy is mandatory for any anomaly scan. The enlargement and echogenicity variations of CSP associate a favorable neonatal outcome. However, long-term follow-up is recommended in the apparently normal neonates and infants, as they may develop abnormal psychological behavior lately. J Clin Gynecol Obstet. 2016;5(4):112-116 doi: https://doi.org/10.14740/jcgo423w

The Ciliopathy Protein CC2D2A Associates with NINL and Functions in RAB8-MICAL3-Regulated Vesicle Trafficking.

Ciliopathies are a group of human disorders caused by dysfunction of primary cilia, ubiquitous microtubule-based organelles involved in transduction of extra-cellular signals to the cell. This function requires the concentration of receptors and channels in the ciliary membrane, which is achieved by complex trafficking mechanisms, in part controlled by the small GTPase RAB8, and by sorting at the transition zone located at the entrance of the ciliary compartment. Mutations in the transition zone gene CC2D2A cause the related Joubert and Meckel syndromes, two typical ciliopathies characterized by central nervous system malformations, and result in loss of ciliary localization of multiple proteins in various models. The precise mechanisms by which CC2D2A and other transition zone proteins control protein entrance into the cilium and how they are linked to vesicular trafficking of incoming cargo remain largely unknown. In this work, we identify the centrosomal protein NINL as a physical interaction partner of CC2D2A. NINL partially co-localizes with CC2D2A at the base of cilia and ninl knockdown in zebrafish leads to photoreceptor outer segment loss, mislocalization of opsins and vesicle accumulation, similar to cc2d2a-/- phenotypes. Moreover, partial ninl knockdown in cc2d2a-/- embryos enhances the retinal phenotype of the mutants, indicating a genetic interaction in vivo, for which an illustration is found in patients from a Joubert Syndrome cohort. Similar to zebrafish cc2d2a mutants, ninl morphants display altered Rab8a localization. Further exploration of the NINL-associated interactome identifies MICAL3, a protein known to interact with Rab8 and to play an important role in vesicle docking and fusion. Together, these data support a model where CC2D2A associates with NINL to provide a docking point for cilia-directed cargo vesicles, suggesting a mechanism by which transition zone proteins can control the protein content of the ciliary compartment.

Congenital Brain and Spinal Cord Malformations and Their Associated Cutaneous Markers

The brain, spinal cord, and skin are all derived from the embryonic ectoderm; this common derivation leads to a high association between central nervous system dysraphic malformations and abnormalities of the overlying skin. A myelomeningocele is an obvious open malformation, the identification of which is not usually difficult. However, the relationship between congenital spinal cord malformations and other cutaneous malformations, such as dimples, vascular anomalies (including infantile hemangiomata and other vascular malformations), congenital pigmented nevi or other hamartomata, or midline hairy patches may be less obvious but no less important. Pediatricians should be aware of these associations, recognize the cutaneous markers associated with congenital central nervous system malformations, and refer children with such markers to the appropriate specialist in a timely fashion for further evaluation and treatment.

Multifetal gestations with assisted reproductive technique before the single-embryo transfer legislation: obstetric, neonatal outcomes and congenital anomalies

Objective: To compare perinatal, neonatal outcome and congenital anomalies of multiple gestations conceived by means of assisted reproductive techniques with spontaneously conceived multiples before the limitation of number of embryo transfer. Methods: Cases consisted of assisted reproductive technique (ART) multifetal gestations and control group comprised of spontaneously conceived multifetal gestations delivered in the same time period. Outcomes were perinatal, neonatal outcome, long-term outcomes and congenital anomalies of multiple gestations. There were 270 multifetal pregnancies for analysis, of which 137 were achieved by ART and 133 were spontaneous in this prospective study. Results: Incidences of preeclampsia, gestational diabetes, deep vein thrombosis, thrombocytopenia, intrahepatic cholestasis and preterm premature rupture of membranes were similar in ART and spontaneous groups. There was no difference in fetal malformation rates between ART and control group, but higher rates of central nervous system malformation were observed (4 (1.5%) in control, 0 in ART group, p = 0.04) in spontaneous group. No difference was seen in the perinatal mortality. Conclusions: Neonatal and maternal outcomes are comparable between ART and spontaneous multifetal gestations. Congenital fetal malformation rates between ART and spontaneous multifetal pregnancies were similar except central nervous system malformation that was more likely in spontaneously conceived ones.

Displasia cefaloesquelética (síndrome de Taybi-Linder): presentación de un caso y consideraciones anestésicas

IntroductionMicrocephalic osteodysplasic primordial dwarfism (Taybi -Linder syndrome) is a rare disease characterized by bone and central nervous system malformations and intrauterine growth retardation. Case presentationWe report the case of a 20 years patient who underwent intestinal surgery for adhesiolysis and intestinal pexia because of intestinal obstruction by postoperative flanges. ConclusionAs anesthetic considerations of these patients highlight the possible impairment of airway secondary to facial malformations and neurological complications, primarily seizures.

Cephaloskeletal dysplasia (Taybi-Linder syndrome): Case report and anesthetic considerations

IntroductionMicrocephalic osteodysplastic primordial dwarfism (or Taybi-Linder syndrome) is a rare disease characterized by bone and central nervous system malformations, in addition to intrauterine retardation. Case presentation20-year-old patient operated on for adhesiolysis and enteropexy due to bowel obstruction from post surgical adhesions. ConclusionThe anesthetic considerations in these patients include the potential airway impairment secondary to facial malformations and neurological complications, primarily seizures.

A case of relapse of Enterococcus faecalis meningitis in a previously healthy infant without any predisposing factors

Enterococcus faecalis meningitis in children generally occurs when some predisposing factors are present, particularly central nervous system malformations and previous neurological surgery. In this article, we present a case of a relapse of E. faecalis meningitis in a 4-month-old previously healthy, well-grown infant who did not have any predisposing factors. He was discharged in good condition following a full 3 week course of an antibiotic that the organism was sensitive to, vancomycin. No cause was identified for the relapse and it was assumed to be due to persistence of the infection in the meningeal and/or parameningeal foci. Subsequent clearance of the infection following three more weeks of therapy suggests there is a need to increase the initial treatment duration of the sensitive antibiotic.

Aicardi syndrome with type 2b interhemispheric cyst

Agenesis of corpus callosum is a rare malformation of the brain. In Aicardi syndrome, it is associated with retinal lacunae and infantile spasms. Once Aicardi syndrome is diagnosed, one should look for other central nervous system malformations. We report a child who presented with developmental delay, chorioretinal lacunae and infantile spasms, due to Aicardi syndrome, associated with a type 2b interhemispheric cyst diagnosed on magnetic resonance imaging.

Urodynamic Findings and Renal Function in Children with Neurogenic Bladder after Myelomeningocele

Introduction: Myelomeningocele (MMC) is a congenital central nervous system malformation caused by a failure of the neurulation process in early pregnancy. Patients with MMC present many abnormalities and the nervous, skeletal and urinary systems are the most affected. The aim of this study was to clinically evaluate patients with MMC, estimate renal and lower urinary tract (LUT) function and to ascertain whether urodynamic findings can predict the deterioration of urinary tract function. Materials and Methods: Medical records of 112 patients were gathered from a database and evaluated retrospectively. The data included age, sex, BMI Z-score WHO, physical activity, urodynamic parameters and diagnosis and renal function. Results: A total of 112 patients with MMC were enrolled in the study. There were no differences in age, sex, BMI Z-score WHO, physical activity, renal function and urodynamic findings (apart from cystometric capacity) between boys and girls. Detrusor overactivity was the most frequent urodynamic diagnosis in all groups of physical activity, level of lesion and in catheterized and non-catheterized children. The correlations between urodynamic findings and renal function tests were found. Conclusions: Patients with neurogenic bladder after MMC most often present detrusor overactivity. LUT function is disturbed in all MMC patients independent of lesion level and physical activity.

P116 – 2582: Palliative care and paediatric neurology

Objective The high frequency of neurological processes of uncertain or incurable prognosis demands an active and global attention of the patient and his family aiming to improve the attention and the quality of life of these patients. The palliative care have to be integrated into the neurology practice. We analyzed the characteristics of pediatric neurological patients admitted to the Pediatric Home Health Care Unit of a major hospital with neurological diseases including epidemiological, diagnostic, developmental and survival data. Methods A retrospective, descriptive study of patients admitted to Home Health Care with neurological diseases for palliative care for 5 years. Results During past 5 years 52 patients were admitted with neurological disorders (10.5% of total). The mean age on admittance was 34.5 months (range 0 to 152 months). The male/female ratio was 24/28. The most frequent disorders were: 10 severe cerebral palsy with difficult to control symptoms, 8 brain tumors, 5 metabolic disorders, 6 central nervous system malformations, 4 hypoxic ischemic encephalopathies, 4 patients with sequels of extremely premature birth, 3 spinal muscular atrophies and 2 chromosomal abnormalities. Provenance was mostly hospital wards (54%), and oncology (15%) and neurology (12%) consultations. In addition to general palliative care, 41 patients required enteral nutrition, 26 requiered oxygen and 7 NIV in their homes. During follow-up, there was at least one hospital admission in 18 patients. The mean stay in the unit was 8.6 months. Of the patients admitted, 13 died, five of them at home. Conclusion Diverse neurological diseases are characterized by a lack of response to the treatment, a progressive evolution of the disease, and in certain cases, a fatal prognosis in a relatively short term. We propose, in these patients, comprehensive care at home to prevent unnecessary hospital admissions, and when the time comes help them at the end of their days

Deletion 1q43‐44 in a patient with clinical diagnosis of Warburg–Micro syndrome

Warburg-Micro syndrome (WARBM) is an autosomal recessive syndrome characterized by microcephaly, microphthalmia, microcornea, congenital cataracts, optic atrophy and central nervous system malformations. This syndrome is caused by mutations in the RAB3GAP1/2 and RAB18 genes, part of the Rab family, and in the TBC1D20 gene, which contributes to lipid droplet formation/metabolism. Here we present a patient with clinical diagnosis of WARBM syndrome, who did not have mutations in either the RAB3GAP1/2 genes, in the main exons of RAB18, nor in the TBC1D20 gene. However, the analysis with CGH-array detected a 9.6 Mb deletion at 1q43-qter. We performed a genotype-phenotype correlation using 20 previously published patients in whom the coordinates of the deleted regions were defined. The comparative analysis revealed that the current patient and three of the other 20 patients share the loss of six genes, four of which are related with the family of G proteins, and are strongly expressed in the brain, retina, heart and kidney. Consequently, their haploinsufficiency may result in different combinations of clinical alterations, including some of those of WARBM syndrome. In addition, the haploinsufficiency of other genes may contribute to other defects and clinical variability. Additionally, for the genotype-phenotype correlation, one must also consider molecular pathways that can result in the observed alterations. To early confirm a genetic diagnosis is essential for the patient and family. The current patient was considered as having a recessive syndrome, but since he had a "de novo" deletion, there was not an increased recurrence risk.

Evaluation of the association of zoonotic Ljungan virus with perinatal deaths and fetal malformation.

More and more epidemiologic and experimental data support the notion that Ljungan virus (LV), originally isolated from some rodent populations in Sweden, Denmark, and the United States, plays an important role in stillbirth and fetal malformation. Mouse dams infected with LV may result in uterine resorption and perinatal deaths that may cross generations, and their offspring may suffer high rates of malformations including cranial, brain, and limb malformations. In humans, researches founded that LV infection is related to malformation, intrauterine fetal death, and even central nervous system malformation. Although molecularly characterized, little is known about the biophysical nature of LV. Consequently, the role of LV infections in sudden infant death syndrome is still confusing, and the mechanism of how LV infections cause diseases is not clear. More research is clearly necessary to explore the mechanisms of LV infection in human and animal diseases to bring improvement to the clinical outcomes.

Birth Prevalence of Overt Congenital Anomalies in Kano Metropolis: Overt Congenital Anomalies in the Kano

Congenital anomalies are abnormalities of prenatal origin, and their prevalence varies worldwide. The objective of this study was to determine the prevalence and spectrum of overt congenital anomalies in live born neonates in selected hospitals in the Kano metropolis of North western Nigeria, as well as the associated maternal, paternal and neonatal risk factors. A descriptive study design was employed. All live born neonates in three major hospitals in Kano metropolis were prospectively studied from April 2013 to December 2013. Detailed family history and clinical data were recorded in a structured questionnaire for each child. A total of 1456 live born neonates were recruited into the study, of which 41 (28.15 per 1000 live births) had overt congenital malformations with 5 (12.20%) having multiple system involvement and 36 (87.80%) having a single system affectation. The most common system involved in neonates with isolated single system malformations were the central nervous system (10 cases) and the genitourinary system (10 cases). The consanguinity rate in the study was 17.83%. Birth weight of the neonates had a significant but negative association with the likelihood of being born with a congenital malformation (OR = 0.374; (95% CI 0.196 - 0.711) P = 0.003). Given the high frequency of potentially preventable central nervous system malformations in this study, emphasis on the primary prevention of congenital malformations by encouraging periconceptional use of folic acid containing multivitamin supplements is recommended.