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1.
Niger Postgrad Med J ; 26(4): 239-243, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31621665

RESUMO

Background: Congenital anomalies (CAs) refer to defects that are present in a newborn but occurred during intrauterine life. They can be due to genetic, modifiable environmental or multifactorial causes. There was no prior report of their burden in our state. Aims: This study aims to describe the incidence, spectrum, predisposing factors and outcome of CAs in our setting. Methods: It was a total population study of all neonates with major birth defects admitted into the unit during the study period. Their clinical-demographic features, diagnoses and outcome were entered into an excel sheet. Clinical detection of birth defects was based on standard diagnostic criteria. The data were analysed using IBM SPSS Statistics for Windows, Version 20.0. Armonk, NY: IBM Corp. Patterns and outcome of birth defects were presented as proportions. Selected characteristics were tested for possible association with birth defect using Fisher's exact test. The level of significance was set at P < 0.05. Results: The incidence of major CAs was 4.3/1000 live births. Female neonates were more affected (59.0%). Participants' mean gestational age was 37.7 ± 3.3 weeks. Central nervous system anomalies were the most common (38.5%) birth defects. These were followed by musculoskeletal, body wall and digestive system anomalies: 28.2%, 23.1% and 10.3%, respectively. One-third (33.3%) of the infants had multiple anomalies. Nearly three quarters of them (74.0%) were referred, 18.0% died while 5.0% were discharged alive. Conclusion: A wide range of CAs occur in our setting with dire consequences. Provision of relevant specialised multidisciplinary care is desirable. Furthermore, pubic enlightenment on its modifiable possible causes can reduce the burden.


Assuntos
Sistema Nervoso Central/anormalidades , Anormalidades Congênitas/epidemiologia , Unidades de Terapia Intensiva Neonatal/estatística & dados numéricos , Grupo com Ancestrais do Continente Africano , Criança , Anormalidades Congênitas/classificação , Estudos Transversais , Anormalidades do Sistema Digestório/epidemiologia , Feminino , Idade Gestacional , Humanos , Incidência , Lactente , Recém-Nascido , Anormalidades Musculoesqueléticas/epidemiologia , Nigéria/epidemiologia
2.
Taiwan J Obstet Gynecol ; 58(1): 15-28, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30638470

RESUMO

The aim of the current review is to report a-CGH abnormalities identified in fetuses with prenatally diagnosed fetal malformations in whom a normal karyotype was diagnosed with conventional cytogenetic analysis. A systematic electronic search of databases (PubMed/Medline, EMBASE/SCOPUS) has been conducted from inception to May, 2017. Bibliographic analysis has been performed according to PRISMA statement for review. The following keywords were used: 'array-CGH' and 'fetal malformations" and "prenatal diagnosis"; alternatively, "microarray", "oligonucleotide array", "molecular biology", "antenatal diagnostics", "fetal diagnostics", "congenital malformations" and "ultrasound" were used to capture both "a-CGH" and "prenatal". One-hundred and twelve fetuses with prenatally diagnosed fetal malformations with normal karyotyping and a-CGH abnormalities detected are described. Single or multiple microarray abnormalities diagnosed have been classified in relation to different organ/system affected. The most frequent a-CGH abnormalities were detected in cases of congenital heart diseases (CDHs), multiple malformations and central nervous system (CNS) malformations. Maternal or paternal carrier-state was seen in 19.64% (22/112), of cases while the number of reported de novo mutations accounted for 46.42% (52/112) of all CNVs microarray abnormalities. Array-comparative genomic hydridization (a-CGH) may become an integral and complemantary genetic testing when fetal malformations are detected prenatally in fetuses with normal cytogenetic karyotype. In addition, a-CGH enables the identification of CNVs and VOUS and improves the calculation of recurrent risk and the genetic counseling.


Assuntos
Anormalidades Múltiplas/genética , Aberrações Cromossômicas/embriologia , Hibridização Genômica Comparativa , Cardiopatias Congênitas/genética , Análise de Sequência com Séries de Oligonucleotídeos , Diagnóstico Pré-Natal/métodos , Anormalidades Múltiplas/diagnóstico , Sistema Nervoso Central/anormalidades , Sistema Nervoso Central/embriologia , Feminino , Cardiopatias Congênitas/diagnóstico , Humanos , Cariotipagem/métodos , Idade Materna , Gravidez , Fatores de Risco
3.
J Hum Genet ; 64(4): 291-296, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30692598

RESUMO

A rare form of osteogenesis imperfecta (OI) caused by Wingless-type MMTV integration site family 1 (WNT1) mutations combines central nervous system (CNS) anomalies with the characteristic increased susceptibility to fractures. We report an additional case where arachnoid cysts extend the phenotype, and that also confirms the association of intellectual disabilities with asymmetric cerebellar hypoplasia here. Interestingly, if the cerebellum is normal in this disorder, intelligence is as well, analogous to an association with similar delays in a subset of patients with sporadic unilateral cerebellar hypoplasia. Those cases typically appear to represent vascular disruptions, and we suggest that most brain anomalies in WNT1-associated OI have vascular origins related to a role for WNT1 in CNS angiogenesis. This unusual combination of benign cerebellar findings with effects on higher functions in these two situations raises the possibility that WNT1 is involved in the pathogenesis of the associated sporadic cases as well. Finally, our patient reacted poorly to pamidronate, which appears ineffective with this form of OI, so that a lack of improvement is an indication for molecular testing that includes WNT1.


Assuntos
Sistema Nervoso Central/fisiopatologia , Deficiência Intelectual/genética , Osteogênese Imperfeita/genética , Proteína Wnt1/genética , Cistos Aracnóideos/diagnóstico por imagem , Cistos Aracnóideos/fisiopatologia , Sistema Nervoso Central/anormalidades , Sistema Nervoso Central/diagnóstico por imagem , Cerebelo/anormalidades , Cerebelo/diagnóstico por imagem , Cerebelo/fisiopatologia , Deficiências do Desenvolvimento/diagnóstico por imagem , Deficiências do Desenvolvimento/genética , Deficiências do Desenvolvimento/fisiopatologia , Lobo Frontal/diagnóstico por imagem , Lobo Frontal/fisiopatologia , Humanos , Deficiência Intelectual/diagnóstico por imagem , Deficiência Intelectual/tratamento farmacológico , Deficiência Intelectual/fisiopatologia , Mutação , Malformações do Sistema Nervoso/diagnóstico por imagem , Malformações do Sistema Nervoso/genética , Malformações do Sistema Nervoso/fisiopatologia , Osteogênese Imperfeita/diagnóstico por imagem , Osteogênese Imperfeita/tratamento farmacológico , Osteogênese Imperfeita/fisiopatologia , Pamidronato/administração & dosagem , Pamidronato/efeitos adversos
4.
J Vis Exp ; (135)2018 05 05.
Artigo em Inglês | MEDLINE | ID: mdl-29781994

RESUMO

The regrowth capacity of damaged neurons governs neuroregeneration and functional recovery after nervous system trauma. Over the past few decades, various intrinsic and extrinsic inhibitory factors involved in the restriction of axon regeneration have been identified. However, simply removing these inhibitory cues is insufficient for successful regeneration, indicating the existence of additional regulatory machinery. Drosophila melanogaster, the fruit fly, shares evolutionarily conserved genes and signaling pathways with vertebrates, including humans. Combining the powerful genetic toolbox of flies with two-photon laser axotomy/dendriotomy, we describe here the Drosophila sensory neuron - dendritic arborization (da) neuron injury model as a platform for systematically screening for novel regeneration regulators. Briefly, this paradigm includes a) the preparation of larvae, b) lesion induction to dendrite(s) or axon(s) using a two-photon laser, c) live confocal imaging post-injury and d) data analysis. Our model enables highly reproducible injury of single labeled neurons, axons, and dendrites of well-defined neuronal subtypes, in both the peripheral and central nervous system.


Assuntos
Sistema Nervoso Central/anormalidades , Drosophila melanogaster/patogenicidade , Drosophila/patogenicidade , Regeneração Nervosa/fisiologia , Animais , Sistema Nervoso Central/patologia , Modelos Animais de Doenças , Sistema Nervoso Periférico/anormalidades , Sistema Nervoso Periférico/patologia
5.
Environ Pollut ; 236: 304-312, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29414352

RESUMO

Triclosan (TCS) is an organic compound with a wide range of antibiotic activity and has been widely used in items ranging from hygiene products to cosmetics; however, recent studies suggest that it has several adverse effects. In particular, TCS can be passed to both fetus and infants, and while some evidence suggests in vitro neurotoxicity, there are currently few studies concerning the mechanisms of TCS-induced developmental neurotoxicity. Therefore, this study aimed to clarify the effect of TCS on neural development using zebrafish models, by analyzing the morphological changes, the alterations observed in fluorescence using HuC-GFP and Olig2-dsRED transgenic zebrafish models, and neurodevelopmental gene expression. TCS exposure decreased the body length, head size, and eye size in a concentration-dependent manner in zebrafish embryos. It increased apoptosis in the central nervous system (CNS) and particularly affected the structure of the CNS, resulting in decreased synaptic density and shortened axon length. In addition, it significantly up-regulated the expression of genes related to axon extension and synapse formation such as α1-Tubulin and Gap43, while decreasing Gfap and Mbp related to axon guidance, myelination and maintenance. Collectively, these changes indicate that exposure to TCS during neurodevelopment, especially during axonogenesis, is toxic. This is the first study to demonstrate the toxicity of TCS during neurogenesis, and suggests a possible mechanism underlying the neurotoxic effects of TCS in developing vertebrates.


Assuntos
Anti-Infecciosos Locais/toxicidade , Axônios/efeitos dos fármacos , Sistema Nervoso Central/efeitos dos fármacos , Embrião não Mamífero/efeitos dos fármacos , Neurogênese/efeitos dos fármacos , Triclosan/toxicidade , Peixe-Zebra/embriologia , Animais , Animais Geneticamente Modificados/anormalidades , Animais Geneticamente Modificados/embriologia , Animais Geneticamente Modificados/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Sistema Nervoso Central/anormalidades , Sistema Nervoso Central/embriologia , Embrião não Mamífero/anormalidades , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Proteínas Luminescentes/genética , Peixe-Zebra/genética
6.
Laryngoscope ; 128 Suppl 1: S1-S9, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29219190

RESUMO

OBJECTIVE: Laryngeal dystonia (LD) is a functionally specific disorder of the afferent-efferent motor coordination system producing action-induced muscle contraction with a varied phenomenology. This report of long-term studies aims to review and better define the phenomenology and central nervous system abnormalities of this disorder and improve diagnosis and treatment. METHODS: Our studies categorized over 1,400 patients diagnosed with LD over the past 33 years, including demographic and medical history records and their phenomenological presentations. Patients were grouped on clinical phenotype (adductor or abductor) and genotype (sporadic and familial) and with DNA analysis and functional magnetic resonance imaging (fMRI) to investigate brain organization differences and characterize neural markers for genotype/phenotype categorization. A number of patients with alcohol-sensitive dystonia were also studied. RESULTS: A spectrum of LD phenomena evolved: adductor, abductor, mixed, singer's, dystonic tremor, and adductor respiratory dystonia. Patients were genetically screened for DYT (dystonia) 1, DYT4, DYT6, and DYT25 (GNAL)-and several were positive. The functional MRI studies showed distinct alterations within the sensorimotor network, and the LD patients with a family history had distinct cortical and cerebellar abnormalities. A linear discriminant analysis of fMRI findings showed a 71% accuracy in characterizing LD from normal and in characterizing adductor from abductor forms. CONCLUSION: Continuous studies of LD patients over 30 years has led to an improved understanding of the phenomenological characteristics of this neurological disorder. Genetic and fMRI studies have better characterized the disorder and raise the possibility of making objective rather than subjective diagnoses, potentially leading to new therapeutic approaches. Laryngoscope, 128:S1-S9, 2018.


Assuntos
Sistema Nervoso Central/anormalidades , Distúrbios Distônicos/genética , Distúrbios Distônicos/fisiopatologia , Doenças da Laringe/genética , Doenças da Laringe/fisiopatologia , Mapeamento Encefálico , Sistema Nervoso Central/diagnóstico por imagem , Genótipo , Humanos , Imagem por Ressonância Magnética , Fenótipo
7.
Am J Hum Genet ; 101(6): 995-1005, 2017 Dec 07.
Artigo em Inglês | MEDLINE | ID: mdl-29198722

RESUMO

A recurrent de novo missense variant within the C-terminal Sin3-like domain of ZSWIM6 was previously reported to cause acromelic frontonasal dysostosis (AFND), an autosomal-dominant severe frontonasal and limb malformation syndrome, associated with neurocognitive and motor delay, via a proposed gain-of-function effect. We present detailed phenotypic information on seven unrelated individuals with a recurrent de novo nonsense variant (c.2737C>T [p.Arg913Ter]) in the penultimate exon of ZSWIM6 who have severe-profound intellectual disability and additional central and peripheral nervous system symptoms but an absence of frontonasal or limb malformations. We show that the c.2737C>T variant does not trigger nonsense-mediated decay of the ZSWIM6 mRNA in affected individual-derived cells. This finding supports the existence of a truncated ZSWIM6 protein lacking the Sin3-like domain, which could have a dominant-negative effect. This study builds support for a key role for ZSWIM6 in neuronal development and function, in addition to its putative roles in limb and craniofacial development, and provides a striking example of different variants in the same gene leading to distinct phenotypes.


Assuntos
Proteínas de Ligação a DNA/genética , Deficiência Intelectual/genética , Transtornos Neurocognitivos/genética , Sistema Nervoso Central/anormalidades , Sistema Nervoso Central/embriologia , Códon sem Sentido/genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Deformidades Congênitas dos Membros/genética , Disostose Mandibulofacial/genética , Sistema Nervoso Periférico/anormalidades , Sistema Nervoso Periférico/enzimologia
8.
Obstet Gynecol ; 130(6): e279-e290, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-29189693

RESUMO

Neural tube defects (NTDs) are congenital structural abnormalities of the central nervous system and vertebral column. Neural tube defects may occur as an isolated malformation, in combination with other malformations, as part of a genetic syndrome, or as a result of teratogenic exposure (1). Neural tube defects are the second-most-common major congenital anomaly (2) after cardiac malformations, and their prevalence varies by geographic region, race, and environmental factors (3). Outcomes and disabilities depend on level and extent of lesion; for instance, anencephaly is incompatible with life but most infants with spina bifida will survive after surgical repair (4). Importantly, and in contrast to many other congenital abnormalities, primary prevention of NTDs is possible with folic acid. In addition, prenatal screening and diagnosis are widely available, and fetal surgery has improved outcomes for some newborns. The purpose of this document is to provide information about NTDs and make management recommendations for the pregnancy complicated by a fetal NTD.


Assuntos
Parto Obstétrico/métodos , Terapias Fetais/métodos , Ácido Fólico/uso terapêutico , Testes para Triagem do Soro Materno/métodos , Defeitos do Tubo Neural , Complicações na Gravidez , Ultrassonografia Pré-Natal/métodos , Sistema Nervoso Central/anormalidades , Sistema Nervoso Central/diagnóstico por imagem , Feminino , Humanos , Recém-Nascido , Masculino , Defeitos do Tubo Neural/diagnóstico , Defeitos do Tubo Neural/terapia , Gravidez , Complicações na Gravidez/diagnóstico , Complicações na Gravidez/terapia , Coluna Vertebral/anormalidades , Coluna Vertebral/diagnóstico por imagem , Estados Unidos , Complexo Vitamínico B/uso terapêutico , alfa-Fetoproteínas/análise
9.
Georgian Med News ; (271): 38-44, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29099699

RESUMO

The purpose of this work was to identify and evaluate the epidemiological features, like the point prevalence of the perinatal risk factors and related to them pathological conditions revealing at the neonatal period. The descriptive population based prospective pilot study of children population of age 0-2 years was con-ducted in the City Tbilisi (in clinical centers "Medcapital", "family center N3" and "Valeo"), also in medical centers of districts of Mtsketa and Dusheti in period January 2015- January 2017. Summary was surveyed 1018 newborns during two years. According to research objectives newborns were di-vided into the three groups: I - 715 (70.2%) low risk group newborns with normal development, not influenced by risk factors, II - 215 (21.1%) risk group newborns with normal development, influenced by risk factors and III - 88 (8.7%) high risk group newborns with some neonatal pathology. Epidemiological evaluations, such as point prevalence and risk ratio (RR) for each risk factor and neonatal outcome, were conducted. At the neonatal period the point prevalence of perinatal risk factors in whole population (1018 newborns) were: mother age (<17 >35) - 175 (17.2%) cases, pathologies of pregnancy - 164 (16.1%) and pathologies of delivery -128 (12.6%) cases. RRs of neonatal outcomes associated with these factors were rated as 15.4/5.7/3.8. A total of 88 (8.6%) newborns were placed in III High risk group. In this population the most frequent pathologies were: preterm birth in 74 cases (7.26%), hypoxic-ischemic encephalopathy in 29 (2.84%) cases, low Apgar scores (<7 at 5 minutes) in 26 (2.6%) cases, neonatal sepsis in 16 (1.6%) cases, CNS malformation in 7 (0.7%) cases, intracranial hemorrhage in 6 (0.6%) cases. 13 newborns (1.28%) from III group were treated at department of emergency therapy. Newborns from II group, despite the impact of perinatal risk factors on them, were born healthy and evaluated as normal. Results of investigation show, that the point preva-lence of maternal age, pregnancy and delivery pathologies as well as neonatal outcomes are determined as risks of pathological conditions and outcomes of newborns.


Assuntos
Doenças do Recém-Nascido/epidemiologia , Complicações na Gravidez/epidemiologia , Adolescente , Adulto , Sistema Nervoso Central/anormalidades , Feminino , República da Geórgia/epidemiologia , Humanos , Recém-Nascido , Sepse Neonatal/epidemiologia , Transtornos do Neurodesenvolvimento/epidemiologia , Complicações do Trabalho de Parto/epidemiologia , Projetos Piloto , Gravidez , Prevalência , Risco , Fatores de Risco , Adulto Jovem
10.
Am J Med Genet C Semin Med Genet ; 175(4): 417-430, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-29178447

RESUMO

CHARGE syndrome (CS) is a genetic disorder whose first description included Coloboma, Heart disease, Atresia of choanae, Retarded growth and development, Genital hypoplasia, and Ear anomalies and deafness, most often caused by a genetic mutation in the CHD7 gene. Two features were then added: semicircular canal anomalies and arhinencephaly/olfactory bulb agenesis, with classification of typical, partial, or atypical forms on the basis of major and minor clinical criteria. The detection rate of a pathogenic variant in the CHD7 gene varies from 67% to 90%. To try to have an overview of this heterogenous clinical condition and specify a genotype-phenotype relation, we conducted a national study of phenotype and genotype in 119 patients with CS. Selected clinical diagnostic criteria were from Verloes (2005), updated by Blake & Prasad (). Besides obtaining a detailed clinical description, when possible, patients underwent a full ophthalmologic examination, audiometry, temporal bone CT scan, gonadotropin analysis, and olfactory-bulb MRI. All patients underwent CHD7 sequencing and MLPA analysis. We found a pathogenic CHD7 variant in 83% of typical CS cases and 58% of atypical cases. Pathogenic variants in the CHD7 gene were classified by the expected impact on the protein. In all, 90% of patients had a typical form of CS and 10% an atypical form. The most frequent features were deafness/semicircular canal hypoplasia (94%), pituitary defect/hypogonadism (89%), external ear anomalies (87%), square-shaped face (81%), and arhinencephaly/anosmia (80%). Coloboma (73%), heart defects (65%), and choanal atresia (43%) were less frequent.


Assuntos
Síndrome CHARGE/diagnóstico , Síndrome CHARGE/genética , Estudos de Associação Genética , Genótipo , Fenótipo , Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/genética , Adolescente , Adulto , Alelos , Substituição de Aminoácidos , Sistema Nervoso Central/anormalidades , Criança , Pré-Escolar , Estudos de Coortes , Nervos Cranianos/anormalidades , DNA Helicases/genética , Proteínas de Ligação a DNA/genética , Feminino , França , Testes Genéticos , Humanos , Lactente , Masculino , Técnicas de Diagnóstico Molecular , Adulto Jovem
11.
Invert Neurosci ; 17(4): 11, 2017 10 17.
Artigo em Inglês | MEDLINE | ID: mdl-29038967

RESUMO

Spider embryogenesis is affected by a range of environmental factors. Any sudden, drastic change in the environment may impair spider development, leading to various body deformities. In the present study, we analyze changes in the morphology and structure of the central nervous system of an Eratigena atrica larva, obtained in a teratological experiment in which embryos were exposed to alternating temperatures of 14 and 32 °C for the first 10 days. The studied larva had three pedipalps on the right side of the prosoma (polymely), two of which were fused along their entire length (total heterosymely). In addition, there was a short, club-shaped stump between the pedipalps. Histological analysis confirmed major changes in the structure of the subesophageal ganglion, i.e., the fusion of all three ganglia of pedipalps.


Assuntos
Sistema Nervoso Central/anormalidades , Malformações do Sistema Nervoso/patologia , Aranhas/embriologia , Animais , Temperatura Ambiente
13.
Hum Genet ; 136(7): 821-834, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28393272

RESUMO

Pathogenic variants in genes encoding subunits of the spliceosome are the cause of several human diseases, such as neurodegenerative diseases. The RNA splicing process is facilitated by the spliceosome, a large RNA-protein complex consisting of small nuclear ribonucleoproteins (snRNPs), and many other proteins, such as heterogeneous nuclear ribonucleoproteins (hnRNPs). The HNRNPU gene (OMIM *602869) encodes the heterogeneous nuclear ribonucleoprotein U, which plays a crucial role in mammalian development. HNRNPU is expressed in the fetal brain and adult heart, kidney, liver, brain, and cerebellum. Microdeletions in the 1q44 region encompassing HNRNPU have been described in patients with intellectual disability (ID) and other clinical features, such as seizures, corpus callosum abnormalities (CCA), and microcephaly. Recently, pathogenic HNRNPU variants were identified in large ID and epileptic encephalopathy cohorts. In this study, we provide detailed clinical information of five novels and review two of the previously published individuals with (likely) pathogenic de novo variants in the HNRNPU gene including three non-sense and two missense variants, one small intragenic deletion, and one duplication. The phenotype in individuals with variants in HNRNPU is characterized by early onset seizures (6/7), severe ID (6/6), severe speech impairment (6/6), hypotonia (6/7), and central nervous system (CNS) (5/6), cardiac (4/6), and renal abnormalities (3/4). In this study, we broaden the clinical and mutational HNRNPU-associated spectrum, and demonstrate that heterozygous HNRNPU variants cause epilepsy, severe ID with striking speech impairment and variable CNS, cardiac, and renal anomalies.


Assuntos
Epilepsia/genética , Ribonucleoproteínas Nucleares Heterogêneas Grupo U/genética , Heterozigoto , Deficiência Intelectual/genética , Idade de Início , Agenesia do Corpo Caloso/genética , Sistema Nervoso Central/anormalidades , Sistema Nervoso Central/patologia , Deleção Cromossômica , Cromossomos Humanos Par 1 , Epilepsia/diagnóstico , Feminino , Variação Genética , Humanos , Lactente , Deficiência Intelectual/diagnóstico , Rim/anormalidades , Masculino , Microcefalia/diagnóstico , Microcefalia/genética , Hipotonia Muscular/diagnóstico , Hipotonia Muscular/genética , Fenótipo , Processamento de RNA , Ribonucleoproteínas Nucleares Pequenas/genética , Convulsões/diagnóstico , Convulsões/genética
14.
Rev. neurol. (Ed. impr.) ; 64(7): 305-312, 1 abr., 2017. ilus, graf, tab
Artigo em Espanhol | IBECS | ID: ibc-161602

RESUMO

Introducción. Las malformaciones cavernosas son lesiones vasculares del sistema nervioso central constituidas por endotelio sinusoidal que forma capilares agrupados o cavernas que carecen de los elementos típicos de una pared arterial madura y ausencia de tejido neural interpuesto. El endotelio está rodeado por una densa capa de fibras colágenas que dejan pequeñas hendiduras por las que se extravasa hemosiderina. Se comunican con el sistema vascular a muy baja presión y su tratamiento puede ser por microcirugía o radiocirugía. Objetivos. Analizar las malformaciones cavernosas supratentoriales tratadas quirúrgicamente en nuestra institución (FLENI), determinar la epidemiología y las características intrínsecas, estudiar la clínica de presentación, determinar las indicaciones quirúrgicas y complicaciones, y establecer el pronóstico. Pacientes y métodos. Estudio retrospectivo analítico de historias clínicas e imágenes de pacientes operados de malformaciones cavernosas supratentoriales en la FLENI desde enero de 1996 hasta diciembre de 2013. Resultados. Evaluamos a 51 pacientes, de 34 años de media, seguidos durante una media de 30 meses. El 1,96% de los pacientes presentó diagnóstico incidental y el resto mostró síntomas. El 23,52% presentó hemorragia en el momento del diagnóstico. En todas las cirugías se logró una exéresis total de las malformaciones cavernosas supratentoriales. Se observó un caso de meningitis postoperatoria. Conclusiones. La tasa de sangrado de las malformaciones cavernosas supratentoriales en nuestro medio es del 1,38% por paciente por año. El tratamiento quirúrgico es eficaz para erradicar o disminuir los síntomas y para evitar un posible resangrado. Presenta una tasa muy baja de complicaciones y un pronóstico neurológico favorable (AU)


Introduction. Cavernous malformations are vascular malformations of the central nervous system formed by a group of capillaries not covered by pia mater and communicated to the vascular system at very low pressure with very slow flow. Surgery or radiosurgery are the treatment modalities. Aims. To analyze our results after surgical treatment of supratentorial cavernous malformations, reviewing clinical presentation, surgical indications and postoperative complications. Patients and methods. Analytical retrospective study of medical records and images of patients who underwent resection of supratentorial cavernomas at FLENI from January 1996 until December 2013. Results. We evaluated 51 patients, mean age 34 years, followed for an average of 30 months. In 1.96% of patients diagnosis was incidental, the rest all presented symptoms. Bleeding at diagnosis was observed in 23.52%. Total excision of supratentorial cavernous malformations was possible in all cases. The only postoperative complication was one case of meningitis. Conclusions. The bleeding rate of supratentorial cavernous malformations in our series was 1.38% per patient per year. Surgical treatment effectively eliminated, or at least reduced symptoms, prevented rebleeding, and decreased need for antiepileptic drug therapy. Surgery have a low complication rate and good outcome (AU)


Assuntos
Humanos , Masculino , Feminino , Adulto , Microcirurgia/métodos , Achados Incidentais , Epilepsia/complicações , Epilepsia/diagnóstico , Angiografia Cerebral , Seio Cavernoso/anormalidades , Seio Cavernoso/cirurgia , Seio Cavernoso , Sistema Nervoso Central/anormalidades , Sistema Nervoso Central/cirurgia , Prognóstico , Estudos Retrospectivos , Cérebro/anormalidades , Cérebro/cirurgia , Cérebro , Neuroimagem
15.
Nat Genet ; 49(4): 606-612, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-28250456

RESUMO

Motor, sensory, and integrative activities of the brain are coordinated by a series of midline-bridging neuronal commissures whose development is tightly regulated. Here we report a new human syndrome in which these commissures are widely disrupted, thus causing clinical manifestations of horizontal gaze palsy, scoliosis, and intellectual disability. Affected individuals were found to possess biallelic loss-of-function mutations in the gene encoding the axon-guidance receptor 'deleted in colorectal carcinoma' (DCC), which has been implicated in congenital mirror movements when it is mutated in the heterozygous state but whose biallelic loss-of-function human phenotype has not been reported. Structural MRI and diffusion tractography demonstrated broad disorganization of white-matter tracts throughout the human central nervous system (CNS), including loss of all commissural tracts at multiple levels of the neuraxis. Combined with data from animal models, these findings show that DCC is a master regulator of midline crossing and development of white-matter projections throughout the human CNS.


Assuntos
Encéfalo/anormalidades , Neoplasias Colorretais/genética , Regulação da Expressão Gênica no Desenvolvimento/genética , Perda de Heterozigosidade/genética , Mutação/genética , Sistema Nervoso Central/anormalidades , Feminino , Humanos , Deficiência Intelectual/genética , Masculino , Neurônios/metabolismo , Fenótipo , Polimorfismo de Nucleotídeo Único/genética , Receptores de Superfície Celular/genética
16.
Am J Pathol ; 187(4): 864-883, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-28342444

RESUMO

Farber disease is a rare autosomal recessive disorder caused by acid ceramidase deficiency that usually presents as early-onset progressive visceral and neurologic disease. To understand the neurologic abnormality, we investigated behavioral, biochemical, and cellular abnormalities in the central nervous system of Asah1P361R/P361R mice, which serve as a model of Farber disease. Behaviorally, the mutant mice had reduced voluntary locomotion and exploration, increased thigmotaxis, abnormal spectra of basic behavioral activities, impaired muscle grip strength, and defects in motor coordination. A few mutant mice developed hydrocephalus. Mass spectrometry revealed elevations of ceramides, hydroxy-ceramides, dihydroceramides, sphingosine, dihexosylceramides, and monosialodihexosylganglioside in the brain. The highest accumulation was in hydroxy-ceramides. Storage compound distribution was analyzed by mass spectrometry imaging and morphologic analyses and revealed involvement of a wide range of central nervous system cell types (eg, neurons, endothelial cells, and choroid plexus cells), most notably microglia and/or macrophages. Coalescing and mostly perivascular granuloma-like accumulations of storage-laden CD68+ microglia and/or macrophages were seen as early as 3 weeks of age and located preferentially in white matter, periventricular zones, and meninges. Neurodegeneration was also evident in specific cerebral areas in late disease. Overall, our central nervous system studies in Asah1P361R/P361R mice substantially extend the understanding of human Farber disease and suggest that this model can be used to advance therapeutic approaches for this currently untreatable disorder.


Assuntos
Sistema Nervoso Central/anormalidades , Lipogranulomatose de Farber/complicações , Lipogranulomatose de Farber/patologia , Malformações do Sistema Nervoso/etiologia , Malformações do Sistema Nervoso/patologia , Ceramidase Ácida/metabolismo , Animais , Comportamento Animal , Sistema Nervoso Central/patologia , Cerebelo/patologia , Cerebelo/ultraestrutura , Cérebro/patologia , Cérebro/ultraestrutura , Homozigoto , Hidrocefalia/patologia , Camundongos , Camundongos Transgênicos , Atividade Motora , Neurônios/patologia , Neurônios/ultraestrutura , Fenótipo , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz , Esfingolipídeos/metabolismo , Fatores de Tempo
17.
BMJ Open ; 7(1): e013810, 2017 01 20.
Artigo em Inglês | MEDLINE | ID: mdl-28110288

RESUMO

OBJECTIVE: Approximately 8-10% of newborns with asymptomatic congenital cytomegalovirus (cCMV) infection develop sensorineural hearing loss (SNHL). However, the relationship between CMV load, SNHL and central nervous system (CNS) damage in cCMV infection remains unclear. This study aimed to examine the relationship between urinary CMV load, SNHL and CNS damage in newborns with cCMV infection. STUDY DESIGN: The study included 23 368 newborns from two maternity hospitals in Saitama Prefecture, Japan. Urine screening for cCMV infection (quantitative real-time PCR) and newborn hearing screening (automated auditory brainstem response (AABR) testing) were conducted within 5 days of birth to examine the incidence of cCMV infection and SNHL, respectively. CNS damage was assessed by MRI of cCMV-infected newborns. RESULTS: The incidence of cCMV infection was 60/23 368 (0.257%; 95% CI 0.192% to 0.322%). The geometric mean urinary CMV DNA copy number in newborns with cCMV was 1.79×106 copies/mL (95% CI 7.97×105 to 4.02×106). AABR testing revealed abnormalities in 171 of the 22 229 (0.769%) newborns whose parents approved hearing screening. Of these 171 newborns, 22 had SNHL (12.9%), and 5 of these 22 were infected with cCMV (22.7%). Newborns with both cCMV and SNHL had a higher urinary CMV DNA copy number than newborns with cCMV without SNHL (p=0.036). MRI revealed CNS damage, including white matter abnormalities, in 83.0% of newborns with cCMV. Moreover, newborns with CNS damage had a significantly greater urinary CMV load than newborns without CNS damage (p=0.013). CONCLUSIONS: We determined the incidence of cCMV infection and urinary CMV DNA copy number in seemingly healthy newborns from two hospitals in Saitama Prefecture. SNHL and CNS damage were associated with urinary CMV DNA copy number. Quantification of urinary CMV load may effectively predict the incidence of late-onset SNHL and neurodevelopmental disorders.


Assuntos
Sistema Nervoso Central/anormalidades , Infecções por Citomegalovirus/diagnóstico , Citomegalovirus , DNA Viral/urina , Perda Auditiva Neurossensorial , Audição , Triagem Neonatal , Sistema Nervoso Central/virologia , Anormalidades Congênitas/urina , Anormalidades Congênitas/virologia , Citomegalovirus/genética , Citomegalovirus/crescimento & desenvolvimento , Infecções por Citomegalovirus/complicações , Infecções por Citomegalovirus/epidemiologia , Infecções por Citomegalovirus/virologia , Potenciais Evocados Auditivos do Tronco Encefálico , Feminino , Perda Auditiva Neurossensorial/epidemiologia , Perda Auditiva Neurossensorial/etiologia , Perda Auditiva Neurossensorial/virologia , Humanos , Incidência , Recém-Nascido , Japão/epidemiologia , Imagem por Ressonância Magnética , Masculino , Reação em Cadeia da Polimerase em Tempo Real , Substância Branca
18.
Urolithiasis ; 45(4): 359-362, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-27573101

RESUMO

Medullary sponge kidney (MSK) is a congenital renal disorder. Its association with several developmental abnormalities in other organs hints at the likelihood of some shared step(s) in the embryogenesis of the kidney and other organs. It has been suggested that the REarranged during Transfection (RET) proto-oncogene and the Glial cell line-Derived Neurotrophic Factor (GDNF) gene are defective in patients with MSK, and both RET and GDNF are known to have a role in the development of the central nervous system, heart, and craniofacial skeleton. Among a cohort of 143 MSK patients being followed up for nephrolithiasis and chronic kidney disease at our institution, we found six with one or more associated non-renal anomalies: one patient probably has congenital hemihyperplasia and hypertrophic cardiomyopathy with adipose metaplasia and mitral valve prolapse; one has Marfan syndrome; and the other four have novel associations between MSK and nerve and skeleton abnormalities described here for the first time. The discovery of disorders involving the central nervous system, cardiovascular system and craniofacial skeleton in MSK patients supports the hypothesis of a genetic alteration on the RET-GDNF axis having a pivotal role in the pathogenesis of MSK, in a subset of patients at least. MSK seems more and more to be a systemic disease, and the identification of extrarenal developmental defects could be important in arousing the suspicion of MSK in recurrent stone formers.


Assuntos
Fator Neurotrófico Derivado de Linhagem de Célula Glial/genética , Cálculos Renais/genética , Rim em Esponja Medular/genética , Adulto , Cardiomiopatia Hipertrófica/congênito , Cardiomiopatia Hipertrófica/genética , Sistema Nervoso Central/anormalidades , Estudos de Coortes , Feminino , Humanos , Hiperplasia/congênito , Hiperplasia/genética , Rim/anormalidades , Cálculos Renais/etiologia , Masculino , Síndrome de Marfan/genética , Rim em Esponja Medular/complicações , Pessoa de Meia-Idade , Mutação , Proteínas Proto-Oncogênicas c-ret/genética , Insuficiência Renal Crônica/genética , Adulto Jovem
19.
Am J Perinatol ; 34(3): 217-222, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-27398707

RESUMO

Objective This study aims to determine if advanced maternal age (AMA) is a risk factor for major congenital anomalies, in the absence of aneuploidy. Study Design Retrospective cohort study of all patients with a singleton gestation presenting for second trimester anatomic survey over a 19-year study period. Aneuploid fetuses were excluded. Study groups were defined by maternal age ≤ 34 and ≥ 35 years. The primary outcome was the presence of one or more major anomalies diagnosed at the second trimester ultrasound. Univariable and multivariable logistic regression analyses were used to estimate the risk of major anomalies in AMA patients. Results Of 76,156 euploid fetuses, 2.4% (n = 1,804) were diagnosed with a major anomaly. There was a significant decrease in the incidence of major fetal anomalies with increasing maternal age until the threshold of age 35 (p < 0.001). Being AMA was significantly associated with an overall decreased risk for major fetal anomalies (adjusted odds ratio: 0.59, 95% confidence interval: 0.52-0.66). The subgroup analysis demonstrated similar results for women ≥ 40 years of age. Conclusion AMA is associated with an overall decreased risk for major anomalies. These findings may suggest that the "all or nothing" phenomenon plays a more robust role in embryonic development with advancing oocyte age, with anatomically normal fetuses being more likely to survive.


Assuntos
Anormalidades Congênitas/epidemiologia , Idade Materna , Parede Abdominal/anormalidades , Adulto , Sistema Nervoso Central/anormalidades , Anormalidades Congênitas/diagnóstico por imagem , Feminino , Cardiopatias Congênitas/epidemiologia , Humanos , Incidência , Rim/anormalidades , Gravidez , Segundo Trimestre da Gravidez , Estudos Retrospectivos , Fatores de Risco , Tórax/anormalidades , Ultrassonografia Pré-Natal , Estados Unidos/epidemiologia , Adulto Jovem
20.
Am J Hum Genet ; 100(1): 128-137, 2017 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-28017372

RESUMO

Early B cell factor 3 (EBF3) is a member of the highly evolutionarily conserved Collier/Olf/EBF (COE) family of transcription factors. Prior studies on invertebrate and vertebrate animals have shown that EBF3 homologs are essential for survival and that loss-of-function mutations are associated with a range of nervous system developmental defects, including perturbation of neuronal development and migration. Interestingly, aristaless-related homeobox (ARX), a homeobox-containing transcription factor critical for the regulation of nervous system development, transcriptionally represses EBF3 expression. However, human neurodevelopmental disorders related to EBF3 have not been reported. Here, we describe three individuals who are affected by global developmental delay, intellectual disability, and expressive speech disorder and carry de novo variants in EBF3. Associated features seen in these individuals include congenital hypotonia, structural CNS malformations, ataxia, and genitourinary abnormalities. The de novo variants affect a single conserved residue in a zinc finger motif crucial for DNA binding and are deleterious in a fly model. Our findings indicate that mutations in EBF3 cause a genetic neurodevelopmental syndrome and suggest that loss of EBF3 function might mediate a subset of neurologic phenotypes shared by ARX-related disorders, including intellectual disability, abnormal genitalia, and structural CNS malformations.


Assuntos
Mutação , Transtornos do Neurodesenvolvimento/genética , Fatores de Transcrição/genética , Anormalidades Múltiplas/genética , Ataxia/genética , Sistema Nervoso Central/anormalidades , Criança , Pré-Escolar , Deficiências do Desenvolvimento/genética , Feminino , Genitália/anormalidades , Humanos , Lactente , Recém-Nascido , Deficiência Intelectual/genética , Masculino , Hipotonia Muscular/genética , Distúrbios da Fala/genética , Síndrome , Dedos de Zinco/genética
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