Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 6.198
Filtrar
1.
Eur J Paediatr Neurol ; 32: 56-65, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33819831

RESUMO

INTRODUCTION: Brain abnormalities in cerebral palsy (CP) are known to relate to motor outcome; however, their association with cognitive functioning is less clear. AIM OF THE STUDY: 1) To investigate the prognostic value of brain abnormalities for cognitive functioning; 2) To explore the added value of prognostic variables across ICF domains: motor function, epilepsy, gestational age, birthweight and educational level of the parents. METHODS: We retrospectively analyzed brain MRI scans of 75 children with CP (GMFCS level I-V, 36% born preterm), as part of a longitudinal study. MRI classification: qualitative classification of brain abnormality pattern and semi-quantitative grading of the extent of damage. Cognitive functioning, measured as non-verbal intelligent quotient (IQ), was dichotomized into 'impaired cognition' (IQ ≤ 70) and 'normal' (IQ > 70). Multivariable logistic regression produced odds ratios (OR) with 95% confidence interval (C.I.) of risk factors for impaired cognition. RESULTS: Overall, 27% of the tested participants had a non-verbal IQ below 70 and 36% of the participants was classified as 'having impaired cognition'. At a young age, a higher degree of white matter damage (OR 1.6, 95% C.I. 0.97-2.67) and a more severe GMFCS level (OR 3.2, 95% C.I. 1.70-5.98) are risk factors for impaired cognition at school-age (4-7 years of age). This model correctly predicts 89% of the cases. Brain damage alone predicts the presence of impaired cognition in 71% of the cases. INTERPRETATION: Brain MRI characteristics and GMFCS level at a young age can each help identify children with CP at risk for impaired cognition at school age and together have a strong predictive value.


Assuntos
Encéfalo/anormalidades , Paralisia Cerebral/complicações , Paralisia Cerebral/patologia , Disfunção Cognitiva/etiologia , Disfunção Cognitiva/patologia , Encéfalo/diagnóstico por imagem , Paralisia Cerebral/diagnóstico por imagem , Criança , Pré-Escolar , Disfunção Cognitiva/diagnóstico por imagem , Estudos de Coortes , Feminino , Humanos , Recém-Nascido , Estudos Longitudinais , Imageamento por Ressonância Magnética/métodos , Masculino , Neuroimagem/métodos , Prognóstico , Estudos Prospectivos
2.
World J Pediatr ; 17(3): 253-262, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33844176

RESUMO

BACKGROUND: Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an emerging disease. The consequences of SARS-CoV-2 exposure in infants remain unknown. Therefore, this study aims to investigate whether neonates born to mothers with COVID-19 have adverse brain development. METHODS: This multicenter observational study was conducted at two designated maternal and children's hospitals in Hubei Province, mainland China from February 1, 2020 to May 15, 2020. Neonates born to mothers with COVID-19 were enrolled. Brain magnetic resonance imaging (MRI) findings, and volumes of grey and white matters, and physical growth parameters were observed at 44 weeks corrected gestational age. RESULTS: Of 72 neonates born to mothers with COVID-19, 8 (11%) were diagnosed with COVID-19, 8 (11%) were critically ill, and no deaths were reported. Among the eight neonates that underwent brain MRI at corrected gestational age of 44 weeks, five neonates were diagnosed with COVID-19. Among these five neonates, three presented abnormal MRI findings including abnormal signal in white matter and delayed myelination in newborn 2, delayed myelination and brain dysplasia in newborn 3, and abnormal signal in the bilateral periventricular in newborn 5. The other three neonates without COVID-19 presented no significantly changes of brain MRI findings and the volumes of grey matter and white matter compared to those of healthy newborns at the equivalent age (P > 0.05). Physical growth parameters for weight, length, and head circumference at gestational age of 44 weeks were all above the 3rd percentile for all neonates. CONCLUSIONS: Some of the neonates born to mothers with COVID-19 had abnormal brain MRI findings but these neonates did not appear to have poor physical growth. These findings may provide the information on the follow-up schedule on the neonates exposed to SARS-CoV-2, but further study is required to evaluate the association between the abnormal MRI findings and the exposure to SARS-CoV-2.


Assuntos
Encéfalo/anormalidades , Encéfalo/diagnóstico por imagem , COVID-19/transmissão , Transmissão Vertical de Doenças Infecciosas , Imageamento por Ressonância Magnética , COVID-19/epidemiologia , China/epidemiologia , Feminino , Humanos , Recém-Nascido , Masculino , Pandemias , Gravidez , SARS-CoV-2
3.
Genes (Basel) ; 12(2)2021 02 20.
Artigo em Inglês | MEDLINE | ID: mdl-33672558

RESUMO

CDC42 (cell division cycle protein 42) belongs to the Rho GTPase family that is known to control the signaling axis that regulates several cellular functions, including cell cycle progression, migration, and proliferation. However, the functional characterization of the CDC42 gene in mammalian physiology remains largely unclear. Here, we report the genetic and functional characterization of a non-consanguineous Saudi family with a single affected individual. Clinical examinations revealed poor wound healing, heterotopia of the brain, pancytopenia, and recurrent infections. Whole exome sequencing revealed a de novo missense variant (c.101C > A, p.Pro34Gln) in the CDC42 gene. The functional assays revealed a substantial reduction in the growth and motility of the patient cells as compared to the normal cells control. Homology three-dimensional (3-D) modeling of CDC42 revealed that the Pro34 is important for the proper protein secondary structure. In conclusion, we report a candidate disease-causing variant, which requires further confirmation for the etiology of CDC42 pathogenesis. This represents the first case from the Saudi population. The current study adds to the spectrum of mutations in the CDC42 gene that might help in genetic counseling and contributes to the CDC42-related genetic and functional characterization. However, further studies into the molecular mechanisms that are involved are needed in order to determine the role of the CDC42 gene associated with aberrant cell migration and immune response.


Assuntos
Encéfalo/anormalidades , Estudos de Associação Genética , Predisposição Genética para Doença , Pancitopenia/genética , Reinfecção/etiologia , Cicatrização/genética , Proteína cdc42 de Ligação ao GTP/deficiência , Biópsia , Encéfalo/diagnóstico por imagem , Biologia Computacional/métodos , Análise Mutacional de DNA , Feminino , Estudos de Associação Genética/métodos , Humanos , Imageamento por Ressonância Magnética , Modelos Moleculares , Mutação , Pancitopenia/diagnóstico , Linhagem , Conformação Proteica , Reinfecção/diagnóstico , Relação Estrutura-Atividade , Sequenciamento Completo do Exoma , Adulto Jovem , Proteína cdc42 de Ligação ao GTP/química
4.
Eur J Paediatr Neurol ; 31: 46-53, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33621819

RESUMO

BACKGROUND: To quantitatively evaluate the brain MRI morphological abnormalities in patients with cyclin-dependent kinase-like 5 deficiency disorder (CDD) on a group level and longitudinally. METHODS: We performed surface-based MRI analysis on high-resolution T1-weighted images on three CDD patients scanned at age of three years, and compared with 12 age- and gender-matched healthy controls. We further examined the longitudinal morphological changes in one patient with a follow-up of 5 years. RESULTS: CDD patients presented significant reductions in total intracranial volume, total gray matter (GM) volume and subcortical GM volume compared to controls. For subcortical regions, significant GM volume reductions were seen in the brain stem, bilateral thalamus, bilateral hippocampus, bilateral cerebellum and left amygdala. Although GM volume of cortical mantle did not show statistical differences overall, significant reduction was detected in bilateral parietal, left occipital and right temporal lobes. Cortical thickness exhibited significant decreases in bilateral occipital, parietal and temporal lobes, while surface area did not show any significant differences. Longitudinal follow-up in one patient revealed a monotonic downward trend of relative volume in the majority of brain regions. The relative surface area appeared to gain age-related growth, whereas the relative cortical thickness exhibited a striking progressive decline over time. CONCLUSIONS: Quantitative morphology analysis in children with CDD showed global volume loss in the cortex and more notably in the subcortical gray matter, with a progressive trend along with the disease course. Cortical thickness is a more sensitive measure to disclose cortical atrophy and disease progression than surface area.


Assuntos
Encéfalo/anormalidades , Encéfalo/diagnóstico por imagem , Síndromes Epilépticas/diagnóstico por imagem , Síndromes Epilépticas/patologia , Espasmos Infantis/diagnóstico por imagem , Espasmos Infantis/patologia , Atrofia/diagnóstico por imagem , Atrofia/genética , Atrofia/patologia , Pré-Escolar , Progressão da Doença , Feminino , Humanos , Lactente , Imageamento por Ressonância Magnética/métodos , Masculino
5.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 38(1): 52-55, 2021 Jan 10.
Artigo em Chinês | MEDLINE | ID: mdl-33423258

RESUMO

OBJECTIVE: To explore the genetic basis for a Chinese pedigree affected with non-syndromic cleft lip and cleft palate (NSCLP). METHODS: With informed consent obtained, members of the pedigree were subjected to clinical examination and history taking to exclude syndromic cleft lip and palate. One affected member was subjected to whole-exome sequencing and bioinformatics analysis. Candidate variant was verified by Sanger sequencing and co-segregation analysis of her family members and 100 unrelated healthy individuals. RESULTS: Whole-exome sequencing and co-segregation analysis showed that all affected members of this pedigree have carried a heterozygous missense c.253A>G (p.Cys85Arg) variant in exon 4 of the IRF6 gene, which has co-segregated with the phenotype and was not found among the 100 unrelated healthy individuals. CONCLUSION: The missense c.253A>G variant in exon 4 of the IRF6 gene probably underlay the NSCLP in this pedigree.


Assuntos
Encéfalo/anormalidades , Fenda Labial , Fissura Palatina , Fatores Reguladores de Interferon , China , Fenda Labial/genética , Fissura Palatina/genética , Feminino , Humanos , Fatores Reguladores de Interferon/genética , Mutação de Sentido Incorreto , Linhagem , Sequenciamento Completo do Exoma
6.
Epilepsia ; 62(2): e35-e41, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33410539

RESUMO

The phosphatidylinositol glycan anchor biosynthesis class S protein (PIGS) gene has recently been implicated in a novel congenital disorder of glycosylation resulting in autosomal recessive inherited glycosylphosphatidylinositol-anchored protein (GPI-AP) deficiency. Previous studies described seven patients with biallelic variants in the PIGS gene, of whom two presented with fetal akinesia and five with global developmental delay and epileptic developmental encephalopathy. We present the molecular and clinical characteristics of six additional individuals from five families with unreported variants in PIGS. All individuals presented with hypotonia, severe global developmental delay, microcephaly, intractable early infantile epilepsy, and structural brain abnormalities. Additional findings include vision impairment, hearing loss, renal malformation, and hypotonic facial appearances with minor dysmorphic features but without a distinctive facial gestalt. Four individuals died due to neurologic complications. GPI anchoring studies performed on one individual revealed a significant decrease in GPI-APs. We confirm that biallelic variants in PIGS cause vitamin pyridoxine-responsive epilepsy due to inherited GPI deficiency and expand the genotype and phenotype of PIGS-related disorder. Further delineation of the molecular spectrum of PIGS-related disorders would improve management, help develop treatments, and encourage the expansion of diagnostic genetic testing to include this gene as a potential cause of neurodevelopmental disorders and epilepsy.


Assuntos
Aciltransferases/genética , Deficiências do Desenvolvimento/genética , Proteínas Ligadas por GPI/deficiência , Malformações do Sistema Nervoso/genética , Espasmos Infantis/genética , Encéfalo/anormalidades , Encéfalo/diagnóstico por imagem , Pré-Escolar , Deficiências do Desenvolvimento/fisiopatologia , Facies , Feminino , Perda Auditiva/genética , Perda Auditiva/fisiopatologia , Humanos , Lactente , Rim/anormalidades , Masculino , Microcefalia/genética , Microcefalia/fisiopatologia , Hipotonia Muscular/genética , Hipotonia Muscular/fisiopatologia , Malformações do Sistema Nervoso/diagnóstico por imagem , Malformações do Sistema Nervoso/fisiopatologia , Fenótipo , Espasmos Infantis/fisiopatologia , Transtornos da Visão/genética , Transtornos da Visão/fisiopatologia
7.
BJOG ; 128(2): 354-365, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-32966672

RESUMO

BACKGROUND: The significant number of qualitative and quantitative ultrasound markers described for first-trimester screening of open spina bifida (OSB) and other posterior brain defects (oPBD) has resulted in their complex implementation and interpretation for a widespread screening and in a lack of consensus regarding diagnostic accuracy. OBJECTIVES: To assess and compare the accuracy of qualitative and quantitative cranial sonographic markers at 11-14 weeks of gestation for the detection of OSB and oPBD. SEARCH STRATEGY: A systematic literature search was performed in MEDLINE and COCHRANE from 2009 to April 2020. SELECTION CRITERIA: Studies assessing the diagnostic accuracy of quantitative and/or qualitative ultrasound signs to predict OSB and oPBD were included. Cohort studies and case-control studies were also considered. DATA COLLECTION AND ANALYSIS: Two reviewers independently extracted data and assessed the risk of bias. The overall pooled estimate and a summary receiver operating characteristic curve was estimated for each subgroup (qualitative and quantitative assessment). MAIN RESULTS: Twenty-three studies were included in our meta-analysis. The pooled sensitivity and specificity for qualitative assessment were 76.5% and 99.6%, and for quantitative assessment were 84.5% and 96.3%, respectively; specificity for the qualitative ultrasound signs was significantly higher (P = 0.001). The overall sensitivity of cranial sonographic markers for the screening of oPBD was 76.7% and specificity was 97.5%. CONCLUSIONS: The qualitative approach demonstrated greater specificity, so this would appear to be more appropriate for daily screening, as a first-line tool, whereas the quantitative approach should be reserved for expert ultrasound. TWEETABLE ABSTRACT: This study highlights the relevance of first-trimester qualitative ultrasound signs in the screening of open spina bifida.


Assuntos
Encéfalo/anormalidades , Encéfalo/diagnóstico por imagem , Doenças Fetais/diagnóstico por imagem , Espinha Bífida Cística/diagnóstico por imagem , Ultrassonografia Pré-Natal , Feminino , Humanos , Gravidez , Primeiro Trimestre da Gravidez , Sensibilidade e Especificidade
9.
BJOG ; 128(7): 1174-1182, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33249730

RESUMO

OBJECTIVES: To assess and analyse the concordance between post-mortem findings and in utero magnetic resonance imaging (iuMRI) in the MERIDIAN (MRI to enhance the diagnosis of fetal developmental brain abnormalities in utero) cohort. DESIGN: Prospective cohort study. SETTING: Fetal medicine units in the UK. POPULATION: Pregnant women with a diagnosis of fetal brain abnormality identified on ultrasound at 18 weeks of gestation or later. METHODS: All pregnancies from the MERIDIAN study that resulted in a abortion were included and the rate of uptake and success of post-mortem examinations were calculated. In the cases in which diagnostic information about the fetal brain was obtained by post-mortem, the results were compared with the diagnoses from iuMRI. MAIN OUTCOME MEASURE: Outcome reference diagnosis from post-mortem examination. RESULTS: A total of 155 from 823 pregnancies (19%) ended in a termination of pregnancy and 71 (46%) had post-mortem brain examinations, 62 of which were diagnostically adequate. Hence, the overall rate of successful post-mortem investigation was 40%, and for those cases there was a concordance rate of 84% between iuMRI and post-mortem examination. Detailed information is provided when the results of the post-mortem examination and the iuMRI study differed. CONCLUSIONS: We have shown tissue-validation of radiological diagnosis is hampered by a low rate of post-mortem studies in fetuses aborted with brain abnormalities, a situation further compounded by a 12% rate of autopsy being technically unsuccessful. The agreement between iuMRI and post-mortem findings is high, but our analysis of the discrepant cases provides valuable clues for improving how we provide information for parents. TWEETABLE ABSTRACT: iuMRI should be considered a reliable indicator of fetal brain abnormalities when post-mortem is not performed.


Assuntos
Encéfalo , Imageamento por Ressonância Magnética , Ultrassonografia Pré-Natal , Aborto Induzido , Autopsia , Encéfalo/anormalidades , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Encefalopatias/diagnóstico por imagem , Encefalopatias/patologia , Estudos de Coortes , Feminino , Humanos , Gravidez
10.
BJOG ; 128(2): 376-383, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-32112473

RESUMO

OBJECTIVE: To investigate cerebral anomalies other than Chiari type 2 malformation in fetuses with myelomeningocele (MMC). DESIGN: A retrospective cohort study in a single tertiary centre. SETTING: A review of associated cerebral anomalies in cases with prenatal diagnosis of myelomeningocele. POPULATION: Seventy cases of fetal myelomeningocele. METHODS: Ultrasound and MRI images were blindly reviewed. Postnatal imaging and results of the postmortem results were also reviewed. The association between cerebral anomalies and the following ultrasound findings was measured: level of the defect, ventriculomegaly, microcephaly and fetal talipes. MAIN OUTCOME MEASURES: A microcephaly was observed in 32/70 cases (46%) and a ventriculomegaly was observed in 39/70 cases (56%). Other cerebral anomalies were diagnosed in 47/70 (67%). RESULTS: Other cerebral anomalies were represented by 42/70 cases with abnormal CC (60%), 8/70 cases with perinodular heterotopia (PNH; 11%), 2/70 cases with abnormal gyration (3%). MRI performed only in fetal surgery cases confirmed the ulltrasound findings in all cases and provided additional findings in two cases (PNH). Risk ratios of fetal cerebral anomalies associated with MMC did not reach significance for microcephaly, ventriculomegaly, talipes or the level of the defect There was an overall good correlation between pre- and postnatal findings with a Kappa value of 0.79 [95% CI 0.57-1] and 82% agreement. CONCLUSION: Fetal brain anomalies other than Chiari type 2 malformation are frequently observed in fetuses with myelomeningocele, predominantly represented by CC anomalies. Whether these associated cerebral anomalies have an impact on selecting cases eligible for fetal surgery needs further evaluation. TWEETABLE ABSTRACT: Fetal cerebral anomalies other than Chiari type 2 malformation, microcephaly, and ventriculomegaly may be associated with MMC in up to 67% of the cases.


Assuntos
Encéfalo/anormalidades , Doenças Fetais/diagnóstico por imagem , Meningomielocele/complicações , Meningomielocele/diagnóstico por imagem , Ultrassonografia Pré-Natal , Adulto , Encéfalo/diagnóstico por imagem , Encéfalo/embriologia , Feminino , Doenças Fetais/etiologia , Humanos , Imageamento por Ressonância Magnética , Meningomielocele/embriologia , Gravidez , Resultado da Gravidez , Estudos Retrospectivos
11.
Neurology ; 96(9): e1319-e1333, 2021 03 02.
Artigo em Inglês | MEDLINE | ID: mdl-33277420

RESUMO

OBJECTIVE: Aiming to detect associations between neuroradiologic and EEG evaluations and long-term clinical outcome in order to detect possible prognostic factors, a detailed clinical and neuroimaging characterization of 67 cases of Aicardi syndrome (AIC), collected through a multicenter collaboration, was performed. METHODS: Only patients who satisfied Sutton diagnostic criteria were included. Clinical outcome was assessed using gross motor function, manual ability, and eating and drinking ability classification systems. Brain imaging studies and statistical analysis were reviewed. RESULTS: Patients presented early-onset epilepsy, which evolved into drug-resistant seizures. AIC has a variable clinical course, leading to permanent disability in most cases; nevertheless, some cases presented residual motor abilities. Chorioretinal lacunae were present in 86.56% of our patients. Statistical analysis revealed correlations between MRI, EEG at onset, and clinical outcome. On brain imaging, 100% of the patients displayed corpus callosum malformations, 98% cortical dysplasia and nodular heterotopias, and 96.36% intracranial cysts (with similar rates of 2b and 2d). As well as demonstrating that posterior fossa abnormalities (found in 63.63% of cases) should also be considered a common feature in AIC, our study highlighted the presence (in 76.36%) of basal ganglia dysmorphisms (never previously reported). CONCLUSION: The AIC neuroradiologic phenotype consists of a complex brain malformation whose presence should be considered central to the diagnosis. Basal ganglia dysmorphisms are frequently associated. Our work underlines the importance of MRI and EEG, both for correct diagnosis and as a factor for predicting long-term outcome. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that for patients with AIC, specific MRI abnormalities and EEG at onset are associated with clinical outcomes.


Assuntos
Síndrome de Aicardi/diagnóstico por imagem , Gânglios da Base/anormalidades , Adolescente , Adulto , Encéfalo/anormalidades , Encéfalo/diagnóstico por imagem , Criança , Pré-Escolar , Ingestão de Líquidos , Epilepsia Resistente a Medicamentos/diagnóstico por imagem , Epilepsia Resistente a Medicamentos/etiologia , Ingestão de Alimentos , Eletroencefalografia , Feminino , Humanos , Lactente , Imageamento por Ressonância Magnética , Destreza Motora , Retina/diagnóstico por imagem , Estudos Retrospectivos , Convulsões/diagnóstico por imagem , Convulsões/etiologia , Convulsões/fisiopatologia , Resultado do Tratamento , Adulto Jovem
12.
PLoS One ; 15(11): e0241436, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33147254

RESUMO

BACKGROUND: Neuroradiological studies have greatly improved the knowledge and diagnoses of cerebral palsy with its underlying pathology, types and accompanying changes in brain morphology. However, there is no published study on cerebral palsy neuroimaging patterns in Ethiopia. METHODS: Retrospective chart and neuroimaging reviews were conducted among pediatric patients, who attended Ayder Comprehensive Specialized Hospital between January 2016 and August 2019, fulfilling the study criteria. The magnetic resonance images and computed tomography scans reviewed by a neuroradiologist and/or pediatric neurologist were included. Data was collected using a structured checklist and analyzed using SPSS statistical software version 22. Results were represented using tables, graphs and images. RESULTS: The median age at neuroimaging was 2 years. There were more males (54.5%) than females (45.5%) with a male: female ratio of 1.2:1. Majority of the patients had magnetic resonance (81.8%) as opposed to computed tomography scans (18.2%). Most of the patients (69.7%) had been born at term with spastic quadriplegia (33.3%) found to be the leading type of cerebral palsy. 30.3% of the patients had normal neuroimaging studies whereas 69.7% had neuroimaging abnormalities. Anomalies included pathologies of the white matter (18.2%), basal ganglia (15.2%), cortex and lobes (27.3%), corpus callosum (6.1%), lateral ventricles (12.1%), cysts (18.2%) and cerebellum (3%), respectively. Other findings were seen in 45.5% of the patients. CONCLUSION: Severe forms of cerebral palsy (spastic quadriplegia) were most common with majorly cortical and subcortical brain involvement.


Assuntos
Paralisia Cerebral/diagnóstico por imagem , Paralisia Cerebral/patologia , Hospitais , Neuroimagem , Adolescente , Encéfalo/anormalidades , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Criança , Pré-Escolar , Etiópia , Feminino , Humanos , Lactente , Masculino
13.
Niger J Clin Pract ; 23(11): 1561-1565, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33221782

RESUMO

Background: Orofacial clefts (OCs) are one of the most common craniofacial anomalies and are reported to be associated with congenital cardiovascular anomalies (CCAs). However, there is paucity of data in African populations on the risk of CCAs in OC patients compared to the general population. Aims: This study aims to determine the odds of congenital cardiovascular anomalies in patients with OC compared to the general population. Subjects and Methods: A case-control study design was used. Case subjects were non-syndromic OC subjects, while controls were non-syndromic subjects without OC. All subjects were thoroughly assessed by a pediatric cardiologist for CCAs; and grouped by OC phenotypic type (cleft lip and/or alveolus, cleft lip and palate, cleft palate only and Tessier cleft). Statistical analysis was done using STATA version 14 (College Station, Texas), and significance was placed at P value ≤0.05. Results: A total of 120 subjects (60 cases and 60 controls) were enrolled in the study. In total, 23.3% of the subjects had CCAs. Among the case group, 40% had CCAs compared to 6.7% in the control group. Patent foramen ovale (18.3%) and atrial septal defects (10.0%) were the most common type of CCAs in cases, respectively. Further, cases had significantly higher odds of CCAs compared to controls (OR: 9.3; CI: 2.8, 39.4). Conclusions: Our finding reveals that the odds of CCAs are significantly higher in patients with OC than the general population. Future studies could assess the effect of CCAs on surgical outcome.


Assuntos
Encéfalo/anormalidades , Doenças Cardiovasculares/congênito , Fenda Labial/epidemiologia , Fissura Palatina/epidemiologia , Doenças Cardiovasculares/diagnóstico por imagem , Doenças Cardiovasculares/epidemiologia , Estudos de Casos e Controles , Pré-Escolar , Ecocardiografia , Feminino , Humanos , Lactente , Masculino , Nigéria/epidemiologia
14.
Science ; 370(6520)2020 11 27.
Artigo em Inglês | MEDLINE | ID: mdl-33243861

RESUMO

The number of disease risk genes and loci identified through human genetic studies far outstrips the capacity to systematically study their functions. We applied a scalable genetic screening approach, in vivo Perturb-Seq, to functionally evaluate 35 autism spectrum disorder/neurodevelopmental delay (ASD/ND) de novo loss-of-function risk genes. Using CRISPR-Cas9, we introduced frameshift mutations in these risk genes in pools, within the developing mouse brain in utero, followed by single-cell RNA-sequencing of perturbed cells in the postnatal brain. We identified cell type-specific and evolutionarily conserved gene modules from both neuronal and glial cell classes. Recurrent gene modules and cell types are affected across this cohort of perturbations, representing key cellular effects across sets of ASD/ND risk genes. In vivo Perturb-Seq allows us to investigate how diverse mutations affect cell types and states in the developing organism.


Assuntos
Transtorno Autístico/genética , Transtorno Autístico/patologia , Encéfalo/anormalidades , Neuroglia/patologia , Neurônios/patologia , Animais , Anquirinas/genética , Anquirinas/metabolismo , Sistemas CRISPR-Cas , Proteínas de Ligação a DNA/genética , Mutação da Fase de Leitura , Perfilação da Expressão Gênica , Loci Gênicos , Humanos , Camundongos , Neuroglia/metabolismo , Neurônios/metabolismo , Proteínas Repressoras/genética , Risco , Fatores de Transcrição/genética
15.
Am J Hum Genet ; 107(6): 1178-1185, 2020 12 03.
Artigo em Inglês | MEDLINE | ID: mdl-33242396

RESUMO

We have previously described a heart-, eye-, and brain-malformation syndrome caused by homozygous loss-of-function variants in SMG9, which encodes a critical component of the nonsense-mediated decay (NMD) machinery. Here, we describe four consanguineous families with four different likely deleterious homozygous variants in SMG8, encoding a binding partner of SMG9. The observed phenotype greatly resembles that linked to SMG9 and comprises severe global developmental delay, microcephaly, facial dysmorphism, and variable congenital heart and eye malformations. RNA-seq analysis revealed a general increase in mRNA expression levels with significant overrepresentation of core NMD substrates. We also identified increased phosphorylation of UPF1, a key SMG1-dependent step in NMD, which most likely represents the loss of SMG8--mediated inhibition of SMG1 kinase activity. Our data show that SMG8 and SMG9 deficiency results in overlapping developmental disorders that most likely converge mechanistically on impaired NMD.


Assuntos
Deficiências do Desenvolvimento/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Degradação do RNAm Mediada por Códon sem Sentido , Adolescente , Encéfalo/anormalidades , Criança , Pré-Escolar , Consanguinidade , Deficiências do Desenvolvimento/metabolismo , Saúde da Família , Feminino , Deleção de Genes , Ligação Genética , Cardiopatias Congênitas/genética , Homozigoto , Humanos , Lactente , Masculino , Linhagem , Fenótipo , Fosforilação , RNA Helicases/metabolismo , RNA Mensageiro/metabolismo , RNA-Seq , Transativadores/metabolismo , Adulto Jovem
16.
Am J Hum Genet ; 107(6): 1129-1148, 2020 12 03.
Artigo em Inglês | MEDLINE | ID: mdl-33186545

RESUMO

The endosomal sorting complexes required for transport (ESCRTs) are essential for multiple membrane modeling and membrane-independent cellular processes. Here we describe six unrelated individuals with de novo missense variants affecting the ATPase domain of VPS4A, a critical enzyme regulating ESCRT function. Probands had structural brain abnormalities, severe neurodevelopmental delay, cataracts, growth impairment, and anemia. In cultured cells, overexpression of VPS4A mutants caused enlarged endosomal vacuoles resembling those induced by expression of known dominant-negative ATPase-defective forms of VPS4A. Proband-derived fibroblasts had enlarged endosomal structures with abnormal accumulation of the ESCRT protein IST1 on the limiting membrane. VPS4A function was also required for normal endosomal morphology and IST1 localization in iPSC-derived human neurons. Mutations affected other ESCRT-dependent cellular processes, including regulation of centrosome number, primary cilium morphology, nuclear membrane morphology, chromosome segregation, mitotic spindle formation, and cell cycle progression. We thus characterize a distinct multisystem disorder caused by mutations affecting VPS4A and demonstrate that its normal function is required for multiple human developmental and cellular processes.


Assuntos
ATPases Associadas a Diversas Atividades Celulares/genética , Complexos Endossomais de Distribuição Requeridos para Transporte/genética , Mutação de Sentido Incorreto , Transtornos do Neurodesenvolvimento/genética , ATPases Vacuolares Próton-Translocadoras/genética , Alelos , Animais , Encéfalo/anormalidades , Ciclo Celular , Centrossomo/metabolismo , Endossomos/metabolismo , Fibroblastos/metabolismo , Genômica , Células HEK293 , Células HeLa , Humanos , Camundongos , Neurônios/metabolismo , Domínios Proteicos , Transporte Proteico , Fuso Acromático/metabolismo
17.
Int J Mol Sci ; 21(20)2020 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-33092303

RESUMO

Mutations in the EPM2A and EPM2B genes, encoding laforin and malin proteins respectively, are responsible for Lafora disease, a fatal form of progressive myoclonus epilepsy with autosomal recessive inheritance. Neuroimaging studies of patients with Lafora disease have shown different degrees of brain atrophy, decreased glucose brain uptake and alterations on different brain metabolites mainly in the frontal cortex, basal ganglia and cerebellum. Mice deficient for laforin and malin present many features similar to those observed in patients, including cognitive, motor, histological and epileptic hallmarks. We describe the neuroimaging features found in two mouse models of Lafora disease. We found altered volumetric values in the cerebral cortex, hippocampus, basal ganglia and cerebellum using magnetic resonance imaging (MRI). Positron emission tomography (PET) of the cerebral cortex, hippocampus and cerebellum of Epm2a-/- mice revealed abnormal glucose uptake, although no alterations in Epm2b-/- mice were observed. Magnetic resonance spectroscopy (MRS) revealed significant changes in the concentration of several brain metabolites, including N-acetylaspartate (NAA), in agreement with previously described findings in patients. These data may provide new insights into disease mechanisms that may be of value for developing new biomarkers for diagnosis, prevention and treatment of Lafora disease using animal models.


Assuntos
Encefalopatias/metabolismo , Encéfalo/anormalidades , Modelos Animais de Doenças , Doença de Lafora/metabolismo , Proteínas Tirosina Fosfatases não Receptoras/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Animais , Atrofia , Gânglios da Base/diagnóstico por imagem , Gânglios da Base/metabolismo , Gânglios da Base/patologia , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Encefalopatias/genética , Encefalopatias/patologia , Cerebelo/diagnóstico por imagem , Cerebelo/metabolismo , Cerebelo/patologia , Córtex Cerebral/diagnóstico por imagem , Córtex Cerebral/metabolismo , Córtex Cerebral/patologia , Glucose/metabolismo , Hipocampo/diagnóstico por imagem , Hipocampo/metabolismo , Hipocampo/patologia , Humanos , Doença de Lafora/genética , Doença de Lafora/patologia , Imageamento por Ressonância Magnética/métodos , Camundongos Knockout , Mutação , Tomografia por Emissão de Pósitrons/métodos , Proteínas Tirosina Fosfatases não Receptoras/genética , Ubiquitina-Proteína Ligases/genética
18.
Am J Med Genet A ; 182(11): 2540-2551, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32864841

RESUMO

There are limited data on the longitudinal frequency and severity of the symptoms and complications of achondroplasia. We undertook a retrospective electronic chart review of 114 patients to develop a more thorough understanding of the lifetime impact of achondroplasia. Craniocervical stenosis (involving the foramen magnum with or without cervical vertebrae C1 and/or C2) was noted in nearly 50% of patients with craniovertebral junction imaging; however, corrective decompression surgery was only needed in 6% of patients. No children in our cohort died at 4 years of age or under. Kyphosis was present in most patients but usually resolved in early childhood. Cervical and lumbar stenosis were diagnosed in children and adults while, genu varum, elbow contractures, and radial head dislocations were identified during childhood. Central sleep apnea and obstructive sleep apnea were present in children, while the diagnosis of obstructive sleep apnea was shown to recur in adulthood. Cardiovascular risk factors were present in only 7% of patients. A range of mental health disorders were identified, with most diagnoses being made before 18 years of age. Our data show that achondroplasia has a significant impact on patients' physical health, and complications continue to be reported and require intervention throughout patients' lifetimes. This highlights the need for continuous support beyond pediatric care, by adult care clinicians experienced with managing the long-term complications of achondroplasia.


Assuntos
Acondroplasia/complicações , Cifose/complicações , Doenças do Sistema Nervoso/complicações , Apneia Obstrutiva do Sono/complicações , Acondroplasia/genética , Adolescente , Adulto , Encéfalo/anormalidades , Vértebras Cervicais/cirurgia , Criança , Pré-Escolar , Constrição Patológica , Bases de Dados Factuais , Feminino , Forame Magno/cirurgia , Humanos , Lactente , Recém-Nascido , Cifose/genética , Cifose/cirurgia , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Doenças do Sistema Nervoso/genética , Ortopedia , Estudos Retrospectivos , Apneia Obstrutiva do Sono/genética , Adulto Jovem
19.
Am J Med Genet C Semin Med Genet ; 184(3): 644-655, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32888375

RESUMO

Mosaic genetic mutations may be somatic, germline, or "gonosomal" and have the potential to cause genetic syndromes, disorders, or malformations. Mutations can occur at any point in embryonic development and the timing determines the extent of distribution of the mutation throughout the body and different tissue types. The eye and visual pathway offer a unique opportunity to study somatic and gonosomal mosaic mutations as the eye consists of tissues derived from all three germ layers allowing disease pathology to be assessed with noninvasive imaging. In this review, we describe systemic and ocular manifestations in a child with mosaic Coffin-Siris syndrome. The patient presented with a significant medical history of accommodative esotropia and hyperopia, macrocephaly, polydactyly, global developmental delay, hypotonia, ureteropelvic junction (UPJ) obstruction, and brain MRI abnormalities. The ophthalmic findings in this patient were nonspecific, however, they are consistent with ocular manifestations reported in other patients with Coffin-Siris syndrome. We also review ophthalmic findings of select mosaic chromosomal and single-gene disorders. Ophthalmic assessment alongside clinical genetic testing may play an important role in diagnosis of genetic syndromes as well as understanding disease pathology, particularly when mosaicism plays a role.


Assuntos
Anormalidades Múltiplas/genética , Encéfalo/diagnóstico por imagem , Proteínas de Ligação a DNA/genética , Face/anormalidades , Predisposição Genética para Doença , Deformidades Congênitas da Mão/genética , Deficiência Intelectual/genética , Micrognatismo/genética , Pescoço/anormalidades , Fatores de Transcrição/genética , Anormalidades Múltiplas/diagnóstico por imagem , Anormalidades Múltiplas/patologia , Encéfalo/anormalidades , Criança , Pré-Escolar , Face/diagnóstico por imagem , Face/patologia , Feminino , Deformidades Congênitas da Mão/diagnóstico por imagem , Deformidades Congênitas da Mão/patologia , Humanos , Lactente , Deficiência Intelectual/diagnóstico por imagem , Deficiência Intelectual/patologia , Masculino , Micrognatismo/diagnóstico por imagem , Micrognatismo/patologia , Mosaicismo , Mutação/genética , Pescoço/diagnóstico por imagem , Pescoço/patologia , Proteínas Nucleares/genética , Fenótipo
20.
AJNR Am J Neuroradiol ; 41(11): 2146-2154, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32943421

RESUMO

BACKGROUND AND PURPOSE: The superior diagnostic accuracy of fetal MR imaging in detecting fetal brain abnormalities has been previously demonstrated; however, the ability of fetal MR imaging to prognosticate postnatal outcome is not well-studied. We performed a retrospective analysis to determine the prognostic accuracy of fetal MR imaging in predicting postnatal neurodevelopmental outcome. MATERIALS AND METHODS: We identified all fetal MR imaging performed at the Children's Hospital of Eastern Ontario during a 10-year period and assessed agreement between prenatal prognosis and postnatal outcome. Prenatal prognosis was determined by a pediatric neurologist who reviewed the fetal MR imaging report and categorized each pregnancy as having a favorable, indeterminate, or poor prognosis. Assessment of postnatal neurodevelopmental outcome was made solely on the basis of the child's Gross Motor Function Classification System score and whether the child developed epilepsy. Postnatal outcome was categorized as favorable, intermediate, or poor. We also assessed the diagnostic accuracy of fetal MR imaging by comparing prenatal and postnatal imaging diagnoses. RESULTS: We reviewed 145 fetal MR images: 114 were included in the assessment of diagnostic accuracy, and 104 were included in the assessment of prognostic accuracy. There was 93.0% agreement between prenatal and postnatal imaging diagnoses. Prognosis was favorable in 44.2%, indeterminate in 50.0%, and poor in 5.8% of pregnancies. There was 93.5% agreement between a favorable prenatal prognosis and a favorable postnatal outcome. CONCLUSIONS: A favorable prenatal prognosis is highly predictive of a favorable postnatal outcome. Further studies are required to better understand the role of fetal MR imaging in prognosticating postnatal development, particularly in pregnancies with indeterminate and poor prognoses.


Assuntos
Encefalopatias , Feto/diagnóstico por imagem , Imageamento por Ressonância Magnética/métodos , Transtornos do Neurodesenvolvimento/etiologia , Diagnóstico Pré-Natal/métodos , Encéfalo/anormalidades , Encéfalo/diagnóstico por imagem , Encefalopatias/complicações , Encefalopatias/congênito , Encefalopatias/diagnóstico por imagem , Feminino , Humanos , Masculino , Gravidez , Prognóstico , Estudos Retrospectivos
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...