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1.
Pediatrics ; 146(3)2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32820067

RESUMO

An 11-week-old unvaccinated, term Amish boy initially presented with poor feeding, microcephaly, failure to thrive, and developmental delays. His physical examination was significant for both weight and head circumference being less than the third percentile, and he was noted to have micrognathia, truncal hypotonia, and head lag. He was admitted to the pediatric hospital medicine service for further diagnostic evaluation. Laboratory studies assessing for endocrinological and metabolic etiologies yielded negative results, and imaging studies (including a chest radiograph, echocardiogram, and abdominal ultrasound) were normal. However, intracranial calcifications were noted on a head ultrasound. The etiology of his constellation of symptoms was initially thought to be infectious, but the ultimate diagnosis was not made until after discharge from the pediatric hospital medicine service.


Assuntos
Doenças Autoimunes do Sistema Nervoso/diagnóstico por imagem , Calcinose/diagnóstico por imagem , Microcefalia/diagnóstico por imagem , Hipotonia Muscular/diagnóstico por imagem , Malformações do Sistema Nervoso/diagnóstico por imagem , Doenças Autoimunes do Sistema Nervoso/sangue , Doenças Autoimunes do Sistema Nervoso/complicações , Calcinose/sangue , Calcinose/complicações , Cefalometria/métodos , Humanos , Lactente , Masculino , Microcefalia/sangue , Microcefalia/complicações , Hipotonia Muscular/sangue , Hipotonia Muscular/complicações , Malformações do Sistema Nervoso/sangue , Malformações do Sistema Nervoso/complicações
2.
Eur J Paediatr Neurol ; 25: 106-112, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32014392

RESUMO

OBJECTIVES: To systematically investigate chromosomal abnormalities and copy number variants (CNVs) in fetuses with different types of ventriculomegaly (VM) by karyotyping and/or chromosomal microarray analysis (CMA). METHODS: This retrospective study included 312 fetuses diagnosed with VM. Amniotic fluid and umbilical blood samples were collected by amniocentesis and cordocentesis, respectively, and subjected to karyotyping and/or CMA. Subgroup analysis by VM type, including mild VM (MVM) and severe VM (SVM), unilateral and bilateral VM, isolated VM (IVM), and non-isolated VM (NIVM), was performed. RESULTS: The detection rate of chromosomal abnormalities was 12.1% (34/281) by karyotyping and 20.6% when CMA was additionally performed (P < 0.05). Abnormalities were identified by CMA in 17.4% (38/218) of fetuses and pathogenic CNVs in 5.0% (11/218). Notably, CMA detected CNVs in 10.6% (23/218) of fetuses with normal karyotypes. The incidence of chromosomal abnormalities by karyotyping was higher in bilateral than in unilateral VM (20.5% versus 6.5%), whereas the incidence detected by CMA was higher in NIVM than in IVM (21.4% versus 10.3%; both P < 0.05). In NIVM, CMA provided an additional detection rate of 11.4% (16/140) and a detection rate of 10.0% for pathogenic CNVs and aneuploidies. Central nervous system (CNS) abnormalities were the most common other ultrasonic abnormalities. CONCLUSIONS: CMA is highly recommended for prenatal diagnosis of fetal VM together with karyotyping, especially in fetuses with bilateral VM and NIVM with abnormal CNS findings. Further study is necessary to explore the relationships between genotypes and phenotypes to facilitate prenatal diagnosis of fetal VM.


Assuntos
Ventrículos Cerebrais/anormalidades , Malformações do Sistema Nervoso/diagnóstico , Malformações do Sistema Nervoso/genética , Análise de Sequência com Séries de Oligonucleotídeos/métodos , Diagnóstico Pré-Natal/métodos , Aberrações Cromossômicas , Variações do Número de Cópias de DNA , Feminino , Feto/anormalidades , Humanos , Hidrocefalia/diagnóstico , Hidrocefalia/etiologia , Cariotipagem/métodos , Malformações do Sistema Nervoso/complicações , Gravidez , Estudos Retrospectivos
3.
Childs Nerv Syst ; 35(11): 2055-2069, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31289853

RESUMO

PURPOSE: Currently, the interest on craniosynostosis in the clinical practice is raised by their increased frequency and their genetic implications other than by the still existing search of less invasive surgical techniques. These reasons, together with the problem of legal issues, make the need of a definite diagnosis for a crucial problem, even in single-suture craniosynostosis (SSC). Although the diagnosis of craniosynostosis is primarily the result of physical examination, craniometrics measuring, and observation of the skull deformity, the radiological assessment currently plays an important role in the confirmation of the diagnosis, the surgical planning, and even the postoperative follow-up. On the other hand, in infants, the use of radiation or the need of sedation/anesthesia raises the problem to reduce them to minimum to preserve such a delicate category of patient from their adverse effects. METHODS, RESULTS AND CONCLUSIONS: This review aims at summarizing the state of the art of the role of radiology in craniosynostosis, mainly focusing on indications and techniques, to provide an update not only to pediatric neurosurgeons or maxillofacial surgeons but also to all the other specialists involved in their management, like neonatologists, pediatricians, clinical geneticists, and pediatric neurologists.


Assuntos
Craniossinostoses/diagnóstico por imagem , Procedimentos Neurocirúrgicos , Procedimentos Cirúrgicos Reconstrutivos , Cefalometria , Craniossinostoses/complicações , Craniossinostoses/cirurgia , Humanos , Imageamento Tridimensional , Lactente , Malformações do Sistema Nervoso/complicações , Malformações do Sistema Nervoso/diagnóstico por imagem , Radiografia , Tomografia Computadorizada por Raios X
4.
Front Immunol ; 10: 1028, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31139185

RESUMO

A hallmark of systemic lupus erythematosus (SLE), and several related autoimmune diseases, is the presence of autoantibodies against nucleic acids and nucleic acid-binding proteins, as well as elevated type I interferons (IFNs), which appear to be instrumental in disease pathogenesis. Here we discuss the sources and proposed mechanisms by which a range of cellular RNA and DNA species can become pathogenic and trigger the nucleic acid sensors that drive type I interferon production. Potentially SLE-promoting DNA may originate from pieces of chromatin, from mitochondria, or from reverse-transcribed cellular RNA, while pathogenic RNA may arise from mis-localized, mis-processed, ancient retroviral, or transposable element-derived transcripts. These nucleic acids may leak out from dying cells to be internalized and reacted to by immune cells or they may be generated and remain to be sensed intracellularly in immune or non-immune cells. The presence of aberrant DNA or RNA is normally counteracted by effective counter-mechanisms, the loss of which result in a serious type I IFN-driven disease called Aicardi-Goutières Syndrome. However, in SLE it remains unclear which mechanisms are most critical in precipitating disease: aberrant RNA or DNA, overly sensitive sensor mechanisms, or faulty counter-acting defenses. We propose that the clinical heterogeneity of SLE may be reflected, in part, by heterogeneity in which pathogenic nucleic acid molecules are present and which sensors and pathways they trigger in individual patients. Elucidation of these events may result in the recognition of distinct "endotypes" of SLE, each with its distinct therapeutic choices.


Assuntos
DNA/imunologia , Lúpus Eritematoso Sistêmico , RNA/imunologia , Animais , Doenças Autoimunes do Sistema Nervoso/complicações , Doenças Autoimunes do Sistema Nervoso/imunologia , Doenças Autoimunes do Sistema Nervoso/patologia , Humanos , Interferon Tipo I/imunologia , Lúpus Eritematoso Sistêmico/etiologia , Lúpus Eritematoso Sistêmico/imunologia , Lúpus Eritematoso Sistêmico/patologia , Lúpus Eritematoso Sistêmico/terapia , Malformações do Sistema Nervoso/complicações , Malformações do Sistema Nervoso/imunologia , Malformações do Sistema Nervoso/patologia
5.
Pediatr Neurol ; 96: 37-39, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30898416

RESUMO

BACKGROUND: Aicardi-Goutières syndrome is an early-onset encephalopathy with presumed immune pathogenesis caused by inherited defects in nucleic acid metabolism. It is a model disease to study systemic autoimmunity, and there are many clinical, genetic, and basic science considerations that underline a possible overlap between Aicardi-Goutières syndrome and systemic lupus erythematosus. RESULTS: We describe a 15-year-old girl with Aicardi-Goutières syndrome due to compound heterozygous pathogenic variants in SAMHD1 (sterile alpha motif domain and HD domain-containing protein 1). Over time, she developed multiple autoimmune diseases (vitiligo, alopecia areata, immune thrombocytopenia, positive antithyroglobulin antibodies) without positive antinuclear antibody or features of systemic lupus erythematosus. Her thrombocytopenia was refractory to treatment with corticosteroids and intravenous immunoglobulin but responded to a standard course of rituximab. CONCLUSION: This is the first report of a multiple autoimmune syndrome in a patient with molecularly proven Aicardi-Goutières syndrome. This study illustrates an emerging pattern of the natural history of Aicardi-Goutières syndrome characterized by early encephalopathic presentation followed by symptoms of systemic autoimmunity.


Assuntos
Alopecia/etiologia , Doenças Autoimunes do Sistema Nervoso/complicações , Doenças Autoimunes/etiologia , Leucoencefalopatias/etiologia , Malformações do Sistema Nervoso/complicações , Trombocitopenia/etiologia , Vitiligo/etiologia , Adolescente , Doenças Autoimunes do Sistema Nervoso/genética , Feminino , Humanos , Malformações do Sistema Nervoso/genética , Proteína 1 com Domínio SAM e Domínio HD/genética
7.
Arthritis Rheumatol ; 71(5): 829-831, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30666809
8.
Prenat Diagn ; 39(2): 124-129, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30499202

RESUMO

OBJECTIVE: To investigate the relationship of ventriculomegaly (VM) with postnatal neurological development. METHODS: Fetuses with isolated VM on MRI (n = 160; VM group) were separated into three subgroups according to lateral ventricle width: subgroup A (10.0-12.0 mm; n = 113), subgroup B (12.1-15.0 mm; n = 37), and subgroup C (>15.0 mm; n = 10). Fifty normal fetuses formed a control group. Post-delivery changes in ventricular width and neurological development were assessed with MRI/ultrasonography and the Gesell Development Schedules (GDS), respectively, at 3, 6, 12, and 18 months. RESULTS: GDS scores of subgroup A and subgroup B did not differ from that of the controls at 3 and 6 months. Subgroup B scores differed significantly from the control scores at 12 and 18 months. Subgroup C scores differed from the control scores at all-time points (all P < 0.05). In the VM group, GDS scores at 12 and 18 months were significantly different from the scores at 3 months, and the score at 18 months was significantly different from the score at 6 months (P < 0.05 for all). CONCLUSION: The milder the VM, the more likely it was to disappear or improve in the postnatal period. However, specific postnatal rehabilitation should be considered when fetal ventricular width is greater than 12.1 mm.


Assuntos
Imagem por Ressonância Magnética , Malformações do Sistema Nervoso/diagnóstico , Transtornos do Neurodesenvolvimento/diagnóstico , Diagnóstico Pré-Natal/métodos , Ultrassonografia Pré-Natal , Adulto , Estudos de Casos e Controles , Ventrículos Cerebrais/anormalidades , Ventrículos Cerebrais/diagnóstico por imagem , Deficiências do Desenvolvimento/diagnóstico , Deficiências do Desenvolvimento/etiologia , Feminino , Humanos , Recém-Nascido , Masculino , Malformações do Sistema Nervoso/complicações , Malformações do Sistema Nervoso/embriologia , Transtornos do Neurodesenvolvimento/etiologia , Valor Preditivo dos Testes , Gravidez , Prognóstico , Adulto Jovem
9.
J Matern Fetal Neonatal Med ; 32(23): 3986-3992, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29865922

RESUMO

Introduction: Despite meticulous investigation of polyhydramnios cases, in many of these cases, congenital anomalies are detected only after birth. The aim of our study was to explore the contribution of fetal brain MRI to the detection of CNS anomalies in cases of polyhydramnios. Materials and methods: This was retrospective cohort study on fetuses referred for the investigation of polyhydramnios at a single tertiary center. All fetuses underwent a detailed sonographic anatomical scan and a fetal brain MRI. Isolated and nonisolated polyhydramnios were differentiated according to associated anomalies. MRI findings were compared between the groups. Results: A total of 46 fetuses were included in the study. Brain anomalies were detected in ultrasound in 12 (26%) cases while MRI detected brain anomalies in 23 (50%) cases. MRI detected more anomalies in fetuses with nonisolated compared to isolated polyhydramnios (62.9% and 31.6%, respectively, p = .019). Conclusions: Fetal brain MRI may contribute to the evaluation of fetuses with polyhydramnios. The clinical value and cost-effectiveness of MRI use in the routine work-up of polyhydramnios should be assessed in future studies.


Assuntos
Encéfalo/diagnóstico por imagem , Imagem por Ressonância Magnética , Malformações do Sistema Nervoso/diagnóstico , Poli-Hidrâmnios/diagnóstico , Diagnóstico Pré-Natal/métodos , Adulto , Encéfalo/anormalidades , Feminino , Feto/diagnóstico por imagem , Idade Gestacional , Humanos , Masculino , Malformações do Sistema Nervoso/complicações , Poli-Hidrâmnios/etiologia , Valor Preditivo dos Testes , Gravidez , Estudos Retrospectivos
10.
Eur Spine J ; 28(2): 421-425, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-29445948

RESUMO

PURPOSE: Documents indicated that the average prevalence of intraspinal neural axis abnormalities (INAAs) in presumed idiopathic scoliosis (PIS) patients was about 17.7%. However, paucity study focuses on the incidence of INAAs in severe spinal deformity (SSDs). In this study, we investigate the incidence of intraspinal neural axis abnormalities (IINAAs) and the clinical relevance in SSD at a single center. METHODS: All the patients with SSDs admitted for spinal surgery were evaluated from 2003 to 2014. INCLUSION CRITERIA: patients who present with coronal Cobb over 90° (and/or the sagittal Cobb ≥ 90°); patients with whole spine magnetic resonance imaging (MRI) done preoperatively; and patients with documented clinical findings preoperatively. EXCLUSION CRITERIA: ankylosing spondylitis, adult onset scoliosis, scoliosis secondary to bone destruction, and spinal dysraphism. RESULTS: 101 patients fulfilled the criteria were included. 43 patients were detected with INAAs (42.6%, 43/101). The most common INAAs was syrinx (S) (16/43, 37.2%). Of which, 43.7% (7/16), 37.5% (6/16), and 18.7% (3/16) were spindle, slit, and swelling types, respectively. Most of them were located in thoracic (6/16, 37.5%) and cervical (5/16, 31.3%) region. MRI revealed Chiari malformation with syringomyelia (C + S) in ten patients (10/43, 23.2%), Chiari malformation (C) in 6 patients (6/43, 13.9%) and others in 11 patients (11/43, 25.6%). As to the etiology, most patients with INAAs were PIS (34/43, 79.1%). On clinical examination, 16 of 101 patients (16/101, 15.8%) had abnormal neurologic signs. 15 of 16 patients (15/16, 93.7%) with abnormal neurologic signs had INAAs on MRI. On the other hand, 28 of 43 patients (28/43, 65.1%) with INAAs on MRI presented neurologically intact. 28 of 85 patients (28/85, 32.9%) with neurologically intact were detected with INAAs on MRI. CONCLUSION: The incidence of INAAs in SSDs was 42.6%. 65.1% of them present intact neurologic status. The most common neural anomaly was syrinx. Preoperative whole spine MRI must be beneficial for SSDs even in the absence of neurological findings. These slides can be retrieved under Electronic Supplementary Material.


Assuntos
Imagem por Ressonância Magnética , Malformações do Sistema Nervoso , Escoliose , Adolescente , Adulto , Criança , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Malformações do Sistema Nervoso/complicações , Malformações do Sistema Nervoso/diagnóstico por imagem , Estudos Retrospectivos , Escoliose/complicações , Escoliose/diagnóstico por imagem , Adulto Jovem
12.
Medicine (Baltimore) ; 97(52): e13893, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30593198

RESUMO

Tetraparesis is usually due to cerebral palsy (CP), inborn errors of metabolism, neurogenetic disorders and spinal cord lesions. However, literature data reported that about 10% of children with tetraparesis show a negative/non-specific neuroradiological findings without a specific etiological cause. Aicardi Goutières Syndrome (AGS) is a genetic encephalopathy that may cause tetraparesis. Interferon signature is a reliable biomarker for AGS and could be performed in sine-causa tetraparesis. The aim of the study was to examine the type I interferon signature and AGS related-genes in children with sine causa tetraparesis, to look for misdiagnosed AGS. A secondary aim was to determine which aspects of the patient history, clinical picture and brain imaging best characterize tetraparesis due to an interferonopathy.Seven out of 78 patients affected by tetraparesis, characterized by unremarkable pre-peri-postnatal history and normal/non-specific brain magnetic resonance imaging (MRI) were selected and underwent anamnestic data collection, clinical examination, brain imaging review, peripheral blood interferon signature and AGS-related genes analysis.At our evaluation time (mean age of 11.9 years), all the 7 patients showed spastic-dystonic tetraparesis. At clinical onset brain MRI was normal in 4 and with non-specific abnormalities in 3; at follow-up 3 patients presented with new white-matter lesions, associated with brain calcification in 1 case. Interferon signature was elevated in one subject who presented also a mutation of the IFIH1 gene.AGS should be considered in sine-causa tetraparesis. Core features of interferonopathy-related tetraparesis are: onset during first year of life, psychomotor regression with tetraparesis evolution, brain white-matter lesions with late calcifications. A positive interferon signature may be a helpful marker to select patients with spastic tetraparesis who should undergo genetic analysis for AGS.


Assuntos
Doenças Autoimunes do Sistema Nervoso/complicações , Doenças Autoimunes do Sistema Nervoso/diagnóstico , Interferon Tipo I/biossíntese , Malformações do Sistema Nervoso/complicações , Malformações do Sistema Nervoso/diagnóstico , Paresia/etiologia , Adolescente , Doenças Autoimunes do Sistema Nervoso/diagnóstico por imagem , Doenças Autoimunes do Sistema Nervoso/genética , Biomarcadores , Encéfalo/diagnóstico por imagem , Criança , Pré-Escolar , Feminino , Humanos , Interferon Tipo I/sangue , Interferon Tipo I/genética , Imagem por Ressonância Magnética , Masculino , Malformações do Sistema Nervoso/diagnóstico por imagem , Malformações do Sistema Nervoso/genética , Projetos Piloto , Adulto Jovem
13.
Neuron ; 100(6): 1354-1368.e5, 2018 12 19.
Artigo em Inglês | MEDLINE | ID: mdl-30449657

RESUMO

Corpus callosum malformations are associated with a broad range of neurodevelopmental diseases. We report that de novo mutations in MAST1 cause mega-corpus-callosum syndrome with cerebellar hypoplasia and cortical malformations (MCC-CH-CM) in the absence of megalencephaly. We show that MAST1 is a microtubule-associated protein that is predominantly expressed in post-mitotic neurons and is present in both dendritic and axonal compartments. We further show that Mast1 null animals are phenotypically normal, whereas the deletion of a single amino acid (L278del) recapitulates the distinct neurological phenotype observed in patients. In animals harboring Mast1 microdeletions, we find that the PI3K/AKT3/mTOR pathway is unperturbed, whereas Mast2 and Mast3 levels are diminished, indicative of a dominant-negative mode of action. Finally, we report that de novo MAST1 substitutions are present in patients with autism and microcephaly, raising the prospect that mutations in this gene give rise to a spectrum of neurodevelopmental diseases.


Assuntos
Agenesia do Corpo Caloso/genética , Cerebelo/anormalidades , Regulação da Expressão Gênica no Desenvolvimento/genética , Malformações do Desenvolvimento Cortical/genética , Proteínas Associadas aos Microtúbulos/genética , Mutação/genética , Malformações do Sistema Nervoso/genética , Agenesia do Corpo Caloso/complicações , Agenesia do Corpo Caloso/diagnóstico por imagem , Agenesia do Corpo Caloso/patologia , Animais , Animais Recém-Nascidos , Apoptose/genética , Encéfalo/metabolismo , Encéfalo/patologia , Células Cultivadas , Cerebelo/diagnóstico por imagem , Criança , Deficiências do Desenvolvimento/complicações , Deficiências do Desenvolvimento/diagnóstico por imagem , Deficiências do Desenvolvimento/genética , Modelos Animais de Doenças , Embrião de Mamíferos , Feminino , Humanos , Masculino , Malformações do Desenvolvimento Cortical/complicações , Malformações do Desenvolvimento Cortical/diagnóstico por imagem , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas Associadas aos Microtúbulos/deficiência , Proteínas do Tecido Nervoso/metabolismo , Malformações do Sistema Nervoso/complicações , Malformações do Sistema Nervoso/diagnóstico por imagem , Fator de Transcrição PAX6/metabolismo
14.
Am J Med Genet A ; 176(11): 2425-2429, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30289607

RESUMO

We report a female patient with a novel, heterozygous, de novo in-frame deletion in the CASK gene (c.2179-2181 del GTA, p.Val727del) who presents with early onset infantile spasms, hypsarrhythmia on electroencephalogram (EEG), and frontal lobe abnormalities on brain magnetic resonance imaging (MRI) without microcephaly and pontocerebellar hypoplasia. This is the first case report of an in-frame deletion in the CASK gene causing early onset infantile spasms and supratentorial focal brain malformation on brain MRI in the literature. This is also the first report of a female with CASK-related disorder with hypsarrhythmia pattern on EEG. This report expands the clinical phenotypic spectrum in CASK-related disorders in female patients. A heterozygous de novo variant in RORA (c.88 C>G, p.Gln 30Glu) was reported in this patient as a variant of uncertain significance.


Assuntos
Guanilato Quinases/genética , Malformações do Sistema Nervoso/complicações , Malformações do Sistema Nervoso/genética , Deleção de Sequência/genética , Espasmos Infantis/complicações , Espasmos Infantis/genética , Adulto , Idade de Início , Pré-Escolar , Eletroencefalografia , Feminino , Humanos , Lactente , Recém-Nascido , Imagem por Ressonância Magnética , Malformações do Sistema Nervoso/diagnóstico por imagem , Fenótipo , Espasmos Infantis/diagnóstico por imagem
15.
Prenat Diagn ; 38(13): 1028-1034, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30229955

RESUMO

BACKGROUND AND PURPOSE: To examine prenatal MRI and postnatal imaging in fetuses with congenital aqueductal stenosis (CAS) to determine the frequency of association of rhombencephalosynapsis (RES) and how it may affect neonatal intensive care unit (NICU) course. MATERIALS AND METHODS: A single center IRB-approved retrospective study of children with CAS was performed. Prenatal MRI, postnatal images, and clinical data were reviewed. Statistical analysis was performed with SAS statistical software package version 9.3. RESULTS: Aqueduct obstruction was confirmed for all 30 participants. Hydrocephalus required shunting in all but one (97%). Fifteen neonates had CAS with rhomboencephalosynapsis (RES) (50%). Although neonatal course between the two groups was comparable, 53% of CAS with RES neonates required feeding assistance versus 20% in CAS only (P = 0.128). Shunting in the CAS with RES group occurred at average of 6 days of life versus CAS group at 55 days (P = 0.196). Biometry measurements showed a statistically significant decrease in pons antero-posterior diameter in both groups (CAS only P = 0.0049 and CAS with RES P = 0.0003) when compared with norms for gestational age. CONCLUSION: CAS has a high association with RES. Feeding assistance in the NICU and earlier neurosurgical intervention may be required in patients with CAS who also have RES.


Assuntos
Cerebelo/anormalidades , Hidrocefalia/diagnóstico por imagem , Malformações do Sistema Nervoso/diagnóstico por imagem , Adulto , Métodos de Alimentação , Feminino , Humanos , Hidrocefalia/complicações , Hidrocefalia/congênito , Recém-Nascido , Unidades de Terapia Intensiva Neonatal , Terapia Intensiva Neonatal , Imagem por Ressonância Magnética , Masculino , Malformações do Sistema Nervoso/complicações , Procedimentos Neurocirúrgicos , Ponte/diagnóstico por imagem , Gravidez , Diagnóstico Pré-Natal , Estudos Retrospectivos , Índice de Gravidade de Doença , Tomografia Computadorizada por Raios X , Adulto Jovem
16.
Mol Genet Metab ; 125(4): 351-358, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30219631

RESUMO

While pulmonary hypertension (PH) is a potentially life threatening complication of many inflammatory conditions, an association between Aicardi Goutières syndrome (AGS), a rare genetic cause of interferon (IFN) overproduction, and the development of PH has not been characterized to date. We analyzed the cardiac function of individuals with AGS enrolled in the Myelin Disorders Bioregistry Project using retrospective chart review (n = 61). Additional prospective echocardiograms were obtained when possible (n = 22). An IFN signature score, a marker of systemic inflammation, was calculated through the measurement of mRNA transcripts of type I IFN-inducible genes (interferon signaling genes or ISG). Pathologic analysis was performed as available from autopsy samples. Within our cohort, four individuals were identified to be affected by PH: three with pathogenic gain-of-function mutations in the IFIH1 gene and one with heterozygous TREX1 mutations. All studied individuals with AGS were noted to have elevated IFN signature scores (Mann-Whitney p < .001), with the highest levels in individuals with IFIH1 mutations (Mann-Whitney p < .0001). We present clinical and histologic evidence of PH in a series of four individuals with AGS, a rare interferonopathy. Importantly, IFIH1 and TREX1 may represent a novel cause of PH. Furthermore, these findings underscore the importance of screening all individuals with AGS for PH.


Assuntos
Doenças Autoimunes do Sistema Nervoso/complicações , Exodesoxirribonucleases/genética , Hipertensão Pulmonar/etiologia , Hipertensão Pulmonar/patologia , Helicase IFIH1 Induzida por Interferon/genética , Mutação , Malformações do Sistema Nervoso/complicações , Fosfoproteínas/genética , Adolescente , Criança , Humanos , Lactente , Recém-Nascido , Masculino , Prognóstico , Estudos Prospectivos , Estudos Retrospectivos
17.
Bull Exp Biol Med ; 165(4): 581-583, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30121915

RESUMO

Genetic program regulating epithelial-mesenchymal transition is activated at the early stages of embryogenesis. Abnormal karyotype of the embryo disrupts the fundamental process of epithelial-mesenchymal transition, which is seen from incomplete morphological rearrangement and reduced migration capacity of cells, as well as low level of expression of epithelial-mesenchymal transition markers (fibronectin, collagen, and glycosaminoglycans). Disturbances of the epithelial-mesenchymal transition affect the proliferative potential of cells with aberrant karyotype, which contributes to the delay of embryonic development and correlates with the formation of abnormal phenotype in carriers of chromosomal abnormalities.


Assuntos
Cariótipo Anormal , Aborto Espontâneo/etiologia , Transição Epitelial-Mesenquimal/fisiologia , Linhagem Celular , Colágeno/genética , Colágeno/metabolismo , Transição Epitelial-Mesenquimal/genética , Fibronectinas/genética , Fibronectinas/metabolismo , Glicosaminoglicanos/genética , Glicosaminoglicanos/metabolismo , Humanos , Malformações do Sistema Nervoso/complicações , Malformações do Sistema Nervoso/genética , Malformações do Sistema Nervoso/metabolismo , Fenótipo , Trissomia/genética
18.
Mol Genet Metab ; 125(1-2): 118-126, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-30031689

RESUMO

Folate metabolism in the brain is critically important and serves a number of vital roles in nucleotide synthesis, single carbon metabolism/methylation, amino acid metabolism, and mitochondrial translation. Genetic defects in almost every enzyme of folate metabolism have been reported to date, and most have neurological sequelae. We report 2 patients presenting with a neurometabolic disorder associated with biallelic variants in the MTHFS gene, encoding 5,10-methenyltetrahydrofolate synthetase. Both patients presented with microcephaly, short stature, severe global developmental delay, progressive spasticity, epilepsy, and cerebral hypomyelination. Baseline CSF 5-methyltetrahydrolate (5-MTHF) levels were in the low-normal range. The first patient was treated with folinic acid, which resulted in worsening cerebral folate deficiency. Treatment in this patient with a combination of oral L-5-methyltetrahydrofolate and intramuscular methylcobalamin was able to increase CSF 5-MTHF levels, was well tolerated over a 4 month period, and resulted in subjective mild improvements in functioning. Measurement of MTHFS enzyme activity in fibroblasts confirmed reduced activity. The direct substrate of the MTHFS reaction, 5-formyl-THF, was elevated 30-fold in patient fibroblasts compared to control, supporting the hypothesis that the pathophysiology of this disorder is a manifestation of toxicity from this metabolite.


Assuntos
Sistemas de Transporte de Aminoácidos Acídicos/deficiência , Antiporters/deficiência , Carbono-Nitrogênio Ligases/genética , Epilepsia/genética , Doenças Desmielinizantes Hereditárias do Sistema Nervoso Central/genética , Microcefalia/genética , Doenças Mitocondriais/genética , Transtornos Psicomotores/genética , Sistemas de Transporte de Aminoácidos Acídicos/líquido cefalorraquidiano , Sistemas de Transporte de Aminoácidos Acídicos/genética , Sistemas de Transporte de Aminoácidos Acídicos/metabolismo , Antiporters/líquido cefalorraquidiano , Antiporters/genética , Antiporters/metabolismo , Encéfalo/metabolismo , Encéfalo/patologia , Carbono-Nitrogênio Ligases/líquido cefalorraquidiano , Carbono-Nitrogênio Ligases/deficiência , Carbono-Nitrogênio Ligases/metabolismo , Epilepsia/líquido cefalorraquidiano , Epilepsia/complicações , Epilepsia/patologia , Feminino , Receptor 1 de Folato/deficiência , Doenças Desmielinizantes Hereditárias do Sistema Nervoso Central/líquido cefalorraquidiano , Doenças Desmielinizantes Hereditárias do Sistema Nervoso Central/complicações , Doenças Desmielinizantes Hereditárias do Sistema Nervoso Central/metabolismo , Humanos , Masculino , Doenças Metabólicas/líquido cefalorraquidiano , Doenças Metabólicas/complicações , Doenças Metabólicas/genética , Doenças Metabólicas/patologia , Microcefalia/líquido cefalorraquidiano , Microcefalia/complicações , Microcefalia/patologia , Doenças Mitocondriais/líquido cefalorraquidiano , Doenças Mitocondriais/complicações , Doenças Mitocondriais/metabolismo , Malformações do Sistema Nervoso/líquido cefalorraquidiano , Malformações do Sistema Nervoso/complicações , Malformações do Sistema Nervoso/genética , Malformações do Sistema Nervoso/metabolismo , Distrofias Neuroaxonais , Transtornos Psicomotores/líquido cefalorraquidiano , Transtornos Psicomotores/complicações , Transtornos Psicomotores/metabolismo , Tetra-Hidrofolatos/líquido cefalorraquidiano , Tetra-Hidrofolatos/metabolismo
19.
Rev Med Brux ; 39(3): 155-160, 2018.
Artigo em Francês | MEDLINE | ID: mdl-29869477

RESUMO

SAMHD1 is one of seven known genes responsible for Aicardi-Goutières syndrome. It has the particularity to associate to this rare pediatric encephalopathy with autoimmune manifestations, a cerebral vasculopathy type Moyamoya. This condition has only been recently reported, less than fifty times in the literature. Our clinical case is a 11 year old boy from an inbred union whose clinical diagnosis confirmed genetically and followed by a review of current data determined an ad hoc management, presently described. He underwent indirect neurosurgical revascularization by a multiple burr hole technique. Through this clinical case, we tried taking stock of what we know -clinical, physiopathological and therapeutical aspects- given the rarity of this disease, first on the syndrome as such, then on the peculiarities of the gene mutations of interest.


Assuntos
Doenças Autoimunes do Sistema Nervoso/complicações , Doença de Moyamoya/complicações , Malformações do Sistema Nervoso/complicações , Proteína 1 com Domínio SAM e Domínio HD/genética , Doenças Autoimunes do Sistema Nervoso/diagnóstico , Doenças Autoimunes do Sistema Nervoso/genética , Criança , Análise Mutacional de DNA , Homozigoto , Humanos , Masculino , Doença de Moyamoya/diagnóstico , Doença de Moyamoya/genética , Mutação , Malformações do Sistema Nervoso/diagnóstico , Malformações do Sistema Nervoso/genética
20.
Brain Pathol ; 28(3): 399-407, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29740948

RESUMO

Aicardi-Goutières syndrome (AGS) is an early-onset, autoimmune and genetically heterogeneous disorder with severe neurologic injury. Molecular studies have established that autosomal recessive mutations in one of the following genes are causative: TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR1 and IFIH1/MDA5. The phenotypic presentation and pathophysiology of AGS is associated with over-production of the cytokine Interferon-alpha (IFN-α) and its downstream signaling, characterized as type I interferonopathy. Astrocytes are one of the major source of IFN in the central nervous system (CNS) and it is proposed that they could be key players in AGS pathology. Astrocytes are the most ubiquitous glial cell in the CNS and perform a number of crucial and complex functions ranging from formation of blood-brain barrier, maintaining ionic homeostasis, metabolic support to synapse formation and elimination in healthy CNS. Involvement of astrocytic dysfunction in neurological diseases-Alexander's disease, Epilepsy, Alzheimer's and amyotrophic lateral sclerosis (ALS)-has been well-established. It is now known that compromised astrocytic function can contribute to CNS abnormalities and severe neurodegeneration, nevertheless, its contribution in AGS is unclear. The current review discusses known molecular and cellular pathways for AGS mutations and how it stimulates IFN-α signaling. We shed light on how astrocytes might be key players in the phenotypic presentations of AGS and emphasize the cell-autonomous and non-cell-autonomous role of astrocytes. Understanding the contribution of astrocytes will help reveal mechanisms underlying interferonopathy and develop targeted astrocyte specific therapeutic treatments in AGS.


Assuntos
Astrócitos/metabolismo , Doenças Autoimunes do Sistema Nervoso/genética , Doenças Autoimunes do Sistema Nervoso/metabolismo , Malformações do Sistema Nervoso/genética , Malformações do Sistema Nervoso/metabolismo , Animais , Doenças Autoimunes do Sistema Nervoso/complicações , Encefalite/complicações , Encefalite/metabolismo , Homeostase , Humanos , Inflamação/complicações , Inflamação/metabolismo , Interferon-alfa/metabolismo , Mutação , Malformações do Sistema Nervoso/complicações , Transdução de Sinais
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