Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 665
Filtrar
1.
Dermatol Clin ; 37(2): 229-239, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30850045

RESUMO

The discoveries of new genes underlying genetic skin diseases have occurred at a rapid pace, supported by advances in DNA sequencing technologies. These discoveries have translated to an improved understanding of disease mechanisms at a molecular level and identified new therapeutic options based on molecular targets. This article highlights just a few of these recent discoveries for a diverse group of skin diseases, including tuberous sclerosis complex, ichthyoses, overgrowth syndromes, interferonopathies, and basal cell nevus syndrome, and how this has translated into novel targeted therapies and improved patient care.


Assuntos
Dermatopatias Genéticas/diagnóstico , Dermatopatias Genéticas/terapia , Doenças Autoimunes do Sistema Nervoso/diagnóstico , Doenças Autoimunes do Sistema Nervoso/genética , Doenças Autoimunes do Sistema Nervoso/terapia , Síndrome do Nevo Basocelular/diagnóstico , Síndrome do Nevo Basocelular/genética , Síndrome do Nevo Basocelular/terapia , Classe I de Fosfatidilinositol 3-Quinases/antagonistas & inibidores , Dermabrasão , Fármacos Dermatológicos/uso terapêutico , Testes Genéticos , Doenças Hereditárias Autoinflamatórias/diagnóstico , Doenças Hereditárias Autoinflamatórias/genética , Doenças Hereditárias Autoinflamatórias/terapia , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Eritrodermia Ictiosiforme Congênita/diagnóstico , Eritrodermia Ictiosiforme Congênita/genética , Eritrodermia Ictiosiforme Congênita/terapia , Inibidores de Janus Quinases/uso terapêutico , Terapia a Laser , Lipoma/diagnóstico , Lipoma/genética , Lipoma/terapia , Técnicas de Diagnóstico Molecular , Mosaicismo , Anormalidades Musculoesqueléticas/diagnóstico , Anormalidades Musculoesqueléticas/genética , Anormalidades Musculoesqueléticas/terapia , Malformações do Sistema Nervoso/diagnóstico , Malformações do Sistema Nervoso/genética , Malformações do Sistema Nervoso/terapia , Nevo/diagnóstico , Nevo/genética , Nevo/terapia , Pitiríase Rubra Pilar/diagnóstico , Pitiríase Rubra Pilar/genética , Pitiríase Rubra Pilar/terapia , Inibidores de Proteínas Quinases/uso terapêutico , Síndrome de Proteu/diagnóstico , Síndrome de Proteu/genética , Síndrome de Proteu/terapia , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Análise de Sequência de DNA , Dermatopatias Genéticas/genética , Protetores Solares/uso terapêutico , Serina-Treonina Quinases TOR/antagonistas & inibidores , Esclerose Tuberosa/diagnóstico , Esclerose Tuberosa/genética , Esclerose Tuberosa/terapia , Ustekinumab/uso terapêutico
2.
Gene ; 695: 12-17, 2019 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-30738969

RESUMO

Microcephaly is a rare condition in which the occipitofrontal circumference in a child is more than two standard deviations below the mean of children of the same age and gender. It is mainly caused by genetic abnormalities that interfere with the growth of the cerebral cortex during early months of fetal development. We present a case of a 12 years old patient with microcephaly. To identify a possible genetic origin of the phenotype, we performed array CGH and exome sequencing in the patient. Exome sequencing revealed the presence of a de novo missense mutation in the TUBB5 gene (E401K). Mutations in the TUBB5 are mainly responsible for microcephaly but the clinical spectrum is wide, from patients with severe developmental delay, and the presence of different brain malformations, to patients with only slightly cognitive impairment and normal motor development. Our patient shows a milder phenotype than other patients carrying the same mutation. These differences in the clinical features suggest that other factors, presumably genetic or epigenetic, could be modulating clinical expressivity of TUBB5. It is therefore evident that more functional studies are needed to understand the pathology that underlies the clinical spectrum of tubulin associated disease states.


Assuntos
Deficiências do Desenvolvimento/genética , Microcefalia/genética , Malformações do Sistema Nervoso/genética , Tubulina (Proteína)/genética , Criança , Deficiências do Desenvolvimento/diagnóstico , Deficiências do Desenvolvimento/fisiopatologia , Exoma/genética , Feminino , Humanos , Masculino , Microcefalia/diagnóstico , Microcefalia/fisiopatologia , Mutação , Malformações do Sistema Nervoso/diagnóstico , Malformações do Sistema Nervoso/fisiopatologia
3.
PLoS Genet ; 15(1): e1007863, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30640919

RESUMO

Many neurons are unable to regenerate after damage. The ability to regenerate after an insult depends on life stage, neuronal subtype, intrinsic and extrinsic factors. C. elegans is a powerful model to test the genetic and environmental factors that affect axonal regeneration after damage, since its axons can regenerate after neuronal insult. Here we demonstrate that diapause promotes the complete morphological regeneration of truncated touch receptor neuron (TRN) axons expressing a neurotoxic MEC-4(d) DEG/ENaC channel. Truncated axons of different lengths were repaired during diapause and we observed potent axonal regrowth from somas alone. Complete morphological regeneration depends on DLK-1 but neuronal sprouting and outgrowth is DLK-1 independent. We show that TRN regeneration is fully functional since animals regain their ability to respond to mechanical stimulation. Thus, diapause induced regeneration provides a simple model of complete axonal regeneration which will greatly facilitate the study of environmental and genetic factors affecting the rate at which neurons die.


Assuntos
Axônios , Proteínas de Caenorhabditis elegans/genética , MAP Quinase Quinase Quinases/genética , Proteínas de Membrana/genética , Regeneração Nervosa/genética , Malformações do Sistema Nervoso/genética , Animais , Caenorhabditis elegans/genética , Caenorhabditis elegans/crescimento & desenvolvimento , Diapausa/genética , Diapausa/fisiologia , Regulação da Expressão Gênica no Desenvolvimento , Necrose/genética , Necrose/patologia , Malformações do Sistema Nervoso/fisiopatologia , Malformações do Sistema Nervoso/reabilitação , Células Receptoras Sensoriais/metabolismo , Tato/genética
4.
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
5.
Nucleic Acids Res ; 47(4): e22, 2019 02 28.
Artigo em Inglês | MEDLINE | ID: mdl-30590609

RESUMO

Adenosine to inosine editing is common in the human transcriptome and changes of this essential activity is associated with disease. Children with ADAR1 mutations develop fatal Aicardi-Goutières syndrome characterized by aberrant interferon expression. In contrast, ADAR1 overexpression is associated with increased malignancy of breast, lung and liver cancer. ADAR1 silencing in breast cancer cells leads to increased apoptosis, suggesting an anti-apoptotic function that promotes cancer progression. Yet, suitable high-throughput editing assays are needed to efficiently screen chemical libraries for modifiers of ADAR1 activity. We describe the development of a bioluminescent reporter system that facilitates rapid and accurate determination of endogenous editing activity. The system is based on the highly sensitive and quantitative Nanoluciferase that is conditionally expressed upon reporter-transcript editing. Stably introduced into cancer cell lines, the system reports on elevated endogenous ADAR1 editing activity induced by interferon as well as knockdown of ADAR1 and ADAR2. In a single-well setup we used the reporter in HeLa cells to screen a small molecule library of 33 000 compounds. This yielded a primary hit rate of 0.9% at 70% inhibition of editing. Thus, we provide a key tool for high-throughput identification of modifiers of A-to-I editing activity in cancer cells.


Assuntos
Adenosina Desaminase/genética , Ensaios de Triagem em Larga Escala , Neoplasias/genética , Proteínas de Ligação a RNA/genética , Adenosina/genética , Apoptose/genética , Doenças Autoimunes do Sistema Nervoso/genética , Doenças Autoimunes do Sistema Nervoso/patologia , Edição de Genes/métodos , Genes Reporter/genética , Células HeLa , Humanos , Inosina/genética , Interferons/genética , Luciferases/genética , Medições Luminescentes/métodos , Nanopartículas/química , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Malformações do Sistema Nervoso/genética , Malformações do Sistema Nervoso/patologia , Bibliotecas de Moléculas Pequenas/química , Transcriptoma/genética
6.
Brain ; 142(1): 23-34, 2019 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-30544177

RESUMO

Brain and spinal arteriovenous malformations are congenital lesions causing intracranial haemorrhage or permanent disability especially in young people. We investigated whether the vast majority or all brain and spinal arteriovenous malformations are associated with detectable tumour-related somatic mutations. In a cohort of 31 patients (21 with brain and 10 with spinal arteriovenous malformations), tissue and paired blood samples were analysed with ultradeep next generation sequencing of a panel of 422 common tumour genes to identify the somatic mutations. We used droplet digital polymerase chain reaction to confirm the panel sequenced mutations and identify the additional low variant frequency mutations. The association of mutation variant frequencies and clinical features were analysed. The average sequencing depth was 1077 ± 298×. High prevalence (87.1%) of KRAS/BRAF somatic mutations was found in brain and spinal arteriovenous malformations with no other replicated tumour-related mutations. The prevalence of KRAS/BRAF mutation was 81.0% (17 of 21) in brain and 100% (10 of 10) in spinal arteriovenous malformations. We detected activating BRAF mutations and two novel mutations in KRAS (p.G12A and p.S65_A66insDS) in CNS arteriovenous malformations for the first time. The mutation variant frequencies were negatively correlated with nidus volumes of brain (P = 0.038) and spinal (P = 0.028) arteriovenous malformations but not ages. Our findings support a causative role of somatic tumour-related mutations of KRAS/BRAF in the overwhelming majority of brain and spinal arteriovenous malformations. This pathway homogeneity and high prevalence implies the development of targeted therapies with RAS/RAF pathway inhibitors without the necessity of tissue genetic diagnosis.10.1093/brain/awy307_video1awy307media15978667388001.


Assuntos
Malformações Arteriovenosas/genética , Encéfalo/anormalidades , Predisposição Genética para Doença/genética , Malformações do Sistema Nervoso/genética , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Medula Espinal/anormalidades , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Sequenciamento de Nucleotídeos em Larga Escala/estatística & dados numéricos , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Prevalência , Análise de Sequência de DNA/estatística & dados numéricos , Adulto Jovem
7.
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
8.
Am J Hum Genet ; 103(6): 948-967, 2018 12 06.
Artigo em Inglês | MEDLINE | ID: mdl-30526868

RESUMO

Neurodevelopmental disorders (NDD) are genetically and phenotypically heterogeneous conditions due to defects in genes involved in development and function of the nervous system. Individuals with NDD, in addition to their primary neurodevelopmental phenotype, may also have accompanying syndromic features that can be very helpful diagnostically especially those with recognizable facial appearance. In this study, we describe ten similarly affected individuals from six unrelated families of different ethnic origins having bi-allelic truncating variants in TMEM94, which encodes for an uncharacterized transmembrane nuclear protein that is highly conserved across mammals. The affected individuals manifested with global developmental delay/intellectual disability, and dysmorphic facial features including triangular face, deep set eyes, broad nasal root and tip and anteverted nostrils, thick arched eye brows, hypertrichosis, pointed chin, and hypertelorism. Birthweight in the upper normal range was observed in most, and all but one had congenital heart defects (CHD). Gene expression analysis in available cells from affected individuals showed reduced expression of TMEM94. Global transcriptome profiling using microarray and RNA sequencing revealed several dysregulated genes essential for cell growth, proliferation and survival that are predicted to have an impact on cardiotoxicity hematological system and neurodevelopment. Loss of Tmem94 in mouse model generated by CRISPR/Cas9 was embryonic lethal and led to craniofacial and cardiac abnormalities and abnormal neuronal migration pattern, suggesting that this gene is important in craniofacial, cardiovascular, and nervous system development. Our study suggests the genetic etiology of a recognizable dysmorphic syndrome with NDD and CHD and highlights the role of TMEM94 in early development.


Assuntos
Deficiências do Desenvolvimento/genética , Cardiopatias Congênitas/genética , Transtornos do Neurodesenvolvimento/genética , Proteínas Nucleares/genética , Anormalidades Múltiplas/genética , Adolescente , Alelos , Animais , Criança , Pré-Escolar , Facies , Feminino , Humanos , Hipertelorismo/genética , Lactente , Deficiência Intelectual/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Malformações do Sistema Nervoso/genética , Fenótipo , Transcriptoma/genética
9.
Proc Natl Acad Sci U S A ; 115(33): E7768-E7775, 2018 08 14.
Artigo em Inglês | MEDLINE | ID: mdl-30061387

RESUMO

The adaptor molecule stimulator of IFN genes (STING) is central to production of type I IFNs in response to infection with DNA viruses and to presence of host DNA in the cytosol. Excessive release of type I IFNs through STING-dependent mechanisms has emerged as a central driver of several interferonopathies, including systemic lupus erythematosus (SLE), Aicardi-Goutières syndrome (AGS), and stimulator of IFN genes-associated vasculopathy with onset in infancy (SAVI). The involvement of STING in these diseases points to an unmet need for the development of agents that inhibit STING signaling. Here, we report that endogenously formed nitro-fatty acids can covalently modify STING by nitro-alkylation. These nitro-alkylations inhibit STING palmitoylation, STING signaling, and subsequently, the release of type I IFN in both human and murine cells. Furthermore, treatment with nitro-fatty acids was sufficient to inhibit production of type I IFN in fibroblasts derived from SAVI patients with a gain-of-function mutation in STING. In conclusion, we have identified nitro-fatty acids as endogenously formed inhibitors of STING signaling and propose for these lipids to be considered in the treatment of STING-dependent inflammatory diseases.


Assuntos
Ácidos Graxos/metabolismo , Herpes Simples/metabolismo , Herpesvirus Humano 2/metabolismo , Proteínas de Membrana/metabolismo , Transdução de Sinais , Animais , Doenças Autoimunes do Sistema Nervoso/genética , Doenças Autoimunes do Sistema Nervoso/metabolismo , Doenças Autoimunes do Sistema Nervoso/patologia , Herpes Simples/genética , Herpes Simples/patologia , Humanos , Interferon Tipo I/genética , Interferon Tipo I/metabolismo , Lipoilação , Lúpus Eritematoso Sistêmico/genética , Lúpus Eritematoso Sistêmico/metabolismo , Lúpus Eritematoso Sistêmico/patologia , Proteínas de Membrana/genética , Camundongos , Camundongos Knockout , Malformações do Sistema Nervoso/genética , Malformações do Sistema Nervoso/metabolismo , Malformações do Sistema Nervoso/patologia , Células RAW 264.7
10.
Science ; 361(6403): 709-712, 2018 08 17.
Artigo em Inglês | MEDLINE | ID: mdl-30115809

RESUMO

Mutations in the fragile X mental retardation 1 gene (FMR1) cause the most common inherited human autism spectrum disorder. FMR1 influences messenger RNA (mRNA) translation, but identifying functional targets has been difficult. We analyzed quiescent Drosophila oocytes, which, like neural synapses, depend heavily on translating stored mRNA. Ribosome profiling revealed that FMR1 enhances rather than represses the translation of mRNAs that overlap previously identified FMR1 targets, and acts preferentially on large proteins. Human homologs of at least 20 targets are associated with dominant intellectual disability, and 30 others with recessive neurodevelopmental dysfunction. Stored oocytes lacking FMR1 usually generate embryos with severe neural defects, unlike stored wild-type oocytes, which suggests that translation of multiple large proteins by stored mRNAs is defective in fragile X syndrome and possibly other autism spectrum disorders.


Assuntos
Transtorno Autístico/metabolismo , Proteínas de Drosophila/fisiologia , Proteína do X Frágil de Retardo Mental/fisiologia , Malformações do Sistema Nervoso/genética , Biossíntese de Proteínas , Animais , Transtorno Autístico/genética , Proteínas de Drosophila/genética , Drosophila melanogaster , Embrião não Mamífero/anormalidades , Proteína do X Frágil de Retardo Mental/genética , Técnicas de Silenciamento de Genes , Humanos , Oócitos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo
11.
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
12.
Semin Pediatr Neurol ; 26: 135-139, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29961505

RESUMO

Intracranial calcifications in young infants, while suggesting intrauterine infections, can also be due to numerous other conditions, including rare genetic disorders. We describe 2 children in whom the presence and pattern of intracranial calcifications led to the diagnosis of uncommon genetic disorders, Adams-Oliver syndrome and Aicardi-Goutieres syndrome. Differentiating genetic conditions from intrauterine infections or other causes of intracranial calcifications enables practitioners to provide accurate counseling regarding prognosis and recurrence risk.


Assuntos
Doenças Autoimunes do Sistema Nervoso/diagnóstico , Encefalopatias/diagnóstico , Calcinose/diagnóstico , Displasia Ectodérmica/diagnóstico , Deformidades Congênitas dos Membros/diagnóstico , Malformações do Sistema Nervoso/diagnóstico , Dermatoses do Couro Cabeludo/congênito , Doenças Autoimunes do Sistema Nervoso/genética , Encéfalo/diagnóstico por imagem , Encefalopatias/genética , Calcinose/genética , Criança , Diagnóstico Diferencial , Displasia Ectodérmica/genética , Feminino , Humanos , Deformidades Congênitas dos Membros/genética , Malformações do Sistema Nervoso/genética , Dermatoses do Couro Cabeludo/diagnóstico , Dermatoses do Couro Cabeludo/genética
13.
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
14.
Dev Biol ; 440(2): 152-166, 2018 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-29792854

RESUMO

Neuronal-glial relationships play a critical role in the maintenance of central nervous system architecture and neuronal specification. A deeper understanding of these relationships can elucidate cellular cross-talk capable of sustaining proper development of neural tissues. In the cerebellum, cerebellar granule neuron precursors (CGNPs) proliferate in response to Purkinje neuron-derived Sonic hedgehog (Shh) before ultimately exiting the cell cycle and migrating radially along Bergmann glial fibers. However, the function of Bergmann glia in CGNP proliferation remains not well defined. Interestingly, the Hh pathway is also activated in Bergmann glia, but the role of Shh signaling in these cells is unknown. In this study, we show that specific ablation of Shh signaling using the tamoxifen-inducible TNCYFP-CreER line to eliminate Shh pathway activator Smoothened in Bergmann glia is sufficient to cause severe cerebellar hypoplasia and a significant reduction in CGNP proliferation. TNCYFP-CreER; SmoF/- (SmoCKO) mice demonstrate an obvious reduction in cerebellar size within two days of ablation of Shh signaling. Mutant cerebella have severely reduced proliferation and increased differentiation of CGNPs due to a significant decrease in Shh activity and concomitant activation of Wnt signaling in SmoCKO CGNPs, suggesting that this pathway is involved in cross-talk with the Shh pathway in regulating CGNP proliferation. In addition, Purkinje cells are ectopically located, their dendrites stunted, and the Bergmann glial network disorganized. Collectively, these data demonstrate a previously unappreciated role for Bergmann glial Shh signaling activity in the proliferation of CGNPs and proper maintenance of cerebellar architecture.


Assuntos
Córtex Cerebelar/embriologia , Proteínas Hedgehog/fisiologia , Neuroglia/fisiologia , Animais , Astrócitos/metabolismo , Diferenciação Celular , Divisão Celular , Proliferação de Células/fisiologia , Células Cultivadas , Córtex Cerebelar/fisiologia , Neoplasias Cerebelares/metabolismo , Cerebelo/anormalidades , Cerebelo/embriologia , Deficiências do Desenvolvimento/genética , Proteínas Hedgehog/metabolismo , Camundongos , Malformações do Sistema Nervoso/embriologia , Malformações do Sistema Nervoso/genética , Células-Tronco Neurais/citologia , Células-Tronco Neurais/metabolismo , Neurônios/metabolismo , Células de Purkinje/metabolismo , Transdução de Sinais , Via de Sinalização Wnt/genética
15.
Am J Case Rep ; 19: 500-504, 2018 Apr 28.
Artigo em Inglês | MEDLINE | ID: mdl-29703882

RESUMO

BACKGROUND Aicardi-Goutières syndrome (AGS) is a rare autosomal recessive encephalopathy of early onset. AGS visual dysfunction range from nystagmus and optic atrophy to cortical blindness in affected individuals; however, congenital glaucoma has been recently noticed among AGS pediatric patients. According to the literature, aniridia has never been recognized among AGS patients. CASE REPORT We report the case of a 4-year-old boy with AGS who had multiple congenital anomalies in the eyes. He was found to have congenital glaucoma, nystagmus, spherophakia with shallow chambers, and aniridia in both eyes. Family history was positive for glaucoma, with consanguineously married parents. According to the genetics report, both parents are carriers of congenital glaucoma genes. A whole-exome sequencing identified IFIH1 heterozygous missense mutation of the patient, which is associated with AGS Type 7. Also, he was diagnosed as having congenital glaucoma with CYP1B1 mutation, homozygous recessive. This case demonstrates the unusual coexistence of bilateral aniridia, a feature not previously reported in ocular findings of AGS. CONCLUSIONS In summary, this is the first reported case of aniridia with AGS-related congenital glaucoma in the literature. This paper summarizes the usual ocular manifestation of AGS, also it highlights atypical ocular features in both; AGS as well as congenital glaucoma. The aim of this paper is to lay the foundation for a national database on AGS in Saudi Arabia, which will help create a bridge between genetic data and clinical findings of AGS patients.


Assuntos
Aniridia/complicações , Doenças Autoimunes do Sistema Nervoso/complicações , Glaucoma/congênito , Malformações do Sistema Nervoso/complicações , Aniridia/genética , Doenças Autoimunes do Sistema Nervoso/genética , Pré-Escolar , Consanguinidade , Citocromo P-450 CYP1B1/genética , Glaucoma/genética , Humanos , Helicase IFIH1 Induzida por Interferon/genética , Masculino , Mutação , Mutação de Sentido Incorreto , Malformações do Sistema Nervoso/genética
16.
Mol Genet Genomic Med ; 6(3): 463-468, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29633571

RESUMO

BACKGROUND: ERCC6L2-associated disorder has recently been described and only five patients were reported so far. The described phenotype included bone marrow, cerebral, and craniofacial abnormalities. The aim of this study was to further define the genetic and phenotypic spectrum of the disorder by summarizing the five published cases and an additional case that we identified through whole-exome sequencing performed at the University of Toronto. METHODS: Clinical data was extracted from the Canadian Inherited Marrow Failure Registry. Whole exome sequencing was performed to identify causative mutations. RESULTS: All six cases had homozygous truncating mutations either at or upstream of the helicase domain of ERCC6L2. All patients displayed bone marrow failure, learning or developmental delay and microcephaly. Our patient was unique in displaying features of cerebellar disease, including ataxia and dysmetria as well as an interval deterioration of the corpus callosum and generalized volume loss on MRI. Another unique feature of our patient was retinal dystrophy with macular involvement. Along with one other patient, our patient displayed craniofacial abnormalities by presenting with low-set prominent ears, a pointed prominent chin, and deep-set eyes. Leukemia is common among patients with inherited bone marrow failure, but thus far, none of the patients have developed this complication. CONCLUSIONS: ERCC6L2-associated disorder is a multisystem disorder. The phenotype spectrum includes bone marrow failure, cerebral, and craniofacial abnormalities, as well as cerebellar and retinal abnormalities.


Assuntos
Anemia Aplástica/genética , Doenças da Medula Óssea/genética , DNA Helicases/genética , Hemoglobinúria Paroxística/genética , Adolescente , Adulto , Anemia Aplástica/fisiopatologia , Doenças da Medula Óssea/fisiopatologia , Canadá , Criança , Pré-Escolar , Anormalidades Craniofaciais/genética , DNA Helicases/fisiologia , Deficiências do Desenvolvimento/genética , Exoma , Feminino , Hemoglobinúria Paroxística/fisiopatologia , Homozigoto , Humanos , Lactente , Deficiência Intelectual/genética , Masculino , Microcefalia/genética , Mutação , Malformações do Sistema Nervoso/genética , Linhagem , Fenótipo
17.
Int J Neurosci ; 128(9): 881-885, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29372643

RESUMO

PURPOSE: Baraitser-Winter cerebrofrontofacial syndrome (BWCFF) is a rare autosomal dominant genetic disorder involving multiple organ systems and primarily characterized by structural brain abnormalities and a distinctive facial appearance. METHODS: To study the clinical characteristics, gene types and seizures of BWCFF. The natural history, clinical data and peripheral blood sample were collected in the child and his patients. To screen the ß-actin gene (ACTB) of a newly diagnosed child, hoping to find the gene mutation. RESULTS: The child had left ptosis, ocular hypertelorism, arched eyebrows, only 30% of the left ear hearing, a slight hypotonia, normal muscle strength, walking instability. The seizures were difficult to control with antiepileptic drugs and presented some degree of psychomotor development delay. Genetic screening showed De Novo in ACTB gene (c.484A> G, p.Thr162Ala). Parents did not detect related gene mutations. CONCLUSIONS: Patients with typical facial features and cerebral cortical malformations associated with refractory epilepsy should be highly suspected BWCFF. Patients are advised to carry out genetic screening to confirm the diagnosis.


Assuntos
Epilepsia/complicações , Malformações do Sistema Nervoso/complicações , Actinas/genética , Criança , Análise Mutacional de DNA , Eletroencefalografia , Epilepsia/diagnóstico por imagem , Epilepsia/genética , Humanos , Imagem por Ressonância Magnética , Modelos Moleculares , Malformações do Sistema Nervoso/diagnóstico por imagem , Malformações do Sistema Nervoso/genética
18.
Eur J Paediatr Neurol ; 22(3): 541-543, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29307700

RESUMO

In the last few years, whole exome sequencing (WES) allowed the identification of PRUNE mutations in patients featuring a complex neurological phenotype characterized by severe neurodevelopmental delay, microcephaly, epilepsy, optic atrophy, and brain or cerebellar atrophy. We describe an additional patient with homozygous PRUNE mutation who presented with spinal muscular atrophy phenotype, in addition to the already known brain developmental disorder. This novel feature expands the clinical consequences of PRUNE mutations and allow to converge PRUNE syndrome with previous descriptions of neurodevelopmental/neurodegenerative disorders linked to altered microtubule dynamics.


Assuntos
Proteínas de Transporte/genética , Neurônios Motores/patologia , Atrofia Muscular Espinal/genética , Encefalopatias/genética , Deficiências do Desenvolvimento/genética , Homozigoto , Humanos , Lactente , Masculino , Mutação , Malformações do Sistema Nervoso/genética , Fenótipo , Síndrome
19.
J Matern Fetal Neonatal Med ; 31(9): 1182-1187, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-28413896

RESUMO

PURPOSE: The so-called lethal malformations pose ethical challenges. Most affected fetuses die before or at birth. Live-born neonates commonly receive palliative care. If the postnatal course is better than expected, redirection towards more treatment may occur. We aimed to analyze this in a Swiss patient cohort. MATERIALS AND METHODS: Over 6 years, fetal malformation was suspected in 1113 cases. We identified patients prenatally assigned to palliative care, assessed pre- and postnatal diagnoses, and outcomes. RESULTS: Fourteen neonates received palliative care. Eleven patients received palliative care following late termination of pregnancy, for three, palliative care was planned and the fetus died during delivery, for two, the outcome was unknown (incomplete documentation). Genetic testing was performed in 50%. The predominant diagnostic group was central nervous system malformations (33%), followed by chromosomal aberrations (20%) and renal anomalies (17%). One child assigned to palliative care was resuscitated. Antenatal findings were anhydramnios and pulmonary hypoplasia. Postnatally, respiration was better than expected. The neonate was admitted to intensive care, died on day one. CONCLUSIONS: Nervous system malformations seem to be a major criterion for foregoing life-sustaining interventions. Redirection towards more treatment is rare. This may reflect precise prenatal prognostication; a degree of self-fulfilling prophecy cannot be excluded.


Assuntos
Anormalidades Congênitas/terapia , Cuidados Críticos , Cuidados Paliativos , Adulto , Aberrações Cromossômicas , Tomada de Decisão Clínica , Anormalidades Congênitas/diagnóstico , Anormalidades Congênitas/genética , Cuidados Críticos/métodos , Tomada de Decisões , Feminino , Morte Fetal , Idade Gestacional , Humanos , Recém-Nascido , Rim/anormalidades , Malformações do Sistema Nervoso/diagnóstico , Malformações do Sistema Nervoso/genética , Malformações do Sistema Nervoso/terapia , Gravidez , Diagnóstico Pré-Natal , Prognóstico , Suíça
20.
Eur J Paediatr Neurol ; 22(1): 186-189, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29221912

RESUMO

Aicardi-Goutières syndrome (AGS) is a hereditary inflammatory encephalopathy resulting in severe neurological damage in the majority of cases. We report on two siblings with AGS6 due to compound heterozygosity for a known and a novel mutation in the ADAR gene and a strikingly variable phenotype. The first sibling presented at 12 months of age with a subacute encephalopathy following a mild respiratory infection. The child developed a spastic tetraparesis, generalized dystonia and dysarthria. In contrast, the younger sibling presented with an acute episode of neurological impairment in his third year of life, from which he recovered without sequelae within a few weeks. These findings illustrate a striking intrafamilial phenotypic variability in patients with AGS6 and describe the first case of a full recovery from an acute encephalopathy in an AGS patient. Our findings also suggest that AGS should be considered as an important differential diagnosis of an infection-triggered encephalopathy in infancy despite the absence of typical neuroimaging findings.


Assuntos
Adenosina Desaminase/genética , Doenças Autoimunes do Sistema Nervoso/diagnóstico , Doenças Autoimunes do Sistema Nervoso/genética , Malformações do Sistema Nervoso/diagnóstico , Malformações do Sistema Nervoso/genética , Proteínas de Ligação a RNA/genética , Adolescente , Pré-Escolar , Feminino , Humanos , Masculino , Mutação , Fenótipo
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA