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1.
Lancet Child Adolesc Health ; 4(5): 378-387, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32199080

RESUMO

BACKGROUND: Congenital Zika syndrome causes a spectrum of neurological symptoms with varying effects on function that require different therapeutic strategies. To date, this spectrum of effects and its clinical implications have not been completely described. We describe the neurological examination findings in toddlers and preschoolers, including predominant symptom complexes and comorbidities. METHODS: This study is a case-series neurological evaluation of 75 children with congenital Zika syndrome in Campina Grande, Brazil. The study is part of a cohort of children with congenital Zika syndrome that started in 2015 and is still ongoing. Children with Zika virus infection detected during pregnancy (mothers exhibited rash and were followed and diagnosed by fetal ultrasound abnormalities or RT-PCR) or through microcephaly screening after birth, using Intergrowth 21 guidelines, were selected by laboratory and radiological criteria. Children were examined during a 10-day period in September, 2018, and underwent neurological interview, examination, and assessment of functional outcomes and comorbidities. Children were divided in groups of predominant corticospinal or neuromuscular clinical signs and the associations between these groups and clinical comorbidities were assessed. FINDINGS: All of the children recruited to the study from Nov 29, 2015 to Nov 30, 2017 had imaging correlates of congenital Zika syndrome. Children were assigned to groups depending on the signs exhibited, either corticospinal or neuromuscular, with or without dyskinetic signs. 75 children completed the evaluation, 38 (51%) girls and 37 (49%) boys. Median age was 33 months (range 26-40 months; IQR 29-34). Microcephaly was present at birth in 56 (75%) children, and 19 (25%) children were born with normal head circumference, 15 of whom later developed microcephaly. Neurological examination grouped four children as having isolated dyskinetic signs, 48 children were assigned to the corticospinal group and 23 into the neuromuscular group. Dyskinetic findings were present in 30 (40%) children, either alone (four [5%]) or combined with corticospinal (19 [40%] of 48) or neuromuscular (seven [30%] of 23) findings. Comorbidities were highly prevalent, and the neuromuscular group had worse functional outcomes, evaluated by gross motor function (p=0·026), manual abilities (p=0·0013), and communication function (p<0·0005) classification scales, than the corticospinal group, whereas pneumonia (p<0·0005) and urinary tract infections (p<0·0005) were more frequent in the corticospinal group. Cortical hyperexcitability was supported by several clinical correlates, such as early onset epilepsy, persistence of primitive reflexes, and dystonia. INTERPRETATION: We describe distinct neurological profiles in the congenital Zika syndrome spectrum, with functional outcomes tending to correlate with these groups. The clinical division of children based on the disease signs proposed here is supported by the literature on central and peripheral nervous system pathology in congenital Zika syndrome. The high prevalence of dyskinetic symptoms merits special attention. FUNDING: Brazilian National Council for Scientific and Technological Development and by the Coordination for the Improvement of Higher Education Personnel.


Assuntos
Discinesias/fisiopatologia , Doenças Neuromusculares/fisiopatologia , Infecção por Zika virus/fisiopatologia , Encéfalo/diagnóstico por imagem , Encefalopatias/diagnóstico por imagem , Encefalopatias/epidemiologia , Brasil/epidemiologia , Calcinose/diagnóstico por imagem , Calcinose/epidemiologia , Pré-Escolar , Comorbidade , Transtornos de Deglutição/epidemiologia , Discinesias/epidemiologia , Epilepsia/epidemiologia , Feminino , Humanos , Estudos Longitudinais , Masculino , Malformações do Desenvolvimento Cortical/diagnóstico por imagem , Malformações do Desenvolvimento Cortical/epidemiologia , Malformações do Desenvolvimento Cortical/fisiopatologia , Microcefalia/epidemiologia , Microcefalia/fisiopatologia , Doenças do Sistema Nervoso/diagnóstico por imagem , Doenças do Sistema Nervoso/epidemiologia , Doenças do Sistema Nervoso/fisiopatologia , Exame Neurológico , Doenças Neuromusculares/epidemiologia , Pneumonia/epidemiologia , Tratos Piramidais/fisiopatologia , Transtornos do Sono-Vigília/epidemiologia , Tomografia Computadorizada por Raios X , Infecções Urinárias/epidemiologia , Infecção por Zika virus/congênito , Infecção por Zika virus/diagnóstico por imagem , Infecção por Zika virus/epidemiologia
2.
Epilepsia ; 61(3): 509-518, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32065676

RESUMO

OBJECTIVE: To estimate the incidence of epilepsy in children with Zika-related microcephaly in the first 24 months of life; to characterize the associated clinical and electrographic findings; and to summarize the treatment responses. METHODS: We followed a cohort of children, born during the 2015-2016 Zika virus (ZIKV) epidemic in Brazil, with congenital microcephaly and evidence of congenital ZIKV infection on neuroimaging and/or laboratory testing. Neurological assessments were performed at ≤3, 6, 12, 15, 18, 21, and 24 months of life. Serial electroencephalograms were performed over the first 24 months. RESULTS: We evaluated 91 children, of whom 48 were female. In this study sample, the cumulative incidence of epilepsy was 71.4% in the first 24 months, and the main type of seizure was infantile spasms (83.1%). The highest incidence of seizures occurred between 3 and 9 months of age, and the risk remained high until 15 months of age. The incidence of infantile spasms peaked between 4 and 7 months and was followed by an increased incidence of focal epilepsy cases after 12 months of age. Neuroimaging results were available for all children, and 100% were abnormal. Cortical abnormalities were identified in 78.4% of the 74 children evaluated by computed tomography and 100% of the 53 children evaluated by magnetic resonance imaging. Overall, only 46.1% of the 65 children with epilepsy responded to treatment. The most commonly used medication was sodium valproate with or without benzodiazepines, levetiracetam, phenobarbital, and vigabatrin. SIGNIFICANCE: Zika-related microcephaly was associated with high risk of early epilepsy. Seizures typically began after the third month of life, usually as infantile spasms, with atypical electroencephalographic abnormalities. The seizure control rate was low. The onset of seizures in the second year was less frequent and, when it occurred, presented as focal epilepsy.


Assuntos
Epilepsias Parciais/fisiopatologia , Malformações do Desenvolvimento Cortical/fisiopatologia , Microcefalia/fisiopatologia , Espasmos Infantis/fisiopatologia , Infecção por Zika virus/fisiopatologia , Anticonvulsivantes/uso terapêutico , Brasil , Córtex Cerebral/diagnóstico por imagem , Pré-Escolar , Eletroencefalografia , Epilepsias Parciais/tratamento farmacológico , Epilepsias Parciais/epidemiologia , Epilepsia/tratamento farmacológico , Epilepsia/epidemiologia , Epilepsia/fisiopatologia , Feminino , Humanos , Lactente , Recém-Nascido , Imagem por Ressonância Magnética , Masculino , Malformações do Desenvolvimento Cortical/diagnóstico por imagem , Microcefalia/diagnóstico por imagem , Espasmos Infantis/tratamento farmacológico , Espasmos Infantis/epidemiologia , Tomografia Computadorizada por Raios X , Resultado do Tratamento , Infecção por Zika virus/congênito , Infecção por Zika virus/diagnóstico por imagem
3.
PLoS Genet ; 15(11): e1008467, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31730647

RESUMO

The primary cilium is a signaling center critical for proper embryonic development. Previous studies have demonstrated that mice lacking Ttc21b have impaired retrograde trafficking within the cilium and multiple organogenesis phenotypes, including microcephaly. Interestingly, the severity of the microcephaly in Ttc21baln/aln homozygous null mutants is considerably affected by the genetic background and mutants on an FVB/NJ (FVB) background develop a forebrain significantly smaller than mutants on a C57BL/6J (B6) background. We performed a Quantitative Trait Locus (QTL) analysis to identify potential genetic modifiers and identified two regions linked to differential forebrain size: modifier of alien QTL1 (Moaq1) on chromosome 4 at 27.8 Mb and Moaq2 on chromosome 6 at 93.6 Mb. These QTLs were validated by constructing congenic strains. Further analysis of Moaq1 identified an orphan G-protein coupled receptor (GPCR), Gpr63, as a candidate gene. We identified a SNP that is polymorphic between the FVB and B6 strains in Gpr63 and creates a missense mutation predicted to be deleterious in the FVB protein. We used CRISPR-Cas9 genome editing to create two lines of FVB congenic mice: one with the B6 sequence of Gpr63 and the other with a deletion allele leading to a truncation of the GPR63 C-terminal tail. We then demonstrated that Gpr63 can localize to the cilium in vitro. These alleles affect ciliary localization of GPR63 in vitro and genetically interact with Ttc21baln/aln as Gpr63;Ttc21b double mutants show unique phenotypes including spina bifida aperta and earlier embryonic lethality. This validated Gpr63 as a modifier of multiple Ttc21b neural phenotypes and strongly supports Gpr63 as a causal gene (i.e., a quantitative trait gene, QTG) within the Moaq1 QTL.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Desenvolvimento Embrionário/genética , Microcefalia/genética , Locos de Características Quantitativas/genética , Receptores Acoplados a Proteínas-G/genética , Alelos , Animais , Sistemas CRISPR-Cas/genética , Mapeamento Cromossômico , Cílios/genética , Embrião de Mamíferos , Genótipo , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Microcefalia/fisiopatologia , Prosencéfalo/crescimento & desenvolvimento , Prosencéfalo/metabolismo , Espinha Bífida Cística/genética , Espinha Bífida Cística/fisiopatologia , Mutações Sintéticas Letais/genética
4.
Epileptic Disord ; 21(5): 466-470, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31617495

RESUMO

Asparagine synthetase deficiency is a rare autosomal recessive neurometabolic disorder caused by mutations in the asparagine synthetase gene. It is characterized by congenital microcephaly, intellectual disability, progressive cerebral atrophy, and intractable seizures. A decrease in asparagine in CSF or plasma guides subsequent investigations in some cases, but normal values are described in other cases. Therefore, reaching a diagnosis is challenging and relies on exome sequencing. We report the case of a child with progressive microcephaly, irritability, startle reflexes, and jitteriness since birth. Focal clonic and myoclonic seizures, status epilepticus, and infantile spasms appeared in the first months of life. At first, the EEG showed multifocal epileptic activity which later turned into modified hypsarrhythmia and discontinuous activity. Brain MRI showed brain atrophy, a simplified gyral pattern, and poor myelination. Plasma asparagine levels were normal. Due to remote parental consanguinity, a study of contiguous regions of runs of homozygosity was performed, showing a 5-Mb region (chr7:95629078-100679007) including the asparagine synthetase gene. The molecular analysis of this gene led to identification of a novel homozygous missense mutation, c.761G>T(p.Gly254Val), in our patient. The peculiar electroclinical phenotype may lead to diagnostic suspicion and molecular analysis which may benefit genetic counselling. [Published with video sequence].


Assuntos
Aspartato-Amônia Ligase/deficiência , Encefalopatias/fisiopatologia , Deficiência Intelectual/fisiopatologia , Microcefalia/fisiopatologia , Atrofia/diagnóstico , Atrofia/fisiopatologia , Encefalopatias/diagnóstico , Encefalopatias/genética , Eletroencefalografia/métodos , Humanos , Recém-Nascido , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/genética , Masculino , Microcefalia/diagnóstico , Microcefalia/genética , Convulsões/genética , Convulsões/fisiopatologia
5.
Clinics (Sao Paulo) ; 74: e798, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31644665

RESUMO

OBJECTIVE: To describe the nutritional profile of newborns with microcephaly and factors associated with worse outcomes during the first 14 days of life. METHODS: This investigation is a longitudinal, descriptive study carried out in 21 full-term neonates exposed vertically to the Zika virus and hospitalized in a neonatal intensive care unit from February to September 2016. Patients receiving parenteral nutrition were excluded. Data analysis was performed using a generalized estimating equation model and Student's t-test to evaluate the association between worsening weight-for-age z-scores and independent clinical, sociodemographic and nutritional variables during hospitalization, with p<0.05 indicating significance. RESULTS: During hospitalization, there was a decrease in the mean values of the weight-for-age z-scores. The factors associated with worse nutritional outcomes were symptomatic exposure to the Zika virus, low maternal schooling, absence of maternal income and consumption of infant formula (p<0.05). Calcification and severe microcephaly were also associated with poor nutritional outcomes. Energy and macronutrient consumption remained below the recommendations and had an upward trend during hospitalization. CONCLUSION: The presence of cerebral calcification, the severity of microcephaly and symptomatic maternal exposure to Zika virus affected the nutritional status of newborns. In terms of nutritional factors, human milk intake had a positive impact, reducing weight loss in the first days of life. Other known factors, such as income and maternal schooling, were still associated with a poor nutritional status.


Assuntos
Microcefalia/fisiopatologia , Estado Nutricional/fisiologia , Infecção por Zika virus/complicações , Adolescente , Adulto , Feminino , Humanos , Recém-Nascido , Estudos Longitudinais , Masculino , Microcefalia/virologia , Fatores de Risco , Índice de Gravidade de Doença , Fatores Socioeconômicos , Adulto Jovem
6.
Yi Chuan ; 41(9): 801-815, 2019 Sep 20.
Artigo em Chinês | MEDLINE | ID: mdl-31549679

RESUMO

Development of the human brain is a strictly complex and precisely regulated process. Brain development includes the proliferation and differentiation of neural progenitor cells, migration and maturation of neurons, myelination of neuronal axons, synaptogenesis and organization of the neural circuits. Abnormalities of these developmental processes can lead to severe malformation and dysfunction of the brain, which may result in brain developmental diseases which have a high medical burden and have attracted global attention. Brain developmental diseases are typically divided into two categories according to abnormal brain morphology and dysfunction: malformation of cortical development (MCD) and neuropsychopathy. Microcephaly and autism spectrum disorder (ASD) are representative disorders of MCD and neuropsychopathy respectively. In this review, we summarize the progresses of these two typical and relevant brain developmental diseases including the mechanism and etiology of their development, gene expression, symptoms, and related to provide theoretical guidance for basic research and management and treatment.


Assuntos
Encéfalo/fisiopatologia , Deficiências do Desenvolvimento/fisiopatologia , Doenças do Sistema Nervoso/patologia , Doenças do Sistema Nervoso/psicologia , Transtorno do Espectro Autista/fisiopatologia , Humanos , Microcefalia/fisiopatologia , Neurogênese , Neurônios
7.
J Hum Genet ; 64(11): 1075-1081, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31506564

RESUMO

Thiamine metabolism dysfunction syndrome-4 (THMD4) includes episodic encephalopathy, often associated with a febrile illness, causing transient neurologic dysfunction and a slowly progressive axonal polyneuropathy. Until now only two mutations (G125S and S194P) have been reported in the SLC25A19 gene as causative for this disease and a third mutation (G177A) as related to the Amish lethal microcephaly. In this work, we describe the clinical and molecular features of a patient carrying a novel mutation (c.576G>C; Q192H) on SLC25A19 gene. Functional studies on this mutation were performed explaining the pathogenetic role of c.576G>C in affecting the translational efficiency and/or stability of hMTPPT protein instead of the mRNA expression. These findings support the pathogenetic role of Q192H (c.576G>C) mutation on SLC25A19 gene. Moreover, despite in other patients the thiamine supplementation leaded to a substantial improvement of peripheral neuropathy, our patient did not show a clinical improvement.


Assuntos
Predisposição Genética para Doença , Microcefalia/genética , Proteínas de Transporte da Membrana Mitocondrial/genética , Deficiência de Tiamina/genética , Adolescente , Encefalopatias/genética , Encefalopatias/fisiopatologia , Humanos , Masculino , Microcefalia/fisiopatologia , Proteínas de Transporte da Membrana Mitocondrial/química , Mutação , Conformação Proteica , RNA Mensageiro/genética , Tiamina/genética , Tiamina/metabolismo , Deficiência de Tiamina/fisiopatologia
8.
Bioessays ; 41(8): e1900011, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31274205

RESUMO

Recent developments in 3D cultures exploiting the self-organization ability of pluripotent stem cells have enabled the generation of powerful in vitro systems termed brain organoids. These 3D tissues recapitulate many aspects of human brain development and disorders occurring in vivo. When combined with improved differentiation methods, these in vitro systems allow the generation of more complex "assembloids," which are able to reveal cell diversities, microcircuits, and cell-cell interactions within their 3D organization. Here, the ways in which human brain organoids have contributed to demystifying the complexities of brain development and modeling of developmental disorders is reviewed and discussed. Furthermore, challenging questions that are yet to be addressed by emerging brain organoid research are discussed.


Assuntos
Encéfalo/citologia , Células-Tronco Pluripotentes Induzidas/citologia , Células-Tronco Neurais/citologia , Organoides , Animais , Encéfalo/crescimento & desenvolvimento , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/fisiopatologia , Técnicas de Cultura de Células , Descoberta de Drogas/métodos , Humanos , Microcefalia/fisiopatologia , Modelos Neurológicos , Transtornos do Neurodesenvolvimento/fisiopatologia
9.
BMC Med Genet ; 20(1): 126, 2019 07 16.
Artigo em Inglês | MEDLINE | ID: mdl-31311520

RESUMO

BACKGROUND: Osteodysplasia of the oral and maxillofacial bone is generally accompanied by systemic bone abnormalities (such as short stature, joint contracture) or other systemic abnormalities (such as renal, dermatological, cardiovascular, optic, or hearing disorders). However, it does not always present this way. Recent reports have suggested that genome-wide sequencing is an effective method for identifying rare or new disorders. Here, we performed whole-exome sequencing (WES) in a patient with a unique form of acquired, local osteodysplasia of the oral and maxillofacial region. CASE PRESENTATION: A 46-year-old woman presented to our hospital with the complaint of gradually moving mandibular teeth (for 6 months), changing facial appearance, and acquired osteolysis of the oral and maxillofacial bones, showing mandibular hypoplasia without family history. Upon skeletal examination, there were no abnormal findings outside of the oral and maxillofacial area; the patient had a height of 157 cm and bone mineral density (according to dual energy x-ray absorptiometry) of 90%. Results of blood and urine tests, including evaluation of bone metabolism markers and neurological and cardiovascular examinations, were normal. We performed WES of genomic DNA extracted from the blood of this patient and her mother, who did not have the disease, as a negative control. We identified 83 new missense variants in the patient, not detected in her mother, including a candidate single nucleotide variant in exon 14 of PCNT (pericentrin). Critical homozygous or compound heterozygous variants in PCNT are a known cause of microcephalic osteodysplastic primordial dwarfism type II accompanied by mandibular hypoplasia, which is similar to the maxillofacial phenotype in this patient. CONCLUSIONS: Protein simulations performed using Polymorphism Phenotyping v2 and Combined Annotation Dependent Depletion software indicated that this missense variant is likely to disrupt the PCNT protein structure. These results suggest that this is a new form of osteolysis related to this PCNT variant.


Assuntos
Antígenos/genética , Nanismo/genética , Retardo do Crescimento Fetal/genética , Predisposição Genética para Doença/genética , Variação Genética/genética , Microcefalia/genética , Osteocondrodisplasias/genética , Antígenos/química , Sequência de Bases , Densidade Óssea , Nanismo/diagnóstico por imagem , Nanismo/fisiopatologia , Éxons , Feminino , Retardo do Crescimento Fetal/diagnóstico por imagem , Retardo do Crescimento Fetal/fisiopatologia , Heterozigoto , Homozigoto , Humanos , Mandíbula/patologia , Microcefalia/diagnóstico por imagem , Microcefalia/fisiopatologia , Pessoa de Meia-Idade , Osteocondrodisplasias/diagnóstico por imagem , Osteocondrodisplasias/fisiopatologia , Osteólise , Fenótipo , Tomógrafos Computadorizados , Doenças Dentárias/congênito , Doenças Dentárias/diagnóstico por imagem , Doenças Dentárias/genética , Raiz Dentária/anormalidades , Raiz Dentária/diagnóstico por imagem , Sequenciamento Completo do Exoma
10.
Eur J Med Genet ; 62(8): 103704, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31207318

RESUMO

Whole exome sequencing undertaken in two siblings with delayed psychomotor development, absent speech, severe intellectual disability and postnatal microcephaly, with brain malformations consisting of cerebellar atrophy in the eldest affected and hypoplastic corpus callosum in the younger sister; revealed a homozygous intragenic deletion in VPS51, which encodes the vacuolar protein sorting-associated protein, one the four subunits of the Golgi-associated retrograde protein (GARP) and endosome-associated recycling protein (EARP) complexes that promotes the fusion of endosome-derived vesicles with the trans-Golgi network (GARP) and recycling endosomes (EARP). This observation supports a pathogenic effect of VPS51 variants, which has only been reported previously once, in a single child with microcephaly. It confirms the key role of membrane trafficking in normal brain development and homeostasis.


Assuntos
Encéfalo/fisiopatologia , Microcefalia/genética , Malformações do Sistema Nervoso/genética , Proteínas de Transporte Vesicular/genética , Encéfalo/diagnóstico por imagem , Criança , Endossomos/genética , Feminino , Humanos , Masculino , Microcefalia/diagnóstico por imagem , Microcefalia/fisiopatologia , Malformações do Sistema Nervoso/diagnóstico por imagem , Malformações do Sistema Nervoso/fisiopatologia , Transporte Proteico/genética , Rede trans-Golgi/genética
11.
J Appl Oral Sci ; 27: e20180276, 2019 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-31116278

RESUMO

OBJECTIVE: The aim of this study was to investigate possible malformations in the soft, bone and/or dental tissues in patients with congenital Zika Virus (ZIKV) by clinical and x-ray evaluation. METHODOLOGY: Thirty children born with ZIKV and 30 children born without ZIKV (control group) were included in the study. Patients were evaluated over 24 consecutive months according to the variables: sex, age, cleft palates, soft tissue lesions, alveolar ridge hyperplasia, short labial and lingual frenums, inadequate posture of the lingual and perioral muscles at rest, micrognathia, narrow palatine vaults, changes in the teeth shape and/or number, sequence eruption, spasms, seizures and eruption delay were evaluated. Chi-square test, Student's t-test and nominal logistic regression were used (p<0.05). RESULTS: Among the 30 babies examined, the mean age of the first dental eruption was 10.8±3.8 with almost two-thirds of the children (n=18, 60%) experiencing eruptions of their first tooth after 9 months of age, nine children (30%) had inadequate lingual posture at rest, more than half of the children (n=18, 60%) had short labial or lingual frenums. ZIKV babies showed a high prevalence of clef palate (p<0.001), inadequate lingual posture at rest (p=0.004), micrognathia (p=0.002), changes in the shape and/or number of teeth (p=0.006), alteration in sequence of dental eruption (p<0.001) and muscles spasms (p=0.002). The delay eruption was associated with inadequate lingual posture at rest (p=0.047), micrognathia (p=0.002) and changes in the shape and/or number of teeth (p=0.021). The delayed eruption (p=0.006) and narrow palatine vaults (p=0.008) were independently associated with ZIKV. Moreover, female patients showed the most narrow palatine vaults (p=0.010). CONCLUSIONS: The children with ZIKV showed a greater tendency to have delayed eruption of the first deciduous tooth, inadequate lingual posture and short labial and lingual frenums.


Assuntos
Anormalidades Dentárias/patologia , Anormalidades Dentárias/virologia , Infecção por Zika virus/congênito , Fatores Etários , Estudos de Casos e Controles , Pré-Escolar , Estudos Transversais , Feminino , Humanos , Lactente , Freio Labial/anormalidades , Freio Lingual/anormalidades , Modelos Logísticos , Masculino , Microcefalia/patologia , Microcefalia/fisiopatologia , Microcefalia/virologia , Análise Multivariada , Radiografia Dentária , Fatores de Tempo , Anormalidades Dentárias/diagnóstico por imagem , Anormalidades Dentárias/fisiopatologia , Erupção Dentária/fisiologia , Infecção por Zika virus/fisiopatologia
12.
Neurobiol Dis ; 129: 130-143, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31102767

RESUMO

Congenital microcephaly is highly associated with intellectual disability. Features of autosomal recessive primary microcephaly subtype 3 (MCPH3) also include hyperactivity and seizures. The disease is caused by biallelic mutations in the Cyclin-dependent kinase 5 regulatory subunit-associated protein 2 gene CDK5RAP2. In the mouse, Cdk5rap2 mutations similar to the human condition result in reduced brain size and a strikingly thin neocortex already at early stages of neurogenesis that persists through adulthood. The microcephaly phenotype in MCPH arises from a neural stem cell proliferation defect. Here, we report a novel role for Cdk5rap2 in the regulation of dendritic development and synaptogenesis of neocortical layer 2/3 pyramidal neurons. Cdk5rap2-deficient murine neurons show poorly branched dendritic arbors and an increased density of immature thin spines and glutamatergic synapses in vivo. Moreover, the excitatory drive is enhanced in ex vivo brain slice preparations of Cdk5rap2 mutant mice. Concurrently, we show that pyramidal neurons receive fewer inhibitory inputs. Together, these findings point towards a shift in the excitation - inhibition balance towards excitation in Cdk5rap2 mutant mice. Thus, MCPH3 is associated not only with a neural progenitor proliferation defect but also with altered function of postmitotic neurons and hence with altered connectivity.


Assuntos
Proteínas de Ciclo Celular/metabolismo , Microcefalia/fisiopatologia , Neocórtex/fisiopatologia , Vias Neurais/fisiopatologia , Neurogênese/fisiologia , Animais , Proteínas de Ciclo Celular/genética , Diferenciação Celular/fisiologia , Camundongos , Camundongos Mutantes , Microcefalia/genética , Microcefalia/metabolismo , Mutação , Neocórtex/metabolismo , Vias Neurais/metabolismo , Células Piramidais/metabolismo , Células Piramidais/patologia , Transmissão Sináptica/fisiologia
13.
Proc Natl Acad Sci U S A ; 116(9): 3662-3667, 2019 02 26.
Artigo em Inglês | MEDLINE | ID: mdl-30808755

RESUMO

Kaufman oculocerebrofacial syndrome (KOS) is a recessive neurodevelopmental disorder characterized by intellectual disability and lack of speech. KOS is caused by inactivating mutations in UBE3B, but the underlying biological mechanisms are completely unknown. We found that loss of Ube3b in mice resulted in growth retardation, decreased grip strength, and loss of vocalization. The brains of Ube3b -/- mice had hypoplasia of the corpus callosum, enlarged ventricles, and decreased thickness of the somatosensory cortex. Ube3b -/- cortical neurons had abnormal dendritic morphology and synapses. We identified 22 UBE3B interactors and found that branched-chain α-ketoacid dehydrogenase kinase (BCKDK) is an in vivo UBE3B substrate. Since BCKDK targets several metabolic pathways, we profiled plasma and cortical metabolomes from Ube3b -/- mice. Nucleotide metabolism and the tricarboxylic acid cycle were among the pathways perturbed. Substrate-induced mitochondrial respiration was reduced in skeletal muscle but not in liver of Ube3b -/- mice. To assess the relevance of these findings to humans, we identified three KOS patients who had compound heterozygous UBE3B mutations. We discovered changes in metabolites from similar pathways in plasma from these patients. Collectively, our results implicate a disease mechanism in KOS, suggest that it is a metabolic encephalomyopathy, and provide an entry to targeted therapies.


Assuntos
Anormalidades do Olho/genética , Deficiência Intelectual/genética , Transtornos do Desenvolvimento da Linguagem/genética , Deformidades Congênitas dos Membros/genética , Microcefalia/genética , Proteínas Quinases/genética , Ubiquitina-Proteína Ligases/genética , Adolescente , Adulto , Animais , Encéfalo/fisiopatologia , Criança , Anormalidades do Olho/fisiopatologia , Facies , Humanos , Deficiência Intelectual/fisiopatologia , Transtornos do Desenvolvimento da Linguagem/fisiopatologia , Deformidades Congênitas dos Membros/fisiopatologia , Masculino , Redes e Vias Metabólicas , Camundongos , Camundongos Knockout , Microcefalia/fisiopatologia , Mutação , Fenótipo , Ubiquitina/genética
14.
J Appl Genet ; 60(2): 151-162, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30706430

RESUMO

Autosomal recessive primary microcephaly (MCPH) is a group of rare neurodevelopmental diseases with severe microcephaly at birth. One type of the disorder, MCPH2, is caused by biallelic mutations in the WDR62 gene, which encodes the WD repeat-containing protein 62. Patients with WDR62 mutation may have a wide range of malformations of cortical development in addition to congenital microcephaly. We describe two patients, a boy and a girl, with severe congenital microcephaly, global developmental delay, epilepsy, and failure to thrive. MRI showed hemispherical asymmetry, diffuse pachygyria, thick gray matter, indistinct gray-white matter junction, and corpus callosum and white matter hypoplasia. Whole exome sequencing revealed the same novel homozygous missense mutation, c.668T>C, p.Phe223Ser in exon 6 of the WDR62 gene. The healthy parents were heterozygous for this mutation. The mutation affects a highly conserved region in one of the WD repeats of the WDR62 protein. Haplotype analysis showed genetic relatedness between the families of the patients. Our findings expand the spectrum of mutations randomly distributed in the WDR62 gene. A review is also provided of the brain malformations described in WDR62 mutations in association with congenital microcephaly.


Assuntos
Deficiências do Desenvolvimento/genética , Microcefalia/genética , Proteínas do Tecido Nervoso/genética , Deficiências do Desenvolvimento/diagnóstico por imagem , Deficiências do Desenvolvimento/fisiopatologia , Feminino , Substância Cinzenta/diagnóstico por imagem , Substância Cinzenta/patologia , Haplótipos , Homozigoto , Humanos , Masculino , Microcefalia/diagnóstico por imagem , Microcefalia/fisiopatologia , Mutação de Sentido Incorreto/genética , Linhagem , Substância Branca/diagnóstico por imagem , Substância Branca/patologia
15.
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
16.
Hum Mol Genet ; 28(11): 1822-1836, 2019 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-30668728

RESUMO

BUB-related 1 (BubR1) encoded by Budding Uninhibited by Benzimidazole 1B (BUB1B) is a crucial mitotic checkpoint protein ensuring proper segregation of chromosomes during mitosis. Mutations of BUB1B are responsible for mosaic variegated aneuploidy (MVA), a human congenital disorder characterized by extensive abnormalities in chromosome number. Although microcephaly is a prominent feature of MVA carrying the BUB1B mutation, how BubR1 deficiency disturbs neural progenitor proliferation and neuronal output and leads to microcephaly is unknown. Here we show that conditional loss of BubR1 in mouse cerebral cortex recapitulates microcephaly. BubR1-deficient cortex includes a strikingly reduced number of late-born, but not of early-born, neurons, although BubR1 expression is substantially reduced from an early stage. Importantly, absence of BubR1 decreases the proportion of neural progenitors in mitosis, specifically in metaphase, suggesting shortened mitosis owing to premature chromosome segregation. In the BubR1 mutant, massive apoptotic cell death, which is likely due to the compromised genomic integrity that results from aberrant mitosis, depletes progenitors and neurons during neurogenesis. There is no apparent alteration in centrosome number, spindle formation or primary cilia, suggesting that the major effect of BubR1 deficiency on neural progenitors is to impair the mitotic checkpoint. This finding highlights the importance of the mitotic checkpoint in the pathogenesis of microcephaly. Furthermore, the ependymal cell layer does not form in the conditional knockout, revealing an unrecognized role of BubR1 in assuring the integrity of the ventricular system, which may account for the presence of hydrocephalus in some patients.


Assuntos
Proteínas de Ciclo Celular/genética , Microcefalia/genética , Mitose/genética , Neurogênese/genética , Proteínas Serina-Treonina Quinases/genética , Alelos , Animais , Apoptose/genética , Proteínas de Ciclo Celular/deficiência , Proliferação de Células/genética , Córtex Cerebral/crescimento & desenvolvimento , Córtex Cerebral/metabolismo , Córtex Cerebral/patologia , Transtornos Cromossômicos/genética , Transtornos Cromossômicos/fisiopatologia , Segregação de Cromossomos/genética , Modelos Animais de Doenças , Humanos , Camundongos , Microcefalia/metabolismo , Microcefalia/fisiopatologia , Mosaicismo , Mutação/genética , Neurônios/metabolismo , Neurônios/patologia , Proteínas Serina-Treonina Quinases/deficiência , Fuso Acromático/genética , Fuso Acromático/patologia
17.
Artigo em Inglês | MEDLINE | ID: mdl-30678125

RESUMO

Zika virus (ZIKV) infection appeared in Brazil in 2015, causing an epidemic outbreak with increased rates of microcephaly and other serious birth disorders. We reviewed 102 cases of children who were diagnosed with microcephaly at birth and who had gestational exposure to ZIKV during the outbreak. We describe the clinical, neuroimaging, and neurophysiological findings. Most mothers (81%) reported symptoms of ZIKV infection, especially cutaneous rash, during the first trimester of pregnancy. The microcephaly was severe in 54.9% of the cases. All infants presented with brain malformations. The most frequent neuroimaging findings were cerebral atrophy (92.1%), ventriculomegaly (92.1%), malformation of cortical development (85.1%), and cortical⁻subcortical calcifications (80.2%). Abnormalities in neurological exams were found in 97.0% of the cases, epileptogenic activity in 56.3%, and arthrogryposis in 10.8% of the infants. The sensorineural screening suggested hearing loss in 17.3% and visual impairment in 14.1% of the infants. This group of infants who presented with microcephaly and whose mothers were exposed to ZIKV early during pregnancy showed clinical and radiological criteria for congenital ZIKV infection. A high frequency of brain abnormalities and signs of early neurological disorders were found, and epileptogenic activity and signs of sensorineural alterations were common. This suggests that microcephaly can be associated with a worst spectrum of neurological manifestations.


Assuntos
Microcefalia/patologia , Microcefalia/fisiopatologia , Infecção por Zika virus/congênito , Brasil/epidemiologia , Feminino , Humanos , Lactente , Recém-Nascido , Microcefalia/diagnóstico , Microcefalia/epidemiologia , Neuroimagem , Exame Neurológico , Gravidez , Complicações Infecciosas na Gravidez/epidemiologia , Infecção por Zika virus/epidemiologia
18.
Nutr J ; 18(1): 4, 2019 01 11.
Artigo em Inglês | MEDLINE | ID: mdl-30634976

RESUMO

BACKGROUND: Children with microcephaly due to vertical exposure to Zika virus are an interesting population for investigation. Highlighted among their unique aspects are those related to nutrition due to its impact on child growth and development. Knowledge about the nutrition of microcephalic infants can help mothers and caregivers provide better care. Thus, this study aimed to describe the nutritional status and feeding practices of infants with microcephaly due to Zika virus exposure at birth and 12-23 months of age. METHODS: This is a descriptive study developed from a cohort of patients attending a public institution of reference. A total of 65 infants attended outpatient nutrition clinics. The food practices were described using the 24-h food recall and food consumption indicators. Anthropometric measurements and consultations were made using the Child Health Handbook to obtain information on the nutritional status (weight, height and head circumference) at the time of consultation and birth. RESULTS: There was a significant decrease in z-scores for weight, height and head circumference (HC) from birth to the time of the consultation. However, most infants did not show weight-for-height deficits. Additionally, HC was correlated with the anthropometric indices weight-for-age, height-for-age, body mass index-for-age and weight-for-height. CONCLUSION: Infants exhibited a worsening of their nutritional status between birth and the time of their consultation, notably when we evaluated the indices of height and head circumference for age. The main inadequacies regarding dietary practices were low food diversity, use of ultra-processed products and low lipid intake.


Assuntos
Dieta , Microcefalia/fisiopatologia , Microcefalia/virologia , Terapia Nutricional/métodos , Estado Nutricional , Infecção por Zika virus/complicações , Antropometria , Estatura , Índice de Massa Corporal , Peso Corporal , Aleitamento Materno , Gorduras na Dieta/administração & dosagem , Feminino , Manipulação de Alimentos , Educação em Saúde , Humanos , Lactente , Fenômenos Fisiológicos da Nutrição do Lactente , Masculino , Microcefalia/terapia , Zika virus
19.
J Infect Dis ; 219(5): 734-745, 2019 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-30256965

RESUMO

BACKGROUND: The innovative human brain organoid model represents a unique opportunity to better understand the genesis of congenital brain abnormalities, particularly microcephaly, caused by Zika virus (ZIKV) infection during early pregnancy. METHODS: A systematic review was conducted to investigate how ZIKV leads to microcephaly in a novel experimental model that mimics early brain development. Studies were gathered by searching MEDLINE/Pubmed, LILACS, and LiSSa for reports on effects of ZIKV infection on human brain organoids. From 146 identified papers, 13 articles were selected for review. RESULTS: This review found that ZIKV of African, Latin American, and Asian lineages caused productive replication after 72 hours, preferentially infected neural progenitor cells over mature neurons, reduced both cell populations, and caused premature differentiation. Limited data involving only African and Latin American lineages showed a reduction in populations of proliferating cells and intermediate cells, and overall decreased viability. Furthermore, all 3 lineages caused heightened apoptosis and reduced organoid size. CONCLUSIONS: This review concludes that, in organoids, ZIKV causes productive replication, infects neural progenitor cells over mature neurons, decreases both populations, causes premature differentiation, induces apoptosis, and reduces size.


Assuntos
Encéfalo/virologia , Microcefalia/fisiopatologia , Microcefalia/virologia , Organoides/virologia , Infecção por Zika virus/complicações , Zika virus/crescimento & desenvolvimento , Zika virus/patogenicidade , Apoptose , Sobrevivência Celular , Humanos , Modelos Biológicos , Neurônios/patologia , Neurônios/virologia , Células-Tronco/patologia , Células-Tronco/virologia
20.
Genet Med ; 21(3): 545-552, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30214071

RESUMO

PURPOSE: Congenital microcephaly (CM) is an important birth defect with long term neurological sequelae. We aimed to perform detailed phenotypic and genomic analysis of patients with Mendelian forms of CM. METHODS: Clinical phenotyping, targeted or exome sequencing, and autozygome analysis. RESULTS: We describe 150 patients (104 families) with 56 Mendelian forms of CM. Our data show little overlap with the genetic causes of postnatal microcephaly. We also show that a broad definition of primary microcephaly -as an autosomal recessive form of nonsyndromic CM with severe postnatal deceleration of occipitofrontal circumference-is highly sensitive but has a limited specificity. In addition, we expand the overlap between primary microcephaly and microcephalic primordial dwarfism both clinically (short stature in >52% of patients with primary microcephaly) and molecularly (e.g., we report the first instance of CEP135-related microcephalic primordial dwarfism). We expand the allelic and locus heterogeneity of CM by reporting 37 novel likely disease-causing variants in 27 disease genes, confirming the candidacy of ANKLE2, YARS, FRMD4A, and THG1L, and proposing the candidacy of BPTF, MAP1B, CCNH, and PPFIBP1. CONCLUSION: Our study refines the phenotype of CM, expands its genetics heterogeneity, and informs the workup of children born with this developmental brain defect.


Assuntos
Microcefalia/genética , Microcefalia/fisiopatologia , Adulto , Criança , Pré-Escolar , Nanismo/genética , Feminino , Genômica/métodos , Genótipo , Humanos , Lactente , Recém-Nascido , Masculino , Mutação/genética , Linhagem , Fenótipo , Sequenciamento Completo do Exoma/métodos
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