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1.
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
2.
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
3.
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
4.
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
5.
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
6.
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
7.
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
8.
World Neurosurg ; 123: e760-e765, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30579032

RESUMO

OBJECTIVE: The new direct gradual cranial expansion surgical technique has been used to treat children with postshunt microcephaly and slit ventricle syndrome. To evaluate the feasibility of this new surgical treatment, we studied intracranial pressure (ICP) in microcephalic children with developmental delay. METHODS: Mean ICP, age, sex, head size, and developmental assessments were compared in 24 microcephalic children with developmental delay who had had continuous ICP monitoring. RESULTS: Children studied included 9 boys and 15 girls with a mean age of 4.9 ± 2.0 years. Mean ICP was 18.7 ± 8.6 mm Hg. Children with high ICP had significantly lower age and higher B wave ratios than children with low ICP. There were no statistically significant differences in developmental scores and head sizes between children with high ICP and children with low ICP. In multiple linear regression analysis, we observed significantly increased risk of mean ICP elevation by B wave ratio and developmental score and decreased risk of mean ICP elevation by age, but not significantly increased risk of mean ICP elevation by head circumferences (z score). CONCLUSIONS: Our findings suggest that a portion of microcephalic children with developmental delay have high ICP that cannot be expected from head sizes, and high ICP has decreasing tendency with age.


Assuntos
Deficiências do Desenvolvimento/fisiopatologia , Hipertensão Intracraniana/fisiopatologia , Microcefalia/fisiopatologia , Cefalometria , Criança , Pré-Escolar , Deficiências do Desenvolvimento/complicações , Eletrodos Implantados , Estudos de Viabilidade , Feminino , Humanos , Hipertensão Intracraniana/complicações , Pressão Intracraniana/fisiologia , Masculino , Microcefalia/complicações , Microcefalia/cirurgia , Monitorização Ambulatorial/instrumentação , Monitorização Fisiológica/instrumentação , Procedimentos Neurocirúrgicos/métodos , Fatores de Risco
9.
PLoS Biol ; 16(12): e2006613, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30566428

RESUMO

Mutations of WD repeat domain 62 (WDR62) lead to autosomal recessive primary microcephaly (MCPH), and down-regulation of WDR62 expression causes the loss of neural progenitor cells (NPCs). However, how WDR62 is regulated and hence controls neurogenesis and brain size remains elusive. Here, we demonstrate that mitogen-activated protein kinase kinase kinase 3 (MEKK3) forms a complex with WDR62 to promote c-Jun N-terminal kinase (JNK) signaling synergistically in the control of neurogenesis. The deletion of Mekk3, Wdr62, or Jnk1 resulted in phenocopied defects, including premature NPC differentiation. We further showed that WDR62 protein is positively regulated by MEKK3 and JNK1 in the developing brain and that the defects of wdr62 deficiency can be rescued by the transgenic expression of JNK1. Meanwhile, WDR62 is also negatively regulated by T1053 phosphorylation, leading to the recruitment of F-box and WD repeat domain-containing protein 7 (FBW7) and proteasomal degradation. Our findings demonstrate that the coordinated reciprocal and bidirectional regulation among MEKK3, FBW7, WDR62, and JNK1, is required for fine-tuned JNK signaling for the control of balanced NPC self-renewal and differentiation during cortical development.


Assuntos
Proteínas de Ciclo Celular/metabolismo , Proteína 7 com Repetições F-Box-WD/fisiologia , MAP Quinase Quinase Quinase 3/fisiologia , Proteínas Associadas aos Microtúbulos/metabolismo , Animais , Diferenciação Celular , Proteína 7 com Repetições F-Box-WD/genética , Feminino , Células HEK293 , Humanos , MAP Quinase Quinase Quinase 3/genética , Sistema de Sinalização das MAP Quinases , Masculino , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Microcefalia/genética , Microcefalia/fisiopatologia , Proteína Quinase 8 Ativada por Mitógeno/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Células-Tronco Neurais/metabolismo , Neurogênese/fisiologia , Fosforilação , Ligação Proteica , Ratos , Ratos Sprague-Dawley , Transdução de Sinais
10.
Congenit Anom (Kyoto) ; 58(1): 16-23, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-28464341

RESUMO

Environmental enrichment (EE) mediates recovery from sensory, motor, and cognitive deficits and emotional abnormalities. In the present study, we examined the effects of EE on locomotor activity and neuronal activity in the amygdala in control and methylazoxymethanol acetate (MAM)-induced micrencephalic rats after challenge in a novel open field. Control rats housed in EE (CR) showed reduced locomotor activity compared to rats housed in a conventional cage (CC), whereas hyperactivity was seen in MAM rats housed in a conventional cage (MC) and in MAM rats housed in EE (MR). Novel open field exposure in both CC and MC resulted in a marked increase in Fos expression in the anterior and posterior parts of the basolateral amygdaloid nucleus, basomedial nucleus, and medial nucleus, whereas these increases in expression were not observed in CR. The effect of EE on Fos expression in the amygdala was different in MR exposed to a novel open field compared to CR. Furthermore, we observed a quite different pattern of Fos expression in the central nucleus of the amygdala between control and MAM rats. The present results suggest that neuronal activity in the amygdala that responds to anxiety is altered in MAM rats, especially when the rats are reared in EE. These alterations may cause behavioral differences between control and MAM rats.


Assuntos
Tonsila do Cerebelo/fisiopatologia , Meio Ambiente , Comportamento Exploratório , Locomoção , Microcefalia/fisiopatologia , Tonsila do Cerebelo/efeitos dos fármacos , Tonsila do Cerebelo/patologia , Animais , Feminino , Expressão Gênica/efeitos dos fármacos , Masculino , Acetato de Metilazoximetanol/toxicidade , Microcefalia/induzido quimicamente , Microcefalia/genética , Microcefalia/patologia , Neurotoxinas/toxicidade , Proteínas Proto-Oncogênicas c-fos/genética , Proteínas Proto-Oncogênicas c-fos/metabolismo , Ratos , Ratos Sprague-Dawley
11.
Clin Dysmorphol ; 27(2): 36-41, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29240611

RESUMO

Structural rearrangements of chromosome band 1p31p32 are rare, and their phenotypic consequences remain poorly delineated. Up to 12 patients with learning difficulties, developmental delay, multiple congenital anomalies and microdeletion of the chromosome band 1p31p32 have been described. Inheritance of this deletion has not been reported previously. We describe the inheritance of the 1p32 deletion and discuss the relevance of this deletion to the described phenotype. The differences in clinical and molecular characteristics between the proband and other published reports are reviewed. Patients were evaluated in Genetics Clinic with history, examination and investigation. The existing literature on interstitial deletions of 1p was reviewed. Here, we report on a three-generation family, where the index patient was an adult female with learning difficulty, dysmorphic features, microcephaly, ambiguous genitalia, congenital hip dislocation and brachydactyly in whom a maternally inherited 1.45 Mbp interstitial deletion was detected at 1p32.3. Both her mother and maternal grandmother have learning difficulties and dysmorphic features. There are 14 OMIM genes in the deleted region including LRP8 and DMRTB1. The NFIA gene is not deleted in this family. The first report of a familial 1p32 microdeletion in three generations of a family carrying the smallest reported a deletion involving this region and brachydactyly as a previously unreported feature.


Assuntos
Anormalidades Múltiplas/genética , Deleção Cromossômica , Deficiências do Desenvolvimento/genética , Microcefalia/genética , Anormalidades Múltiplas/fisiopatologia , Adulto , Cromossomos Humanos Par 1/genética , Hibridização Genômica Comparativa , Proteínas de Ligação a DNA/genética , Deficiências do Desenvolvimento/fisiopatologia , Feminino , Humanos , Proteínas Relacionadas a Receptor de LDL/genética , Masculino , Microcefalia/fisiopatologia , Linhagem , Fenótipo , Fatores de Transcrição/genética
12.
BMC Res Notes ; 10(1): 743, 2017 Dec 19.
Artigo em Inglês | MEDLINE | ID: mdl-29258560

RESUMO

OBJECTIVES: Children with microcephaly face lifelong psychomotor, cognitive, and communications skills disabilities. Etiology of microcephaly is heterogeneous but presentation often includes seizures, hypotonia, ataxia, stereotypic movements, attention deficits, excitability, cognitive delays, and poor communication skills. Molecular diagnostics have outpaced available interventions and most children receive generic physical, speech, and occupational therapies with little attention to the efficacy of such treatments. Mutations in the X-linked intellectual disability gene (XLID) CASK is one etiology associated with microcephaly which produces mental retardation and microcephaly with pontine and cerebellar hypoplasia (MICPCH; OMIM# 300749). We pilot-tested an intensive therapy in three girls with heterozygous mutation in the gene CASK and MICPCH. Child A = 54 months; Child B = 89 months; and Child C = 24 months received a targeted treatment to improve gross/fine motor skills, visual-motor coordination, social interaction, and communication. Treatment was 4 h each weekday for 10 treatment days. Operant training promoted/refined goal-directed activities. The Peabody Developmental Motor Scales 2 was administered pre- and post-treatment. RESULTS: Child A gained 14 developmental months; Child B gained 20 developmental months; and Child C gained 39 developmental months. This case series suggests that children with MICPCH are responsive to intensive therapy aimed at increasing functional skills/independence. Trial Registration ClinicalTrials.gov Registration Number: NCT03325946; Release Date: October 30, 2017.


Assuntos
Cognição/fisiologia , Guanilato Quinases/genética , Destreza Motora/fisiologia , Mutação , Reabilitação Neurológica/métodos , Criança , Pré-Escolar , Feminino , Humanos , Retardo Mental Ligado ao Cromossomo X/genética , Retardo Mental Ligado ao Cromossomo X/fisiopatologia , Retardo Mental Ligado ao Cromossomo X/terapia , Microcefalia/genética , Microcefalia/fisiopatologia , Microcefalia/terapia , Projetos Piloto , Resultado do Tratamento
13.
J Genet ; 96(2): 383-387, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28674240

RESUMO

Autosomal recessive primary microcephaly is a rare genetic disorder that is characterized by reduced head circumference and a varying degree of intellectual disability. Genetic studies on consanguineous families with primary microcephaly have identified 15 (MCPH) causative genes that include MCPH1, WDR62, CDK5RAP2, CASC5, ASPM, CENPJ, STIL, CEP135, CEP152, ZNF335, PHC1, CDK6, CENPE, SASS6 MFSD2A ANKLE2 and CIT (Khan et al. 2014; Yamamoto et al. 2014; Alakbarzade et al. 2015;Morris-Rosendahl and Kaindl 2015; Basit et al. 2016). Physiologically, most of these MCPH proteins are involved in cell cycle and its regulation. In the present clinical genetic study, we have present two consanguineous Pakistani families segregating primary microcephaly and intellectual disability. These families were ascertained from the Saraiki ethnic part of Khyber-Pakhtunkhwa province in Pakistan. Whole exome sequencing in one family revealed a novel 1-bp deletion NM_018136.4: c.10013delA (p.Asp3338Valfs*2), while the other family showed a previously reported nonsense mutation NM_018136.4: c.9730C>T (rs199422195 (p.Arg3244*)) in ASPM gene. The novel frame-shift mutation (p.Asp3338Valfs*2) in ASPM presumably truncates the protein synthesis that results in loss of armadillo-type fold domain.


Assuntos
Deficiência Intelectual/genética , Microcefalia/genética , Proteínas do Tecido Nervoso/genética , Sequenciamento Completo do Exoma , Consanguinidade , Feminino , Humanos , Deficiência Intelectual/fisiopatologia , Masculino , Microcefalia/fisiopatologia , Mutação , Paquistão
14.
PLoS One ; 12(7): e0180220, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28686621

RESUMO

INTRODUCTION: Given the severity and impact of the current Zika virus (ZIKV) outbreak in the Americas, numerous countries have rushed to develop research studies to assess ZIKV and its potential health consequences. In an effort to ensure that studies are comprehensive, both internally and externally valid, and with reliable results, the World Health Organization, the Pan American Health Organization, Institut Pasteur, the networks of Fiocruz, the Consortia for the Standardization of Influenza Seroepidemiology (CONSISE) and the International Severe Acute Respiratory and Emerging Infection Consortium (ISARIC) have generated six standardized clinical and epidemiological research protocols and questionnaires to address key public health questions on ZIKV. METHODS: We conducted a systematic search of ongoing study protocols related to ZIKV research. We analyzed the content of protocols of 32 cohort studies and 13 case control studies for systematic bias that could produce erroneous results. Additionally we aimed to characterize the risks of bias and confounding in observational studies related to ZIKV and to propose ways to minimize them, including the use of six newly standardized research protocols. RESULTS: Observational studies of ZIKV face an array of challenges, including measurement of exposure and outcomes (microcephaly and Guillain-Barré Syndrome). Potential confounders need to be measured where known and controlled for in the analysis. Selection bias due to non-random selection is a significant issue, particularly in the case-control design, and losses to follow-up is equally important for the cohort design. CONCLUSION: Observational research seeking to answer key questions on the ZIKV should consider these restrictions and take precautions to minimize bias in an effort to provide reliable and valid results. Utilization of the standardized research protocols developed by the WHO, PAHO, Institut Pasteur, and CONSISE will harmonize the key methodological aspects of each study design to minimize bias at different stages of the study. Biases need to be considered by researchers implementing the standardized protocols as well as by users of observational epidemiological studies of ZIKV.


Assuntos
Síndrome de Guillain-Barré/epidemiologia , Microcefalia/epidemiologia , Complicações Infecciosas na Gravidez/epidemiologia , Infecção por Zika virus/epidemiologia , Estudos de Casos e Controles , Estudos de Coortes , Surtos de Doenças , Feminino , Síndrome de Guillain-Barré/etiologia , Síndrome de Guillain-Barré/fisiopatologia , Humanos , Microcefalia/etiologia , Microcefalia/fisiopatologia , Gravidez , Complicações Infecciosas na Gravidez/etiologia , Complicações Infecciosas na Gravidez/patologia , Complicações Infecciosas na Gravidez/virologia , Saúde Pública , Fatores de Risco , Organização Mundial da Saúde , Zika virus/patogenicidade , Infecção por Zika virus/complicações , Infecção por Zika virus/patologia , Infecção por Zika virus/virologia
15.
J Neurosci ; 37(31): 7347-7361, 2017 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-28663201

RESUMO

Angelman syndrome (AS) is a debilitating neurodevelopmental disorder caused by loss of function of the maternally inherited UBE3A allele. It is currently unclear how the consequences of this genetic insult unfold to impair neurodevelopment. We reasoned that by elucidating the basis of microcephaly in AS, a highly penetrant syndromic feature with early postnatal onset, we would gain new insights into the mechanisms by which maternal UBE3A loss derails neurotypical brain growth and function. Detailed anatomical analysis of both male and female maternal Ube3a-null mice reveals that microcephaly in the AS mouse model is primarily driven by deficits in the growth of white matter tracts, which by adulthood are characterized by densely packed axons of disproportionately small caliber. Our results implicate impaired axon growth in the pathogenesis of AS and identify noninvasive structural neuroimaging as a potentially valuable tool for gauging therapeutic efficacy in the disorder.SIGNIFICANCE STATEMENT People who maternally inherit a deletion or nonfunctional copy of the UBE3A gene develop Angelman syndrome (AS), a severe neurodevelopmental disorder. To better understand how loss of maternal UBE3A function derails brain development, we analyzed brain structure in a maternal Ube3a knock-out mouse model of AS. We report that the volume of white matter (WM) is disproportionately reduced in AS mice, indicating that deficits in WM development are a major factor underlying impaired brain growth and microcephaly in the disorder. Notably, we find that axons within the WM pathways of AS model mice are abnormally small in caliber. This defect is associated with slowed nerve conduction, which could contribute to behavioral deficits in AS, including motor dysfunction.


Assuntos
Síndrome de Angelman/patologia , Axônios/patologia , Microcefalia/patologia , Fibras Nervosas/patologia , Ubiquitina-Proteína Ligases/genética , Substância Branca/patologia , Síndrome de Angelman/fisiopatologia , Animais , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Microcefalia/fisiopatologia , Substância Branca/fisiopatologia
16.
Adv Exp Med Biol ; 1002: 19-45, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28600781

RESUMO

Development requires cell proliferation, differentiation and spatial organization of daughter cells to occur in a highly controlled manner. The mode of cell division, the extent of proliferation and the spatial distribution of mitosis allow the formation of tissues of the right size and with the correct structural organization. All these aspects depend on cell cycle duration, correct chromosome segregation and spindle orientation. The centrosome, which is the main microtubule-organizing centre (MTOC) of animal cells, contributes to all these processes. As one of the most structurally complex organs in our body, the brain is particularly susceptible to centrosome dysfunction. Autosomal recessive primary microcephaly (MCPH), primordial dwarfism disease Seckel syndrome (SCKS) and microcephalic osteodysplastic primordial dwarfism type II (MOPD-II) are often connected to mutations in centrosomal genes. In this chapter, we discuss the consequences of centrosome dysfunction during development and how they can contribute to the etiology of human diseases.


Assuntos
Encéfalo/anormalidades , Centrossomo/patologia , Microcefalia/patologia , Mitose , Animais , Evolução Biológica , Encéfalo/metabolismo , Encéfalo/fisiopatologia , Centrossomo/metabolismo , Modelos Animais de Doenças , Regulação da Expressão Gênica no Desenvolvimento , Humanos , Microcefalia/genética , Microcefalia/fisiopatologia , Morfogênese , Especificidade da Espécie
17.
Am J Med Genet A ; 173(8): 2081-2087, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28573701

RESUMO

Interstitial 2p15p16.1 microdeletion is a rare chromosomal syndrome previously reported in 33 patients. It is characterized by intellectual disability, developmental delay, autism spectrum disorders, microcephaly, short stature, dysmorphic features, and multiple congenital organ defects. It is defined as a contiguous gene syndrome and two critical regions have been proposed at 2p15 and 2p16.1 loci. Nevertheless, patients with deletion of both critical regions shared similar features of the phenotype and the correlation genotype-phenotype is still unclear. We review all published cases and describe three additional patients, to define the phenotype-genotype correlation more precisely. We reported on two patients including the first prenatal case described so far, carrying a 2p15 deletion affecting two genes: XPO1 and part of USP34. Both patients shared similar features including facial dysmorphism and cerebral abnormalities. We considered the genes involved in the deleted segment to further understand the abnormal phenotype. The third case we described here was a 4-year-old boy with a heterozygous de novo 427 kb deletion encompassing BCL11A and PAPOLG at 2p16.1. He displayed speech delay, autistic traits, and motor stereotypies associated with brain structure abnormalities. We discuss the contribution of the genes included in the deletion to the abnormal phenotype. Our three new patients compared to previous cases, highlighted that despite two critical regions, both distal deletion at 2p16.1 and proximal deletion at 2p15 are associated with phenotypes that are very close to each other. Finally, we also discuss the genetic counseling of this microdeletion syndrome particularly in the course of prenatal diagnosis.


Assuntos
Anormalidades Múltiplas/genética , Deleção Cromossômica , Deficiências do Desenvolvimento/genética , Microcefalia/genética , Anormalidades Múltiplas/diagnóstico por imagem , Anormalidades Múltiplas/fisiopatologia , Encéfalo/diagnóstico por imagem , Encéfalo/fisiopatologia , Proteínas de Transporte/genética , Pré-Escolar , Cromossomos Humanos Par 2/genética , Deficiências do Desenvolvimento/diagnóstico por imagem , Deficiências do Desenvolvimento/fisiopatologia , Feminino , Humanos , Lactente , Carioferinas/genética , Imagem por Ressonância Magnética , Masculino , Microcefalia/diagnóstico por imagem , Microcefalia/fisiopatologia , Proteínas Nucleares/genética , Fenótipo , Receptores Citoplasmáticos e Nucleares/genética , Proteases Específicas de Ubiquitina/genética
18.
Am J Med Genet A ; 173(8): 2246-2250, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28574218

RESUMO

GMPPA encodes the GDP-mannose pyrophosphorylase A protein (GMPPA). The function of GMPPA is not well defined, however it is a homolog of GMPPB which catalyzes the reaction that converts mannose-1-phosphate and guanosine-5'-triphosphate to GDP-mannose. Previously, biallelic mutations in GMPPA were reported to cause a disorder characterized by achalasia, alacrima, neurological deficits, and intellectual disability. In this study, we report a female proband with achalasia, alacrima, hypohydrosis, apparent intellectual disability, seizures, microcephaly, esotropia, and craniofacial dysmorphism. Exome sequencing identified a previously unreported homozygous c.853+1G>A variant in GMPPA in the proband and her affected sister. Their unaffected parents were heterozygous, and unaffected brother homozygous wild type for this variant. Lymphoblast cells from the affected sisters showed complete loss of the GMPPA protein by Western blotting, and increased levels of GDP-mannose in lymphoblasts on high performance liquid chromatography. Based on our findings and the previous report describing patients with an overlapping phenotype, we conclude that this novel variant in GMPPA, identified by exome sequencing in the proband and her affected sister, is the genetic cause of their phenotype and may expand the known phenotype of this recently described glycosylation disorder.


Assuntos
Anormalidades Múltiplas/genética , Epilepsia/genética , Deficiência Intelectual/genética , Atrofia Muscular/genética , Nucleotidiltransferases/genética , Anormalidades Múltiplas/fisiopatologia , Criança , Pré-Escolar , Anormalidades Craniofaciais/complicações , Anormalidades Craniofaciais/genética , Anormalidades Craniofaciais/fisiopatologia , Epilepsia/complicações , Epilepsia/fisiopatologia , Exoma/genética , Facies , Feminino , Heterozigoto , Humanos , Deficiência Intelectual/complicações , Deficiência Intelectual/fisiopatologia , Microcefalia/complicações , Microcefalia/genética , Microcefalia/fisiopatologia , Atrofia Muscular/fisiopatologia , Mutação de Sentido Incorreto , Linhagem , Fenótipo , Convulsões/complicações , Convulsões/genética , Convulsões/fisiopatologia
19.
Am J Med Genet A ; 173(9): 2485-2488, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28631888

RESUMO

Cohen Syndrome (CS) is a rare autosomal recessive disorder caused by homozygous or compound heterozygous pathogenic variants in VPS13B, also known as COH1. Over 100 pathogenic variants in VSP13B, primarily truncations, and copy number variants, have been found in patients with CS. Here, we present an 11-month-old girl with CS caused by two multi-exonic small deletions in VSP13B in trans. Array comparative genomic hybridization has revolutionized the field of genome copy number analysis down to the exonic level, however it has its limitations. It cannot detect balanced structural variation nor determine the phase of copy number variants. Heterozygous multi-exonic copy number variation in autosomal recessive genes should be interpreted in the context of a clinical phenotype, and, if warranted, phase analysis should be performed before sequence analysis for that gene is pursued. This patient emphasizes the need of obtaining clinical information and determining the phase in multi-exonic copy number variants for accurate diagnosis and risk counseling.


Assuntos
Variações do Número de Cópias de DNA/genética , Dedos/anormalidades , Deficiência Intelectual/genética , Microcefalia/genética , Hipotonia Muscular/genética , Miopia/genética , Obesidade/genética , Proteínas de Transporte Vesicular/genética , Hibridização Genômica Comparativa , Deficiências do Desenvolvimento/genética , Deficiências do Desenvolvimento/fisiopatologia , Éxons/genética , Feminino , Dedos/fisiopatologia , Heterozigoto , Humanos , Lactente , Deficiência Intelectual/fisiopatologia , Microcefalia/fisiopatologia , Hipotonia Muscular/fisiopatologia , Miopia/fisiopatologia , Obesidade/fisiopatologia , Degeneração Retiniana , Deleção de Sequência
20.
Acta Obstet Gynecol Scand ; 96(9): 1039-1044, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28646619

RESUMO

Fetal infection by the Zika virus has been implicated in the exceptional rise in the number of microcephalic newborns recorded by the end of 2015 in Brazil. The mechanism by which this teratogenic effect is produced in the developing brain has not been fully established. Very early in the outbreak, we addressed this question by evaluating available initial data from a gestational and postnatal clinical investigation in the Brazilian state of Pernambuco. The present study was undertaken to test the hypothesis that the subtractive dysmorphic brain malformations observed in Zika-related microcephaly are primarily due to the massive induction of apoptosis of neuroprogenitor cells. We designed a physiopathological algorithm based on the examination of the following medical findings: epidemiological data, ultrasound images, computed tomography scans, placental tissue, cerebral fluid analysis, eye fundoscopy, neurological examination and necroscopy findings.


Assuntos
Surtos de Doenças , Microcefalia/epidemiologia , Complicações Infecciosas na Gravidez , Infecção por Zika virus , Zika virus/patogenicidade , Apoptose , Brasil/epidemiologia , Sistema Nervoso Central/patologia , Sistema Nervoso Central/virologia , Feminino , Humanos , Recém-Nascido , Microcefalia/fisiopatologia , Gravidez , Teratogênios/toxicidade
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