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Pediatrics and Neonatology Jul 2021Microcephaly is defined by an occipital-frontal head circumference (OFD) 2 standard deviations (SD) smaller than the average expected for age, gender and population. Its... (Review)
Review
Microcephaly is defined by an occipital-frontal head circumference (OFD) 2 standard deviations (SD) smaller than the average expected for age, gender and population. Its incidence has been reported between 1.3 and 150 cases per 100,000 births. Currently, new clinical characteristics, causes and pathophysiological mechanisms related to microcephaly continue to be identified. Its etiology is varied and heterogeneous, with genetic and non-genetic factors that produce alterations in differentiation, proliferation, migration, repair of damage to deoxyribonucleic acid and neuronal apoptosis. It requires a multidisciplinary diagnostic approach that includes a medical history, detailed prenatal and postnatal clinical evaluation, cerebral magnetic resonance imaging, neuropsychological evaluation, and in some cases complementary tests such as metabolic screening, tests to rule out infectious processes and genetic testing. There is no specific treatment or intervention to increase cerebral growth; however, timely intervention strategies and programs can be established to improve motor and neurocognitive development, as well as to provide genetic counseling. The objective of this work is to review the available information and reinforce the proposal to carry out an etiopathogenic approach for microcephaly diagnosis and management.
Topics: Cephalometry; Female; Genetic Testing; Humans; Magnetic Resonance Imaging; Microcephaly; Pregnancy
PubMed: 34112604
DOI: 10.1016/j.pedneo.2021.05.008 -
Nature Reviews. Neurology Nov 2022The current understanding of neurological diseases is derived mostly from direct analysis of patients and from animal models of disease. However, most patient studies do... (Review)
Review
The current understanding of neurological diseases is derived mostly from direct analysis of patients and from animal models of disease. However, most patient studies do not capture the earliest stages of disease development and offer limited opportunities for experimental intervention, so rarely yield complete mechanistic insights. The use of animal models relies on evolutionary conservation of pathways involved in disease and is limited by an inability to recreate human-specific processes. In vitro models that are derived from human pluripotent stem cells cultured in 3D have emerged as a new model system that could bridge the gap between patient studies and animal models. In this Review, we summarize how such organoid models can complement classical approaches to accelerate neurological research. We describe our current understanding of neurodevelopment and how this process differs between humans and other animals, making human-derived models of disease essential. We discuss different methodologies for producing organoids and how organoids can be and have been used to model neurological disorders, including microcephaly, Zika virus infection, Alzheimer disease and other neurodegenerative disorders, and neurodevelopmental diseases, such as Timothy syndrome, Angelman syndrome and tuberous sclerosis. We also discuss the current limitations of organoid models and outline how organoids can be used to revolutionize research into the human brain and neurological diseases.
Topics: Animals; Humans; Organoids; Brain; Microcephaly; Neurodegenerative Diseases; Zika Virus Infection; Zika Virus; Neurology
PubMed: 36253568
DOI: 10.1038/s41582-022-00723-9 -
Annual Review of Neuroscience Jul 2019In 2015, public awareness of Zika virus (ZIKV) rose in response to alarming statistics of infants with microcephaly being born to women who were infected with the virus... (Review)
Review
In 2015, public awareness of Zika virus (ZIKV) rose in response to alarming statistics of infants with microcephaly being born to women who were infected with the virus during pregnancy, triggering global concern over these potentially devastating consequences. Although we have discovered a great deal about the genome and pathogenesis of this reemergent flavivirus since this recent outbreak, we still have much more to learn, including the nature of the virus-host interactions and mechanisms that determine its tropism and pathogenicity in the nervous system, which are in turn shaped by the continual evolution of the virus. Inevitably, we will find out more about the potential long-term effects of ZIKV exposure on the nervous system from ongoing longitudinal studies. Integrating clinical and epidemiological data with a wider range of animal and human cell culture models will be critical to understanding the pathogenetic mechanisms and developing more specific antiviral compounds and vaccines.
Topics: Adult; Animals; Brain; Cells, Cultured; Communicable Diseases, Emerging; Disease Outbreaks; Female; Gene Expression Regulation, Developmental; Gene Expression Regulation, Viral; Genetic Vectors; Host Microbial Interactions; Humans; Infant, Newborn; Macaca mulatta; Mice; Microbiota; Microcephaly; Microglia; Models, Animal; Nervous System Diseases; Neurogenesis; Pregnancy; Pregnancy Complications, Infectious; Receptors, Virus; Twin Studies as Topic; Viral Vaccines; Zika Virus; Zika Virus Infection
PubMed: 31283901
DOI: 10.1146/annurev-neuro-080317-062231 -
Brain : a Journal of Neurology Jan 2023Variants in the AUTS2 gene are associated with a broad spectrum of neurological conditions characterized by intellectual disability, microcephaly, and congenital brain...
Variants in the AUTS2 gene are associated with a broad spectrum of neurological conditions characterized by intellectual disability, microcephaly, and congenital brain malformations. Here, we use a human cerebral organoid model to investigate the pathophysiology of a heterozygous de novo missense AUTS2 variant identified in a patient with multiple neurological impairments including primary microcephaly and profound intellectual disability. Proband cerebral organoids exhibit reduced growth, deficits in neural progenitor cell (NPC) proliferation and disrupted NPC polarity within ventricular zone-like regions compared to control cerebral organoids. We used CRISPR-Cas9-mediated gene editing to correct this variant and demonstrate rescue of impaired organoid growth and NPC proliferative deficits. Single-cell RNA sequencing revealed a marked reduction of G1/S transition gene expression and alterations in WNT-β-catenin signalling within proband NPCs, uncovering a novel role for AUTS2 in NPCs during human cortical development. Collectively, these results underscore the value of cerebral organoids to investigate molecular mechanisms underlying AUTS2 syndrome.
Topics: Humans; Microcephaly; Intellectual Disability; Autistic Disorder; Neural Stem Cells; Organoids; Cytoskeletal Proteins; Transcription Factors
PubMed: 35802027
DOI: 10.1093/brain/awac244 -
American Journal of Medical Genetics.... May 2021Neurodevelopmental disorder with dysmorphic facies and distal limb anomalies (NEDDFL), defined primarily by developmental delay/intellectual disability, speech delay,...
Neurodevelopmental disorder with dysmorphic facies and distal limb anomalies (NEDDFL), defined primarily by developmental delay/intellectual disability, speech delay, postnatal microcephaly, and dysmorphic features, is a syndrome resulting from heterozygous variants in the dosage-sensitive bromodomain PHD finger chromatin remodeler transcription factor BPTF gene. To date, only 11 individuals with NEDDFL due to de novo BPTF variants have been described. To expand the NEDDFL phenotypic spectrum, we describe the clinical features in 25 novel individuals with 20 distinct, clinically relevant variants in BPTF, including four individuals with inherited changes in BPTF. In addition to the previously described features, individuals in this cohort exhibited mild brain abnormalities, seizures, scoliosis, and a variety of ophthalmologic complications. These results further support the broad and multi-faceted complications due to haploinsufficiency of BPTF.
Topics: Abnormalities, Multiple; Adolescent; Adult; Child; Child, Preschool; Chromatin Assembly and Disassembly; Chromosome Deletion; Developmental Disabilities; Epilepsy; Facies; Female; Haploinsufficiency; Humans; Infant; Intellectual Disability; Language Development Disorders; Male; Microcephaly; Middle Aged; Neurodevelopmental Disorders; Phenotype; Transcription Factors; Young Adult
PubMed: 33522091
DOI: 10.1002/ajmg.a.62102 -
Cell Stem Cell Aug 2021Viral infection in early pregnancy is a major cause of microcephaly. However, how distinct viruses impair human brain development remains poorly understood. Here we use...
Viral infection in early pregnancy is a major cause of microcephaly. However, how distinct viruses impair human brain development remains poorly understood. Here we use human brain organoids to study the mechanisms underlying microcephaly caused by Zika virus (ZIKV) and herpes simplex virus (HSV-1). We find that both viruses efficiently replicate in brain organoids and attenuate their growth by causing cell death. However, transcriptional profiling reveals that ZIKV and HSV-1 elicit distinct cellular responses and that HSV-1 uniquely impairs neuroepithelial identity. Furthermore, we demonstrate that, although both viruses fail to potently induce the type I interferon system, the organoid defects caused by their infection can be rescued by distinct type I interferons. These phenotypes are not seen in 2D cultures, highlighting the superiority of brain organoids in modeling viral infections. These results uncover virus-specific mechanisms and complex cellular immune defenses associated with virus-induced microcephaly.
Topics: Female; Herpesvirus 1, Human; Humans; Microcephaly; Organoids; Pregnancy; Zika Virus; Zika Virus Infection
PubMed: 33838105
DOI: 10.1016/j.stem.2021.03.004 -
Cells Jan 2022MCPH1, or BRIT1, is often mutated in human primary microcephaly type 1, a neurodevelopmental disorder characterized by a smaller brain size at birth, due to its... (Review)
Review
MCPH1, or BRIT1, is often mutated in human primary microcephaly type 1, a neurodevelopmental disorder characterized by a smaller brain size at birth, due to its dysfunction in regulating the proliferation and self-renewal of neuroprogenitor cells. In the last 20 years or so, genetic and cellular studies have identified MCPH1 as a multifaceted protein in various cellular functions, including DNA damage signaling and repair, the regulation of chromosome condensation, cell-cycle progression, centrosome activity and the metabolism. Yet, genetic and animal model studies have revealed an unpredicted essential function of MPCH1 in gonad development and tumorigenesis, although the underlying mechanism remains elusive. These studies have begun to shed light on the role of MPCH1 in controlling various pathobiological processes of the disorder. Here, we summarize the biological functions of MCPH1, and lessons learnt from cellular and mouse models of MCPH1.
Topics: Animals; Brain; Cytoskeletal Proteins; Disease Models, Animal; Genetic Predisposition to Disease; Humans; Microcephaly; Neurogenesis
PubMed: 35053391
DOI: 10.3390/cells11020275 -
Boletin Medico Del Hospital Infantil de... 2023In February 2016, the World Health Organization declared Zika virus (ZIKV) infection a public health emergency of international concern because it caused congenital Zika...
In February 2016, the World Health Organization declared Zika virus (ZIKV) infection a public health emergency of international concern because it caused congenital Zika syndrome (CZS). The CZS is considered a specific pattern of birth defects caused by ZIKV infection, which is transmitted by the bite of the Aedes aegypti mosquito. The CZS clinical manifestations are broad and nonspecific, including microcephaly, subcortical calcifications, ocular alterations, congenital contractures, early hypertonia, and pyramidal as well as extrapyramidal symptoms. The ZIKV has gained great importance because it has affected a large percentage of the population worldwide during the last few years, despite the measures implemented by international organizations. The pathophysiology and non-vectorial transmission routes of the virus are still under study. The diagnosis is made upon suspicion of ZIKV infection, the patient's clinical manifestations, and it is confirmed by molecular laboratory tests demonstrating the presence of viral particles. Unfortunately, there is no specific treatment or vaccine for this condition; however, patients receive multidisciplinary care and constant monitoring. Therefore, the strategies that have been implemented are directed toward preventive measures and vector control.
Topics: Animals; Humans; Zika Virus Infection; Zika Virus; Microcephaly
PubMed: 36867568
DOI: 10.24875/BMHIM.22000110 -
Cells Dec 2019Regulators of mitotic division, when dysfunctional or expressed in a deregulated manner (over- or underexpressed) in somatic cells, cause chromosome instability, which... (Review)
Review
Regulators of mitotic division, when dysfunctional or expressed in a deregulated manner (over- or underexpressed) in somatic cells, cause chromosome instability, which is a predisposing condition to cancer that is associated with unrestricted proliferation. Genes encoding mitotic regulators are growingly implicated in neurodevelopmental diseases. Here, we briefly summarize existing knowledge on how microcephaly-related mitotic genes operate in the control of chromosome segregation during mitosis in somatic cells, with a special focus on the role of kinetochore factors. Then, we review evidence implicating mitotic apparatus- and kinetochore-resident factors in the origin of congenital microcephaly. We discuss data emerging from these works, which suggest a critical role of correct mitotic division in controlling neuronal cell proliferation and shaping the architecture of the central nervous system.
Topics: Cell Proliferation; Chromosome Segregation; Humans; Kinetochores; Microcephaly; Mitosis; Neurodevelopmental Disorders; Spindle Apparatus
PubMed: 31878213
DOI: 10.3390/cells9010049 -
Cells Jul 2022How the brain develops and achieves its final size is a fascinating issue that questions cortical evolution across species and man's place in the animal kingdom.... (Review)
Review
How the brain develops and achieves its final size is a fascinating issue that questions cortical evolution across species and man's place in the animal kingdom. Although animal models have so far been highly valuable in understanding the key steps of cortical development, many human specificities call for appropriate models. In particular, microcephaly, a neurodevelopmental disorder that is characterized by a smaller head circumference has been challenging to model in mice, which often do not fully recapitulate the human phenotype. The relatively recent development of brain organoid technology from induced pluripotent stem cells (iPSCs) now makes it possible to model human microcephaly, both due to genetic and environmental origins, and to generate developing cortical tissue from the patients themselves. These 3D tissues rely on iPSCs differentiation into cortical progenitors that self-organize into neuroepithelial rosettes mimicking the earliest stages of human neurogenesis in vitro. Over the last ten years, numerous protocols have been developed to control the identity of the induced brain areas, the reproducibility of the experiments and the longevity of the cultures, allowing analysis of the later stages. In this review, we describe the different approaches that instruct human iPSCs to form cortical organoids, summarize the different microcephalic conditions that have so far been modeled by organoids, and discuss the relevance of this model to decipher the cellular and molecular mechanisms of primary and secondary microcephalies.
Topics: Animals; Humans; Induced Pluripotent Stem Cells; Mice; Microcephaly; Neurogenesis; Organoids; Reproducibility of Results
PubMed: 35883578
DOI: 10.3390/cells11142135