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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 -
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 -
Clinics in Perinatology Sep 2022One of the most common definitions of microcephaly cited is that of an occipitofrontal circumference (OFC) of the head that is less than two standard deviations below... (Review)
Review
One of the most common definitions of microcephaly cited is that of an occipitofrontal circumference (OFC) of the head that is less than two standard deviations below the average for age (or gestational age, if identified prenatally) and sex. Similarly, severe microcephaly is defined as an OFC that is less than three standard deviations below the average. Microcephaly is not a diagnosis, but rather, a finding that is secondary to a multitude of etiologies that can be categorized as prenatal versus postnatal, genetic versus environmental, and congenital versus acquired.
Topics: Female; Gestational Age; Humans; Microcephaly; Pregnancy; Ultrasonography, Prenatal
PubMed: 36113930
DOI: 10.1016/j.clp.2022.04.004 -
The American Journal of Medicine Jul 2022
Topics: Accidents, Traffic; Humans; Microcephaly; Zika Virus; Zika Virus Infection
PubMed: 35151616
DOI: 10.1016/j.amjmed.2022.01.040 -
American Journal of Obstetrics and... Dec 2020
Review
Topics: Abortion, Induced; Chromosome Aberrations; Encephalocele; Female; Genetic Testing; Humans; Hydrocephalus; Imaging, Three-Dimensional; Magnetic Resonance Imaging; Microarray Analysis; Microcephaly; Neurology; Neurosurgery; Pregnancy; Prognosis; Referral and Consultation; Ultrasonography, Prenatal
PubMed: 33168216
DOI: 10.1016/j.ajog.2020.08.177 -
American Journal of Medical Genetics.... Jan 2024DYRK1A Syndrome (OMIM #614104) is caused by pathogenic variations in the DYRK1A gene located on 21q22. Haploinsufficiency of DYRK1A causes a syndrome with global...
DYRK1A Syndrome (OMIM #614104) is caused by pathogenic variations in the DYRK1A gene located on 21q22. Haploinsufficiency of DYRK1A causes a syndrome with global psychomotor delay and intellectual disability. Low birth weight, growth restriction with feeding difficulties, stature insufficiency, and microcephaly are frequently reported. This study aims to create specific growth charts for individuals with DYRK1A Syndrome and identify parameters for size prognosis. Growth parameters were obtained for 92 individuals with DYRK1A Syndrome (49 males vs. 43 females). The data were obtained from pediatric records, parent reporting, and scientific literature. Growth charts for height, weight, body mass index (BMI), and occipitofrontal circumference (OFC) were generated using generalized additive models through R package gamlss. The growth curves include height, weight, and OFC measurements for patients aged 0-5 years. In accordance with the literature, the charts show that individuals are more likely to present intrauterine growth restriction with low birth weight and microcephaly. The growth is then characterized by severe microcephaly, low weight, and short stature. This study proposes growth charts for widespread use in the management of patients with DYRK1A syndrome.
Topics: Male; Female; Child; Humans; Microcephaly; Growth Charts; Intellectual Disability; Syndrome; Body Mass Index; Body Height
PubMed: 37740550
DOI: 10.1002/ajmg.a.63412 -
Biology of the Cell Jun 2022Improper expansion of neural stem and progenitor cells during brain development manifests in primary microcephaly. This disease is characterized by a reduced head... (Review)
Review
Improper expansion of neural stem and progenitor cells during brain development manifests in primary microcephaly. This disease is characterized by a reduced head circumference, which correlates with a reduction in brain size. This often corresponds to a general underdevelopment of the brain and entails cognitive, behavioral and motoric retardation. In the past decade significant research efforts have been undertaken to identify genes and the molecular mechanisms underlying microcephaly. One such gene set encompasses factors required for DNA replication. Intriguingly, a growing body of evidence indicates that a substantial number of these genes mediate faithful centrosome and cilium function in addition to their canonical function in genome duplication. Here, we summarize, which DNA replication factors are associated with microcephaly syndromes and to which extent they impact on centrosomes and cilia.
Topics: Centrosome; Cilia; DNA Replication; Humans; Microcephaly; Syndrome
PubMed: 35182397
DOI: 10.1111/boc.202100061 -
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 -
NeoReviews Apr 2022
Topics: Female; Humans; Infant, Newborn; Microcephaly; Pregnancy; Pregnancy Complications, Infectious
PubMed: 35362040
DOI: 10.1542/neo.23-4-e279