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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 -
Genetics in Medicine : Official Journal... Mar 2019Congenital microcephaly (CM) is an important birth defect with long term neurological sequelae. We aimed to perform detailed phenotypic and genomic analysis of patients...
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.
Topics: Adult; Child; Child, Preschool; Dwarfism; Female; Genomics; Genotype; Humans; Infant; Infant, Newborn; Male; Microcephaly; Mutation; Pedigree; Phenotype; Exome Sequencing
PubMed: 30214071
DOI: 10.1038/s41436-018-0140-3 -
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 -
European Journal of Human Genetics :... Mar 2011The widespread clinical utilization of array comparative genome hybridization, has led to the unraveling of many new copy number variations (CNVs). Although some of...
The widespread clinical utilization of array comparative genome hybridization, has led to the unraveling of many new copy number variations (CNVs). Although some of these CNVs are clearly pathogenic, the phenotypic consequences of others, such as those in 16p13.11 remain unclear. Whereas deletions of 16p13.11 have been associated with multiple congenital anomalies, the relevance of duplications of the region is still being debated. We report detailed clinical and molecular characterization of 10 patients with duplication and 4 patients with deletion of 16p13.11. We found that patients with duplication of the region have varied clinical features including behavioral abnormalities, cognitive impairment, congenital heart defects and skeletal manifestations, such as hypermobility, craniosynostosis and polydactyly. These features were incompletely penetrant. Patients with deletion of the region presented with microcephaly, developmental delay and behavioral abnormalities as previously described. The CNVs were of varying sizes and were likely mediated by non-allelic homologous recombination between low copy repeats. Our findings expand the repertoire of clinical features observed in patients with CNV in 16p13.11 and strengthen the hypothesis that this is a dosage sensitive region with clinical relevance.
Topics: Abnormalities, Multiple; Child; Chromosome Deletion; Chromosome Duplication; Chromosomes, Human, Pair 16; Cohort Studies; Comparative Genomic Hybridization; Developmental Disabilities; Female; Humans; Infant; Male; Microcephaly; Phenotype; Segmental Duplications, Genomic
PubMed: 21150890
DOI: 10.1038/ejhg.2010.184 -
Cell Stem Cell Oct 2013A major barrier in understanding nervous system development is modeling the cellular interactions that form the human brain. Recently, in the journal Nature, Lancaster...
A major barrier in understanding nervous system development is modeling the cellular interactions that form the human brain. Recently, in the journal Nature, Lancaster et al. (2013) established a protocol for culturing pluripotent stem cell (PSC)-derived "cerebral organoids" that mimics the developing human brain's cellular organization, segregates into distinct brain regions, and models microcephaly.
Topics: Animals; Brain; Humans; Microcephaly; Models, Biological; Organoids; Tissue Culture Techniques
PubMed: 24094317
DOI: 10.1016/j.stem.2013.09.010 -
Medicina 2018Microcephaly is defined as a head circumference more than two standard deviations below the mean for gender and age. It is an important neurological sign and predictor...
Microcephaly is defined as a head circumference more than two standard deviations below the mean for gender and age. It is an important neurological sign and predictor of future disability. One of its diagnostic difficulties lies in the ranks of the head circumference reference against which we measure each child. The WHO developed growth curves that could be used universally, topic on which there may be discrepancies. Recently, Zika virus epidemic demanded to review the criteria for the diagnosis of microcephaly. The classification of the microcephaly in congenital and postnatal makes it possible to define the etiology, the associated symptoms and the prognosis. The evaluation of a child with microcephaly requires a thorough analysis of its history, clinical examination and complementary studies. MRI is the first step in the etiologic research. Genetic causes forming part of a syndrome or not, and prenatal infections are the most frequent etiologies but in half of the cases, no cause is found. The comparative hybridization genomic array (array-CGH) and full exome sequencing are techniques that more and more help us in the evaluation of patients with microcephaly. Depending on the cause and severity, children with microcephaly may have different problems such as intellectual disabilities, development retardation, epilepsy, cerebral palsy, as well as vision and hearing disorders. The microcephaly requires a multidisciplinary approach both in its initial assessment as it is its post-program monitoring.
Topics: Brazil; Developmental Disabilities; Female; Humans; Intellectual Disability; Male; Microcephaly; Pregnancy; Pregnancy Complications, Infectious; Prognosis; Zika Virus; Zika Virus Infection
PubMed: 30199373
DOI: No ID Found -
Cell Death & Disease Jan 2018Cell division and differentiation are two fundamental physiological processes that need to be tightly balanced to achieve harmonious development of an organ or a tissue... (Review)
Review
Cell division and differentiation are two fundamental physiological processes that need to be tightly balanced to achieve harmonious development of an organ or a tissue without jeopardizing its homeostasis. The role played by the centriolar protein STIL is highly illustrative of this balance at different stages of life as deregulation of the human STIL gene expression has been associated with either insufficient brain development (primary microcephaly) or cancer, two conditions resulting from perturbations in cell cycle and chromosomal segregation. This review describes the recent advances on STIL functions in the control of centriole duplication and mitotic spindle integrity, and discusses how pathological perturbations of its finely tuned expression result in chromosomal instability in both embryonic and postnatal situations, highlighting the concept that common key factors are involved in developmental steps and tissue homeostasis.
Topics: Humans; Intracellular Signaling Peptides and Proteins; Microcephaly; Neoplasms
PubMed: 29352115
DOI: 10.1038/s41419-017-0101-9 -
Current Biology : CB Dec 2014
Topics: Brain; Cell Cycle Proteins; Centrosome; Chromosomal Proteins, Non-Histone; Cytoskeletal Proteins; Humans; Kinesins; Microcephaly; Mutation; Nerve Tissue Proteins
PubMed: 25465325
DOI: 10.1016/j.cub.2014.09.063 -
Wiley Interdisciplinary Reviews.... Jul 2017A recent outbreak of Zika virus (ZIKV) in Brazil is associated with microcephaly in infants born of infected mothers. As this pandemic spreads, rapid scientific... (Review)
Review
A recent outbreak of Zika virus (ZIKV) in Brazil is associated with microcephaly in infants born of infected mothers. As this pandemic spreads, rapid scientific investigation is shedding new light on how prenatal infection with ZIKV causes microcephaly. In this analysis we provide an overview of both microcephaly and ZIKV, explore the connection between prenatal ZIKV infection and microcephaly, and highlight recent insights into how prenatal ZIKV infection depletes the pool of neural progenitors in the developing brain. WIREs Dev Biol 2017, 6:e273. doi: 10.1002/wdev.273 For further resources related to this article, please visit the WIREs website.
Topics: Animals; Humans; Microcephaly; Zika Virus; Zika Virus Infection
PubMed: 28383800
DOI: 10.1002/wdev.273 -
Epidemiologia E Servicos de Saude :... 2016
Topics: Animals; Disease Vectors; Humans; Microcephaly; Zika Virus; Zika Virus Infection
PubMed: 27861673
DOI: 10.5123/S1679-49742016000100001