-
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 -
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 -
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 -
Epidemiologia E Servicos de Saude :... 2016
Topics: Animals; Disease Vectors; Humans; Microcephaly; Zika Virus; Zika Virus Infection
PubMed: 27861673
DOI: 10.5123/S1679-49742016000100001 -
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 -
Advances in Experimental Medicine and... 2017The cell cycle culminates in mitosis with the purpose of dividing the cell's DNA content equally over two daughter cells. Error-free segregation relies on correct... (Review)
Review
The cell cycle culminates in mitosis with the purpose of dividing the cell's DNA content equally over two daughter cells. Error-free segregation relies on correct connections between chromosomes and spindle microtubules. Kinetochores are complex multi-protein assemblies that mediate these connections and are the platforms for attachment-error-correction and spindle assembly checkpoint signaling. Proper kinetochore function is therefore key in preventing aneuploidization. Mutations in genes encoding kinetochore proteins are associated with several severe developmental disorders associated with microcephaly, and kinetochore defects contribute to chromosomal instability in certain cancers. This chapter gives an overview of the processes necessary for faithful chromosome segregation and how kinetochore malfunction causes various human pathologies.
Topics: Aneuploidy; Animals; Chromosomal Instability; Chromosome Segregation; Genetic Predisposition to Disease; Humans; Kinetochores; Microcephaly; Mitosis; Mutation; Neoplasms
PubMed: 28600783
DOI: 10.1007/978-3-319-57127-0_4 -
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 -
BMJ (Clinical Research Ed.) Jun 2018