-
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 -
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 -
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 -
Journal of Medical Genetics May 2003MWS is a multiple congenital anomaly syndrome, first clinically delineated by Mowat et al in 1998. Over 45 cases have now been reported. All patients have typical... (Review)
Review
MWS is a multiple congenital anomaly syndrome, first clinically delineated by Mowat et al in 1998. Over 45 cases have now been reported. All patients have typical dysmorphic features in association with severe intellectual disability, and nearly all have microcephaly and seizures. Congenital anomalies, including Hirschsprung disease (HSCR), congenital heart disease, hypospadias, genitourinary anomalies, agenesis of the corpus callosum, and short stature are common. The syndrome is the result of heterozygous deletions or truncating mutations of the ZFHX1B (SIP1) gene on chromosome 2q22.
Topics: Abnormalities, Multiple; Chromosomes, Human, Pair 2; Genotype; Heart Diseases; Hirschsprung Disease; Homeodomain Proteins; Humans; Microcephaly; Phenotype; Repressor Proteins; Syndrome; Zinc Finger E-box Binding Homeobox 2
PubMed: 12746390
DOI: 10.1136/jmg.40.5.305 -
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 -
BMC Pregnancy and Childbirth Mar 2021Prevalence of neonatal microcephaly in populations without Zika-epidemics is sparse. The study aimed to report baseline prevalence of congenital microcephaly and its...
BACKGROUND
Prevalence of neonatal microcephaly in populations without Zika-epidemics is sparse. The study aimed to report baseline prevalence of congenital microcephaly and its relationship with prenatal factors in an area at risk of Zika outbreak.
METHODS
This study included singletons born after 24 gestational weeks in 2017-2018 at four hospitals in Guangzhou, China. Microcephaly was defined as a head circumference at birth >3SD below the mean for sex and gestational age. Prevalence of microcephaly was estimated by binomial exact method. Multivariable logistic regression was used to examine the associations of microcephaly with prenatal factors. The population attributable fraction (PAF) for associated risk factors was calculated.
RESULTS
Of 46,610 live births included, 154 (3.3, 95% CI 2.8-3.9 per 1000 live births) microcephalies were identified. Maternal hepatitis B virus carriers (HBV, OR 1.80, 95% CI 1.05-3.10) and primipara (OR 2.68, 95% CI 1.89-3.81) had higher risk of having a microcephalic baby. Higher prevalence of microcephaly was observed in women who had premature labor (OR 1.98, 95% CI 1.17-3.34) and had a baby with fetal growth restriction (OR 16.38, 95% CI 11.81-22.71). Four identified factors (HBV, primiparity, preterm labor, and fetal growth restriction) contributed to 66.4% of the risk of microcephaly.
CONCLUSIONS
The prevalence of microcephaly in Guangzhou was higher than expected. This study identified four prenatal risk factors that, together, contributed to two-thirds of the increased risk of microcephaly. This is the first reported association between maternal HBV carrier status and microcephaly.
Topics: Adult; China; Female; Fetal Growth Retardation; Gestational Age; Hepatitis B; Humans; Infant, Newborn; Infant, Newborn, Diseases; Microcephaly; Parity; Pregnancy; Pregnancy Complications, Infectious; Premature Birth; Prevalence; Risk Assessment; Risk Factors; Zika Virus; Zika Virus Infection
PubMed: 33731027
DOI: 10.1186/s12884-021-03705-9 -
Viruses Apr 2021The emergence of the Zika virus (ZIKV) mirrors its evolutionary nature and, thus, its ability to grow in diversity or complexity (i.e., related to genome, host response,... (Review)
Review
The emergence of the Zika virus (ZIKV) mirrors its evolutionary nature and, thus, its ability to grow in diversity or complexity (i.e., related to genome, host response, environment changes, tropism, and pathogenicity), leading to it recently joining the circle of closed congenital pathogens. The causal relation of ZIKV to microcephaly is still a much-debated issue. The identification of outbreak foci being in certain endemic urban areas characterized by a high-density population emphasizes that mixed infections might spearhead the recent appearance of a wide range of diseases that were initially attributed to ZIKV. Globally, such coinfections may have both positive and negative effects on viral replication, tropism, host response, and the viral genome. In other words, the possibility of coinfection may necessitate revisiting what is considered to be known regarding the pathogenesis and epidemiology of ZIKV diseases. ZIKV viral coinfections are already being reported with other arboviruses (e.g., chikungunya virus (CHIKV) and dengue virus (DENV)) as well as congenital pathogens (e.g., human immunodeficiency virus (HIV) and cytomegalovirus (HCMV)). However, descriptions of human latent viruses and their impacts on ZIKV disease outcomes in hosts are currently lacking. This review proposes to select some interesting human latent viruses (i.e., herpes simplex virus 2 (HSV-2), Epstein-Barr virus (EBV), human herpesvirus 6 (HHV-6), human parvovirus B19 (B19V), and human papillomavirus (HPV)), whose virological features and co-exposition with ZIKV may provide evidence of the syndemism process, shedding some light on the emergence of the ZIKV-induced global congenital syndrome in South America.
Topics: Biological Coevolution; Coinfection; Disease Reservoirs; Humans; Microcephaly; South America; Viral Tropism; Virus Diseases; Virus Latency; Virus Replication; Zika Virus; Zika Virus Infection
PubMed: 33924398
DOI: 10.3390/v13040669