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Developmental Medicine and Child... Jan 2020Comprehensive reviews of the clinical characteristics and pathogenesis of Aicardi-Goutières syndrome (AGS), particularly its contextualization within a putative type I... (Review)
Review
Comprehensive reviews of the clinical characteristics and pathogenesis of Aicardi-Goutières syndrome (AGS), particularly its contextualization within a putative type I interferonopathy framework, already exist. However, recent reports of attempts at treatment suggest that an assessment of the field from a therapeutic perspective is warranted at this time. Here, we briefly summarize the neurological phenotypes associated with mutations in the seven genes so far associated with AGS, rehearse current knowledge of the pathology as it relates to possible treatment approaches, critically appraise the potential utility of therapies, and discuss the challenges in assessing clinical efficacy. WHAT THIS PAPER ADDS: Progress in understanding AGS disease pathogenesis has led to the first attempts at targeted treatment. Further rational therapies are expected to become available in the short- to medium-term.
Topics: Autoimmune Diseases of the Nervous System; Humans; Nervous System Malformations
PubMed: 31175662
DOI: 10.1111/dmcn.14268 -
Ultrasound in Obstetrics & Gynecology :... Feb 2021Most brain abnormalities are present in the first trimester, but only a few are detected so early in gestation. According to current recommendations for first-trimester... (Review)
Review
Most brain abnormalities are present in the first trimester, but only a few are detected so early in gestation. According to current recommendations for first-trimester ultrasound, the fetal head structures that should be visualized are limited to the cranial bones, the midline falx and the choroid-plexus-filled ventricles. Using this basic approach, almost all cases of acrania, alobar holoprosencephaly and cephalocele are detected. However, the majority of other fetal brain abnormalities remain undiagnosed until the midtrimester. Such anomalies would be potentially detectable if the sonographic study were to be extended to include additional anatomic details not currently included in existing guidelines. The aim of this review article is to describe how best to assess the normal fetal brain by first-trimester expert multiplanar neurosonography and to demonstrate the early sonographic findings that characterize some major fetal brain abnormalities. © 2020 International Society of Ultrasound in Obstetrics and Gynecology.
Topics: Encephalocele; Female; Fetus; Holoprosencephaly; Humans; Nervous System Malformations; Pregnancy; Pregnancy Trimester, First; Ultrasonography, Prenatal
PubMed: 33049801
DOI: 10.1002/uog.23149 -
PloS One 2020The signs and symptoms of Zika virus infection are usually mild and self-limited. However, the disease has been linked to neurological complications such as...
BACKGROUND
The signs and symptoms of Zika virus infection are usually mild and self-limited. However, the disease has been linked to neurological complications such as Guillain-Barré syndrome and peripheral nerve involvement, and also to abortion and fetal deaths due to vertical transmission, resulting in various congenital malformations in newborns, including microcephaly. This review aimed to describe the o signs and symptoms that characterize the congenital Zika syndrome.
METHODS AND FINDINGS
A systematic review was performed with a protocol and described according to the recommendations of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. The search strategy yielded 2,048 studies. After the exclusion of duplicates and application of inclusion criteria, 46 studies were included. The main signs and symptoms associated with the congenital Zika syndrome were microcephaly, parenchymal or cerebellar calcifications, ventriculomegaly, central nervous system hypoplasia or atrophy, arthrogryposis, ocular findings in the posterior and anterior segments, abnormal visual function and low birthweight for gestational age.
CONCLUSIONS
Zika virus infection during pregnancy can cause a series of changes in the growth and development of children, while impacting the healthcare system due to the severity of cases. Our findings outline the disease profile in newborns and infants and may contribute to the development and updating of more specific clinical protocols.
Topics: Child Development; Female; Guillain-Barre Syndrome; Humans; Infant; Infant, Newborn; Infectious Disease Transmission, Vertical; Nervous System Malformations; Pregnancy; Pregnancy Complications, Infectious; Syndrome; Zika Virus; Zika Virus Infection
PubMed: 33320867
DOI: 10.1371/journal.pone.0242367 -
Molecular Cell Feb 2021Cyclic GMP-AMP synthase (cGAS) recognition of cytosolic DNA is critical for the immune response to cancer and pathogen infection. Here, we discover that cGAS-DNA phase...
Cyclic GMP-AMP synthase (cGAS) recognition of cytosolic DNA is critical for the immune response to cancer and pathogen infection. Here, we discover that cGAS-DNA phase separation is required to resist negative regulation and allow efficient sensing of immunostimulatory DNA. We map the molecular determinants of cGAS condensate formation and demonstrate that phase separation functions to limit activity of the cytosolic exonuclease TREX1. Mechanistically, phase separation forms a selective environment that suppresses TREX1 catalytic function and restricts DNA degradation to an outer shell at the droplet periphery. We identify a TREX1 mutation associated with the severe autoimmune disease Aicardi-Goutières syndrome that increases penetration of TREX1 into the repressive droplet interior and specifically impairs degradation of phase-separated DNA. Our results define a critical function of cGAS-DNA phase separation and reveal a molecular mechanism that balances cytosolic DNA degradation and innate immune activation.
Topics: Autoimmune Diseases of the Nervous System; Catalysis; Cell Line, Tumor; Cytosol; DNA; Exodeoxyribonucleases; HEK293 Cells; Humans; Mutation; Nervous System Malformations; Nucleotidyltransferases; Phosphoproteins
PubMed: 33606975
DOI: 10.1016/j.molcel.2021.01.024 -
Human Mutation Apr 2020IFIH1 gain-of-function has been reported as a cause of a type I interferonopathy encompassing a spectrum of autoinflammatory phenotypes including Aicardi-Goutières...
IFIH1 gain-of-function has been reported as a cause of a type I interferonopathy encompassing a spectrum of autoinflammatory phenotypes including Aicardi-Goutières syndrome and Singleton Merten syndrome. Ascertaining patients through a European and North American collaboration, we set out to describe the molecular, clinical and interferon status of a cohort of individuals with pathogenic heterozygous mutations in IFIH1. We identified 74 individuals from 51 families segregating a total of 27 likely pathogenic mutations in IFIH1. Ten adult individuals, 13.5% of all mutation carriers, were clinically asymptomatic (with seven of these aged over 50 years). All mutations were associated with enhanced type I interferon signaling, including six variants (22%) which were predicted as benign according to multiple in silico pathogenicity programs. The identified mutations cluster close to the ATP binding region of the protein. These data confirm variable expression and nonpenetrance as important characteristics of the IFIH1 genotype, a consistent association with enhanced type I interferon signaling, and a common mutational mechanism involving increased RNA binding affinity or decreased efficiency of ATP hydrolysis and filament disassembly rate.
Topics: Alleles; Autoimmune Diseases of the Nervous System; DNA Mutational Analysis; Female; Gain of Function Mutation; Genetic Association Studies; Genotype; High-Throughput Nucleotide Sequencing; Humans; Interferon-Induced Helicase, IFIH1; Male; Models, Molecular; Nervous System Malformations; Phenotype; Protein Conformation; Structure-Activity Relationship
PubMed: 31898846
DOI: 10.1002/humu.23975 -
Cell Mar 2019The presence of DNA in the cytoplasm is normally a sign of microbial infections and is quickly detected by cyclic GMP-AMP synthase (cGAS) to elicit anti-infection immune...
The presence of DNA in the cytoplasm is normally a sign of microbial infections and is quickly detected by cyclic GMP-AMP synthase (cGAS) to elicit anti-infection immune responses. However, chronic activation of cGAS by self-DNA leads to severe autoimmune diseases for which no effective treatment is available yet. Here we report that acetylation inhibits cGAS activation and that the enforced acetylation of cGAS by aspirin robustly suppresses self-DNA-induced autoimmunity. We find that cGAS acetylation on either Lys384, Lys394, or Lys414 contributes to keeping cGAS inactive. cGAS is deacetylated in response to DNA challenges. Importantly, we show that aspirin can directly acetylate cGAS and efficiently inhibit cGAS-mediated immune responses. Finally, we demonstrate that aspirin can effectively suppress self-DNA-induced autoimmunity in Aicardi-Goutières syndrome (AGS) patient cells and in an AGS mouse model. Thus, our study reveals that acetylation contributes to cGAS activity regulation and provides a potential therapy for treating DNA-mediated autoimmune diseases.
Topics: Acetylation; Amino Acid Sequence; Animals; Aspirin; Autoimmune Diseases; Autoimmune Diseases of the Nervous System; Autoimmunity; Cell Line; DNA; Disease Models, Animal; Exodeoxyribonucleases; HEK293 Cells; HeLa Cells; Humans; Mice; Mice, Inbred C57BL; Models, Molecular; Mutation; Nervous System Malformations; Nucleotidyltransferases; Self Tolerance; THP-1 Cells
PubMed: 30799039
DOI: 10.1016/j.cell.2019.01.016 -
Ultrasound in Obstetrics & Gynecology :... Dec 2018
Topics: Female; Fetus; Humans; Nervous System Malformations; Pregnancy; Prenatal Diagnosis
PubMed: 30516327
DOI: 10.1002/uog.20154 -
Cell Feb 2018Aberrant activation of innate immune receptors can cause a spectrum of immune disorders, such as Aicardi-Goutières syndrome (AGS). One such receptor is MDA5, a viral...
Aberrant activation of innate immune receptors can cause a spectrum of immune disorders, such as Aicardi-Goutières syndrome (AGS). One such receptor is MDA5, a viral dsRNA sensor that induces antiviral immune response. Using a newly developed RNase-protection/RNA-seq approach, we demonstrate here that constitutive activation of MDA5 in AGS results from the loss of tolerance to cellular dsRNAs formed by Alu retroelements. While wild-type MDA5 cannot efficiently recognize Alu-dsRNAs because of its limited filament formation on imperfect duplexes, AGS variants of MDA5 display reduced sensitivity to duplex structural irregularities, assembling signaling-competent filaments on Alu-dsRNAs. Moreover, we identified an unexpected role of an RNA-rich cellular environment in suppressing aberrant MDA5 oligomerization, highlighting context dependence of self versus non-self discrimination. Overall, our work demonstrates that the increased efficiency of MDA5 in recognizing dsRNA comes at a cost of self-recognition and implicates a unique role of Alu-dsRNAs as virus-like elements that shape the primate immune system.
Topics: A549 Cells; Alu Elements; Autoimmune Diseases of the Nervous System; Humans; Inflammation; Interferon-Induced Helicase, IFIH1; Muramidase; Nervous System Malformations; Peptide Fragments; Protein Multimerization; RNA, Double-Stranded; Self Tolerance; THP-1 Cells
PubMed: 29395326
DOI: 10.1016/j.cell.2017.12.016 -
Continuum (Minneapolis, Minn.) Feb 2018This article provides an overview of the most common nervous system malformations and serves as a reference for the latest advances in diagnosis and treatment. (Review)
Review
PURPOSE OF REVIEW
This article provides an overview of the most common nervous system malformations and serves as a reference for the latest advances in diagnosis and treatment.
RECENT FINDINGS
Major advances have occurred in recognizing the genetic basis of nervous system malformations. Environmental causes of nervous system malformations, such as perinatal infections including Zika virus, are also reviewed. Treatment for nervous system malformations begins prior to birth with prevention. Folic acid supplementation reduces the risk of neural tube defects and is an important part of health maintenance for pregnant women. Fetal surgery is now available for prenatal repair of myelomeningocele and has been demonstrated to improve outcomes.
SUMMARY
Each type of nervous system malformation is relatively uncommon, but, collectively, they constitute a large population of neurologic patients. The diagnosis of nervous system malformations begins with radiographic characterization. Genetic studies, including chromosomal microarray, targeted gene sequencing, and next-generation sequencing, are increasingly important aspects of the assessment. A genetic diagnosis may identify an associated medical condition and is necessary for family planning. Treatment consists primarily of supportive therapies for developmental delays and epilepsy, but prenatal surgery for myelomeningocele offers a glimpse of future possibilities. Prognosis depends on multiple clinical factors, including the examination findings, imaging characteristics, and genetic results. Treatment is best conducted in a multidisciplinary setting with neurology, neurosurgery, developmental pediatrics, and genetics working together as a comprehensive team.
Topics: Adult; Central Nervous System; Female; Humans; Infant, Newborn; Nervous System Malformations; Neurogenesis; Pregnancy
PubMed: 29432238
DOI: 10.1212/CON.0000000000000561 -
Viruses Mar 2020Deoxynucleoside triphosphate (dNTP) molecules are essential for the replication and maintenance of genomic information in both cells and a variety of viral pathogens.... (Review)
Review
Deoxynucleoside triphosphate (dNTP) molecules are essential for the replication and maintenance of genomic information in both cells and a variety of viral pathogens. While the process of dNTP biosynthesis by cellular enzymes, such as ribonucleotide reductase (RNR) and thymidine kinase (TK), has been extensively investigated, a negative regulatory mechanism of dNTP pools was recently found to involve sterile alpha motif (SAM) domain and histidine-aspartate (HD) domain-containing protein 1, SAMHD1. When active, dNTP triphosphohydrolase activity of SAMHD1 degrades dNTPs into their 2'-deoxynucleoside (dN) and triphosphate subparts, steadily depleting intercellular dNTP pools. The differential expression levels and activation states of SAMHD1 in various cell types contributes to unique dNTP pools that either aid (i.e., dividing T cells) or restrict (i.e., nondividing macrophages) viral replication that consumes cellular dNTPs. Genetic mutations in SAMHD1 induce a rare inflammatory encephalopathy called Aicardi-Goutières syndrome (AGS), which phenotypically resembles viral infection. Recent publications have identified diverse roles for SAMHD1 in double-stranded break repair, genome stability, and the replication stress response through interferon signaling. Finally, a series of SAMHD1 mutations were also reported in various cancer cell types while why SAMHD1 is mutated in these cancer cells remains to investigated. Here, we reviewed a series of studies that have begun illuminating the highly diverse roles of SAMHD1 in virology, immunology, and cancer biology.
Topics: Autoimmune Diseases of the Nervous System; DNA Repair; Deoxyribonucleotides; Humans; Immunity, Innate; Mutation; Neoplasms; Nervous System Malformations; Protein Domains; Protein Processing, Post-Translational; SAM Domain and HD Domain-Containing Protein 1; Virus Diseases; Virus Replication
PubMed: 32244340
DOI: 10.3390/v12040382