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    Mitochondrial Nucleic Acid as a Driver of Pathogenic Type I Interferon Induction in Mendelian Disease. Lepelley Alice,Wai Timothy,Crow Yanick J Frontiers in immunology The immune response to viral infection involves the recognition of pathogen-derived nucleic acids by intracellular sensors, leading to type I interferon (IFN), and downstream IFN-stimulated gene, induction. Ineffective discrimination of self from non-self nucleic acid can lead to autoinflammation, a phenomenon implicated in an increasing number of disease states, and well highlighted by the group of rare genetic disorders referred to as the type I interferonopathies. To understand the pathogenesis of these monogenic disorders, and polyfactorial diseases associated with pathogenic IFN upregulation, such as systemic lupus erythematosus and dermatomyositis, it is important to define the self-derived nucleic acid species responsible for such abnormal IFN induction. Recently, attention has focused on mitochondria as a novel source of immunogenic self nucleic acid. Best appreciated for their function in oxidative phosphorylation, metabolism and apoptosis, mitochondria are double membrane-bound organelles that represent vestigial bacteria in the cytosol of eukaryotic cells, containing their own DNA and RNA enclosed within the inner mitochondrial membrane. There is increasing recognition that a loss of mitochondrial integrity and compartmentalization can allow the release of mitochondrial nucleic acid into the cytosol, leading to IFN induction. Here, we provide recent insights into the potential of mitochondrial-derived DNA and RNA to drive IFN production in Mendelian disease. Specifically, we summarize current understanding of how nucleic acids are detected as foreign when released into the cytosol, and then consider the findings implicating mitochondrial nucleic acid in type I interferonopathy disease states. Finally, we discuss the potential for IFN-driven pathology in primary mitochondrial disorders. 10.3389/fimmu.2021.729763
    Co-occurrence of Aicardi-Goutières syndrome type 6 and dyschromatosis symmetrica hereditaria due to compound heterozygous pathogenic variants in ADAR1: a case series from India. Sathishkumar D,Muthusamy K,Gupta A,Malhotra M,Thomas M,Koshy B,Jasper A,Danda S,George R Clinical and experimental dermatology Aicardi-Goutières syndrome type 6 (AGS6) and dyschromatosis symmetrica hereditaria (DSH) are allelic disorders caused respectively by biallelic and heterozygous pathogenic variants in ADAR1. We report three unrelated children presenting with features of both AGS6 and DSH, two of whom had compound heterozygous pathogenic variants in ADAR1. We also describe the novel genetic variants in our cases and review the literature on association of ADAR1-related AGS6 and DSH with these phenotypes. 10.1111/ced.14531
    The RNA-editing enzyme ADAR1 controls innate immune responses to RNA. Mannion Niamh M,Greenwood Sam M,Young Robert,Cox Sarah,Brindle James,Read David,Nellåker Christoffer,Vesely Cornelia,Ponting Chris P,McLaughlin Paul J,Jantsch Michael F,Dorin Julia,Adams Ian R,Scadden A D J,Ohman Marie,Keegan Liam P,O'Connell Mary A Cell reports The ADAR RNA-editing enzymes deaminate adenosine bases to inosines in cellular RNAs. Aberrant interferon expression occurs in patients in whom ADAR1 mutations cause Aicardi-Goutières syndrome (AGS) or dystonia arising from striatal neurodegeneration. Adar1 mutant mouse embryos show aberrant interferon induction and die by embryonic day E12.5. We demonstrate that Adar1 embryonic lethality is rescued to live birth in Adar1; Mavs double mutants in which the antiviral interferon induction response to cytoplasmic double-stranded RNA (dsRNA) is prevented. Aberrant immune responses in Adar1 mutant mouse embryo fibroblasts are dramatically reduced by restoring the expression of editing-active cytoplasmic ADARs. We propose that inosine in cellular RNA inhibits antiviral inflammatory and interferon responses by altering RLR interactions. Transfecting dsRNA oligonucleotides containing inosine-uracil base pairs into Adar1 mutant mouse embryo fibroblasts reduces the aberrant innate immune response. ADAR1 mutations causing AGS affect the activity of the interferon-inducible cytoplasmic isoform more severely than the nuclear isoform. 10.1016/j.celrep.2014.10.041
    Aicardi-Goutières syndrome: differential diagnosis and aetiopathogenesis. Lanzi Giovanni,D'Arrigo Stefano,Drumbl Gea,Uggetti Carla,Fazzi Elisa Functional neurology Aicardi-Goutières syndrome (AGS) is a progressive encephalopathy with onset in the first year of life and a recessive autosomal pattern of inheritance. The syndrome is characterised by acquired microcephaly, basal ganglia calcifications, white matter abnormalities, chronic cerebrospinal fluid (CSF) lymphocytosis and raised interferon-alpha (INF-alpha) in the CSF. AGS is diagnosed on the basis of a clinical picture characterised by microcephaly and by the onset of encephalopathy associated with severe psychomotor delay, spasticity and extrapyramidal signs. CT is very important in the diagnosis of AGS, demonstrating clearly the presence of calcifications at basal ganglia level: these are often bilateral and symmetrical. CT scan and MRI reveal leukodystrophy and progressive cerebral atrophy. A raised level of INF-alpha in the CSF constitutes a marker of the syndrome: this level, which falls with age, is higher in the CSF than in the serum, suggesting intrathecal synthesis. Differential diagnosis in AGS is carried out to exclude the presence of other neurological and endocrinological pathologies characterised by the presence of intracranial calcification; considering the white matter abnormalities, it is necessary to exclude forms of leukodystrophy associated with metabolic defects, known or otherwise. One fundamental aspect that remains to be clarified is the aetiopathogenetic mechanism underlying AGS: the most well-founded hypotheses are reported. There does not exist, to date, any causal therapy for AGS, although genetic studies, particularly those focusing on interferon-regulating genes, may well provide some therapeutic indications.
    Mutations in ADAR1, IFIH1, and RNASEH2B presenting as spastic paraplegia. Crow Yanick J,Zaki Maha S,Abdel-Hamid Mohamed S,Abdel-Salam Ghada,Boespflug-Tanguy Odile,Cordeiro Nuno J V,Gleeson Joseph G,Gowrinathan Nirmala Rani,Laugel Vincent,Renaldo Florence,Rodriguez Diana,Livingston John H,Rice Gillian I Neuropediatrics BACKGROUND:Hereditary spastic paraplegia is a neurodegenerative phenotype characterized by a progressive loss of corticospinal motor tract function. In a majority of affected individuals the pathogenesis remains undetermined. METHODS:We identified a series of patients with a phenotype of nonsyndromic spastic paraplegia in whom no diagnosis had been reached before exome sequencing. We measured the expression of interferon stimulated genes (ISGs) in peripheral blood from these patients. RESULTS:Five patients from four families with previously unexplained spastic paraplegia were identified with mutations in either ADAR1 (one patient), IFIH1 (one patient), or RNASEH2B (three patients from two families). All patients were developmentally normal before the onset of features beginning in the second year of life. All patients remain of normal intellect. Four patients demonstrated normal neuroimaging, while a single patient had features of nonspecific dysmyelination. The patients with ADAR1 and IFIH1-related disease showed a robust interferon signature. The patients with mutations in RNASEH2B demonstrated no (two patients) or a minimal (one patient) upregulation of ISGs compared with controls. CONCLUSIONS:Mutations in ADAR1, IFIH1, and RNASEH2B can cause a phenotype of spastic paraplegia with normal neuroimaging, or in association with nonspecific dysmyelination. Although the presence of an interferon signature can be helpful in interpreting the significance of gene variants in this context, patients with pathogenic mutations in RNASEH2B may demonstrate no upregulation of ISGs in peripheral blood. However, it remains possible that type I interferons act as a neurotoxin in the context of all genotypes. 10.1055/s-0034-1389161
    Megalencephalic leukoencephalopathy with subcortical cysts: Characterization of disease variants. Hamilton Eline M C,Tekturk Pinar,Cialdella Fia,van Rappard Diane F,Wolf Nicole I,Yalcinkaya Cengiz,Çetinçelik Ümran,Rajaee Ahmad,Kariminejad Ariana,Paprocka Justyna,Yapici Zuhal,Bošnjak Vlatka Mejaški,van der Knaap Marjo S, Neurology OBJECTIVE:To provide an overview of clinical and MRI characteristics of the different variants of the leukodystrophy megalencephalic leukoencephalopathy with subcortical cysts (MLC) and identify possible differentiating features. METHODS:We performed an international multi-institutional, cross-sectional observational study of the clinical and MRI characteristics in patients with genetically confirmed MLC. Clinical information was obtained by questionnaires for physicians and retrospective chart review. RESULTS:We included 204 patients with classic MLC, 187 of whom had recessive mutations in (MLC1 variant) and 17 in (MLC2A variant) and 38 patients with remitting MLC caused by dominant mutations (MLC2B variant). We observed a relatively wide variability in neurologic disability among patients with classic MLC. No clinical differences could be identified between patients with MLC1 and MLC2A. Patients with MLC2B invariably had a milder phenotype with preservation of motor function, while intellectual disability and autism were relatively frequent. Systematic MRI review revealed no MRI features that distinguish between MLC1 and MLC2A. Radiologic improvement was observed in all patients with MLC2B and also in 2 patients with MLC1. In MRIs obtained in the early disease stage, absence of signal abnormalities of the posterior limb of the internal capsule and cerebellar white matter and presence of only rarefied subcortical white matter instead of true subcortical cysts were suggestive of MLC2B. CONCLUSION:Clinical and MRI features did not distinguish between classic MLC with or mutations. Absence of signal abnormalities of the internal capsule and cerebellar white matter are MRI findings that point to the remitting phenotype. 10.1212/WNL.0000000000005334
    Neuroimaging Findings of Congenital Toxoplasmosis, Cytomegalovirus, and Zika Virus Infections: A Comparison of Three Cases. Werner Heron,Daltro Pedro,Fazecas Tatiana,Zare Mehrjardi Mohammad,Araujo Júnior Edward Journal of obstetrics and gynaecology Canada : JOGC = Journal d'obstetrique et gynecologie du Canada : JOGC OBJECTIVE:Toxoplasmosis, cytomegalovirus (CMV), and Zika virus (ZIKV) are among the common infectious agents that may infect the fetuses vertically. Clinical presentations of these congenital infections overlap significantly, and it is usually impossible to determine the causative agent clinically. The objective was the comparison of neuroimaging findings in three fetuses who underwent intrauterine infection by toxoplasmosis, CMV, and ZIKV. METHODS:Three confirmed cases of congenital toxoplasmosis, CMV, and ZIKV infections were included in the study over 7 months prospectively. Prenatal ultrasound, fetal brain MRI, and postnatal neuroimaging (CT or MRI) were performed on all of the included cases and interpreted by an expert radiologist. RESULTS:The mean GA at the time of prenatal imaging was 34.5 ± 3.5 weeks. The main neuroimaging findings in congenital toxoplasmosis were randomly distributed brain calcifications and ventricular dilatation on ultrasounds (US), as well as white matter signal change on fetal brain MRI. The main neuroimaging findings of congenital CMV infection included microcephaly, ventriculomegaly, and periventricular calcifications on US, as well as pachygyria revealed by fetal MRI. The case of congenital ZIKV infection showed microcephaly, ventriculomegaly, and periventricular calcifications on ultrasound, as well as brain atrophy and brain surface smoothness on fetal MRI. CONCLUSION:Although the neuroimaging findings in congenital infections are not pathognomonic, in combination with the patient history may be suggestive of one of the infectious agents, which will guide the management strategy. 10.1016/j.jogc.2017.05.013
    Band-like intracranial calcification with simplified gyration and polymicrogyria: a distinct "pseudo-TORCH" phenotype. Briggs T A,Wolf N I,D'Arrigo S,Ebinger F,Harting I,Dobyns W B,Livingston J H,Rice G I,Crooks D,Rowland-Hill C A,Squier W,Stoodley N,Pilz D T,Crow Y J American journal of medical genetics. Part A The combination of intracranial calcification and polymicrogyria is usually seen in the context of intrauterine infection, most frequently due to cytomegalovirus. Rare familial occurrences have been reported. We describe five patients-two male-female sibling pairs, one pair born to consanguineous parents, and an unrelated female-with a distinct pattern of band-like intracranial calcification associated with simplified gyration and polymicrogyria. Clinical features include severe post-natal microcephaly, seizures and profound developmental arrest. Testing for infectious agents was negative. We consider that these children have the same recognizable "pseudo-TORCH" phenotype inherited as an autosomal recessive trait. 10.1002/ajmg.a.32614
    Evaluation of the frequency of neuroimaging findings in congenital infection by Zika virus and differences between computed tomography and magnetic resonance imaging in the detection of alterations. Ribeiro Bruno Niemeyer de Freitas,Muniz Bernardo Carvalho,Marchiori Edson Revista da Sociedade Brasileira de Medicina Tropical INTRODUCTION:Congenital infection by the Zika virus (ZIKV) is responsible for severe abnormalities in the development of the central nervous system. The aim of this study was to evaluate and compare the ability of computed tomography (CT) and magnetic resonance (MR) to detect patterns of involvement of the central nervous system in congenital ZIKV syndrome. METHODS:We retrospectively analyzed CT and MR images from 34 patients with congenital ZIKV syndrome and evaluated the differences between the two methods in detecting alterations. RESULTS:The predominant radiographic finding was a simplified gyral pattern, present in 97% of cases. The second most common finding was the presence of calcifications (94.1%), followed by ventriculomegaly (85.3%), dysgenesis of the corpus callosum (85.3%), craniofacial disproportion and redundant scalp (79.4%), complete opercular opening (79.4%), occipital prominence (44.1%), cerebellar hypoplasia (14.7%), and pontine hypoplasia (11.8%). The gyral pattern was extensively simplified in most cases, and calcifications were located predominantly at the cortical-subcortical junction. CT was able to better identify calcifications (94.1% × 88.2%), while MRI presented better spatial resolution for the characterization of gyral pattern (97% × 94.1%) and corpus callosum dysgenesis (85.3% × 79.4%). CONCLUSIONS:Although congenital ZIKV syndrome does not present pathognomonic neuroimaging findings, some aspects, such as calcifications at the cortical-subcortical junction, especially when associated with compatible clinical and laboratory findings, are suggestive of intrauterine ZIKV infection. 10.1590/0037-8682-0557-2019
    A type I interferon signature identifies bilateral striatal necrosis due to mutations in ADAR1. Livingston John H,Lin Jean-Pierre,Dale Russell C,Gill Deepak,Brogan Paul,Munnich Arnold,Kurian Manju A,Gonzalez-Martinez Victoria,De Goede Christian G E L,Falconer Alastair,Forte Gabriella,Jenkinson Emma M,Kasher Paul R,Szynkiewicz Marcin,Rice Gillian I,Crow Yanick J Journal of medical genetics BACKGROUND:We recently observed mutations in ADAR1 to cause a phenotype of bilateral striatal necrosis (BSN) in a child with the type I interferonopathy Aicardi-Goutières syndrome (AGS). We therefore decided to screen patients with apparently non-syndromic BSN for ADAR1 mutations, and for an upregulation of interferon-stimulated genes (ISGs). METHODS:We performed Sanger sequencing of ADAR1 in a series of patients with BSN presenting to us during our routine clinical practice. We then undertook detailed clinical and neuroradiological phenotyping in nine mutation-positive children. We also measured the expression of ISGs in peripheral blood from these patients, and in children with BSN who did not have ADAR1 mutations. RESULTS:Nine ADAR1 mutation-positive patients from seven families demonstrated an acute (five cases) or subacute (four cases) onset of refractory, four-limb dystonia starting between 8 months and 5 years of age. Eight patients were developmentally normal at initial presentation. In seven cases, the disease was inherited as an autosomal recessive trait, while two related patients were found to have a heterozygous (dominant) ADAR1 mutation. All seven mutation-positive patients assayed showed an upregulation of ISGs (median: 12.50, IQR: 6.43-36.36) compared to controls (median: 0.93, IQR: 0.57-1.30), a so-called interferon signature, present many years after disease onset. No interferon signature was present in four children with BSN negative for mutations in ADAR1 (median: 0.63, IQR: 0.47-1.10). CONCLUSIONS:ADAR1-related disease should be considered in the differential diagnosis of apparently non-syndromic BSN with severe dystonia of varying evolution. The finding of an interferon signature provides a useful screening test for the presence of ADAR1 mutations in this context, and may suggest novel treatment approaches. 10.1136/jmedgenet-2013-102038
    Pons Calcifications and Striatal Necrosis in ADAR1 Aicardi-Goutières Syndrome. Movement disorders clinical practice 10.1002/mdc3.13320
    SAMHD1-deficient fibroblasts from Aicardi-Goutières Syndrome patients can escape senescence and accumulate mutations. Franzolin Elisa,Coletta Sara,Ferraro Paola,Pontarin Giovanna,D'Aronco Giulia,Stevanoni Martina,Palumbo Elisa,Cagnin Stefano,Bertoldi Loris,Feltrin Erika,Valle Giorgio,Russo Antonella,Bianchi Vera,Rampazzo Chiara FASEB journal : official publication of the Federation of American Societies for Experimental Biology In mammalian cells, the catabolic activity of the dNTP triphosphohydrolase SAMHD1 sets the balance and concentration of the four dNTPs. Deficiency of SAMHD1 leads to unequally increased pools and marked dNTP imbalance. Imbalanced dNTP pools increase mutation frequency in cancer cells, but it is not known if the SAMHD1-induced dNTP imbalance favors accumulation of somatic mutations in non-transformed cells. Here, we have investigated how fibroblasts from Aicardi-Goutières Syndrome (AGS) patients with mutated SAMHD1 react to the constitutive pool imbalance characterized by a huge dGTP pool. We focused on the effects on dNTP pools, cell cycle progression, dynamics and fidelity of DNA replication, and efficiency of UV-induced DNA repair. AGS fibroblasts entered senescence prematurely or upregulated genes involved in G1/S transition and DNA replication. The normally growing AGS cells exhibited unchanged DNA replication dynamics and, when quiescent, faster rate of excision repair of UV-induced DNA damages. To investigate whether the lack of SAMHD1 affects DNA replication fidelity, we compared de novo mutations in AGS and WT cells by exome next-generation sequencing. Somatic variant analysis indicated a mutator phenotype suggesting that SAMHD1 is a caretaker gene whose deficiency is per se mutagenic, promoting genome instability in non-transformed cells. 10.1096/fj.201902508R
    A SAMHD1 mutation associated with Aicardi-Goutières syndrome uncouples the ability of SAMHD1 to restrict HIV-1 from its ability to downmodulate type I interferon in humans. White Tommy E,Brandariz-Nuñez Alberto,Martinez-Lopez Alicia,Knowlton Caitlin,Lenzi Gina,Kim Baek,Ivanov Dmitri,Diaz-Griffero Felipe Human mutation Mutations in the human SAMHD1 gene are known to correlate with the development of the Aicardi-Goutières syndrome (AGS), which is an inflammatory encephalopathy that exhibits neurological dysfunction characterized by increased production of type I interferon (IFN); this evidence has led to the concept that the SAMHD1 protein negatively regulates the type I IFN response. Additionally, the SAMHD1 protein has been shown to prevent efficient HIV-1 infection of macrophages, dendritic cells, and resting CD4+ T cells. To gain insights on the SAMHD1 molecular determinants that are responsible for the deregulated production of type I IFN, we explored the biochemical, cellular, and antiviral properties of human SAMHD1 mutants known to correlate with the development of AGS. Most of the studied SAMHD1 AGS mutants exhibit defects in the ability to oligomerize, decrease the levels of cellular deoxynucleotide triphosphates in human cells, localize exclusively to the nucleus, and restrict HIV-1 infection. At least half of the tested variants preserved the ability to be degraded by the lentiviral protein Vpx, and all of them interacted with RNA. Our investigations revealed that the SAMHD1 AGS variant p.G209S preserve all tested biochemical, cellular, and antiviral properties, suggesting that this residue is a determinant for the ability of SAMHD1 to negatively regulate the type I IFN response in human patients with AGS. Overall, our work genetically separated the ability of SAMHD1 to negatively regulate the type I IFN response from its ability to restrict HIV-1. 10.1002/humu.23201
    Interferon-α and the calcifying microangiopathy in Aicardi-Goutières syndrome. Klok Melanie D,Bakels Hannah S,Postma Nienke L,van Spaendonk Rosalina M L,van der Knaap Marjo S,Bugiani Marianna Annals of clinical and translational neurology Aicardi-Goutières syndrome is a leukoencephalopathy with calcifications and increased cerebrospinal fluid interferon-α. The relation between interferon-α and brain pathology is poorly understood. We report a patient with mutations in the disease-associated gene SAMHD1. Neuropathology showed an extensive microangiopathy with calcifications consistently associate with blood vessels. In an in vitro model of the microangiopathy, interferon-α enhanced vascular smooth muscle cell-derived calcifications. The noninfarcted white matter harbored apoptotic oligodendrocytes and increased numbers of oligodendrocyte progenitors. These findings better define the white matter pathology and provide evidence that interferon-α plays a direct pathogenetic role in the calcifying angiopathy typical of this disease. 10.1002/acn3.213
    R-spondin2, a novel target of NOBOX: identification of variants in a cohort of women with primary ovarian insufficiency. Bouilly Justine,Beau Isabelle,Barraud Sara,Bernard Valérie,Delemer Brigitte,Young Jacques,Binart Nadine Journal of ovarian research BACKGROUND:R-spondin2 (Rspo2) is a secreted agonist of the canonical Wnt/β-catenin signaling pathway. Rspo2 plays a key role in development of limbs, lungs and hair follicles, and more recently during ovarian follicle development. Rspo2 heterozygous deficient female mice become infertile around 4 months of age mimicking primary ovarian insufficiency (POI). The study aimed to investigate the regulation of RSPO2 and its potential involvement in pathophysiology of POI. METHODS:We cloned the RSPO2 promoter and performed transcriptional assays to determine if RSPO2 can be regulated by NOBOX, an ovarian transcription factor. Then, we evaluated 100 infertile women after obtaining a detailed history of the disease and follicle-stimulating hormone measurements, besides karyotype determination and fragile-X premutation syndrome investigation. All exons, intron-exon boundaries and untranslated regions of the RSPO2 gene were identified by sequencing, and the results were statistically analyzed. RESULTS:We found that RSPO2 can be regulated by NOBOX via the presence of NOBOX Binding Element in its promoter. Among 9 identified variants in POI women, 4 of them were equally homozygous, 4 have never been described (c.-359C > G, c.-190G > A, c.-170 + 13C > T and c.-169-8 T > A), only one c.557 T > C was predicted to alter a single amino acid in the RSPO2 protein (p.Leu186Pro). CONCLUSIONS:RSPO2 is a novel target gene of the NOBOX key transcription factor, confirming its important role during the follicular growth in ovary. However, RSPO2 mutations are rare or uncommon in women with POI. 10.1186/s13048-017-0345-0
    Expanding the phenotypic spectrum of lupus erythematosus in Aicardi-Goutières syndrome. Ramantani Georgia,Kohlhase Jürgen,Hertzberg Christoph,Innes A Micheil,Engel Kerstin,Hunger Susan,Borozdin Wiktor,Mah Jean K,Ungerath Kristina,Walkenhorst Hartmut,Richardt Hans-Helmut,Buckard Johannes,Bevot Andrea,Siegel Corinna,von Stülpnagel Celina,Ikonomidou Chrysanthy,Thomas Kara,Proud Virginia,Niemann Frank,Wieczorek Dagmar,Häusler Martin,Niggemann Pascal,Baltaci Volkan,Conrad Karsten,Lebon Pierre,Lee-Kirsch Min Ae Arthritis and rheumatism OBJECTIVE:Aicardi-Goutières syndrome (AGS) is an early-onset encephalopathy resembling congenital viral infection that is characterized by basal ganglia calcifications, loss of white matter, cerebrospinal fluid (CSF) lymphocytosis, and elevated interferon-alpha levels in the CSF. Studies have shown that AGS is an autosomal-recessive disease linked to mutations in 5 genes, encoding the 3'-repair DNA exonuclease 1 (TREX1), the 3 subunits of ribonuclease H2 (RNASEH2A-C), and sterile alpha motif domain and HD domain-containing protein 1 (SAMHD1). In this study we further characterized the phenotypic spectrum of this disease. METHODS:Clinical and laboratory data were obtained from 26 patients fulfilling the clinical diagnostic criteria for AGS. Genomic DNA was screened for mutations in all 5 AGS genes by direct sequencing, and sera were analyzed for autoantibodies. RESULTS:In 20 patients with AGS, 20 mutations, 12 of which were novel, were identified in all 5 AGS genes. Clinical and laboratory investigations revealed a high prevalence of features (some not previously described in patients with AGS) that are commonly seen in patients with systemic lupus erythematosus (SLE), such as thrombocytopenia, leukocytopenia, antinuclear antibodies, erythematous lesions, oral ulcers, and arthritis, which were observed in 12 (60%) of 20 patients with AGS. Moreover, the coexistence of AGS and SLE, was for the first time, demonstrated in 2 patients with molecularly proven AGS. CONCLUSION:These findings expand the phenotypic spectrum of lupus erythematosus in AGS and provide further insight into its disease mechanisms by showing that activation of the innate immune system as a result of inherited defects in nucleic acid metabolism could lead to systemic autoimmunity. 10.1002/art.27367
    MDA5-Associated Neuroinflammation and the Singleton-Merten Syndrome: Two Faces of the Same Type I Interferonopathy Spectrum. Buers Insa,Rice Gillian I,Crow Yanick J,Rutsch Frank Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research In 1973, Singleton and Merten described a new syndrome in 2 female probands with aortic and cardiac valve calcifications, early loss of secondary dentition, and widened medullary cavities of the phalanges. In 1984, Aicardi and Goutières defined a phenotype resembling congenital viral infection with basal ganglia calcification and increased protein content in the cerebrospinal fluid. Between 2006 and 2012, mutations in 6 different genes were described to be associated with Aicardi-Goutières syndrome, specifically-TREX1, RNASEH2A, RNASEH2B, RNASEH2C, ADAR, and SAMHD1. More recently, mutations in IFIH1 were reported in a variety of neuroimmunological phenotypes, including Aicardi-Goutières syndrome, while a specific Arg822Gln mutation in IFIH1 was described in 3 discrete families with Singleton-Merten syndrome (SMS). IFIH1 encodes for melanoma differentiation-associated gene 5 (MDA5), and all mutations identified to date have been associated with an enhanced interferon response in affected individuals. In this study, we present a male child demonstrating recurrent febrile episodes, spasticity, and basal ganglia calcification suggestive of Aicardi-Goutières syndrome, who carries the same Arg822Gln mutation in IFIH1 previously associated with SMS. We conclude that both diseases are part of the interferonopathy grouping and that the Arg822Gln mutation in IFIH1 can cause a spectrum of disease, including neurological involvement. 10.1089/jir.2017.0004
    Assessment of interferon-related biomarkers in Aicardi-Goutières syndrome associated with mutations in TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, and ADAR: a case-control study. Rice Gillian I,Forte Gabriella M A,Szynkiewicz Marcin,Chase Diana S,Aeby Alec,Abdel-Hamid Mohamed S,Ackroyd Sam,Allcock Rebecca,Bailey Kathryn M,Balottin Umberto,Barnerias Christine,Bernard Genevieve,Bodemer Christine,Botella Maria P,Cereda Cristina,Chandler Kate E,Dabydeen Lyvia,Dale Russell C,De Laet Corinne,De Goede Christian G E L,Del Toro Mireia,Effat Laila,Enamorado Noemi Nunez,Fazzi Elisa,Gener Blanca,Haldre Madli,Lin Jean-Pierre S-M,Livingston John H,Lourenco Charles Marques,Marques Wilson,Oades Patrick,Peterson Pärt,Rasmussen Magnhild,Roubertie Agathe,Schmidt Johanna Loewenstein,Shalev Stavit A,Simon Rogelio,Spiegel Ronen,Swoboda Kathryn J,Temtamy Samia A,Vassallo Grace,Vilain Catheline N,Vogt Julie,Wermenbol Vanessa,Whitehouse William P,Soler Doriette,Olivieri Ivana,Orcesi Simona,Aglan Mona S,Zaki Maha S,Abdel-Salam Ghada M H,Vanderver Adeline,Kisand Kai,Rozenberg Flore,Lebon Pierre,Crow Yanick J The Lancet. Neurology BACKGROUND:Aicardi-Goutières syndrome (AGS) is an inflammatory disorder caused by mutations in any of six genes (TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, and ADAR). The disease is severe and effective treatments are urgently needed. We investigated the status of interferon-related biomarkers in patients with AGS with a view to future use in diagnosis and clinical trials. METHODS:In this case-control study, samples were collected prospectively from patients with mutation-proven AGS. The expression of six interferon-stimulated genes (ISGs) was measured by quantitative PCR, and the median fold change, when compared with the median of healthy controls, was used to create an interferon score for each patient. Scores higher than the mean of controls plus two SD (>2·466) were designated as positive. Additionally, we collated historical data for interferon activity, measured with a viral cytopathic assay, in CSF and serum from mutation-positive patients with AGS. We also undertook neutralisation assays of interferon activity in serum, and looked for the presence of autoantibodies against a panel of interferon proteins. FINDINGS:74 (90%) of 82 patients had a positive interferon score (median 12·90, IQR 6·14-20·41) compared with two (7%) of 29 controls (median 0·93, IQR 0·57-1·30). Of the eight patients with a negative interferon score, seven had mutations in RNASEH2B (seven [27%] of all 26 patients with mutations in this gene). Repeat sampling in 16 patients was consistent for the presence or absence of an interferon signature on 39 of 41 occasions. Interferon activity (tested in 147 patients) was negatively correlated with age (CSF, r=-0·604; serum, r=-0·289), and was higher in CSF than in serum in 104 of 136 paired samples. Neutralisation assays suggested that measurable antiviral activity was related to interferon α production. We did not record significantly increased concentrations of autoantibodies to interferon subtypes in patients with AGS, or an association between the presence of autoantibodies and interferon score or serum interferon activity. INTERPRETATION:AGS is consistently associated with an interferon signature, which is apparently sustained over time and can thus be used to differentiate patients with AGS from controls. If future studies show that interferon status is a reactive biomarker, the measurement of an interferon score might prove useful in the assessment of treatment efficacy in clinical trials. FUNDING:European Union's Seventh Framework Programme; European Research Council. 10.1016/S1474-4422(13)70258-8
    Developmental Outcomes of Aicardi Goutières Syndrome. Adang Laura,Gavazzi Francesco,De Simone Micaela,Fazzi Elisa,Galli Jessica,Koh Jamie,Kramer-Golinkoff Julia,De Giorgis Valentina,Orcesi Simona,Peer Kyle,Ulrick Nicole,Woidill Sarah,Shults Justine,Vanderver Adeline Journal of child neurology Aicardi Goutières syndrome is a monogenic interferonopathy caused by abnormalities in the intracellular nucleic acid sensing machinery (, , , , , , or ). Most individuals affected by Aicardi Goutières syndrome exhibit some degree of neurologic impairment, from spastic paraparesis with relatively preserved cognition to tetraparesis and severe intellectual disability. Because of this heterogeneity, it is important to fully characterize the developmental trajectory in Aicardi Goutières syndrome. To characterize the clinical presentation in Aicardi Goutières syndrome, early features were collected from an international cohort of children (n = 100) with genetically confirmed Aicardi Goutières syndrome. There was a heterogeneous age of onset, with overlapping clusters of presenting symptoms: altered mental status, systemic inflammatory symptoms, and acute neurologic disability. Next, we created genotype-specific developmental milestone acquisition curves. Individuals with microcephaly or related Aicardi Goutières syndrome secondary were the most severely affected and less likely to reach milestones, including head control, sitting, and nonspecific mama/dada. Individuals affected by , , and attained the most advanced milestones, with 44% achieving verbal communication and 31% independently ambulating. Retrospective function scales (Gross Motor Function Classification System, Manual Ability Classification System, and Communication Function Classification System) demonstrated that two-thirds of the Aicardi Goutières syndrome population are severely affected. Our results suggest multifactorial influences on developmental trajectory, including a strong contribution from genotype. Further studies are needed to identify the additional factors that influence overall outcomes to better counsel families and to design clinical trials with appropriate clinical endpoints. 10.1177/0883073819870944
    [Clinical and genetic analysis of a family with Aicardi-Goutières syndrome and literature review]. Ji Taoyun,Wang Jingmin,Li Huijuan,Zhao Lirong,Sang Yan,Wu Ye Zhonghua er ke za zhi = Chinese journal of pediatrics OBJECTIVE:Aicardi-Goutières syndrome (AGS) is a rare early-onset genetic encephalopathy. The aim of this study was to explore the clinical, imaging and genetic features of a family with AGS, which may contribute to definite diagnosis, genetic counseling and prenatal diagnosis of this rare disease in China. We summarized the characteristics of AGS through reviewing related references. METHOD:Information of the proband and other family members as well as their DNA samples were collected. All the exons and exon-intron boundaries of pathogenic genes were amplified with PCR and were directly sequenced for genomic DNA. And we reviewed the reports of 252 cases. RESULT:(1) The proband was a 6 years plus 7 months old boy. He presented with severe developmental delay and abnormal posture mainly as torsion of limbs. By physical examination he was found to have some chilblain-like skin lesions at the end of limbs and microcephaly. The CT scan of his head displayed multiple calcification, especially in the basal ganglia. The MRI of his head displayed a hypointense signal in T1-weighted (T1W) images and a hyperintense signal in T2-weighted (T2W) in cerebral white matter and cystic lesions in temporal white matter. The younger sister of the proband presented with chilblain-like skin lesions on her face and the end of limbs had no developmental delay. The CT of her head showed multiple calcification, especially in the basal ganglia. (2) Two mutations were identified in TREX1, one was a novel nonsense mutation (c.294_295insA), and the other was a known pathogenic mutation (c.868_885del). (3) The common performances of AGS included mental retardation [92% (231/252) ], dystonia [75% (189/252)], microcephaly [63% (159/252) ], chilblain [42% (106/252) ], basal ganglia calcification [100% (252/252)], brain atrophy[88% (222/252)] and cerebral white matter lesions [86% (217/252)]. TREX1 [38% (96/252) ] and RNASEH2B [23% (58/252)]are the most common pathogenic genes. CONCLUSION:We determined pathogenic gene of these patients which is the basis of genetic counseling for this family. c.294_295insA mutation is a novel mutation not reported around the world yet.
    The Aircardi-Goutières syndrome: variable clinical expression in two siblings. Verrips A,Hiel J A,Gabreëls F J,Wesseling P,Rotteveel J J Pediatric neurology We report 2 siblings with the Aicardi-Goutières syndrome (encephalopathy, basal ganglia calcifications, and persistent cerebrospinal fluid pleiocytosis). The eldest sibling is severely retarded; his younger brother has only mild, slowly progressive neurological deficits. To our knowledge, such a striking difference in clinical expression has not been reported previously.
    Characterization of six recombinant human RNase H2 bearing Aicardi-Goutiéres syndrome causing mutations. Nishimura Takuto,Baba Misato,Ogawa Saori,Kojima Kenji,Takita Teisuke,Crouch Robert J,Yasukawa Kiyoshi Journal of biochemistry Mammalian RNase H2 is a heterotrimeric enzyme consisting of one catalytic subunit (A) and two accessory subunits (B and C). RNase H2 is involved in the removal of a single ribonucleotide embedded in genomic DNA and removal of RNA of RNA/DNA hybrids. In humans, mutation of the RNase H2 gene causes a severe neuroinflammatory disorder Aicardi-Goutières syndrome (AGS). Here, we examined the activity and stability of six recombinant human RNase H2 variants bearing one AGS-causing mutation, A-G37S (Gly37 in the A subunit is replaced with Ser), A-N212I, A-R291H, B-A177T, B-V185G, or C-R69W. The activity of A-G37S was 0.3-1% of that of the wild-type RNase H2 (WT), while those of other five variants were 51-120%. In circular dichroism measurement, the melting temperatures of variants were 50-53°C, lower than that of WT (56°C). These results suggested that A-G37S had decreased activity and stability than WT, while other five variants had decreased stability but retained activity. In gel filtration chromatography of the purified enzyme preparation, WT migrated as a heterotrimer, while A-R291H eluted in two separate peaks containing either the heterotrimer or only the A subunit, suggesting that some AGS-causing mutations affect the heterotrimer-forming stability of RNase H2. 10.1093/jb/mvz073
    Molecular Genetics and Interferon Signature in the Italian Aicardi Goutières Syndrome Cohort: Report of 12 New Cases and Literature Review. Garau Jessica,Cavallera Vanessa,Valente Marialuisa,Tonduti Davide,Sproviero Daisy,Zucca Susanna,Battaglia Domenica,Battini Roberta,Bertini Enrico,Cappanera Silvia,Chiapparini Luisa,Crasà Camilla,Crichiutti Giovanni,Dalla Giustina Elvio,D'Arrigo Stefano,De Giorgis Valentina,De Simone Micaela,Galli Jessica,La Piana Roberta,Messana Tullio,Moroni Isabella,Nardocci Nardo,Panteghini Celeste,Parazzini Cecilia,Pichiecchio Anna,Pini Antonella,Ricci Federica,Saletti Veronica,Salvatici Elisabetta,Santorelli Filippo M,Sartori Stefano,Tinelli Francesca,Uggetti Carla,Veneselli Edvige,Zorzi Giovanna,Garavaglia Barbara,Fazzi Elisa,Orcesi Simona,Cereda Cristina Journal of clinical medicine Aicardi-Goutières syndrome (AGS) is a genetically determined early onset encephalopathy characterized by cerebral calcification, leukodystrophy, and increased expression of interferon-stimulated genes (ISGs). Up to now, seven genes () have been associated with an AGS phenotype. Next Generation Sequencing (NGS) analysis was performed on 51 AGS patients and interferon signature (IS) was investigated in 18 AGS patients and 31 healthy controls. NGS identified mutations in 48 of 51 subjects, with three patients demonstrating a typical AGS phenotype but not carrying mutations in known AGS-related genes. Five mutations, in , and gene, were not previously reported. Eleven patients were positive and seven negatives for the upregulation of interferon signaling (IS > 2.216). This work presents, for the first time, the genetic data of an Italian cohort of AGS patients, with a higher percentage of mutations in and a lower frequency of mutations in than those seen in international series. mutated patients showed a prevalence of negative IS consistent with data reported in the literature. We also identified five novel pathogenic mutations that warrant further functional investigation. Exome/genome sequencing will be performed in future studies in patients without a mutation in AGS-related genes. 10.3390/jcm8050750
    Phenotypic and Molecular Spectrum of Aicardi-Goutières Syndrome: A Study of 24 Patients. Al Mutairi Fuad,Alfadhel Majid,Nashabat Marwan,El-Hattab Ayman W,Ben-Omran Tawfeg,Hertecant Jozef,Eyaid Wafaa,Ali Rehab,Alasmari Ali,Kara Majdi,Al-Twaijri Waleed,Filimban Rana,Alshenqiti Abduljabbar,Al-Owain Mohammed,Faqeih Eissa,Alkuraya Fowzan S Pediatric neurology BACKGROUND:Aicardi-Goutières syndrome is a rare genetic neurological disorder with variable clinical manifestations. Molecular detection of specific mutations is required to confirm the diagnosis. The aim of this study was to review the clinical and molecular diagnostic findings in 24 individuals with Aicardi-Goutières syndrome who presented during childhood in an Arab population. MATERIALS AND METHODS:We reviewed the records of 24 patients from six tertiary hospitals in different Arab countries. All included patients had a molecular diagnosis of Aicardi-Goutières syndrome. RESULTS:Six individuals with Aicardi-Goutières syndrome (25%) had a neonatal presentation, whereas the remaining patients presented during the first year of life. Patients presented with developmental delay (24 cases, 100%); spasticity (24 cases, 100%); speech delay (23 cases, 95.8%); profound intellectual disability (21 cases, 87.5%); truncal hypotonia (21 cases, 87.5%); seizures (eighteen cases, 75%); and epileptic encephalopathy (15 cases, 62.5%). Neuroimaging showed white matter abnormalities (22 cases, 91.7%), cerebral atrophy (75%), and small, multifocal calcifications in the lentiform nuclei and deep cerebral white matter (54.2%). Homozygous mutations were identified in RNASEH2B (54.2%), RNASEH2A (20.8%), RNASEH2C (8.3%), SAMHD1 (8.3%), TREX1 (4.2%), and heterozygous mutations in IFIH1 (4.2%), with c.356A>G (p.Asp119Gly) in RNASEH2B being the most frequent mutation. Three novel mutations c.987delT and c.625 + 1G>A in SAMHD1 gene and c.961G>T in the IFIHI1 gene were identified. CONCLUSIONS:This is the largest molecularly confirmed Aicardi-Goutières syndrome cohort from Arabia. By presenting these clinical and molecular findings, we hope to raise awareness of Aicardi-Goutières syndrome and to demonstrate the importance of specialist referral and molecular diagnosis. 10.1016/j.pediatrneurol.2017.09.002
    Interferon-Stimulated Gene Expression as a Preferred Biomarker for Disease Activity in Aicardi-Goutières Syndrome. Wang Ben X,Grover Stephanie A,Kannu Peter,Yoon Grace,Laxer Ronald M,Yeh E Ann,Fish Eleanor N Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research Aicardi-Goutières syndrome (AGS) is an early-onset, genetic disease characterized by recurrent fever, multifocal lesions of the brain, and systemic autoimmunity. We report on 3 AGS patients, 2 siblings with an RNASEH2A gene mutation and 1 patient with a SAMHD1 gene mutation. Serial analysis of peripheral blood from all 3 AGS patients showed consistently elevated expression of the interferon-stimulated genes (ISGs): ISG15, RSAD2, and IFI27, not observed in unaffected family members. Enumeration of circulating white blood cells and platelets and examination of C-reactive protein showed no significant deviation from the normal range for Patient 2 with the RNASEH2A mutation and Patient 3 with the SAMHD1 mutation, even when Patient 2 had magnetic resonance imaging abnormalities and ongoing febrile episodes. Erythrocyte sedimentation rates fluctuated within the normal range for Patient 2, with some elevation, yet, were in the normal range during the second febrile episode when there were accompanying neurological abnormalities. These preliminary data suggest that ISG expression may be a more specific indicator of disease activity in comparison to standard inflammatory markers. 10.1089/jir.2016.0117
    RNaseH2A is involved in human gliomagenesis through the regulation of cell proliferation and apoptosis. Dai Bin,Zhang Peng,Zhang Yisong,Pan Changcun,Meng Guolu,Xiao Xinru,Wu Zhen,Jia Wang,Zhang Junting,Zhang Liwei Oncology reports Mutations in the RNaseH2A gene are involved in Aicardi‑Goutieres syndrome, an autosomal recessive neurological dysfunction; however, studies assessing RNaseH2A in relation to glioma are scarce. This study aimed to assess the role of RNaseH2A in glioma and to unveil the underlying mechanisms. RNaseH2A was silenced in glioblastoma cell lines U87 and U251. Gene expression was assessed in the cells transfected with RNaseH2A shRNA or scramble shRNA by microarrays, validated by quantitative real time PCR. Protein expression was evaluated by western blot analysis. Cell proliferation was assessed by the MTT assay; cell cycle distribution and apoptosis were analyzed by flow cytometry. Finally, the effects of RNaseH2A on colony formation and tumorigenicity were assessed in vitro and in a mouse xenograft model, respectively. RNaseH2A was successively knocked down in U87 and U251 cells. Notably, RNaseH2A silencing resulted in impaired cell proliferation, with 70.7 and 57.8% reduction in the U87 and U251 cells, respectively, with the cell cycle being blocked in the G0/G1 phase in vitro. Meanwhile, clone formation was significantly reduced by RNaseH2A knockdown, which also increased cell apoptosis by approximately 4.5-fold. In nude mice, tumor size was significantly decreased after RNaseH2A knockdown: 219.29±246.43 vs. 1160.26±222.61 mm3 for the control group; similar findings were obtained for tumor weight (0.261±0.245 and 1.127±0.232 g) in the shRNA and control groups, respectively). In the microarray data, RNaseH2A was shown to modulate several signaling pathways responsible for cell proliferation and apoptosis, such as IL-6 and FAS pathways. RNaseH2A may be involved in human gliomagenesis, likely by regulating signaling pathways responsible for cell proliferation and apoptosis. 10.3892/or.2016.4802
    Systemic inflammation and chronic kidney disease in a patient due to the RNASEH2B defect. He Tingyan,Xia Yu,Yang Jun Pediatric rheumatology online journal INTRODUCTION:Aicardi-Goutières (AGS) is a rare immune dysregulated disease due to mutations in TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR1, or IFIH1. Clinical features include basal ganglia calcifications, white matter abnormalities, and cerebral atrophy. Severe systemic inflammation and chronic kidney disease (CKD) are extremely rare in AGS. Herein, we report a patient presenting with systemic inflammation and CKD to broaden the clinical phenotype spectrum of the RNASEH2B defect. METHODS:All testing and molecular genetic analysis were performed after obtaining the informed consent of the parents. Demographic, clinical, and laboratory findings were abstracted from outpatient and inpatient encounters. Cerebral magnetic resonance imaging (MRI), computed tomography (CT) scans, and renal biopsy histopathology reports were reviewed and summarized. Whole exome sequencing (WES) was performed on peripheral blood cells. After exposure to cGAMP in vitro for 24 h, mRNA expression of 12 IFN-stimulated cytokine genes in PBMCs was assessed. Serum cytokine levels were detected by Milliplex. RESULTS:A 11-year-old girl presented with recurrent aseptic fever, arthritis, chilblains, failure to thrive, mild hearing loss, and neurological manifestations. Laboratory and immunologic findings demonstrated lymphopenia, low complement levels, positive autoantibodies, elevated levels of acute-phase reactants and inflammatory cytokines. Cerebral imaging showed cerebral atrophy, white matter abnormalities, and intracranial calcification. Renal biopsy showed glomerular sclerosis in 3 of 14 glomeruli, infiltration of lymphocytes and other mononuclear cells. WES revealed a homozygous and heterozygous mutations in RNASEH2B. Over-expression of IFN-stimulated cytokine genes was observed, including IFI44, IFI27, IFIT1, IFIT2, IFIT3, ISG15, OAS1, and SIGLEC1. CONCLUSIONS:To date, only two cases with AGS have been reported to have renal disease. Here, we describe a patient with both homozygous and heterozygous variants in RNASEH2B, presenting with neurological manifestations, persistently systemic autoinflammation, and CKD. CKD has never been reported in patients with AGS due to the RNASEH2B defect. TRIAL REGISTRATION:Not applicable; this was a retrospective study. 10.1186/s12969-021-00497-2
    Bilateral striatal necrosis in two subjects with Aicardi-Goutières syndrome due to mutations in ADAR1 (AGS6). La Piana Roberta,Uggetti Carla,Olivieri Ivana,Tonduti Davide,Balottin Umberto,Fazzi Elisa,Orcesi Simona American journal of medical genetics. Part A Aicardi-Goutières syndrome (AGS) is a genetic inflammatory disease. The classic neuroradiological picture mimics that of congenital infections in that Aicardi-Goutières syndrome is characterized by leukoencephalopathy, brain atrophy and intracranial calcifications. To date, bilateral striatal necrosis has not been reported in patients with AGS. We report on two patients with clinical diagnosis of Aicardi-Goutières syndrome in which brain MRI and CT scans demonstrated bilateral striatal necrosis. The diagnosis of Aicardi-Goutières syndrome in these two patients was genetically confirmed after the recent discovery that mutations in the ADAR1 (AGS6) gene may cause Aicardi-Goutières syndrome. This is the first report of bilateral striatal necrosis in association with Aicardi-Goutières syndrome. These results expand the neuroradiological phenotype of Aicardi-Goutières syndrome. 10.1002/ajmg.a.36360
    [Phenotypic variations in Aicardi-Goutieres syndrome caused by RNASEH2B gene mutations: report of two new cases]. Ortiz-Madinaveitia Saturnino,Conejo-Moreno David,López-Pisón Javier,Peña-Segura José Luis,Serrano-Madrid M Luisa,Durán-Palacios Ingrid C,Peláez-Cabo Pilar Revista de neurologia INTRODUCTION:Aicardi-Goutieres syndrome is a rare immune disorder due to mutations in seven different genes that encode proteins called TREX1, ribonuclease H2 complex, SAMHD1, ADAR and IDIH1 (MDA5), which are involved in acid nucleic metabolism. Two cases are described in detail below caused by RNASEH2B gene mutation, one of which displays a mutation no described to date. CASE REPORTS:Case 1: male consulting because from 5-month-old shows loss of maturity items acquired until then, coming with several fever episodes. Case 2: a 4-month-old boy showing since 2-month-old great irritability and oral-feeding trouble with severe psychomotor impairment. In both cases it was found an increase of pterines in the cerebrospinal fluid, mainly neopterine, with calcifications in the basal ganglia. The diagnosis was proved by sequencing RNASEH2B gene, founding in case 2 a new mutation not described previously. CONCLUSIONS:The reported cases belong to the description already done by Aicardi-Goutieres, it should be noticed this syndrome in a patient with a subacute encephalopathy of debut in the first year of life, dystonia/spasticity in variable degree and important affectation/regression of psychomotor development, particularly in those with increase of pterines (neopterine) in the cerebrospinal fluid and calcifications in the basal ganglia.
    A novel pathogenic variant p.Asp797Val in IFIH1 in a Japanese boy with overlapping Singleton-Merten syndrome and Aicardi-Goutières syndrome. Hasegawa Kosei,Tanaka Hiroyuki,Futagawa Natsuko,Miyahara Hiroyuki,Higuchi Yousuke,Tsukahara Hirokazu American journal of medical genetics. Part A Pathogenic-activating variants of interferon induced with Helicase C domain 1 (IFIH1) cause Singleton-Merten (S-M) syndrome, which accompanies acro-osteolysis, loss of permanent teeth, and aortic calcification, as well as causing Aicardi-Goutières (A-G) syndrome, which shows progressive encephalopathy, spastic paraplegia, and calcification of basal ganglia. Recently, patients with overlapping syndromes presenting with features of S-M syndrome and A-G syndrome were reported. However, progression of clinical features of this condition has not been fully understood. We report a Japanese boy with a novel pathogenic IFIH1 variant who presented with clinical features of S-M syndrome and A-G syndrome. 10.1002/ajmg.a.62478
    Aicardi-Goutières syndrome: unusual neuro-radiological manifestations. Abdel-Salam Ghada M H,Abdel-Hamid Mohamed S,Mohammad Shaimaa A,Abdel-Ghafar Sherif F,Soliman Doaa R,El-Bassyouni Hala T,Effat Laila,Zaki Maha S Metabolic brain disease Aicardi-Goutières syndrome (AGS) is one of the expanding group of inherited congenital infection like syndromes. Here, we describe the detailed clinical and imaging findings of two sibs with AGS. Each shows scattered periventricular intracranial calcifications, severe global delay, seizures, microcephaly and spasticity. Interestingly, chilblains were observed in the two sisters as well as their parents and a paternal uncle. The brain MRI of the older sister showed marked ventricular dilatation as a result of unusual associated porencephalic cysts. Unexpectedly, unilateral cerebellar hypoplasia was also noted. In comparison, her younger sister displayed the classic atrophic changes and white matter loss of AGS. The diagnosis of AGS was confirmed by sequence analysis, which identified a previously reported homozygous RNASEH2B mutation, c.554 T > G (p.V185G). Parents were heterozygous for the same mutation. Further molecular analysis excluded mutations in potentially related manifestations of COL4A1 gene. This is the first report of chilblains associated with heterozygous RNASEH2B mutation. Further, the brain imaging findings appear particularly interesting, which until now has not been reported in any AGS patient. We discuss the possible reasons for this unusual presentation. 10.1007/s11011-017-9993-4
    [An Aicardi-Goutières syndrome associated with a quasi-Moyamoya by a biallelic mutation in SAMHD1]. Barrit S Revue medicale de Bruxelles SAMHD1 is one of seven known genes responsible for Aicardi-Goutières syndrome. It has the particularity to associate to this rare pediatric encephalopathy with autoimmune manifestations, a cerebral vasculopathy type Moyamoya. This condition has only been recently reported, less than fifty times in the literature. Our clinical case is a 11 year old boy from an inbred union whose clinical diagnosis confirmed genetically and followed by a review of current data determined an ad hoc management, presently described. He underwent indirect neurosurgical revascularization by a multiple burr hole technique. Through this clinical case, we tried taking stock of what we know -clinical, physiopathological and therapeutical aspects- given the rarity of this disease, first on the syndrome as such, then on the peculiarities of the gene mutations of interest. 10.30637/2018.16-030
    Unusual Association of Aniridia with Aicardi-Goutières Syndrome-Related Congenital Glaucoma in a Tertiary Care Center. Musalem Hebah M,Dirar Qais S,Al-Hazzaa Selwa A F,Al Zoba Abdul-Aziz A,El-Mansoury Jeylan The American journal of case reports BACKGROUND Aicardi-Goutières syndrome (AGS) is a rare autosomal recessive encephalopathy of early onset. AGS visual dysfunction range from nystagmus and optic atrophy to cortical blindness in affected individuals; however, congenital glaucoma has been recently noticed among AGS pediatric patients. According to the literature, aniridia has never been recognized among AGS patients. CASE REPORT We report the case of a 4-year-old boy with AGS who had multiple congenital anomalies in the eyes. He was found to have congenital glaucoma, nystagmus, spherophakia with shallow chambers, and aniridia in both eyes. Family history was positive for glaucoma, with consanguineously married parents. According to the genetics report, both parents are carriers of congenital glaucoma genes. A whole-exome sequencing identified IFIH1 heterozygous missense mutation of the patient, which is associated with AGS Type 7. Also, he was diagnosed as having congenital glaucoma with CYP1B1 mutation, homozygous recessive. This case demonstrates the unusual coexistence of bilateral aniridia, a feature not previously reported in ocular findings of AGS. CONCLUSIONS In summary, this is the first reported case of aniridia with AGS-related congenital glaucoma in the literature. This paper summarizes the usual ocular manifestation of AGS, also it highlights atypical ocular features in both; AGS as well as congenital glaucoma. The aim of this paper is to lay the foundation for a national database on AGS in Saudi Arabia, which will help create a bridge between genetic data and clinical findings of AGS patients. 10.12659/AJCR.908036
    Diagnosis of Aicardi-Goutières Syndrome in Adults: A Case Series. Movement disorders clinical practice INTRODUCTION:Aicardi-Goutières syndrome (AGS) is a genetic disease presenting with early-onset encephalopathy, generalized dystonia, spasticity, and cognitive disability. Diagnosis may be difficult in adults, as the clinical course seems static from infancy. METHODS:AGS patients from an adult movement disorders outpatient clinic were retrospectively analyzed. RESULTS:A total of 5 patients and 1 asymptomatic carrier from 3 different families were identified. All had a homozygous c.529G>A,p.A177T mutation in exon 7 of the gene. Two patients had neonatal-onset AGS, 2 had later onset forms, and 1 was slightly symptomatic. All were diagnosed in adulthood after chilblains, and basal ganglia calcifications were identified on computed tomography scans. DISCUSSION:AGS patients have marked phenotypic variability regarding psychomotor development and morbidity. The present series included 1 asymptomatic carrier and 1 slightly symptomatic patient, both with homozygous mutations. Chilblains and basal ganglia calcifications identified on computed tomography scan (but not on magnetic resonance imaging) are important clues for late diagnosis. 10.1002/mdc3.12903
    Genetic Testing Contributes to Diagnosis in Cerebral Palsy: Aicardi-Goutières Syndrome as an Example. Beysen Diane,De Cordt Chania,Dielman Charlotte,Ogunjimi Benson,Dandelooy Julie,Reyniers Edwin,Janssens Katrien,Meuwissen Marije M E Frontiers in neurology Cerebral palsy (CP) is a non-progressive neurodevelopmental disorder characterized by motor impairments, often accompanied by co-morbidities such as intellectual disability, epilepsy, visual and hearing impairment and speech and language deficits. Despite the established role of hypoxic-ischemic injury in some CP cases, several studies suggest that birth asphyxia is actually an uncommon cause, accounting for <10% of CP cases. For children with CP in the absence of traditional risk factors, a genetic basis to their condition is increasingly suspected. Several recent studies indeed confirm copy number variants and single gene mutations with large genetic heterogeneity as an etiology in children with CP. Here, we report three patients with spastic cerebral palsy and a genetically confirmed diagnosis of Aicardi-Goutières syndrome (AGS), with highly variable phenotypes ranging from clinically suggestive to non-specific symptomatology. Our findings suggest that AGS may be a rather common cause of CP, that frequently remains undiagnosed without additional genetic testing, as in only one case a clinical suspicion of AGS was raised. Our data show that a diagnosis of AGS must be considered in cases with spastic CP, even in the absence of characteristic brain abnormalities. Importantly, a genetic diagnosis of AGS may have significant therapeutic consequences, as targeted therapies are being developed for type 1 interferonopathies, the group of diseases to which AGS belongs. Our findings demonstrate the importance of next generation sequencing in CP patients without an identifiable cause, since targeted diagnostic testing is hampered by the often non-specific presentation. 10.3389/fneur.2021.617813
    Recurrent Encephalopathy with Spinal Cord Involvement: An Atypical Manifestation of Aicardi-Goutières Syndrome. Samanta Debopam,Ramakrishnaiah Raghu Annals of Indian Academy of Neurology Aicardi-Goutières syndrome (AGS) is a rare, genetic inflammatory disease due to mutations in any of the seven genes discovered to date (, and ). Clinical onset is seen most commonly or in infancy; irritability, feeding difficulties, jitteriness, microcephaly, abnormal movements, seizures, bone marrow suppression, and liver dysfunction are seen either during the neonatal age group or within the first few months of life with abrupt onset of neurologic regression and slowing of head growth. Diffusely abnormal white matters with swelling of frontal or temporal lobes, cerebral atrophy, and intracranial calcification are typical neuroradiologic abnormalities. However, mutation, a recently discovered AGS gene, can cause late-onset acute or subacute onset of severe dystonia and features of bilateral striatal necrosis on neuroimaging, in the absence of other typical features of AGS. We report a detailed description of a 5-year-old boy who had a recurrent encephalopathic presentation in the setting of infection. Magnetic resonance imaging (MRI) of brain revealed prominent and fairly symmetrical signal abnormalities in the cerebellar peduncles, thalamus, midbrain, and pons. His throat swab was positive for influenza B, and he was initially diagnosed with influenza encephalopathy. He had a recurrence after 18 months of his initial presentation, and his brain MRI showed extensive areas of signal abnormality similar to, but more extensive than, his previous scan. Extensive spinal cord swelling was also seen. His chronic skin finding was recognized as dyschromatosis symmetrica hereditaria (DSH), and genetic testing revealed compound heterozygous mutations of gene - causative for AGS. This is the first presentation of recurrent acute encephalopathy in the setting of documented mutation with the longest interval documented between two acute presentations. This is also the first documentation of extensive spinal cord involvement, which will expand its phenotype. This case also highlights the importance of early identification of DSH, a subtle but characteristic skin lesion of mutations, for prompt diagnosis of this rare condition. 10.4103/aian.AIAN_12_18
    Novel and emerging treatments for Aicardi-Goutières syndrome. Tonduti Davide,Fazzi Elisa,Badolato Raffaele,Orcesi Simona Expert review of clinical immunology : Aicardi-Goutières syndrome (AGS) is the prototype of the type I interferonopathies, a new heterogeneous group of autoinflammatory disorders in which type I interferon plays a pivotal role. The disease usually manifests itself during infancy, primarily affecting the brain and the skin, and is characterized by cerebrospinal fluid chronic lymphocytosis and raised levels of interferon-alpha and by cardinal neuroradiological features: cerebral calcification, leukoencephalopathy and cerebral atrophy. Recently many aspects of the pathogenesis of AGS have been clarified, making it possible to hypothesize new therapeutic strategies.: We here review recent data concerning pathogenesis and novel therapeutic strategies in AGS, including the use of Janus kinase inhibitors, reverse transcriptase inhibitors, anti-IFN-α antibodies, anti-interleukin antibodies, antimalarial drugs and other cGAS inhibitors.: Thanks to the identification of the molecular basis of AGS, many aspects of its pathogenesis have been clarified, making it possible to propose new therapeutic strategies for AGS and type I interferonopathies. A number of therapeutic options are now becoming possible, even though their efficacy is still to be proven. However, in spite of research advances coming from clinical trials and case series, there are still a number of open questions, which urgently need to be addressed. 10.1080/1744666X.2019.1707663
    Clinical and pathologic features of Aicardi-Goutières syndrome due to an IFIH1 mutation: A pediatric case report. Marguet Florent,Laquerrière Annie,Goldenberg Alice,Guerrot Anne-Marie,Quenez Olivier,Flahaut Philippe,Vanhulle Catherine,Dumant-Forest Clémentine,Charbonnier Françoise,Vezain Myriam,Bekri Soumeya,Tournier Isabelle,Frébourg Thierry,Nicolas Gaël American journal of medical genetics. Part A We describe the case of a young patient with calcifying encephalopathy, born to asymptomatic parents. An extensive hypothesis-driven etiological assessment was performed and failed to detect the precise etiology during many years. We therefore decided to perform whole exome sequencing of the child-unaffected parents trio. A de novo pathogenic variant in the IFIH1 gene which has recently been shown to cause autosomal dominant forms of Aicardi-Goutières syndrome was identified. This child presented with a severe form with neonatal thrombocytopenia and hepatomegaly, the latter having been detected during late gestation. Although first milestones were uneventful, he progressively lost motor skills from the age of 12 months and developed severe spastic paraplegia. Brain imaging revealed white matter abnormalities and extensive calcifications. He also presented atypical skin lesions, different from chilblains. His medical history was marked by two episodes of acute pancreatitis. We provide herein the results of pathological examination including detailed description of the neuropathological hallmarks. To our knowledge, this the first detailed clinico-pathological description of a patient with an IFIH1 pathogenic variant. 10.1002/ajmg.a.37577
    [Aicardi-Goutieres syndrome due to mutation of the IFIH1 gene with pontine involvement. A case report]. Florido-Rodriguez A,Eiris-Punal J,Barros-Angueira F,Toledo-Bravo de Laguna L,Santana-Artiles A,Sebastian-Garcia I,Santana-Rodriguez A,Cabrera-Lopez J C Revista de neurologia INTRODUCTION:Aicardi-Goutieres syndrome is a rare progressive subacute encephalopathy of early onset - generally in the first year of life - characterised by psychomotor retardation, microcephaly, alterations in the white matter of the brain, intracranial calcifications, pleocytosis and elevated levels of interferon alpha in the cerebrospinal fluid. It is associated to an increase in the expression of genes stimulated by interferon in peripheral blood, a fact known as the interferon signature. The levels of genes stimulated by interferon has been postulated as a good biomarker, as they remain high in peripheral blood over time and are more sensitive, in comparison to determinations of interferon alpha and neopterins in cerebrospinal fluid, which descend as of one year of life. To date, mutations have been reported in seven genes that overstimulate the interferon alpha pathway, and the last to be discovered is IFIH1 (interferon induced with helicase C domain 1), with a pattern of dominant autosomal inheritance. CASE REPORT:We present the first case reported in the Hispanic literature caused by a de novo mutation in the IFIH1 gene. The clinical features, studies conducted and review of the clinical, neuroradiological and genetic aspects are described. CONCLUSIONS:The inheritance of the mutations reported for Aicardi-Goutieres syndrome was classically considered as being recessive autosomal, but these findings show that dominant autosomal mutations in the IFIH1 gene can cause the disease. As a previously unreported neuroimaging finding, it presents a lesion consisting in cystic encephalomalacia in the pons.
    Moyamoya Syndrome in an Infant with Aicardi-Goutières and Williams Syndromes: A Case Report. Neuropediatrics Stroke in infancy is a rare phenomenon but can lead to significant long-term disability. We present the story of a 6-month-old Old Order Amish infant with underlying Williams syndrome, a rare neurodevelopmental disorder caused by a microdeletion, encompassing the elastin gene that produces abnormalities in elastic fibers of the lungs and vessels. This infant presented with lethargy, irritability, and a new-onset generalized tonic-clonic seizure. Brain magnetic resonance imaging (MRI) was consistent with ischemic stroke in the supratentorial regions. MR angiogram demonstrated bilateral narrowing of the internal carotid arteries with "ivy sign," suggestive of Moyamoya. Moyamoya disease/syndrome is a cerebrovascular condition that is associated with progressive stenosis of the intracranial vessels and can cause ischemic stroke in young children. Targeted mutation analysis revealed a homozygous c.1411-2A > G splice site variant in the SAMHD1 gene, consistent with a diagnosis of Aicardi-Goutières syndrome type 5 (AGS5), an autosomal recessive condition with multisystem involvement. In our unique case of infantile stroke with Moyamoya syndrome and dual diagnosis of Williams syndrome and AGS5, both diagnoses likely contributed to the cerebrovascular pathology. This case report highlights the importance of suspecting and testing for multiple genetic abnormalities in children presenting with Moyamoya-related stroke. 10.1055/s-0041-1739131
    Combination of exome sequencing and immune testing confirms Aicardi-Goutières syndrome type 5 in a challenging pediatric neurology case. Haskell Gloria T,Mori Mari,Powell Cynthia,Amrhein Timothy J,Rice Gillian I,Bailey Lauren,Strande Natasha,Weck Karen E,Evans James P,Berg Jonathan S,Kishnani Priya Cold Spring Harbor molecular case studies Exome sequencing is increasingly being used to help diagnose pediatric neurology cases when clinical presentations are not specific. However, interpretation of equivocal results that include variants of uncertain significance remains a challenge. In those cases, follow-up testing and clinical correlation can help clarify the clinical relevance of the molecular findings. In this report, we describe the diagnostic odyssey of a 4-year-old girl who presented with global developmental delay and seizures, with leukodystrophy seen on MRI. Clinical evaluation, MRI, and comprehensive metabolic testing were performed, followed by whole-exome sequencing (WES), parental testing, follow-up testing, and retrospective detailed clinical evaluation. WES identified two candidate causative pathogenic variants in , a gene associated with the recessive condition Aicardi-Goutières syndrome (AGS) type 5 (OMIM 612952): a previously reported pathogenic variant NM_015474 c.602T>A (p.I201N), maternally inherited, and a rare missense variant of uncertain significance, c.1293A>T(p.L431F). Analysis of type I interferon-related biomarkers demonstrated that the patient has an interferon signature characteristic of AGS. Retrospective detailed clinical evaluation showed that the girl has a phenotype consistent with AGS5, a rare neurological condition. These results further define the phenotypic spectrum associated with specific variants, including heterozygous variants in AGS carriers, and support the idea that autoinflammatory dysregulation is part of the disease pathophysiology. More broadly, this work highlights the issues and methodology involved in ascribing clinical relevance to interpretation of variants detected by WES. 10.1101/mcs.a002758
    Whole-genome sequencing identifies complex contributions to genetic risk by variants in genes causing monogenic systemic lupus erythematosus. Almlöf Jonas Carlsson,Nystedt Sara,Leonard Dag,Eloranta Maija-Leena,Grosso Giorgia,Sjöwall Christopher,Bengtsson Anders A,Jönsen Andreas,Gunnarsson Iva,Svenungsson Elisabet,Rönnblom Lars,Sandling Johanna K,Syvänen Ann-Christine Human genetics Systemic lupus erythematosus (SLE, OMIM 152700) is a systemic autoimmune disease with a complex etiology. The mode of inheritance of the genetic risk beyond familial SLE cases is currently unknown. Additionally, the contribution of heterozygous variants in genes known to cause monogenic SLE is not fully understood. Whole-genome sequencing of DNA samples from 71 Swedish patients with SLE and their healthy biological parents was performed to investigate the general genetic risk of SLE using known SLE GWAS risk loci identified using the ImmunoChip, variants in genes associated to monogenic SLE, and the mode of inheritance of SLE risk alleles in these families. A random forest model for predicting genetic risk for SLE showed that the SLE risk variants were mainly inherited from one of the parents. In the 71 patients, we detected a significant enrichment of ultra-rare ( ≤ 0.1%) missense and nonsense mutations in 22 genes known to cause monogenic forms of SLE. We identified one previously reported homozygous nonsense mutation in the C1QC (Complement C1q C Chain) gene, which explains the immunodeficiency and severe SLE phenotype of that patient. We also identified seven ultra-rare, coding heterozygous variants in five genes (C1S, DNASE1L3, DNASE1, IFIH1, and RNASEH2A) involved in monogenic SLE. Our findings indicate a complex contribution to the overall genetic risk of SLE by rare variants in genes associated with monogenic forms of SLE. The rare variants were inherited from the other parent than the one who passed on the more common risk variants leading to an increased genetic burden for SLE in the child. Higher frequency SLE risk variants are mostly passed from one of the parents to the offspring affected with SLE. In contrast, the other parent, in seven cases, contributed heterozygous rare variants in genes associated with monogenic forms of SLE, suggesting a larger impact of rare variants in SLE than hitherto reported. 10.1007/s00439-018-01966-7
    Generation of three induced pluripotent cell lines (iPSCs) from an Aicardi-Goutières syndrome (AGS) patient harboring a deletion in the genomic locus of the sterile alpha motif and HD domain containing protein 1 (SAMHD1). Fuchs Nina V,Schieck Maximilian,Neuenkirch Michaela,Tondera Christiane,Schmitz Heike,Wendeburg Lena,Steinemann Doris,Elpers Christiane,Rutsch Frank,König Renate Stem cell research Aicardi-Goutières syndrome (AGS) is a hereditary early onset encephalopathy. AGS patients display variable clinical manifestations including intracranial calcification, cerebral atrophy, white matter abnormalities and characteristic leukocytosis as well as a constitutive upregulation of type I IFN production indicative of a type I interferonopathy. Seven genes (SAMHD1, TREX1, RNASEH2B, RNASEH2C, RNASEH2A, ADAR1, IFIH1) have been associated with the AGS phenotype, up to now. Here, we describe the generation of three induced pluripotent stem cell lines from a patient with a deletion of coding exons 14 and 15 of the SAMHD1 gene. 10.1016/j.scr.2019.101697
    Clinical and molecular phenotype of Aicardi-Goutieres syndrome. Rice Gillian,Patrick Teresa,Parmar Rekha,Taylor Claire F,Aeby Alec,Aicardi Jean,Artuch Rafael,Montalto Simon Attard,Bacino Carlos A,Barroso Bruno,Baxter Peter,Benko Willam S,Bergmann Carsten,Bertini Enrico,Biancheri Roberta,Blair Edward M,Blau Nenad,Bonthron David T,Briggs Tracy,Brueton Louise A,Brunner Han G,Burke Christopher J,Carr Ian M,Carvalho Daniel R,Chandler Kate E,Christen Hans-Jurgen,Corry Peter C,Cowan Frances M,Cox Helen,D'Arrigo Stefano,Dean John,De Laet Corinne,De Praeter Claudine,Dery Catherine,Ferrie Colin D,Flintoff Kim,Frints Suzanna G M,Garcia-Cazorla Angels,Gener Blanca,Goizet Cyril,Goutieres Francoise,Green Andrew J,Guet Agnes,Hamel Ben C J,Hayward Bruce E,Heiberg Arvid,Hennekam Raoul C,Husson Marie,Jackson Andrew P,Jayatunga Rasieka,Jiang Yong-Hui,Kant Sarina G,Kao Amy,King Mary D,Kingston Helen M,Klepper Joerg,van der Knaap Marjo S,Kornberg Andrew J,Kotzot Dieter,Kratzer Wilfried,Lacombe Didier,Lagae Lieven,Landrieu Pierre Georges,Lanzi Giovanni,Leitch Andrea,Lim Ming J,Livingston John H,Lourenco Charles M,Lyall E G Hermione,Lynch Sally A,Lyons Michael J,Marom Daphna,McClure John P,McWilliam Robert,Melancon Serge B,Mewasingh Leena D,Moutard Marie-Laure,Nischal Ken K,Ostergaard John R,Prendiville Julie,Rasmussen Magnhild,Rogers R Curtis,Roland Dominique,Rosser Elisabeth M,Rostasy Kevin,Roubertie Agathe,Sanchis Amparo,Schiffmann Raphael,Scholl-Burgi Sabine,Seal Sunita,Shalev Stavit A,Corcoles C Sierra,Sinha Gyan P,Soler Doriette,Spiegel Ronen,Stephenson John B P,Tacke Uta,Tan Tiong Yang,Till Marianne,Tolmie John L,Tomlin Pam,Vagnarelli Federica,Valente Enza Maria,Van Coster Rudy N A,Van der Aa Nathalie,Vanderver Adeline,Vles Johannes S H,Voit Thomas,Wassmer Evangeline,Weschke Bernhard,Whiteford Margo L,Willemsen Michel A A,Zankl Andreas,Zuberi Sameer M,Orcesi Simona,Fazzi Elisa,Lebon Pierre,Crow Yanick J American journal of human genetics Aicardi-Goutieres syndrome (AGS) is a genetic encephalopathy whose clinical features mimic those of acquired in utero viral infection. AGS exhibits locus heterogeneity, with mutations identified in genes encoding the 3'-->5' exonuclease TREX1 and the three subunits of the RNASEH2 endonuclease complex. To define the molecular spectrum of AGS, we performed mutation screening in patients, from 127 pedigrees, with a clinical diagnosis of the disease. Biallelic mutations in TREX1, RNASEH2A, RNASEH2B, and RNASEH2C were observed in 31, 3, 47, and 18 families, respectively. In five families, we identified an RNASEH2A or RNASEH2B mutation on one allele only. In one child, the disease occurred because of a de novo heterozygous TREX1 mutation. In 22 families, no mutations were found. Null mutations were common in TREX1, although a specific missense mutation was observed frequently in patients from northern Europe. Almost all mutations in RNASEH2A, RNASEH2B, and RNASEH2C were missense. We identified an RNASEH2C founder mutation in 13 Pakistani families. We also collected clinical data from 123 mutation-positive patients. Two clinical presentations could be delineated: an early-onset neonatal form, highly reminiscent of congenital infection seen particularly with TREX1 mutations, and a later-onset presentation, sometimes occurring after several months of normal development and occasionally associated with remarkably preserved neurological function, most frequently due to RNASEH2B mutations. Mortality was correlated with genotype; 34.3% of patients with TREX1, RNASEH2A, and RNASEH2C mutations versus 8.0% RNASEH2B mutation-positive patients were known to have died (P=.001). Our analysis defines the phenotypic spectrum of AGS and suggests a coherent mutation-screening strategy in this heterogeneous disorder. Additionally, our data indicate that at least one further AGS-causing gene remains to be identified. 10.1086/521373
    Characterization of human disease phenotypes associated with mutations in TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR, and IFIH1. Crow Yanick J,Chase Diana S,Lowenstein Schmidt Johanna,Szynkiewicz Marcin,Forte Gabriella M A,Gornall Hannah L,Oojageer Anthony,Anderson Beverley,Pizzino Amy,Helman Guy,Abdel-Hamid Mohamed S,Abdel-Salam Ghada M,Ackroyd Sam,Aeby Alec,Agosta Guillermo,Albin Catherine,Allon-Shalev Stavit,Arellano Montse,Ariaudo Giada,Aswani Vijay,Babul-Hirji Riyana,Baildam Eileen M,Bahi-Buisson Nadia,Bailey Kathryn M,Barnerias Christine,Barth Magalie,Battini Roberta,Beresford Michael W,Bernard Geneviève,Bianchi Marika,Billette de Villemeur Thierry,Blair Edward M,Bloom Miriam,Burlina Alberto B,Carpanelli Maria Luisa,Carvalho Daniel R,Castro-Gago Manuel,Cavallini Anna,Cereda Cristina,Chandler Kate E,Chitayat David A,Collins Abigail E,Sierra Corcoles Concepcion,Cordeiro Nuno J V,Crichiutti Giovanni,Dabydeen Lyvia,Dale Russell C,D'Arrigo Stefano,De Goede Christian G E L,De Laet Corinne,De Waele Liesbeth M H,Denzler Ines,Desguerre Isabelle,Devriendt Koenraad,Di Rocco Maja,Fahey Michael C,Fazzi Elisa,Ferrie Colin D,Figueiredo António,Gener Blanca,Goizet Cyril,Gowrinathan Nirmala R,Gowrishankar Kalpana,Hanrahan Donncha,Isidor Bertrand,Kara Bülent,Khan Nasaim,King Mary D,Kirk Edwin P,Kumar Ram,Lagae Lieven,Landrieu Pierre,Lauffer Heinz,Laugel Vincent,La Piana Roberta,Lim Ming J,Lin Jean-Pierre S-M,Linnankivi Tarja,Mackay Mark T,Marom Daphna R,Marques Lourenço Charles,McKee Shane A,Moroni Isabella,Morton Jenny E V,Moutard Marie-Laure,Murray Kevin,Nabbout Rima,Nampoothiri Sheela,Nunez-Enamorado Noemi,Oades Patrick J,Olivieri Ivana,Ostergaard John R,Pérez-Dueñas Belén,Prendiville Julie S,Ramesh Venkateswaran,Rasmussen Magnhild,Régal Luc,Ricci Federica,Rio Marlène,Rodriguez Diana,Roubertie Agathe,Salvatici Elisabetta,Segers Karin A,Sinha Gyanranjan P,Soler Doriette,Spiegel Ronen,Stödberg Tommy I,Straussberg Rachel,Swoboda Kathryn J,Suri Mohnish,Tacke Uta,Tan Tiong Y,te Water Naude Johann,Wee Teik Keng,Thomas Maya Mary,Till Marianne,Tonduti Davide,Valente Enza Maria,Van Coster Rudy Noel,van der Knaap Marjo S,Vassallo Grace,Vijzelaar Raymon,Vogt Julie,Wallace Geoffrey B,Wassmer Evangeline,Webb Hannah J,Whitehouse William P,Whitney Robyn N,Zaki Maha S,Zuberi Sameer M,Livingston John H,Rozenberg Flore,Lebon Pierre,Vanderver Adeline,Orcesi Simona,Rice Gillian I American journal of medical genetics. Part A Aicardi-Goutières syndrome is an inflammatory disease occurring due to mutations in any of TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR or IFIH1. We report on 374 patients from 299 families with mutations in these seven genes. Most patients conformed to one of two fairly stereotyped clinical profiles; either exhibiting an in utero disease-onset (74 patients; 22.8% of all patients where data were available), or a post-natal presentation, usually within the first year of life (223 patients; 68.6%), characterized by a sub-acute encephalopathy and a loss of previously acquired skills. Other clinically distinct phenotypes were also observed; particularly, bilateral striatal necrosis (13 patients; 3.6%) and non-syndromic spastic paraparesis (12 patients; 3.4%). We recorded 69 deaths (19.3% of patients with follow-up data). Of 285 patients for whom data were available, 210 (73.7%) were profoundly disabled, with no useful motor, speech and intellectual function. Chilblains, glaucoma, hypothyroidism, cardiomyopathy, intracerebral vasculitis, peripheral neuropathy, bowel inflammation and systemic lupus erythematosus were seen frequently enough to be confirmed as real associations with the Aicardi-Goutieres syndrome phenotype. We observed a robust relationship between mutations in all seven genes with increased type I interferon activity in cerebrospinal fluid and serum, and the increased expression of interferon-stimulated gene transcripts in peripheral blood. We recorded a positive correlation between the level of cerebrospinal fluid interferon activity assayed within one year of disease presentation and the degree of subsequent disability. Interferon-stimulated gene transcripts remained high in most patients, indicating an ongoing disease process. On the basis of substantial morbidity and mortality, our data highlight the urgent need to define coherent treatment strategies for the phenotypes associated with mutations in the Aicardi-Goutières syndrome-related genes. Our findings also make it clear that a window of therapeutic opportunity exists relevant to the majority of affected patients and indicate that the assessment of type I interferon activity might serve as a useful biomarker in future clinical trials. 10.1002/ajmg.a.36887
    Neurologic Phenotypes Associated with Mutations in TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR1, and IFIH1: Aicardi-Goutières Syndrome and Beyond. Livingston John H,Crow Yanick J Neuropediatrics The Aicardi-Goutières syndrome (AGS) was first described in 1984, and over the following years was defined by the clinical and radiological features of an early onset, severe, neurologic disorder with intracranial calcification, leukoencephalopathy, and cerebral atrophy, usually associated with a cerebrospinal fluid (CSF) pleocytosis and elevated CSF interferon α activity. It is now recognized that mutations in any of the following seven genes may result in the classical AGS phenotype: (AGS1), (AGS2), (AGS3), (AGS4), (AGS5), (AGS6), and (AGS7). All of these genes encode proteins involved in nucleotide metabolism and/or sensing. Mutations in these genes result in the induction of type 1 interferon production and an upregulation of interferon stimulated genes. As more patients harboring mutations in these genes have been described, in particular facilitated by the advent of whole exome sequencing, a remarkably broad spectrum of associated neurologic phenotypes has been revealed, which we summarize here. We propose that the term AGS has continued clinical utility in the designation of a characteristic phenotype, which suggests relevant diagnostic investigations and can inform outcome predictions. However, we also suggest that the use of the term "type 1 interferonopathy" is appropriate for the wider spectrum of disease consequent upon dysfunction of these genes and proteins since it implies the possibility of a common "anti-interferon" approach to therapy as such treatments become available. 10.1055/s-0036-1592307
    Synonymous mutations in RNASEH2A create cryptic splice sites impairing RNase H2 enzyme function in Aicardi-Goutières syndrome. Rice Gillian I,Reijns Martin A M,Coffin Stephanie R,Forte Gabriella M A,Anderson Beverley H,Szynkiewicz Marcin,Gornall Hannah,Gent David,Leitch Andrea,Botella Maria P,Fazzi Elisa,Gener Blanca,Lagae Lieven,Olivieri Ivana,Orcesi Simona,Swoboda Kathryn J,Perrino Fred W,Jackson Andrew P,Crow Yanick J Human mutation Aicardi-Goutières syndrome is an inflammatory disorder resulting from mutations in TREX1, RNASEH2A/2B/2C, SAMHD1, or ADAR1. Here, we provide molecular, biochemical, and cellular evidence for the pathogenicity of two synonymous variants in RNASEH2A. Firstly, the c.69G>A (p.Val23Val) mutation causes the formation of a splice donor site within exon 1, resulting in an out of frame deletion at the end of exon 1, leading to reduced RNase H2 protein levels. The second mutation, c.75C>T (p.Arg25Arg), also introduces a splice donor site within exon 1, and the internal deletion of 18 amino acids. The truncated protein still forms a heterotrimeric RNase H2 complex, but lacks catalytic activity. However, as a likely result of leaky splicing, a small amount of full-length active protein is apparently produced in an individual homozygous for this mutation. Recognition of the disease causing status of these variants allows for diagnostic testing in relevant families. 10.1002/humu.22336
    Gene Co-Expression Analysis of Human Reveals Functional Networks Associated with DNA Replication, DNA Damage Response, and Cell Cycle Regulation. Biology Ribonuclease (RNase) H2 is a key enzyme for the removal of RNA found in DNA-RNA hybrids, playing a fundamental role in biological processes such as DNA replication, telomere maintenance, and DNA damage repair. RNase H2 is a trimer composed of three subunits, being the catalytic subunit. expression levels have been shown to be upregulated in transformed and cancer cells. In this study, we used a bioinformatics approach to identify co-expressed genes in different human tissues to underscore biological processes associated with expression. Our analysis shows functional networks for involvement such as DNA replication and DNA damage response and a novel putative functional network of cell cycle regulation. Further bioinformatics investigation showed increased gene expression in different types of actively cycling cells and tissues, particularly in several cancers, supporting a biological role for but not for the other two subunits of RNase H2 in cell proliferation. Mass spectrometry analysis of -bound proteins identified players functioning in cell cycle regulation. Additional bioinformatic analysis showed that correlates with cancer progression and cell cycle related genes in Cancer Cell Line Encyclopedia (CCLE) and The Cancer Genome Atlas (TCGA) Pan Cancer datasets and supported our mass spectrometry findings. 10.3390/biology10030221
    Development of a neurologic severity scale for Aicardi Goutières Syndrome. Molecular genetics and metabolism BACKGROUND AND PURPOSE:Aicardi Goutières Syndrome (AGS) is a severe, autoinflammatory leukodystrophy characterized by global neurologic dysfunction. Our goal was to create an easy-to-apply scale relevant to the unique developmental challenges associated with AGS. METHODS:All individuals were recruited through our natural history study. Individuals were classified by AGS severity as mild, moderate, or severe, and clinical encounters were assigned a composite score for neurologic function calculated from the sum of three functional classification scales. Through expert consensus, we identified 11 key items to reflect the severity of AGS across gross motor, fine motor, and cognitive skills to create the AGS Scale. There was strong interrater reliability. The AGS scale was applied across available medical records to evaluate neurologic function over time. The AGS scale was compared to performance on a standard measure of gross motor function (Gross Motor Function Measure-88, GMFM-88) and a putative diagnostic biomarker of disease, the interferon signaling gene expression score (ISG). RESULTS:The AGS scale score correlated with severity classifications and the composite neurologic function scores. When retrospectively applied across our natural history study, the majority of individuals demonstrated an initial decline in function followed by stable scores. Within the first 6 months of disease, the AGS score was the most dynamic. The AGS scale correlated with performance by the GMFM-88, but did not correlate with ISG levels. CONCLUSIONS:This study demonstrates the utility of the AGS scale as a multimodal tool for the assessment of neurologic function in AGS. The AGS scale correlates with clinical severity and with a more labor-intensive tool, GMFM-88. This study underscores the limitations of the ISG score as a marker of disease severity. With the AGS scale, we found that AGS neurologic severity is the most dynamic early in disease. This novel AGS scale is a promising tool to longitudinally follow neurologic function in this unique population. 10.1016/j.ymgme.2020.03.008
    Phenotypic variation in Aicardi-Goutières syndrome explained by cell-specific IFN-stimulated gene response and cytokine release. Cuadrado Eloy,Michailidou Iliana,van Bodegraven Emma J,Jansen Machiel H,Sluijs Jacqueline A,Geerts Dirk,Couraud Pierre-Olivier,De Filippis Lidia,Vescovi Angelo L,Kuijpers Taco W,Hol Elly M Journal of immunology (Baltimore, Md. : 1950) Aicardi-Goutières syndrome (AGS) is a monogenic inflammatory encephalopathy caused by mutations in TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR1, or MDA5. Mutations in those genes affect normal RNA/DNA intracellular metabolism and detection, triggering an autoimmune response with an increase in cerebral IFN-α production by astrocytes. Microangiopathy and vascular disease also contribute to the neuropathology in AGS. In this study, we report that AGS gene silencing of TREX1, SAMHD1, RNASEH2A, and ADAR1 by short hairpin RNAs in human neural stem cell-derived astrocytes, human primary astrocytes, and brain-derived endothelial cells leads to an antiviral status of these cells compared with nontarget short hairpin RNA-treated cells. We observed a distinct activation of the IFN-stimulated gene signature with a substantial increase in the release of proinflammatory cytokines (IL-6) and chemokines (CXCL10 and CCL5). A differential impact of AGS gene silencing was noted; silencing TREX1 gave rise to the most dramatic in both cell types. Our findings fit well with the observation that patients carrying mutations in TREX1 experience an earlier onset and fatal outcome. We provide in the present study, to our knowledge for the first time, insight into how astrocytic and endothelial activation of antiviral status may differentially lead to cerebral pathology, suggesting a rational link between proinflammatory mediators and disease severity in AGS. 10.4049/jimmunol.1401334
    Aicardi-Goutières syndrome with muscle involvement in early infancy. Deigendesch N,Morales-Gonzalez S,Weschke B,Goebel H-H,Schuelke M,Stenzel W Neuropathology and applied neurobiology 10.1111/nan.12454
    Neuroradiologic patterns and novel imaging findings in Aicardi-Goutières syndrome. La Piana Roberta,Uggetti Carla,Roncarolo Federico,Vanderver Adeline,Olivieri Ivana,Tonduti Davide,Helman Guy,Balottin Umberto,Fazzi Elisa,Crow Yanick J,Livingston John,Orcesi Simona Neurology OBJECTIVE:To perform an updated characterization of the neuroradiologic features of Aicardi-Goutières syndrome (AGS). METHODS:The neuroradiologic data of 121 subjects with AGS were collected. The CT and MRI data were analyzed with a systematic approach. Moreover, we evaluated if an association exists between the neuroradiologic findings, clinical features, and genotype. RESULTS:Brain calcifications were present in 110 subjects (90.9%). Severe calcification was associated with TREX1 mutations and early age at onset. Cerebral atrophy was documented in 111 subjects (91.8%). Leukoencephalopathy was present in 120 children (99.2%), with 3 main patterns: frontotemporal, diffuse, and periventricular. White matter rarefaction was found in 54 subjects (50.0%), strongly associated with mutations in TREX1 and an early age at onset. Other novel radiologic features were identified: deep white matter cysts, associated with TREX1 mutations, and delayed myelination, associated with RNASEH2B mutations and early age at onset. CONCLUSIONS:We demonstrate that the AGS neuroradiologic phenotype is expanding by adding new patterns and findings to the classic criteria. The heterogeneity of neuroradiologic patterns is partly explained by the timing of the disease onset and reflects the complexity of the pathogenic mechanisms. 10.1212/WNL.0000000000002228
    Early-Onset Aicardi-Goutières Syndrome: Magnetic Resonance Imaging (MRI) Pattern Recognition. Vanderver Adeline,Prust Morgan,Kadom Nadja,Demarest Scott,Crow Yanick J,Helman Guy,Orcesi Simona,La Piana Roberta,Uggetti Carla,Wang Jichuan,Gordisch-Dressman Heather,van der Knaap Marjo S,Livingston John H Journal of child neurology Aicardi-Goutières syndrome is an inherited leukodystrophy with calcifying microangiopathy and abnormal central nervous system myelination. As fewer diagnostic computed tomographic (CT) scans are being performed due to increased availability of magnetic resonance imaging (MRI), there is a potential for missed diagnoses on the basis of calcifications. We review a series of patients with MRIs selected from IRB-approved leukodystrophy biorepositories to identify MRI patterns for recognition of early-onset Aicardi-Goutières syndrome and scored for a panel of radiologic predictors. Each individual predictor was tested against disease status using exact logistic regression. Features for pattern recognition of Aicardi-Goutières syndrome are temporal lobe swelling followed by atrophy with temporal horn dilatation, early global cerebral atrophy and visible calcifications, as evidenced by 94.44% of cases of Aicardi-Goutières syndrome correctly classified with a sensitivity of 90.9% and specificity of 96.9%. We identify a panel of MRI features predictive of Aicardi-Goutières syndrome in young patients that would differentiate it from other leukoencephalopathies. 10.1177/0883073814562252
    Astrocytes, an active player in Aicardi-Goutières syndrome. Sase Sunetra,Takanohashi Asako,Vanderver Adeline,Almad Akshata Brain pathology (Zurich, Switzerland) Aicardi-Goutières syndrome (AGS) is an early-onset, autoimmune and genetically heterogeneous disorder with severe neurologic injury. Molecular studies have established that autosomal recessive mutations in one of the following genes are causative: TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR1 and IFIH1/MDA5. The phenotypic presentation and pathophysiology of AGS is associated with over-production of the cytokine Interferon-alpha (IFN-α) and its downstream signaling, characterized as type I interferonopathy. Astrocytes are one of the major source of IFN in the central nervous system (CNS) and it is proposed that they could be key players in AGS pathology. Astrocytes are the most ubiquitous glial cell in the CNS and perform a number of crucial and complex functions ranging from formation of blood-brain barrier, maintaining ionic homeostasis, metabolic support to synapse formation and elimination in healthy CNS. Involvement of astrocytic dysfunction in neurological diseases-Alexander's disease, Epilepsy, Alzheimer's and amyotrophic lateral sclerosis (ALS)-has been well-established. It is now known that compromised astrocytic function can contribute to CNS abnormalities and severe neurodegeneration, nevertheless, its contribution in AGS is unclear. The current review discusses known molecular and cellular pathways for AGS mutations and how it stimulates IFN-α signaling. We shed light on how astrocytes might be key players in the phenotypic presentations of AGS and emphasize the cell-autonomous and non-cell-autonomous role of astrocytes. Understanding the contribution of astrocytes will help reveal mechanisms underlying interferonopathy and develop targeted astrocyte specific therapeutic treatments in AGS. 10.1111/bpa.12600
    Spontaneous MRI improvement and absence of cerebral calcification in Aicardi-Goutières syndrome: Diagnostic and disease-monitoring implications. Tonduti Davide,Izzo Giana,D'Arrigo Stefano,Riva Daria,Moroni Isabella,Zorzi Giovanna,Cavallera Vanessa,Pichiecchio Anna,Uggetti Carla,Veggiotti Pierangelo,Orcesi Simona,Chiapparini Luisa,Parazzini Cecilia Molecular genetics and metabolism BACKGROUND:Aicardi-Goutières syndrome (AGS) is a rare genetic leukoencephalopathy related to inappropriate activation of type I interferon. Neuroradiological findings are typically characterized by white matter abnormalities, cerebral atrophy and cerebral calcification. The disease usually manifests itself during the first year of life in the form of an initial "encephalitic-like" phase followed by a chronic phase of stabilization of the neurological signs. Recently new therapeutic strategies have been proposed aimed at blocking the abnormal activation of the interferon cascade. MATERIALS AND METHODS:We reviewed clinical and MRI findings in three young RNASEH2B-mutated patients studied with serial CT and MRI studies. RESULTS:All three patients presented clinical and MRI features consistent with AGS but, very unexpectedly, an improving neuroradiological course. In patient 1, the MRI improvement was noted some months after treatment with high-dose steroid and IVIg treatment; in patients 2 and 3 it occurred spontaneously. Patient 2 did not show cerebral calcification on CT images. CONCLUSIONS:Our series highlights the possibility of spontaneous neuroradiological improvement in AGS2 patients, as well as the possibility of absence of cerebral calcification in AGS. The study underlines the need for extreme caution when using MRI as an outcome measure in therapeutic trials specific for this disease. MRI follow-up studies in larger series are necessary to describe the natural course of AGS. 10.1016/j.ymgme.2019.02.006
    Multiple Autoimmune Disorders in Aicardi-Goutières Syndrome. Samanta Debopam,Ramakrishnaiah Raghu,Crary Shelley E,Sukumaran Sukesh,Burrow Thomas A Pediatric neurology BACKGROUND:Aicardi-Goutières syndrome is an early-onset encephalopathy with presumed immune pathogenesis caused by inherited defects in nucleic acid metabolism. It is a model disease to study systemic autoimmunity, and there are many clinical, genetic, and basic science considerations that underline a possible overlap between Aicardi-Goutières syndrome and systemic lupus erythematosus. RESULTS:We describe a 15-year-old girl with Aicardi-Goutières syndrome due to compound heterozygous pathogenic variants in SAMHD1 (sterile alpha motif domain and HD domain-containing protein 1). Over time, she developed multiple autoimmune diseases (vitiligo, alopecia areata, immune thrombocytopenia, positive antithyroglobulin antibodies) without positive antinuclear antibody or features of systemic lupus erythematosus. Her thrombocytopenia was refractory to treatment with corticosteroids and intravenous immunoglobulin but responded to a standard course of rituximab. CONCLUSION:This is the first report of a multiple autoimmune syndrome in a patient with molecularly proven Aicardi-Goutières syndrome. This study illustrates an emerging pattern of the natural history of Aicardi-Goutières syndrome characterized by early encephalopathic presentation followed by symptoms of systemic autoimmunity. 10.1016/j.pediatrneurol.2019.01.017
    Neuropathological Findings in a Case of -Related Aicardi-Goutières Syndrome. Gilani Ahmed,Adang Laura A,Vanderver Adeline,Collins Abigail,Kleinschmidt-DeMasters B K Pediatric and developmental pathology : the official journal of the Society for Pediatric Pathology and the Paediatric Pathology Society Aicardi-Goutières syndrome (AGS) is a rare syndrome characterized by calcification, diffuse demyelination, and variable degree of brain atrophy. The syndrome is genetically heterogeneous with mutations in 7 genes, including , , , , , , and (interferon-induced helicase c domain-containing protein 1) associated with the syndrome, so far. These mutations lead to the overproduction of α-interferon within the central nervous system. Mutations in have been recently described in a subset of AGS, with only 1 previous report of neuropathological findings. We report neuropathological findings in a second case of AGS with a known mutation in gene. The patient is a 16-year-old adolescent boy with early-onset symptoms that progressed to profound loss of cognitive and motor functions. The patient experienced sudden cardiopulmonary arrest at the age of 16 years. At autopsy, the cause of death was determined to be pulmonary thromboembolism. Neuropathological examination revealed microcephaly (brain weight: 916 g) with relatively mild brain atrophy on gross examination. Microscopic examination revealed multifocal calcifications limited to small to medium central nervous system arteries (no evidence of calcification in other organs), involving bilateral cerebral cortex, basal ganglia, thalamus, and cerebellum. Ultrastructural examination showed Calcospherules limited to the vessel walls and the perivasulcar area without evidence of neuronal ferrugination or tubuloreticular bodies. The extent of calcifications was variable across different brain regions, resembling findings in previously reported cases and correlated with the extent of IFIH1 protein expression (data derived from Allen Brain Institute). AGS is a rare cause of brain calcifications that can closely mimic congenital and neonatal infections such as Rubella and similar infections. 10.1177/1093526619837797
    [Aicardi-Goutieres syndrome: a family case due to alteration of the RNASEH2B gene]. Viguera-Elías D,de la Iglesia-Nagore I,Toledo-Gotor C,Domínguez-Garrido E,Poch-Olivé M L Revista de neurologia INTRODUCTION:Aicardi-Goutieres syndrome is a progressive encephalopathy with onset in the first year of life that conditions psychomotor retardation, microcephaly and pyramidal dysfunction. It has a prevalence of 1-5 in 10,000 newly live births. Most cases have autosomal recessive transmission, due to alteration in seven genes involved in the metabolism of interferon, which causes an increase in its levels in the blood and cerebrospinal fluid, and affects the brain (leukodystrophy, corticosubcortical atrophy, calcifications in the basal ganglia…), the skin and the immune system. CLINICAL CASE:They are two brothers who present the homozygous p.Ala177Thr variant in the RNASEH2B gene; both of them parents, consanguineous, are carriers. The first sibling started at 10 months with axial hypotonia, hypertonia of the extremities, psychomotor regression and dystonic movements. The second brother presented from the birth low axial tone with hypertonia of the extremities, at 4 months calcifications were found in the nuclei lenticulostriated by transfontalar ultrasound and, at 6 months, she started dystonic movements and intermittent nystagmus. Both have developed spastic tetraparesis and remain stable at 8 and 10 years, despite complications typical of the syndrome. CONCLUSIONS:The Aicardi-Goutieres syndrome is a rare entity that should be taken into account in situations that occur with altered psychomotor development and intracranial calcifications; we highlight the importance of diagnosis both to know the prognosis of our patients based on their genetic alteration and to offer genetic counseling to their families. 10.33588/rn.7211.2021071
    Phenotypic variability of a TREX1 variant in Aicardi-Goutieres type 1 patients from the Indian subcontinent. Abraham Suneetha Susan Cleave,Yoganathan Sangeetha,Koshy Beena,Oommen Samuel Philip,Simon Anna,Mathai Sarah,Korula Sophy,Mathew Lydia,Sathishkumar Dharshini,Jasper Anitha,George Renu,Danda Sumita European journal of medical genetics Aicardi-Goutieres Syndrome (AGS) is a heterogeneous genetic syndrome, manifesting early as encephalopathy and is associated with abnormal neurologic findings, hepatosplenomegaly, elevated liver enzymes, thrombocytopenia and intracranial calcification. The most severe neonatal type, AGS1, is caused by biallelic disease-causing variants in TREX1. In this study, we describe four patients with TREX1-related AGS1 whose phenotype overlaps with intra-uterine infections and neonatal lupus. Exome sequencing identified a previously reported TREX1 variant, c.223dup (NM_016381.5; p. Glu75GlyfsTer82) in all the four patients belonging to the Indian subcontinent. The functional consequence of the disease-causing variant was predicted by using a new combination of bioinformatics softwares. The recurrence of this pathogenic variant indicates a possible founder effect in TREX1 for AGS1 in this population. The phenotypic variability in those with this founder mutation can mimic intrauterine infections and neonatal lupus, thereby leading to misdiagnosis warranting a targeted genetic testing approach to be a part of the diagnostic workup to obtain a definite, early and cost-effective diagnosis in patients from Indian subcontinent with early onset encephalopathy. 10.1016/j.ejmg.2021.104291
    Intracerebral large artery disease in Aicardi-Goutières syndrome with TREX1 mutation: a case report. Wu Chang-Chun,Peng Steven Shinn-Forng,Lee Wang-Tso Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology We report a patient diagnosed with Aicardi-Goutières syndrome (AGS) with homozygous TREX1 gene mutation. Her magnetic resonance angiography (MRA) showed intracerebral large artery disease, which was rarely reported in the past in TREX1 AGS patients. Her younger sister also had homozygous TREX1 gene mutation and died of necrotizing enterocolitis. Intracerebral large artery involvement has been seen as a particular feature of SAMHD1-related disease. Our patient also had arthropathy, which is a finding more commonly mentioned in SAMHD1-related diseases. The observations in our case may contribute to our understanding of the pathogenetic mechanism of TREX1 AGS, involving the intracerebral large arteries, arthropathy, and possibly the gastrointestinal tract. 10.1007/s10072-020-04516-0
    Opsoclonus-myoclonus in Aicardi-Goutières syndrome. Alburaiky Salam,Dale Russell C,Crow Yanick J,Jones Hannah F,Wassmer Evangeline,Melki Isabelle,Boespflug-Tanguy Odile,Do Cao Jeremy,Gras Domitille,Sharpe Cynthia Developmental medicine and child neurology Aicardi-Goutières syndrome (AGS) is a rare genetic neuroinflammatory disorder caused by abnormal upregulation of type 1 interferon signalling. Opsoclonus-myoclonus syndrome is a rare autoimmune phenotype demonstrating a disturbance in the humoral immune response mostly seen in the context of paraneoplastic or postinfectious states, although its pathophysiology is incompletely understood. We report the first three children described with AGS demonstrating transient opsoclonus and myoclonus after irritability and/or developmental regression, suggesting a pathological association. We describe the presentation, clinical features, progress, cerebrospinal fluid (CSF) inflammatory markers, electroencephalogram (EEG), and magnetic resonance imaging (MRI) findings in these children. Two patients had developmental regression but demonstrated a positive response to JAK1/2 inhibition clinically and on serial examination of CSF inflammatory markers. These findings suggest that AGS should be considered in children presenting with opsoclonus-myoclonus, and that the association between AGS and opsoclonus-myoclonus further supports the role of immune dysregulation as causal in the rare neurological phenomenon opsoclonus and myoclonus. What this paper adds There is a phenotypic association between opsoclonus-myoclonus syndrome and Aicardi-Goutières syndrome. There is clinical evidence of immune dysregulation in the pathogenesis of opsoclonus and myoclonus. 10.1111/dmcn.14969
    PNPT1 mutations may cause Aicardi-Goutières-Syndrome. Bamborschke Daniel,Kreutzer Mona,Koy Anne,Koerber Friederike,Lucas Nadja,Huenseler Christoph,Herkenrath Peter,Lee-Kirsch Min Ae,Cirak Sebahattin Brain & development BACKGROUND:Aicardi-Goutières syndrome (AGS) is a clinically and genetically heterogenous autoinflammatory disorder caused by constitutive activation of the type I interferon axis. It has been associated with the genes TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR1, IFIH1. The clinical diagnosis of AGS is usually made in the context of early-onset encephalopathy in combination with basal ganglia calcification or white matter abnormalities on cranial MRI and laboratory prove of interferon I activation. CASE PRESENTATION:We report a patient with early-onset encephalopathy, severe neurodevelopmental regression, progressive secondary microcephaly, epilepsy, movement disorder, and white matter hyperintensities on T2 weighted MRI images. Via whole-exome sequencing, we identified a novel homozygous missense variant (c.1399C > T, p.Pro467Ser) in PNPT1 (NM_033109). Longitudinal assessment of the interferon signature showed a massively elevated interferon score and chronic type I interferon-mediated autoinflammation. CONCLUSION:Bi-allelic mutations in PNPT1 have been reported in early-onset encephalopathy. Insufficient nuclear RNA import into mitochondria with consecutive disruption of the respiratory chain was proposed as the main underlying pathomechanism. Recent studies have shown that PNPT1 deficiency causes an accumulation of double-stranded mtRNAs in the cytoplasm, leading to aberrant type I interferon activation, however, longitudinal assessment has been lacking. Here, we present a case of AGS with continuously elevated type I interferon signature with a novel likely-pathogenic homozygous PNTP1 variant. We highlight the clinical value of assessing the interferon signature in children with encephalopathy of unknown origin and suggest all patients presenting with a phenotype of AGS should be screened for mutations in PNPT1. 10.1016/j.braindev.2020.10.005
    Late-Onset Aicardi-Goutières Syndrome: A Characterization of Presenting Clinical Features. Piccoli Cara,Bronner Nowa,Gavazzi Francesco,Dubbs Holly,De Simone Micaela,De Giorgis Valentina,Orcesi Simona,Fazzi Elisa,Galli Jessica,Masnada Silvia,Tonduti Davide,Varesio Costanza,Vanderver Adeline,Vossough Arastoo,Adang Laura Pediatric neurology BACKGROUND:Aicardi-Goutières syndrome (AGS) is a genetic interferonopathy characterized by early onset of severe neurological injury with intracranial calcifications, leukoencephalopathy, and systemic inflammation. Increasingly, a spectrum of neurological dysfunction and presentation beyond the infantile period is being recognized in AGS. The aim of this study was to characterize late-infantile and juvenile-onset AGS. METHODS:We conducted a multi-institution review of individuals with AGS who were older than one year at the time of presentation, including medical history, imaging characteristics, and suspected diagnoses at presentation. RESULTS:Thirty-four individuals were identified, all with pathogenic variants in RNASEH2B, SAMHD1, ADAR1, or IFIH1. Most individuals had a history of developmental delay and/or systemic symptoms, such as sterile pyrexias and chilblains, followed by a prodromal period associated with increasing symptoms. This was followed by an abrupt onset of neurological decline (fulminant phase), with a median onset at 1.33 years (range 1.00 to 17.68 years). Most individuals presented with a change in gross motor skills (97.0%), typically with increased tone (78.8%). Leukodystrophy was the most common magnetic resonance imaging finding (40.0%). Calcifications were less common (12.9%). CONCLUSIONS:This is the first study to characterize the presentation of late-infantile and juvenile onset AGS and its phenotypic spectrum. Late-onset AGS can present insidiously and lacks classical clinical and neuroimaging findings. Signs of early systemic dysfunction before fulminant disease onset and loss of motor symptoms were common. We strongly recommend genetic testing when there is concern for sustained inflammation of unknown origins or changes in motor skills in children older than one year. 10.1016/j.pediatrneurol.2020.10.012
    Case Report: Novel Compound Heterozygous Mutations Cause Aicardi-Goutières Syndrome. Garau Jessica,Masnada Silvia,Dragoni Francesca,Sproviero Daisy,Fogolari Federico,Gagliardi Stella,Izzo Giana,Varesio Costanza,Orcesi Simona,Veggiotti Pierangelo,Zuccotti Gian Vincenzo,Pansarasa Orietta,Tonduti Davide,Cereda Cristina Frontiers in immunology Aicardi-Goutières Syndrome (AGS) is a rare disorder characterized by neurological and immunological signs. In this study we have described a child with a phenotype consistent with AGS carrying a novel compound heterozygous mutation in gene. Next Generation Sequencing revealed two heterozygous variants in gene. We also highlighted a reduction of RNase H2B transcript and protein levels in all the family members. Lower protein levels of RNase H2A have been observed in all the members of the family as well, whereas a deep depletion of RNase H2C has only been identified in the affected child. The structural analysis showed that both mutations remove many intramolecular contacts, possibly introducing conformational rearrangements with a decrease of the stability of RNase H2B and strongly destabilizing the RNase H2 complex. Taken together, these results highlight the importance of an integrated diagnostic approach which takes into consideration clinical, genetic, and molecular analyses. 10.3389/fimmu.2021.672952
    Case Report: Aicardi-Goutières Syndrome and Singleton-Merten Syndrome Caused by a Gain-of-Function Mutation in IFIH1. Xiao Wei,Feng Jie,Long Hongyu,Xiao Bo,Luo Zhaohui H Frontiers in genetics The gene encodes melanoma differentiation-associated gene 5 (MDA5) and has been associated with Aicardi-Goutières syndrome (AGS), Singleton-Merten syndrome (SMS), and other autoimmune diseases. The mechanisms responsible for how a functional change in a single gene can cause so many different phenotypes remain unknown. Moreover, there is significant controversy as to whether these distinct phenotypes represent the same disease continuum or mutation-specific disorders. Here, we describe the case of a patient with a novel c.1465G > T (p.Ala489Ser) mutation in the gene. The patient presented with spastic paraplegia, dystonia, psychomotor retardation, joint deformities, intracranial calcification, abnormal dentition, characteristic facial features, lymphadenopathy, and autoimmunity. His phenotype appeared to represent an overlap of the phenotypes for AGS and SMS. The patient also experienced unexplained pancytopenia, suggesting that the hemic system may have been affected by a gain-of-function mutation in the gene. In summary, we provide further evidence that SMS and AGS exhibit the same disease spectrum following a gain-of-function mutation in the gene. Our data highlight the genetic heterogeneity of these conditions and expand our knowledge of differential phenotypes created by gain-of-function mutation. 10.3389/fgene.2021.660953
    Case Report: Aicardi-Goutières Syndrome Caused by Novel TREX1 Variants. Wu De,Fang Liwei,Huang Ting,Ying Songcheng Frontiers in pediatrics TREX1 (three prime repair exonuclease 1) gene encodes DNA 3' end repair exonuclease that plays an important role in DNA repair. Mutations in TREX1 gene have been identified as the cause of a rare autoimmune neurological disease, Aicardi-Goutières syndrome (AGS). Here, we report an AGS case of a 6-month-old Chinese girl with novel TREX1 variants. The patient had mild rashes on the face and legs, increased muscle tensions in the limbs, and positive cervical correction reflex. Cranial magnetic resonance imaging showed that there were patches of slightly longer T1 and T2 signals in the bilateral cerebral hemisphere and brainstem white matter, mainly in the frontotemporal lobe, together with decreased white matter volume, enlarged ventricles, and widened sulcus fissure. Total exon sequencing showed that the TREX1 gene of the child had mutations of c.137_138insC and c.292_293insA, which had not been reported before. In addition, elevated type I interferons were detected by using enzyme-linked immunosorbent assay in the patient's serum. Together, our study demonstrated that novel TREX1 variants (c.137_138insC and c.292_293insA) cause AGS for the first time. 10.3389/fped.2021.634281
    Ruxolitinib in Aicardi-Goutières syndrome. Mura Eleonora,Masnada Silvia,Antonello Clara,Parazzini Cecilia,Izzo Giana,Garau Jessica,Sproviero Daisy,Cereda Cristina,Orcesi Simona,Veggiotti Pierangelo,Zuccotti Gianvincenzo,Dilillo Dario,Penagini Francesca,Tonduti Davide Metabolic brain disease Aicardi-Goutières Syndrome (AGS) is a monogenic leukodystrophy with pediatric onset, clinically characterized by a variable degree of neurologic impairment. It belongs to a group of condition called type I interferonopathies that are characterized by abnormal overproduction of interferon alpha, an inflammatory cytokine which action is mediated by the activation of two of the four human Janus Kinases. Thanks to an ever-increasing knowledge of the molecular basis and pathogenetic mechanisms of the disease, Janus Kinase inhibitors (JAKIs) have been proposed as a treatment option for selected interferonopathies. Here we reported the 24 months follow-up of the fifth AGS patient treated with ruxolitinib described so far in literature. The treatment was globally well tolerated; clinical examinations and radiological images demonstrated a progressively improving course. It is however to note that patients presenting with mild and spontaneously improving course have been reported. Large natural history studies on AGS spectrum are strongly required in order to get a better understanding of the results emerging from ongoing therapeutic trials on such rare disease. 10.1007/s11011-021-00716-5
    Aicardi-Goutières syndrome may present with positive newborn screen for X-linked adrenoleukodystrophy. Tise Christina G,Morales Jose Andres,Lee Ariel S,Velez-Bartolomei Frances,Floyd Brendan J,Levy Rebecca J,Cusmano-Ozog Kristina P,Feigenbaum Annette S,Ruzhnikov Maura R Z,Lee Chung U,Enns Gregory M American journal of medical genetics. Part A We report three unrelated probands, two male and one female, diagnosed with Aicardi-Goutières syndrome (AGS) after screening positive on California newborn screening (CA NBS) for X-linked adrenoleukodystrophy (X-ALD) due to elevated C26:0 lysophosphatidylcholine (C26:0-LPC). Follow-up evaluation was notable for elevated C26:0, C26:1, and C26:0/C22:0 ratio, and normal red blood cell plasmalogens levels in all three probands. Diagnoses were confirmed by molecular sequencing prior to 12 months of age after clinical evaluation was inconsistent with X-ALD or suggestive of AGS. For at least one proband, the early diagnosis of AGS enabled candidacy for enrollment into a therapeutic clinical trial. This report demonstrates the importance of including AGS on the differential diagnosis for individuals who screen positive for X-ALD, particularly infants with abnormal neurological features, as this age of onset would be highly unusual for X-ALD. While AGS is not included on the Recommended Universal Screening Panel, affected individuals can be identified early through state NBS programs so long as providers are aware of a broader differential that includes AGS. This report is timely, as state NBS algorithms for X-ALD are actively being established, implemented, and refined. 10.1002/ajmg.a.62160
    Computational Insights into the Structural Dynamics of MDA5 Variants Associated with Aicardi-Goutières Syndrome and Singleton-Merten Syndrome. Gosu Vijayakumar,Sasidharan Santanu,Saudagar Prakash,Lee Hak-Kyo,Shin Donghyun Biomolecules Melanoma differentiation-associated protein 5 (MDA5) is a crucial RIG-I-like receptor RNA helicase enzyme encoded by in humans. Single nucleotide polymorphisms in the results in fatal genetic disorders such as Aicardi-Goutières syndrome and Singleton-Merten syndrome, and in increased risk of type I diabetes in humans. In this study, we chose four different amino acid substitutions of the MDA5 protein responsible for genetic disorders: MDA5, MDA5, MDA5, and MDA5 and analyzed their structural and functional relationships using molecular dynamic simulations. Our results suggest that the mutated complexes are relatively more stable than the wild-type MDA5. The radius of gyration, interaction energies, and intra-hydrogen bond analysis indicated the stability of mutated complexes over the wild type, especially MDA5 and MDA5. The dominant motions exhibited by the wild-type and mutant complexes varied significantly. Moreover, the betweenness centrality of the wild-type and mutant complexes showed shared residues for intra-signal propagation. The observed results indicate that the mutations lead to a gain of function, as reported in previous studies, due to increased interaction energies and stability between RNA and MDA5 in mutated complexes. These findings are expected to deepen our understanding of MDA5 variants and may assist in the development of relevant therapeutics against the disorders. 10.3390/biom11081251
    Case Report: The JAK-Inhibitor Ruxolitinib Use in Aicardi-Goutieres Syndrome Due to Mutation. Cattalini Marco,Galli Jessica,Zunica Fiammetta,Ferraro Rosalba Monica,Carpanelli Marialuisa,Orcesi Simona,Palumbo Giovanni,Pinelli Lorenzo,Giliani Silvia,Fazzi Elisa,Badolato Raffaele Frontiers in pediatrics Type I Interferonopathies comprise inherited inflammatory diseases associated with perturbation of the type I IFN response. Use of kinase (JAK) inhibitors has been recently reported as possible tools for treating some of those rare diseases. We describe herein the clinical picture and treatment response to the JAK-inhibitor ruxolitinib in a 5-year-old girl affected by Aicardi-Goutières Syndrome type 6 (AGS6) due to mutation. The girl's interferon score (IS) was compared with that of her older brother, suffering from the same disorder, who was not treated. We observed a limited, but distinct neurological improvement (Gross Motor Function and Griffiths Mental Development Scales). Analysis of IS values of the two siblings during the treatment showed several changes, especially related to infections; the IS values of the child treated with ruxolitinib were consistently lower than those measured in her brother. Based on these observations we suggest that the use of ruxolitinib in children with the same condition might be effective in inhibiting type I interferon response and that starting this therapy at early age in children with AGS could mitigate the detrimental effects of type I interferon hyperproduction. 10.3389/fped.2021.725868
    Severe diarrhea in a 10-year-old girl with Aicardi-Goutières syndrome due to IFIH1 gene mutation. Lu Meiping,Zhu Kun,Zheng Qi,Ma Xiaohui,Zou Lixia American journal of medical genetics. Part A Interferon-induced with helicase C domain 1 (IFIH1) is a cytosolic sensor of dsRNA that induces an anti-viral Type I interferon (IFN) state. A gain-of-function mutation in IFIH1 can cause increased Type I IFN activity and is clinically associated with Aicardi-Goutières syndrome (AGS). AGS is a multisystem disease, characterized as an early-onset progressive encephalopathy with basal ganglia calcification and systemic lupus erythematosus-like features. Gastrointestinal manifestation is rare in AGS patients. We described a 10-year-old female patient with a heterozygous IFIH1 gene mutation who presented with gastrointestinal colitis, cystitis and very severe diarrhea as initial major manifestations of AGS. Proteinuria with high titer of antinuclear antibody and anti-double-stranded DNA was found in this patient. She also had growth retardation and a history of seizures (about two episodes each year) but without attacks until 7 years old. Serum cytokines detected by flow cytometry indicated extremely high level of interleukin 6 (1970.1 pg/ml) and IFN-α (204.1 pg/ml). A contrast-enhanced CT scan of the whole abdomen and an intestinal hydro-MRI indicated that the walls of her stomach, small bowel, colon, and bladder were in various degrees of edema and thickened states. Whole exome sequencing analysis indicated that she harbors an IFIH1 heterozygous mutation (c.2336G > A (p.R779H)) in both blood and intestinal samples. Abundant inflammatory cells infiltration into the intestinal epithelium was observed by immunohistochemical staining. Positive staining of caspase 4 and caspase 5 suggested that the signaling pathway of pyroptosis was involved in the mechanism of intestinal inflammation in AGS. Diarrhea was significantly improved after steroids and intravenous immunoglobulin treatments. Gastrointestinal colitis and cystitis can be rare manifestations of AGS with IFIH1 mutation. Caspase and its related inflammasome pathway may involve in the pathogenesis of AGS. 10.1002/ajmg.a.62397