The Experts below are selected from a list of 360 Experts worldwide ranked by ideXlab platform
Yanick J Crow - One of the best experts on this subject based on the ideXlab platform.
-
cerebrospinal fluid neopterin as a biomarker of treatment response to janus kinase inhibition in Aicardi Goutieres Syndrome
Developmental Medicine & Child Neurology, 2021Co-Authors: Yanick J Crow, Russell C Dale, Hannah F Jones, Velda X Han, Shekeeb S Mohammad, Sushil BandodkarAbstract:Janus kinase (JAK) 1 inhibition represents a precision medicine approach in the treatment of Aicardi-Goutieres Syndrome (AGS), through targeting of type I interferon-mediated cell signalling. Blood interferon mRNAseq has been proposed as a biomarker of disease with utility in therapeutic monitoring. Objective cerebrospinal fluid (CSF) biomarkers tracking treatment efficacy are currently lacking. Here, we report a retrospective case series of 13 patients (median age 6y, range 2y 6mo-17y; five females, eight males) with AGS demonstrating significantly elevated CSF neopterin levels at first sampling (median 200nmol/L, range 45-2024nmol/L), compared to 13 age-matched controls with non-inflammatory neurological conditions (median 23nmol/L, range 5-34nmol/L, p<0.001). Five patients with AGS treated with JAK inhibitors demonstrated a median 81.5% reduction of CSF neopterin (range -36% to -88% change from baseline), compared to eight untreated patients with AGS demonstrating a median 7% reduction in CSF neopterin (range -63% to +117% change) (p=0.047). Our data indicate a biological effect of JAK inhibitors, and the potential role of CSF neopterin as a biomarker of treatment response.
-
opsoclonus myoclonus in Aicardi Goutieres Syndrome
Developmental Medicine & Child Neurology, 2021Co-Authors: Salam Alburaiky, Yanick J Crow, Russell C Dale, Hannah F Jones, Evangeline Wassmer, Isabelle Melki, Odile Boespflugtanguy, Jeremy Do Cao, Domitille GrasAbstract:Aicardi-Goutieres 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.
-
treatments in Aicardi Goutieres Syndrome
Developmental Medicine & Child Neurology, 2020Co-Authors: Jayakara Shetty, Yanick J Crow, John H LivingstonAbstract:Comprehensive reviews of the clinical characteristics and pathogenesis of Aicardi-Goutieres Syndrome (AGS), particularly its contextualization within a putative type I interferonopathy framework, already exist. However, recent reports of attempts at treatment suggest that an assessment of the field from a therapeutic perspective is warranted at this time. Here, we briefly summarize the neurological phenotypes associated with mutations in the seven genes so far associated with AGS, rehearse current knowledge of the pathology as it relates to possible treatment approaches, critically appraise the potential utility of therapies, and discuss the challenges in assessing clinical efficacy. WHAT THIS PAPER ADDS: Progress in understanding AGS disease pathogenesis has led to the first attempts at targeted treatment. Further rational therapies are expected to become available in the short- to medium-term.
-
neuroradiologic patterns and novel imaging findings in Aicardi Goutieres Syndrome
Neurology, 2016Co-Authors: Roberta La Piana, Adeline Vanderver, Guy Helman, Elisa Fazzi, Ivana Olivieri, Davide Tonduti, Umberto Balottin, C Uggetti, Federico Roncarolo, Yanick J CrowAbstract:Objective: To perform an updated characterization of the neuroradiologic features of Aicardi-Goutieres 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.
-
early onset Aicardi Goutieres Syndrome magnetic resonance imaging mri pattern recognition
Journal of Child Neurology, 2015Co-Authors: Adeline Vanderver, Morgan Prust, Scott Demarest, Simona Orcesi, Nadja Kadom, Roberta La Piana, Guy Helman, Yanick J Crow, Carla UggettiAbstract:Aicardi-Goutieres 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-Goutieres 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-Goutieres 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-Goutieres Syndrome correctly classified with a sensitivity of 90.9% and specificity of 96.9%. We identify a panel of MRI features predictive of Aicardi-Goutieres Syndrome in young patients that would differentiate it from other leukoencephalopathies.
Simona Orcesi - One of the best experts on this subject based on the ideXlab platform.
-
case report novel compound heterozygous rnaseh2b mutations cause Aicardi Goutieres Syndrome
Frontiers in Immunology, 2021Co-Authors: Jessica Garau, Simona Orcesi, Silvia Masnada, Giana Izzo, Daisy Sproviero, Francesca Dragoni, Federico Fogolari, Stella Gagliardi, Costanza Varesio, Pierangelo VeggiottiAbstract:Aicardi-Goutieres 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 RNASEH2B gene. Next Generation Sequencing revealed two heterozygous variants in RNASEH2B 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.
-
ruxolitinib in Aicardi Goutieres Syndrome
Metabolic Brain Disease, 2021Co-Authors: Eleonora Mura, Simona Orcesi, Silvia Masnada, Clara E Antonello, Cecilia Parazzini, Giana Izzo, Jessica Garau, Daisy Sproviero, Cristina Cereda, Pierangelo VeggiottiAbstract:Aicardi-Goutieres 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.
-
late onset Aicardi Goutieres Syndrome a characterization of presenting clinical features
Pediatric Neurology, 2021Co-Authors: Cara Piccoli, Simona Orcesi, Francesco Gavazzi, Micaela De Simone, Elisa Fazzi, Jessica Galli, Valentina De Giorgis, Nowa Bronner, Holly Dubbs, Silvia MasnadaAbstract:Abstract Background Aicardi-Goutieres 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.
-
novel and emerging treatments for Aicardi Goutieres Syndrome
Expert Review of Clinical Immunology, 2020Co-Authors: Davide Tonduti, Elisa Fazzi, Raffaele Badolato, Simona OrcesiAbstract:Introduction: Aicardi-Goutieres 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.Areas covered: 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.Expert opinion: 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.
-
developmental outcomes of Aicardi Goutieres Syndrome
Journal of Child Neurology, 2019Co-Authors: Laura Adang, Simona Orcesi, Francesco Gavazzi, Micaela De Simone, Elisa Fazzi, Jessica Galli, Jamie Koh, Julia Kramergolinkoff, Valentina De Giorgis, Kyle PeerAbstract:Aicardi Goutieres Syndrome is a monogenic interferonopathy caused by abnormalities in the intracellular nucleic acid sensing machinery (TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR1, or IFIH1). Most individuals affected by Aicardi Goutieres 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 Goutieres Syndrome. To characterize the clinical presentation in Aicardi Goutieres Syndrome, early features were collected from an international cohort of children (n = 100) with genetically confirmed Aicardi Goutieres 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 TREX1-related Aicardi Goutieres Syndrome secondary were the most severely affected and less likely to reach milestones, including head control, sitting, and nonspecific mama/dada. Individuals affected by SAMHD1, IFIH1, and ADAR 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 Goutieres 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.
Elisa Fazzi - One of the best experts on this subject based on the ideXlab platform.
-
late onset Aicardi Goutieres Syndrome a characterization of presenting clinical features
Pediatric Neurology, 2021Co-Authors: Cara Piccoli, Simona Orcesi, Francesco Gavazzi, Micaela De Simone, Elisa Fazzi, Jessica Galli, Valentina De Giorgis, Nowa Bronner, Holly Dubbs, Silvia MasnadaAbstract:Abstract Background Aicardi-Goutieres 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.
-
novel and emerging treatments for Aicardi Goutieres Syndrome
Expert Review of Clinical Immunology, 2020Co-Authors: Davide Tonduti, Elisa Fazzi, Raffaele Badolato, Simona OrcesiAbstract:Introduction: Aicardi-Goutieres 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.Areas covered: 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.Expert opinion: 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.
-
developmental outcomes of Aicardi Goutieres Syndrome
Journal of Child Neurology, 2019Co-Authors: Laura Adang, Simona Orcesi, Francesco Gavazzi, Micaela De Simone, Elisa Fazzi, Jessica Galli, Jamie Koh, Julia Kramergolinkoff, Valentina De Giorgis, Kyle PeerAbstract:Aicardi Goutieres Syndrome is a monogenic interferonopathy caused by abnormalities in the intracellular nucleic acid sensing machinery (TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR1, or IFIH1). Most individuals affected by Aicardi Goutieres 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 Goutieres Syndrome. To characterize the clinical presentation in Aicardi Goutieres Syndrome, early features were collected from an international cohort of children (n = 100) with genetically confirmed Aicardi Goutieres 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 TREX1-related Aicardi Goutieres Syndrome secondary were the most severely affected and less likely to reach milestones, including head control, sitting, and nonspecific mama/dada. Individuals affected by SAMHD1, IFIH1, and ADAR 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 Goutieres 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.
-
exploring autoimmunity in a cohort of children with genetically confirmed Aicardi Goutieres Syndrome
Journal of Clinical Immunology, 2016Co-Authors: Marco Cattalini, Simona Orcesi, Jessica Galli, Ivana Olivieri, Laura Andreoli, Giada Ariaudo, Micaela Fredi, A Tincani, Elisa FazziAbstract:Purpose The purpose of this study was to explore the presence of autoimmune manifestations and characterize the autoantibody production in a cohort of patients with Aicardi–Goutieres Syndrome (AGS).
-
neuroradiologic patterns and novel imaging findings in Aicardi Goutieres Syndrome
Neurology, 2016Co-Authors: Roberta La Piana, Adeline Vanderver, Guy Helman, Elisa Fazzi, Ivana Olivieri, Davide Tonduti, Umberto Balottin, C Uggetti, Federico Roncarolo, Yanick J CrowAbstract:Objective: To perform an updated characterization of the neuroradiologic features of Aicardi-Goutieres 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.
Adeline Vanderver - One of the best experts on this subject based on the ideXlab platform.
-
janus kinase inhibition in the Aicardi Goutieres Syndrome
The New England Journal of Medicine, 2020Co-Authors: Adeline Vanderver, Guy Helman, Laura Adang, Francesco Gavazzi, Katherine Mcdonald, David B Frank, Nicole Jaffe, Sabrina W Yum, Abigail Collins, Stephanie KellerAbstract:JAK Inhibition in the Aicardi–Goutieres Syndrome Patients with the Aicardi–Goutieres Syndrome, an autosomal recessive disorder that affects the central nervous system, immune system, and skin, have...
-
neuropathological findings in a case of ifih1 related Aicardi Goutieres Syndrome
Pediatric and Developmental Pathology, 2019Co-Authors: Ahmed Gilani, Adeline Vanderver, Laura Adang, Abigail Collins, B K KleinschmidtdemastersAbstract:Aicardi–Goutieres Syndrome (AGS) is a rare Syndrome characterized by calcification, diffuse demyelination, and variable degree of brain atrophy. The Syndrome is genetically heterogeneous with mutat...
-
astrocytes an active player in Aicardi Goutieres Syndrome
Brain Pathology, 2018Co-Authors: Sunetra Sase, Adeline Vanderver, Asako Takanohashi, Akshata AlmadAbstract:Aicardi-Goutieres 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.
-
neuroradiologic patterns and novel imaging findings in Aicardi Goutieres Syndrome
Neurology, 2016Co-Authors: Roberta La Piana, Adeline Vanderver, Guy Helman, Elisa Fazzi, Ivana Olivieri, Davide Tonduti, Umberto Balottin, C Uggetti, Federico Roncarolo, Yanick J CrowAbstract:Objective: To perform an updated characterization of the neuroradiologic features of Aicardi-Goutieres 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.
-
Aicardi Goutieres Syndrome harbours abundant systemic and brain reactive autoantibodies
Annals of the Rheumatic Diseases, 2015Co-Authors: Eloy Cuadrado, Simona Orcesi, Adeline Vanderver, Machiel H Jansen, Jasper J Anink, Asako Takanohashi, Kristy J Brown, Annie Sandza, Brian Herron, Ivana OlivieriAbstract:Objectives Aicardi–Goutieres Syndrome (AGS) is an autoimmune disorder that shares similarities with systemic lupus erythematous. AGS inflammatory responses specially target the cerebral white matter. However, it remains uncertain why the brain is the most affected organ, and little is known about the presence of autoantibodies in AGS. Here, we aim to profile specific autoantibodies in AGS and to determine whether these autoantibodies target cerebral epitopes. Methods Using a multiplex microarray, we assessed the spectrum of serum autoantibodies in 56 genetically confirmed patients with AGS. We investigated the presence of immunoglobulins in AGS brain specimens using immunohistochemistry and studied the reactivity of sera against brain epitopes with proteomics. Results Serum from patients exhibited high levels of IgGs against nuclear antigens (gP210, Nup62, PCNA, Ro/SSA, Sm/RNP complex, SS-A/SS-B), components of the basement membrane (entactin, laminin), fibrinogen IV and gliadin. Upon testing whether antibodies in AGS could be found in the central nervous system, IgGs were identified to target in vivo endothelial cells in vivo and astrocytes in brain sections of deceased patients with AGS. Using a proteomics approach, we were able to confirm that IgGs in serum samples from AGS patients bind epitopes present in the cerebral white matter. Conclusions Patients with AGS produce a broad spectrum of autoantibodies unique from other autoimmune diseases. Some of these autoantibodies target endothelial cells and astrocytes in the brain of the affected patients, perhaps explaining the prominence of neurological disease in the AGS phenotype.
Gillian I. Rice - One of the best experts on this subject based on the ideXlab platform.
-
reverse transcriptase inhibitors in the Aicardi Goutieres Syndrome
The New England Journal of Medicine, 2018Co-Authors: Gillian I. Rice, Candice Meyzer, Naim Bouazza, Marie Hully, Nathalie Boddaert, Michaela Semeraro, Leo A H Zeef, Flore Rozenberg, Vincent Bondet, Darragh DuffyAbstract:ART for the Aicardi–Goutieres Syndrome The genetic encephalopathy Aicardi–Goutieres Syndrome is thought to be due to misidentification of self-derived nucleic acids and the induction of a type I in...
-
clinical radiological and possible pathological overlap of cystic leukoencephalopathy without megalencephaly and Aicardi Goutieres Syndrome
European Journal of Paediatric Neurology, 2016Co-Authors: Davide Tonduti, Simona Orcesi, John H Livingston, Gillian I. Rice, Emma M Jenkinson, Imen Dorboz, Florence Renaldo, Celeste Panteghini, Marco Henneke, Monique ElmalehAbstract:Abstract Background Cystic leukoencephalopathy without megalencephaly is a disorder related in some cases to RNASET2 mutations and characterized by bilateral anterior temporal subcortical cysts and multifocal lobar white matter lesions with sparing of central white matter structures. This phenotype significantly overlaps with the sequelae of in utero cytomegalovirus (CMV) infection, including the presence of intracranial calcification in some cases. Aicardi-Goutieres Syndrome (AGS) is another inherited leukodystrophy with cerebral calcification mimicking congenital infection. Clinical, radiological and biochemical criteria for the diagnosis of AGS have been established, although the breadth of phenotype associated with mutations in the AGS-related genes is much greater than previously envisaged. Patients and Methods We describe the clinical, biochemical and radiological findings of five patients demonstrating a phenotype reminiscent of AGS. Results All patients were found to carry biallelic mutations of RNASET2. Conclusions Our patients illustrate the clinical and radiological overlap that can be seen between RNASET2-related leukodystrophy and AGS in some cases. Our data highlight the need to include both disorders in the same differential diagnosis, and hint at possible shared pathomechanisms related to auto-inflammation which are worthy of further investigation.
-
therapies in Aicardi Goutieres Syndrome
Clinical and Experimental Immunology, 2014Co-Authors: Simona Orcesi, Adeline Vanderver, Yanick J Crow, Gillian I. Rice, Taco W KuijpersAbstract:Aicardi–Goutieres Syndrome (AGS) is a genetically determined disorder, affecting most particularly the brain and the skin, characterized by the inappropriate induction of a type I interferon-mediated immune response. In most, but not all, cases the condition is severe, with a high associated morbidity and mortality. A number of important recent advances have helped to elucidate the biology of the AGS-related proteins, thus providing considerable insight into disease pathology. In this study, we outline the clinical phenotype of AGS, paying particular attention to factors relevant to therapeutic intervention. We then discuss the pathogenesis of AGS from a molecular and cell biology perspective. Finally, we suggest possible treatment strategies in light of these emerging insights.
-
synonymous mutations in rnaseh2a create cryptic splice sites impairing rnase h2 enzyme function in Aicardi Goutieres Syndrome
Human Mutation, 2013Co-Authors: Gillian I. Rice, Gabriella Forte, Marcin Szynkiewicz, Stephanie R Coffin, Martin A M Reijns, Beverley AndersonAbstract:Aicardi-Goutieres 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.
-
mutations in adar1 cause Aicardi Goutieres Syndrome associated with a type i interferon signature
Nature Genetics, 2012Co-Authors: Gillian I. Rice, Paul R Kasher, Gabriella Forte, Niamh M Mannion, Sam M Greenwood, Marcin Szynkiewicz, Jonathan E Dickerson, Sanjeev S Bhaskar, Massimiliano Zampini, Tracy A BriggsAbstract:Adenosine deaminases acting on RNA (ADARs) catalyze the hydrolytic deamination of adenosine to inosine in double-stranded RNA (dsRNA) and thereby potentially alter the information content and structure of cellular RNAs. Notably, although the overwhelming majority of such editing events occur in transcripts derived from Alu repeat elements, the biological function of non-coding RNA editing remains uncertain. Here, we show that mutations in ADAR1 (also known as ADAR) cause the autoimmune disorder Aicardi-Goutieres Syndrome (AGS). As in Adar1-null mice, the human disease state is associated with upregulation of interferon-stimulated genes, indicating a possible role for ADAR1 as a suppressor of type I interferon signaling. Considering recent insights derived from the study of other AGS-related proteins, we speculate that ADAR1 may limit the cytoplasmic accumulation of the dsRNA generated from genomic repetitive elements.