Treatments in Aicardi–Goutières syndrome

Crow, Yanick J.; Shetty, Jay; Livingston, John H.

doi:10.1111/dmcn.14268

Cited by 81 publications

(89 citation statements)

References 30 publications

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“…Ruxolitinib led to an improvement of psychomotor delay with a reduction in dystonic movements in two patients with AGS2 [20]. However, ruxolitinib failed to prevent the onset of clinical signs in a patient with RNASEH2B mutation [21]. Tofacitinib demonstrated a partial response in this patient, failing to ameliorate autoin ammation and chronic kidney disease completely.…”

Section: Discussionmentioning

confidence: 85%

Systemic inflammation and chronic kidney disease in a patient due to the RNASEH2B defect

Xia

Yang

2020

Preprint

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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 hours, mRNA expression of twelve 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 three of fourteen 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 .

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Section: Discussionmentioning

confidence: 85%

Systemic inflammation and chronic kidney disease in a patient due to the RNASEH2B defect

Xia

Yang

2020

Preprint

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“…While the neurological damage accrued early in the disease course is likely irreversible, the identification of a relapsing–remitting disease course in AGS may present an opportunity for initiation of treatment to attenuate further decline . Type I interferon upregulation in AGS is not limited to the initial encephalopathic disease stage and may be a lifelong phenomenon.…”

Section: Discussionmentioning

confidence: 99%

“…While the neurological damage accrued early in the disease course is likely irreversible, the identification of a relapsing-remitting disease course in AGS may present an opportunity for initiation of treatment to attenuate further decline. 15 Type I interferon upregulation in AGS is not limited to the initial encephalopathic disease stage and may be a lifelong phenomenon. Therapies to block interferon signaling may therefore be of utility in patients exhibiting recurrent symptomatology, and several Janus kinase inhibitors have shown early promise in several type I interferonopathies.…”

Section: Discussionmentioning

confidence: 99%

Relapsing–remitting clinical course expands the phenotype of Aicardi–Goutières syndrome

Lambe

Murphy

et al. 2020

Ann Clin Transl Neurol

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Aicardi–Goutières syndrome (AGS) is a rare and likely underdiagnosed genetic leukoencephalopathy, typically presenting in infancy with encephalopathy and characteristic neuroimaging features, with residual static neurological deficits. We describe a patient who, following an initial presentation at the age of 12 months in keeping with AGS, exhibited a highly atypical relapsing course of neurological symptoms in adulthood with essentially normal neuroimaging. Whole‐exome sequencing confirmed a pathogenic RNASEH2B gene variant consistent with AGS. This case highlights the expanding phenotypes associated with AGS and the potential role of whole‐exome sequencing in facilitating an increase in the rate of diagnosis.

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“…Aicardi-Goutières syndrome (AGS) is a genetically heterogeneous encephalopathy. AGS patients' clinical manifestations include cerebral atrophy, intracranial calcification, and leukodystrophy, as well as increased interferon alpha (α-IFN, IFNA1) and leukocytosis in the cerebrospinal fluid [187]. Progressive microcephaly, psychomotor retardation associated with the demyelination of motor neurons, and death in early childhood are also common.…”

Section: Aicardi-goutières' Syndrome-causing Genesmentioning

confidence: 99%

Protective Mechanisms Against DNA Replication Stress in the Nervous System

Charlier

Martins

2020

Genes

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The precise replication of DNA and the successful segregation of chromosomes are essential for the faithful transmission of genetic information during the cell cycle. Alterations in the dynamics of genome replication, also referred to as DNA replication stress, may lead to DNA damage and, consequently, mutations and chromosomal rearrangements. Extensive research has revealed that DNA replication stress drives genome instability during tumorigenesis. Over decades, genetic studies of inherited syndromes have established a connection between the mutations in genes required for proper DNA repair/DNA damage responses and neurological diseases. It is becoming clear that both the prevention and the responses to replication stress are particularly important for nervous system development and function. The accurate regulation of cell proliferation is key for the expansion of progenitor pools during central nervous system (CNS) development, adult neurogenesis, and regeneration. Moreover, DNA replication stress in glial cells regulates CNS tumorigenesis and plays a role in neurodegenerative diseases such as ataxia telangiectasia (A-T). Here, we review how replication stress generation and replication stress response (RSR) contribute to the CNS development, homeostasis, and disease. Both cell-autonomous mechanisms, as well as the evidence of RSR-mediated alterations of the cellular microenvironment in the nervous system, were discussed.

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Treatments in Aicardi–Goutières syndrome

Cited by 81 publications

References 30 publications

Systemic inflammation and chronic kidney disease in a patient due to the RNASEH2B defect

Systemic inflammation and chronic kidney disease in a patient due to the RNASEH2B defect

Relapsing–remitting clinical course expands the phenotype of Aicardi–Goutières syndrome

Protective Mechanisms Against DNA Replication Stress in the Nervous System

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