Thais Armangue1, Joseph J Orsini2, Asako Takanohashi3, Francesco Gavazzi4, Alex Conant5, Nicole Ulrick6, Mark A Morrissey7, Norah Nahhas8, Guy Helman9, Heather Gordish-Dressman10, Simona Orcesi11, Davide Tonduti12, Chloe Stutterd13, Keith van Haren14, Camilo Toro15, Alejandro D Iglesias16, Marjo S van der Knaap17, Raphaela Goldbach Mansky18, Anne B Moser19, Richard O Jones20, Adeline Vanderver21. 1. Neuroimmunology Program, IDIBAPS-Hospital Clinic, University of Barcelona, Barcelona, Spain; Department of Neurology, Children's National Health System, Washington, DC, USA; Pediatric Neuroimmunology and Neuroinfectious Unit, Neurology Service, Sant Joan de Deu Children's Hospital, University of Barcelona, Barcelona, Spain; CIBERER (Consortium of Rare Diseases), Spain. Electronic address: armangue@clinic.cat. 2. Wadsworth Center, New York State Department of Health, Newborn Screening Program, Albany, NY, USA. Electronic address: joseph.orsini@health.ny.gov. 3. Center For Genetic Medicine, Children's National Health System, Washington, DC, USA; Children's Hospital of Philadelphia, University of Pennsylvania, Philadelphia, PA, USA. Electronic address: takanohashi@email.chop.edu. 4. Child Neurology and Psychiatry Department, Children's Hospital of Brescia, Spedali Civili of Brescia, Brescia, Italy; Clinical and Experimental Sciences Department, University of Brescia, Brescia, Italy. 5. Department of Neurology, Children's National Health System, Washington, DC, USA; Center For Genetic Medicine, Children's National Health System, Washington, DC, USA. 6. Department of Neurology, Children's National Health System, Washington, DC, USA; Children's Hospital of Philadelphia, University of Pennsylvania, Philadelphia, PA, USA. Electronic address: ulrickn@email.chop.edu. 7. Wadsworth Center, New York State Department of Health, Newborn Screening Program, Albany, NY, USA. 8. Department of Neurology, Children's National Health System, Washington, DC, USA. 9. Department of Neurology, Children's National Health System, Washington, DC, USA; Institute for Molecular Bioscience, University of Queensland, Brisbane, Australia. Electronic address: guy.helman@uq.net.au. 10. Center For Genetic Medicine, Children's National Health System, Washington, DC, USA. Electronic address: hgordish@childrensnational.org. 11. Child Neurology and Psychiatry Unit, 'C. Mondino' National Neurological Institute, Pavia, Italy. Electronic address: simona.orcesi@mondino.it. 12. Department of Child Neurology, C. Besta Neurological Institute IRCCS Foundation, Milano, Italy. 13. Department of Neurology, Royal Children's Hospital of Melbourne, Melbourne, Australia; Victorian Clinical Genetics Service, Murdoch Childrens Research Institute, Melbourne, Australia. Electronic address: chloe.stutterd@vcgs.org.au. 14. Neurology and Neurological Sciences, Stanford University Medical Center, Palo Alto, CA, USA. Electronic address: kpv@stanford.edu. 15. Undiagnosed Diseases Program, National Human Genome Research Institute, NIH, Bethesda, MD, USA. Electronic address: toroc@mail.nih.gov. 16. Division of Clinical Genetics, Columbia University Medical Center, NY, USA. Electronic address: ai2269@cumc.columbia.edu. 17. Department of Child neurology, The Center for Childhood White Matter Disorders, VU University Medical Center, Amsterdam Neuroscience, Amsterdam, The Netherlands. Electronic address: ms.vanderknaap@vumc.nl. 18. Translational Autoinflammatory Disease Studies (TADS), NIH, NIAID, USA. Electronic address: raphaela.goldbach-mansky@nih.gov. 19. Peroxisomal Diseases Laboratory, Kennedy Krieger Institute, Baltimore, MD, USA. Electronic address: mosera@kennedykrieger.org. 20. Peroxisomal Diseases Laboratory, Kennedy Krieger Institute, Baltimore, MD, USA. Electronic address: jonesri@kennedykrieger.org. 21. Department of Neurology, Children's National Health System, Washington, DC, USA; Center For Genetic Medicine, Children's National Health System, Washington, DC, USA; Children's Hospital of Philadelphia, University of Pennsylvania, Philadelphia, PA, USA; Department of Integrated Systems Biology and Pediatrics, George Washington University, Washington, DC, USA; Perlman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. Electronic address: vandervera@email.chop.edu.
Abstract
BACKGROUND: Aicardi Goutières Syndrome (AGS) is a heritable interferonopathy associated with systemic autoinflammation causing interferon (IFN) elevation, central nervous system calcifications, leukodystrophy and severe neurologic sequelae. An infant with TREX1 mutations was recently found to have abnormal C26:0 lysophosphatidylcholine (C26:0 Lyso-PC) in a newborn screening platform for X-linked adrenoleukodystrophy, prompting analysis of this analyte in retrospectively collected samples from individuals affected by AGS. METHODS: In this study, we explored C26:0 Lyso-PC levels and IFN signatures in newborn blood spots and post-natal blood samples in 19 children with a molecular and clinical diagnosis of AGS and in the blood spots of 22 healthy newborns. We used Nanostring nCounter™ for IFN-induced gene analysis and a high-performance liquid chromatography with tandem mass spectrometry (HPLC MS/MS) newborn screening platform for C26:0 Lyso-PC analysis. RESULTS: Newborn screening cards from patients across six AGS associated genes were collected, with a median disease presentation of 2months. Thirteen out of 19 (68%) children with AGS had elevations of first tier C26:0 Lyso-PC (>0.4μM), that would have resulted in a second screen being performed in a two tier screening system for X-linked adrenoleukodystrophy (X-ALD). The median (95%CI) of first tier C26:0 Lyso-PC values in AGS individuals (0.43μM [0.37-0.48]) was higher than that seen in controls (0.21μM [0.21-0.21]), but lower than X-ALD individuals (0.72μM [0.59-0.84])(p<0.001). Fourteen of 19 children had elevated expression of IFN signaling on blood cards relative to controls (Sensitivity 73.7%, 95%CI 51-88%, Specificity 95%, 95% CI 78-99%) including an individual with delayed disease presentation (36months of age). All five AGS patients with negative IFN signature at birth had RNASEH2B mutations. Consistency of agreement between IFN signature in neonatal and post-natal samples was high (0.85). CONCLUSION: This suggests that inflammatory markers in AGS can be identified in the newborn period, before symptom onset. Additionally, since C26:0 Lyso-PC screening is currently used in X-ALD newborn screening panels, clinicians should be alert to the fact that AGS infants may present as false positives during X-ALD screening.
BACKGROUND: Aicardi Goutières Syndrome (AGS) is a heritable interferonopathy associated with systemic autoinflammation causing interferon (IFN) elevation, central nervous system calcifications, leukodystrophy and severe neurologic sequelae. An infant with TREX1 mutations was recently found to have abnormal C26:0 lysophosphatidylcholine (C26:0 Lyso-PC) in a newborn screening platform for X-linked adrenoleukodystrophy, prompting analysis of this analyte in retrospectively collected samples from individuals affected by AGS. METHODS: In this study, we explored C26:0 Lyso-PC levels and IFN signatures in newborn blood spots and post-natal blood samples in 19 children with a molecular and clinical diagnosis of AGS and in the blood spots of 22 healthy newborns. We used Nanostring nCounter™ for IFN-induced gene analysis and a high-performance liquid chromatography with tandem mass spectrometry (HPLC MS/MS) newborn screening platform for C26:0 Lyso-PC analysis. RESULTS: Newborn screening cards from patients across six AGS associated genes were collected, with a median disease presentation of 2months. Thirteen out of 19 (68%) children with AGS had elevations of first tier C26:0 Lyso-PC (>0.4μM), that would have resulted in a second screen being performed in a two tier screening system for X-linked adrenoleukodystrophy (X-ALD). The median (95%CI) of first tier C26:0 Lyso-PC values in AGS individuals (0.43μM [0.37-0.48]) was higher than that seen in controls (0.21μM [0.21-0.21]), but lower than X-ALD individuals (0.72μM [0.59-0.84])(p<0.001). Fourteen of 19 children had elevated expression of IFN signaling on blood cards relative to controls (Sensitivity 73.7%, 95%CI 51-88%, Specificity 95%, 95% CI 78-99%) including an individual with delayed disease presentation (36months of age). All five AGS patients with negative IFN signature at birth had RNASEH2B mutations. Consistency of agreement between IFN signature in neonatal and post-natal samples was high (0.85). CONCLUSION: This suggests that inflammatory markers in AGS can be identified in the newborn period, before symptom onset. Additionally, since C26:0 Lyso-PC screening is currently used in X-ALD newborn screening panels, clinicians should be alert to the fact that AGS infants may present as false positives during X-ALD screening.
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