Neonatal detection of Aicardi Goutières Syndrome by increased C26: 0 lysophosphatidylcholine and interferon signature on newborn screening blood spots

Thais Armangue, Joseph J. Orsini, Asako Takanohashi, Francesco Gavazzi, Alex Conant, Nicole Ulrick, Mark A. Morrissey, Norah Nahhas, Guy Helman, Heather Gordish-Dressman, Simona Orcesi, Davide Tonduti, Chloe Stutterd, Keith van Haren, Camilo Toro, Alejandro D. Iglesias, Marjo S. van der Knaap, Raphaela Goldbach Mansky, Anne B. Moser, Richard O. Jones & 1 others Adeline Vanderver

Research output: Contribution to journalArticle

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 2. months. Thirteen out of 19 (68%) children with AGS had elevations of first tier C26:0 Lyso-PC (>. 0.4. μM), 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 (0.43. μM [0.37-0.48]) was higher than that seen in controls (0.21. μM [0.21-0.21]), but lower than X-ALD individuals (0.72. μM [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 (36. months 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.

Original languageEnglish (US)
JournalMolecular Genetics and Metabolism
DOIs
StateAccepted/In press - 2017

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Aicardi Syndrome
Lysophosphatidylcholines
Interferons
Newborn Infant
Dental Materials
Blood
Adrenoleukodystrophy
Supravalvular Aortic Stenosis
Cyclic AMP Receptor Protein
Blood Flow Velocity
High Pressure Liquid Chromatography
Mutation
Genes
Defecation
Neurology
Exercise Test
Tandem Mass Spectrometry
Nervous System
Central Nervous System

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Biochemistry
  • Molecular Biology
  • Genetics
  • Endocrinology

Cite this

Neonatal detection of Aicardi Goutières Syndrome by increased C26 : 0 lysophosphatidylcholine and interferon signature on newborn screening blood spots. / Armangue, Thais; Orsini, Joseph J.; Takanohashi, Asako; Gavazzi, Francesco; Conant, Alex; Ulrick, Nicole; Morrissey, Mark A.; Nahhas, Norah; Helman, Guy; Gordish-Dressman, Heather; Orcesi, Simona; Tonduti, Davide; Stutterd, Chloe; van Haren, Keith; Toro, Camilo; Iglesias, Alejandro D.; van der Knaap, Marjo S.; Goldbach Mansky, Raphaela; Moser, Anne B.; Jones, Richard O.; Vanderver, Adeline.

In: Molecular Genetics and Metabolism, 2017.

Research output: Contribution to journalArticle

Armangue, T, Orsini, JJ, Takanohashi, A, Gavazzi, F, Conant, A, Ulrick, N, Morrissey, MA, Nahhas, N, Helman, G, Gordish-Dressman, H, Orcesi, S, Tonduti, D, Stutterd, C, van Haren, K, Toro, C, Iglesias, AD, van der Knaap, MS, Goldbach Mansky, R, Moser, AB, Jones, RO & Vanderver, A 2017, 'Neonatal detection of Aicardi Goutières Syndrome by increased C26: 0 lysophosphatidylcholine and interferon signature on newborn screening blood spots' Molecular Genetics and Metabolism. DOI: 10.1016/j.ymgme.2017.07.006

Armangue, Thais; Orsini, Joseph J.; Takanohashi, Asako; Gavazzi, Francesco; Conant, Alex; Ulrick, Nicole; Morrissey, Mark A.; Nahhas, Norah; Helman, Guy; Gordish-Dressman, Heather; Orcesi, Simona; Tonduti, Davide; Stutterd, Chloe; van Haren, Keith; Toro, Camilo; Iglesias, Alejandro D.; van der Knaap, Marjo S.; Goldbach Mansky, Raphaela; Moser, Anne B.; Jones, Richard O.; Vanderver, Adeline / Neonatal detection of Aicardi Goutières Syndrome by increased C26 : 0 lysophosphatidylcholine and interferon signature on newborn screening blood spots.

In: Molecular Genetics and Metabolism, 2017.

Research output: Contribution to journalArticle

@article{459b2e171c8f446d8012fbbdf0ff93cb,
title = "Neonatal detection of Aicardi Goutières Syndrome by increased C26: 0 lysophosphatidylcholine and interferon signature on newborn screening blood spots",
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 2. months. Thirteen out of 19 (68%) children with AGS had elevations of first tier C26:0 Lyso-PC (>. 0.4. μM), 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 (0.43. μM [0.37-0.48]) was higher than that seen in controls (0.21. μM [0.21-0.21]), but lower than X-ALD individuals (0.72. μM [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 (36. months 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.",
author = "Thais Armangue and Orsini, {Joseph J.} and Asako Takanohashi and Francesco Gavazzi and Alex Conant and Nicole Ulrick and Morrissey, {Mark A.} and Norah Nahhas and Guy Helman and Heather Gordish-Dressman and Simona Orcesi and Davide Tonduti and Chloe Stutterd and {van Haren}, Keith and Camilo Toro and Iglesias, {Alejandro D.} and {van der Knaap}, {Marjo S.} and {Goldbach Mansky}, Raphaela and Moser, {Anne B.} and Jones, {Richard O.} and Adeline Vanderver",
year = "2017",
doi = "10.1016/j.ymgme.2017.07.006",
journal = "Molecular Genetics and Metabolism",
issn = "1096-7192",
publisher = "Academic Press Inc.",

}

TY - JOUR

T1 - Neonatal detection of Aicardi Goutières Syndrome by increased C26

T2 - Molecular Genetics and Metabolism

AU - Armangue,Thais

AU - Orsini,Joseph J.

AU - Takanohashi,Asako

AU - Gavazzi,Francesco

AU - Conant,Alex

AU - Ulrick,Nicole

AU - Morrissey,Mark A.

AU - Nahhas,Norah

AU - Helman,Guy

AU - Gordish-Dressman,Heather

AU - Orcesi,Simona

AU - Tonduti,Davide

AU - Stutterd,Chloe

AU - van Haren,Keith

AU - Toro,Camilo

AU - Iglesias,Alejandro D.

AU - van der Knaap,Marjo S.

AU - Goldbach Mansky,Raphaela

AU - Moser,Anne B.

AU - Jones,Richard O.

AU - Vanderver,Adeline

PY - 2017

Y1 - 2017

N2 - 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 2. months. Thirteen out of 19 (68%) children with AGS had elevations of first tier C26:0 Lyso-PC (>. 0.4. μM), 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 (0.43. μM [0.37-0.48]) was higher than that seen in controls (0.21. μM [0.21-0.21]), but lower than X-ALD individuals (0.72. μM [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 (36. months 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.

AB - 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 2. months. Thirteen out of 19 (68%) children with AGS had elevations of first tier C26:0 Lyso-PC (>. 0.4. μM), 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 (0.43. μM [0.37-0.48]) was higher than that seen in controls (0.21. μM [0.21-0.21]), but lower than X-ALD individuals (0.72. μM [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 (36. months 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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DO - 10.1016/j.ymgme.2017.07.006

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SN - 1096-7192

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