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. and Vanderver, Adeline (2017) Neonatal detection of Aicardi Goutières Syndrome by increased C26:0 lysophosphatidylcholine and interferon signature on newborn screening blood spots. Molecular Genetics and Metabolism, 122 3: 134-139. doi:10.1016/j.ymgme.2017.07.006

Author 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
Title Neonatal detection of Aicardi Goutières Syndrome by increased C26:0 lysophosphatidylcholine and interferon signature on newborn screening blood spots
Journal name Molecular Genetics and Metabolism   Check publisher's open access policy
ISSN 1096-7206
Publication date 2017-07-20
Year available 2017
Sub-type Article (original research)
DOI 10.1016/j.ymgme.2017.07.006
Open Access Status Not yet assessed
Volume 122
Issue 3
Start page 134
End page 139
Total pages 6
Place of publication Waltham, MA, United States
Publisher Academic Press
Language eng
Subject 2712 Endocrinology, Diabetes and Metabolism
1303 Biochemistry
1312 Molecular Biology
1311 Genetics
1310 Endocrinology
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.
Keyword X-Linked Adrenoleukodystrophy
Q-Index Code C1
Q-Index Status Provisional Code
Grant ID K23 NS087151
U01 HD082806
UL1 TR000075
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: HERDC Pre-Audit
Institute for Molecular Bioscience - Publications
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