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

被引：37

作者：

Armangue, Thais ^{[1
,2
,3
,4
]}

Orsini, Joseph J. ^{[5
]}

Takanohashi, Asako ^{[6
,7
]}

Gavazzi, Francesco ^{[8
,9
]}

Conant, Alex ^{[2
,6
]}

Ulrick, Nicole ^{[2
,7
]}

Morrissey, Mark A. ^{[5
]}

Nahhas, Norah ^{[2
]}

Helman, Guy ^{[2
,10
]}

Gordish-Dressman, Heather ^{[6
]}

Orcesi, Simona ^{[11
]}

Tonduti, Davide ^{[12
]}

Stutterd, Chloe ^{[13
,14
]}

van Haren, Keith ^{[15
]}

Toro, Camillo ^{[16
]}

Iglesias, Alejandro D. ^{[17
]}

van der Knaap, Marjo S. ^{[18
]}

Mansky, Raphaela Goldbach ^{[19
]}

Moser, Anne B. ^{[20
]}

Jones, Richard O. ^{[20
]}

Vanderver, Adeline ^{[2
,6
,7
,21
,22
]}

机构：

[1] Univ Barcelona, Hosp Clin, IDIBAPS, Neuroimmunol Program, Barcelona, Spain

[2] Childrens Natl Hlth Syst, Dept Neurol, Washington, DC USA

[3] Univ Barcelona, St Joan de Deu Childrens Hosp, Pediat Neuroimmunol & Neuroinfect Unit, Barcelona, Spain

[4] CIBERER Consortium Rare Dis, Madrid, Spain

[5] New York State Dept Hlth, Wadsworth Ctr, Newborn Screening Program, Albany, NY USA

[6] Childrens Natl Hlth Syst, Ctr Genet Med, Washington, DC USA

[7] Univ Penn, Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA

[8] Spedali Civili Brescia, Childrens Hosp Brescia, Child Neurol & Psychiat Dept, Brescia, Italy

[9] Univ Brescia, Clin & Expt Sci Dept, Brescia, Italy

[10] Univ Queensland, Inst Mol Biosci, Brisbane, Qld, Australia

[11] C Mondino Natl Neurol Inst, Child Neurol & Psychiat Unit, Pavia, Italy

[12] C Besta Neurol Inst IRCCS Fdn, Dept Child Neurol, Milan, Italy

[13] Royal Childrens Hosp Melbourne, Dept Neurol, Melbourne, Vic, Australia

[14] Murdoch Childrens Res Inst, Victorian Clin Genet Serv, Melbourne, Vic, Australia

[15] Stanford Univ, Med Ctr, Neurol & Neurol Sci, Palo Alto, CA 94304 USA

[16] NHGRI, Undiagnosed Dis Program, NIH, Bethesda, MD 20892 USA

[17] Columbia Univ, Med Ctr, Div Clin Genet, New York, NY 10027 USA

[18] Vrije Univ Amsterdam, Dept Child Neurol, Amsterdam Neurosci, Ctr Childhood White Matter Disorders,Med Ctr, Amsterdam, Netherlands

[19] NIAID, TADS, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA

[20] Kennedy Krieger Inst, Peroxisomal Dis Lab, Baltimore, MD USA

[21] George Washington Univ, Dept Integrated Syst Biol & Pediat, Washington, DC USA

[22] Univ Penn, Perlman Sch Med, Philadelphia, PA 19104 USA

来源：

MOLECULAR GENETICS AND METABOLISM | 2017年 / 122卷 / 03期

基金：

澳大利亚国家健康与医学研究理事会;

关键词：

X-LINKED ADRENOLEUKODYSTROPHY; BIOCHEMICAL-DIAGNOSIS; PRENATAL-DIAGNOSIS; FATTY-ACIDS; MUTATIONS; DISEASE; SAMHD1; TREX1; CLASSIFICATION; DISORDERS;

D O I：

10.1016/j.ymgme.2017.07.006

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

Background: Aicardi Goutieres Syndrome (AGS) is a heritable interferonopathy associated with systemic auto inflammation 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 postnatal 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 (TM) for IFN-induced gene analysis and a high-performance liquidchromatography 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 mu M), 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 mu M [0.37-0.48]) was higher than that seen in controls (0.21 mu M [0.21-0.21]), but lower than X-ALD individuals (0.72 mu M [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.

引用

页码：134 / 139

页数：6

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