Aicardi‐Goutières syndrome may present with positive newborn screen for X‐linked adrenoleukodystrophy

Abstract

We report three unrelated probands, two male and one female, diagnosed with Aicardi‐Goutières syndrome (AGS) after screening positive on California newborn screening (CA NBS) for X‐linked adrenoleukodystrophy (X‐ALD) due to elevated C26:0 lysophosphatidylcholine (C26:0‐LPC). Follow‐up evaluation was notable for elevated C26:0, C26:1, and C26:0/C22:0 ratio, and normal red blood cell plasmalogens levels in all three probands. Diagnoses were confirmed by molecular sequencing prior to 12 months of age after clinical evaluation was inconsistent with X‐ALD or suggestive of AGS. For at least one proband, the early diagnosis of AGS enabled candidacy for enrollment into a therapeutic clinical trial. This report demonstrates the importance of including AGS on the differential diagnosis for individuals who screen positive for X‐ALD, particularly infants with abnormal neurological features, as this age of onset would be highly unusual for X‐ALD. While AGS is not included on the Recommended Universal Screening Panel, affected individuals can be identified early through state NBS programs so long as providers are aware of a broader differential that includes AGS. This report is timely, as state NBS algorithms for X‐ALD are actively being established, implemented, and refined.

Current Status of Newborn Bloodspot Screening Worldwide 2024: A Comprehensive Review of Recent Activities (2020–2023)

“…Integration of a strong follow-up system into the CA NBS has resulted in better definitions of the conditions screened and other clinical possibilities during differential diagnosis of various conditions: elevated C26:0-lysophosphatidylcholine, the screen for ALD, warrants consideration of Aicardi–Goutières syndrome [ 203 ] and Lupus [ 204 ] as clinical possibilities; and a low citrulline NBS for CIT has been shown to lead to identification of MT- ATP6 mitochondrial disease but further studies are needed to establish the prevalence and natural history this disease and to determine if it is an appropriate condition to nominate to the RUSP [ 205 ].…”

Newborn Screening for X-Linked Adrenoleukodystrophy: Past, Present, and Future

“…Other peroxisomal disorders may be identified, including in children with the Zellweger spectrum disorder and single-enzyme defects in peroxisomal beta oxidation. It was not expected that a subset of children with Aicardi-Goutieres syndrome [19,20] would be flagged. This has brought an added dimension in the evaluation of the child who is being seen in follow up.…”

The type I interferonopathies: 10 years on

“…In this regard, intriguing recent data have suggested that AGS might be associated with a disturbance of very long chain fatty acid metabolism. Specifically, Armangue et al 41 and Tise et al 42 described cases of AGS identified through newborn screening programmes for X-linked adrenoleukodystrophy, raising the possibility that AGS might be ascertained presymptomatically. The mechanism here remains unknown, perhaps relating to a disturbance of central nervous system (CNS) myelination or of a link between antiviral signalling and peroxisome integrity worthy of further investigation 43 , 44 .…”