A type I interferon signature identifies bilateral striatal necrosis due to mutations inADAR1

Abstract

ADAR1-related disease should be considered in the differential diagnosis of apparently non-syndromic BSN with severe dystonia of varying evolution. The finding of an interferon signature provides a useful screening test for the presence of ADAR1 mutations in this context, and may suggest novel treatment approaches.

Bilateral striatal necrosis caused by ADAR mutations in two siblings with dystonia and freckles-like skin changes that should be differentiated from Leigh syndrome

“…Bilateral putaminal lesions found in MRI were not specific enough to establish a final diagnosis but together with the secondary abnormalities in lactate and alanine concentrations led us to consider for a long time a mitochondrial disease as the most frequent cause of such features in children. Our patients similar to those described in a cohort of children with nonsyndromic BSN [7] did not have any signs of calcification in the striatum or other localizations that were reported by Kumar et al [5] in AGS brains.…”

“…Our patients developed signs of the disease as a sequel of the infection, the finding pointed also by Livingston et al [7]. Freckles-like skin changes on the face and the dorsal surface of hands were noticed in their medical documentation but were neglected in the differential diagnostics.…”

“…Recently, they have been also found in patients with nonsyndromic bilateral striatal necrosis (BSN) [6,7] that is a frequent but nonspecific MRI feature observed in patients with an extrapyramidal syndrome, some of which had DSH [1]. Bilateral striatal necrosis was the most frequently reported in individuals with mitochondrial pathology presenting Leigh syndrome (LS) and MTATP6 mutation [3], thiamine metabolism dysfunction syndrome related to SLC25A19 pathogenic variants [11], and glutaric aciduria I with GCDH variants [4], but rarely in Wilson's and Huntington diseases and other of inherited etiology as well as of certain acquired causes [1].…”

“…Bilateral striatal necrosis was the most frequently reported in individuals with mitochondrial pathology presenting Leigh syndrome (LS) and MTATP6 mutation [3], thiamine metabolism dysfunction syndrome related to SLC25A19 pathogenic variants [11], and glutaric aciduria I with GCDH variants [4], but rarely in Wilson's and Huntington diseases and other of inherited etiology as well as of certain acquired causes [1]. The prognosis for BSN is variable, with patients completely recovered and others developing severe dystonia or a more akinetic-rigid phenotype [7]. The ADAR gene (1q21.3) codes for specific deaminase which converses adenosine to inosine in double-stranded RNA, influences glutamate receptor transcripts and acts as a suppressor of type I interferon signaling [10].…”

Leigh map: A novel computational diagnostic resource for mitochondrial disease

“…The outermost compartment represents the cytosol, where it is possible to find the nucleus and the mitochondrion. Three nuclear genes, nuclear envelope protein NUP62 , nuclear export protein RANBP2 , and adenosine deaminase ADAR , have been included in our network as genes causing a clinical and radiological phenotype closely resembling Leigh syndrome 14, 15, 16. The mitochondrion is visualized in its double membrane structure, and mitochondrial genes are grouped according to function and can be found in their submitochondrial location (eg, outer membrane, matrix).…”