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Case report

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

Dorota Piekutowska-Abramczuk, Hanna Mierzewska, Monika Bekiesińska-Figatowska, Elżbieta Ciara, Joanna Trubicka, Maciej Pronicki, Dariusz Rokicki, Małgorzata Rydzanicz, Rafał Płoski, Ewa Pronicka

Folia Neuropathol 2016; 54 (4): 405-409
Article file
- Bilateral.pdf  [0.14 MB]


Pathogenic molecular variants in the ADAR gene [OMIM*146920] are a known cause of an Aicardi- Goutières syndrome type 6 (ASG6) [OMIM#615010], an autosomal recessive severe infantile encephalo­pathy with intracranial calcifications [10] and a dys­chromatosis symmetrica hereditaria (DSH) [OMIM #127400], a rare dominant disease demonstrated mainly in Asian adults [8]. 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]. 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]. It is ubiquitously expressed in all tissues, but until today it has not been known why the signs of its dysfunction are limited to the nervous system and skin.

Case study

Here, we present two Polish siblings, the only children of unrelated parents, born after uneventful pregnancy and delivery. They both demonstrated acute onset with an episode of ataxia that occurred after a nonspecific infantile febrile infection followed by slowly progressive extrapyramidal syndrome (Table I). In infancy their development was mildly delayed, mainly in motor skills as they moved on their fours up to 2 and 3 years (Case 1 and 2, respectively). When they started to walk independently, their movements were disturbed by an increased muscle tone with worsening during emotional stress. Tendency to retropulsion of the head, involuntary movements of facial muscles, athetotic movements of digits as well as dysarthric speech, dysphagia and frequent choking during eating were noticed. They both had small mild freckles-like skin changes on their faces and dorsal surfaces of hands. Both children were small for their age (weight and length < 2.5 SD, OCF < 3SD). Magnetic resonance imaging (MRI) examination (Fig. 1A-C) showed bilateral lesions in putamen on T2-weighted and FLAIR sequences that were suggestive for LS. Magnetic resonance spectroscopy (MRS) did not show any abnormalities. Muscle biopsy investigations did not reveal morphological changes and respiratory chain dysfunction.
During the following years, the clinical course of the disease was slowly progressive with the dominance of dystonic disorder, but intellectual ability was relatively preserved. At present (14 and 12 years), the siblings are wheel-chair bound and need full assistance with dressing and feeding.
Molecular screening for SURF1, SCO2, POLG, MTATP6, MTTL1, and MTTK mutations most frequent­ly detected in Polish LS patients [9] was negative. Whole exome sequencing (WES) did not reveal deleterious mutations in genes responsible for known mitochondrial diseases (MD). Finally, two rare molecular variants (Fig. 1D, E) in non-mitochondria related ADAR gene (Ref Seq. NM_001111.4; NP_001102.2) included one novel splicing variant c.3202+1G>A (p.?) and a known recurrent substitution c.577C>G (p.Pro193Ala) were identified by thorough filtration of WES data and confirmed by Sanger sequencing in both siblings.
The study was approved by the Bioethical Com­mis­sion of the CMHI.


In the reported family the extended metabolic and mitochondrial investigations have been inconclusive for approximately 14 years. 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. 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.
It is worth noting that the c.577C>G (p.Pro193Ala) substitution was detected earlier in at least eleven AGS6 families [7,10] and it was identified in the general population. The minor allele frequency (MAF) already recorded in ExAC database of 65000 exom­es was 0.002142 (http://exac.broadinstitute.org), in 1000 Genomes was 0.0013 (http://browser.1000genomes.org), and in our in-house-made 400 exomes database it was evaluated as 0.0014. It is located in the highly evolutionary conserved z-alpha adenosine deaminase domain and results in removing important atomic interactions between protein and DNA/RNA [2].


In conclusion, we suggest that the disease should be always differentiated from LS to prevent diagnosis delay. We would like to underline that presence of specific MRI features of bilateral striatal necrosis and freckles-like skin changes should direct differential diagnosis to the ADAR mutations screening.


We thank the family for participation in the study. The study was partly supported by the CMHI project no. S136/13 and NSC grant no. 2012/05/B/NZ2/01627.


Authors report no conflict of interest.


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Copyright: © 2016 Mossakowski Medical Research Centre Polish Academy of Sciences and the Polish Association of Neuropathologists. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International (CC BY-NC-SA 4.0) License (http://creativecommons.org/licenses/by-nc-sa/4.0/), allowing third parties to copy and redistribute the material in any medium or format and to remix, transform, and build upon the material, provided the original work is properly cited and states its license.
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