+ Site Statistics
References:
54,258,434
Abstracts:
29,560,870
PMIDs:
28,072,757
+ Search Articles
+ Subscribe to Site Feeds
Most Shared
PDF Full Text
+ PDF Full Text
Request PDF Full Text
+ Follow Us
Follow on Facebook
Follow on Twitter
Follow on LinkedIn
+ Translate
+ Recently Requested

A type I interferon signature identifies bilateral striatal necrosis due to mutations in ADAR1



A type I interferon signature identifies bilateral striatal necrosis due to mutations in ADAR1



Journal of Medical Genetics 51(2): 76-82



We recently observed mutations in ADAR1 to cause a phenotype of bilateral striatal necrosis (BSN) in a child with the type I interferonopathy Aicardi-Goutières syndrome (AGS). We therefore decided to screen patients with apparently non-syndromic BSN for ADAR1 mutations, and for an upregulation of interferon-stimulated genes (ISGs). We performed Sanger sequencing of ADAR1 in a series of patients with BSN presenting to us during our routine clinical practice. We then undertook detailed clinical and neuroradiological phenotyping in nine mutation-positive children. We also measured the expression of ISGs in peripheral blood from these patients, and in children with BSN who did not have ADAR1 mutations. Nine ADAR1 mutation-positive patients from seven families demonstrated an acute (five cases) or subacute (four cases) onset of refractory, four-limb dystonia starting between 8 months and 5 years of age. Eight patients were developmentally normal at initial presentation. In seven cases, the disease was inherited as an autosomal recessive trait, while two related patients were found to have a heterozygous (dominant) ADAR1 mutation. All seven mutation-positive patients assayed showed an upregulation of ISGs (median: 12.50, IQR: 6.43-36.36) compared to controls (median: 0.93, IQR: 0.57-1.30), a so-called interferon signature, present many years after disease onset. No interferon signature was present in four children with BSN negative for mutations in ADAR1 (median: 0.63, IQR: 0.47-1.10). 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.

(PDF emailed within 0-6 h: $19.90)

Accession: 051281102

Download citation: RISBibTeXText

PMID: 24262145

DOI: 10.1136/jmedgenet-2013-102038


Related references

Bilateral striatal necrosis in two subjects with Aicardi-Goutières syndrome due to mutations in ADAR1 (AGS6). American Journal of Medical Genetics. Part a 164a(3): 815-819, 2014

Mutations in ADAR1 cause Aicardi-Goutieres syndrome associated with a type I interferon signature. 2012

Compulsive behavior of the obsessional type with bilateral circumscribed pallido striatal necrosis encephalopathy following a wasp sting. Revue Neurologique (Paris) 137(4): 269-276, 1981

Characterization of the 5'-flanking region of the human RNA-specific adenosine deaminase ADAR1 gene and identification of an interferon-inducible ADAR1 promoter. Gene (Amsterdam) 229(1-2): 203-213, March 18, 1999

Deficiency in type I interferon signaling prevents the early interferon-induced gene signature in pancreatic islets but not type 1 diabetes in NOD mice. Diabetes 63(3): 1032-1040, 2014

A CD133-related gene expression signature identifies an aggressive glioblastoma subtype with excessive mutations. Proceedings of the National Academy of Sciences of the United States of America 108(4): 1591-1596, 2011

Infantile bilateral striatal necrosis. Journal of Pediatrics 119(4): 675, 1991

Bilateral infantile striatal necrosis. Anales Espanoles de Pediatria 35(1): 55-58, 1991

A type I interferon signature in monocytes is associated with poor response to interferon-beta in multiple sclerosis. Brain 132(Pt 12): 3353-3365, 2010

Ubiquitin-dependent Turnover of Adenosine Deaminase Acting on RNA 1 (ADAR1) Is Required for Efficient Antiviral Activity of Type I Interferon. Journal of Biological Chemistry 291(48): 24974-24985, 2016

Correlation of cutaneous disease activity with type 1 interferon gene signature and interferon β in dermatomyositis. British Journal of Dermatology 176(5): 1224-1230, 2016

Relevance of the type I interferon signature in multiple sclerosis towards a personalized medicine approach for interferon-beta therapy. Discovery Medicine 15(80): 51-60, 2013

Infantile bilateral striatal necrosis following measles. Brain & Development 22(4): 221-223, June, 2000

Serial MRI in infantile bilateral striatal necrosis. Pediatric Neurology 10(2): 157-160, 1994