TY - JOUR
T1 - Genetic, Phenotypic, and Interferon Biomarker Status in ADAR1-Related Neurological Disease
AU - Rice, Gillian I.
AU - Kitabayashi, Naoki
AU - Barth, Magalie
AU - Briggs, Tracy A.
AU - Burton, Annabel C.E.
AU - Carpanelli, Maria Luisa
AU - Cerisola, Alfredo M.
AU - Colson, Cindy
AU - Dale, Russell C.
AU - Danti, Federica Rachele
AU - Darin, Niklas
AU - De Azua, Begoña
AU - De Giorgis, Valentina
AU - De Goede, Christian G.L.
AU - Desguerre, Isabelle
AU - De Laet, Corinne
AU - Eslahi, Atieh
AU - Fahey, Michael C.
AU - Fallon, Penny
AU - Fay, Alex
AU - Fazzi, Elisa
AU - Gorman, Mark P.
AU - Gowrinathan, Nirmala Rani
AU - Hully, Marie
AU - Kurian, Manju A.
AU - Leboucq, Nicolas
AU - Lin, Jean Pierre S.M.
AU - Lines, Matthew A.
AU - Mar, Soe S.
AU - Maroofian, Reza
AU - Martí-Sanchez, Laura
AU - McCullagh, Gary
AU - Mojarrad, Majid
AU - Narayanan, Vinodh
AU - Orcesi, Simona
AU - Ortigoza-Escobar, Juan Dario
AU - Pérez-Dueñas, Belén
AU - Petit, Florence
AU - Ramsey, Keri M.
AU - Rasmussen, Magnhild
AU - Rivier, François
AU - Rodríguez-Pombo, Pilar
AU - Roubertie, Agathe
AU - Stödberg, Tommy I.
AU - Toosi, Mehran Beiraghi
AU - Toutain, Annick
AU - Uettwiller, Florence
AU - Ulrick, Nicole
AU - Vanderver, Adeline
AU - Waldman, Amy
AU - Livingston, John H.
AU - Crow, Yanick J.
PY - 2017/6/1
Y1 - 2017/6/1
N2 - We investigated the genetic, phenotypic, and interferon status of 46 patients from 37 families with neurological disease due to mutations in ADAR1. The clinicoradiological phenotype encompassed a spectrum of Aicardi-Goutières syndrome, isolated bilateral striatal necrosis, spastic paraparesis with normal neuroimaging, a progressive spastic dystonic motor disorder, and adult-onset psychological difficulties with intracranial calcification. Homozygous missense mutations were recorded in five families. We observed a p.Pro193Ala variant in the heterozygous state in 22 of 23 families with compound heterozygous mutations. We also ascertained 11 cases from nine families with a p.Gly1007Arg dominant-negative mutation, which occurred de novo in four patients, and was inherited in three families in association with marked phenotypic variability. In 50 of 52 samples from 34 patients, we identified a marked upregulation of type I interferon-stimulated gene transcripts in peripheral blood, with a median interferon score of 16.99 (interquartile range [IQR]: 10.64-25.71) compared with controls (median: 0.93, IQR: 0.57-1.30). Thus, mutations in ADAR1 are associated with a variety of clinically distinct neurological phenotypes presenting from early infancy to adulthood, inherited either as an autosomal recessive or dominant trait. Testing for an interferon signature in blood represents a useful biomarker in this context.
AB - We investigated the genetic, phenotypic, and interferon status of 46 patients from 37 families with neurological disease due to mutations in ADAR1. The clinicoradiological phenotype encompassed a spectrum of Aicardi-Goutières syndrome, isolated bilateral striatal necrosis, spastic paraparesis with normal neuroimaging, a progressive spastic dystonic motor disorder, and adult-onset psychological difficulties with intracranial calcification. Homozygous missense mutations were recorded in five families. We observed a p.Pro193Ala variant in the heterozygous state in 22 of 23 families with compound heterozygous mutations. We also ascertained 11 cases from nine families with a p.Gly1007Arg dominant-negative mutation, which occurred de novo in four patients, and was inherited in three families in association with marked phenotypic variability. In 50 of 52 samples from 34 patients, we identified a marked upregulation of type I interferon-stimulated gene transcripts in peripheral blood, with a median interferon score of 16.99 (interquartile range [IQR]: 10.64-25.71) compared with controls (median: 0.93, IQR: 0.57-1.30). Thus, mutations in ADAR1 are associated with a variety of clinically distinct neurological phenotypes presenting from early infancy to adulthood, inherited either as an autosomal recessive or dominant trait. Testing for an interferon signature in blood represents a useful biomarker in this context.
KW - Aicardi-Goutières syndrome
KW - bilateral striatal necrosis
KW - dystonia
KW - idiopathic basal ganglia calcification
KW - spastic paraparesis
UR - http://www.scopus.com/inward/record.url?scp=85017438586&partnerID=8YFLogxK
U2 - 10.1055/s-0037-1601449
DO - 10.1055/s-0037-1601449
M3 - Article
C2 - 28561207
AN - SCOPUS:85017438586
VL - 48
SP - 166
EP - 184
JO - Neuropediatrics
JF - Neuropediatrics
SN - 0174-304X
IS - 3
ER -