Genetic, Phenotypic, and Interferon Biomarker Status in ADAR1-Related Neurological Disease.

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.
Competing Interests: Authors' Contributions: J.H.L. and Y.J.C. collated and reviewed all clinical and radiological data. G.I.R. performed quantitative PCR analysis, with assistance from N.K., M.B., T.A.B., A.C.E.B., M.L.C., A.M.C., C.C., R.C.D., F.R.D., N.D., B. De A., V. De G., C.G.E.L. De G., I.D., C De L., A.E., M.C.F., P.F., A.F., E.F., M.P.G., N.R.G., M.H., M.A.K., N.L., J.-P.S.-M.L., M.A.L., S.S.M., R.M., L.M.-S., G.M., M.M., V.N., S.O., J.D.O.-E., B.P.-D., F.P., K.M.R., M.R., F.R., P.R.-P., A.R., T.I.S., M.B.T., A.T., F.U., N.U., A.V., and A.W. provided clinical samples and critically reviewed clinical and immunological patient data. Y.J.C. conceived the study and wrote the initial draft with the assistance of G.I.R. All authors critically reviewed the article and agreed to its publication. Financial Disclosure None of the authors have any financial disclosure to report.
(Georg Thieme Verlag KG Stuttgart · New York.)