{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T21:52:54Z","timestamp":1790545974457,"version":"4.1.0"},"reference-count":37,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2020,12,15]],"date-time":"2020-12-15T00:00:00Z","timestamp":1607990400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100013859","name":"Damp Stiftung","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100013859","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100008383","name":"Stichting ParkinsonFonds","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100008383","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Annals of Neurology"],"published-print":{"date-parts":[[2021,3]]},"abstract":"<jats:sec><jats:title>Objective<\/jats:title><jats:p>The study was undertaken to identify a monogenic cause of early onset, generalized dystonia.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Methods consisted of genome\u2010wide linkage analysis, exome and Sanger sequencing, clinical neurological examination, brain magnetic resonance imaging, and protein expression studies in skin fibroblasts from patients.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We identified a heterozygous variant, c.388G&gt;A, p.Gly130Arg, in the eukaryotic translation initiation factor 2 alpha kinase 2 (<jats:italic>EIF2AK2<\/jats:italic>) gene, segregating with early onset isolated generalized dystonia in 5 patients of a Taiwanese family. <jats:italic>EIF2AK2<\/jats:italic> sequencing in 191 unrelated patients with unexplained dystonia yielded 2 unrelated Caucasian patients with an identical heterozygous c.388G&gt;A, p.Gly130Arg variant, occurring de novo in one case, another patient carrying a different heterozygous variant, c.413G&gt;C, p.Gly138Ala, and one last patient, born from consanguineous parents, carrying a third, homozygous variant c.95A&gt;C, p.Asn32Thr. These 3 missense variants are absent from gnomAD, and are located in functional domains of the encoded protein. In 3 patients, additional neurological manifestations were present, including intellectual disability and spasticity. <jats:italic>EIF2AK2<\/jats:italic> encodes a kinase (protein kinase R [PKR]) that phosphorylates eukaryotic translation initiation factor 2 alpha (eIF2\u03b1), which orchestrates the cellular stress response. Our expression studies showed abnormally enhanced activation of the cellular stress response, monitored by PKR\u2010mediated phosphorylation of eIF2\u03b1, in fibroblasts from patients with <jats:italic>EIF2AK2<\/jats:italic> variants. Intriguingly, PKR can also be regulated by PRKRA (protein interferon\u2010inducible double\u2010stranded RNA\u2010dependent protein kinase activator A), the product of another gene causing monogenic dystonia.<\/jats:p><\/jats:sec><jats:sec><jats:title>Interpretation<\/jats:title><jats:p>We identified <jats:italic>EIF2AK2<\/jats:italic> variants implicated in early onset generalized dystonia, which can be dominantly or recessively inherited, or occur de novo. Our findings provide direct evidence for a key role of a dysfunctional eIF2\u03b1 pathway in the pathogenesis of dystonia. 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