EIF2AK2 missense variants associated with early-onset generalized dystonia.

OBJECTIVE To identify a monogenic cause of early-onset, generalized dystonia. METHODS Genome-wide linkage analysis, exome and Sanger sequencing, clinical neurological examination, brain MRI, and protein expression studies in skin fibroblasts from patients. RESULTS We identified a heterozygous variant, c.388G>A, p.Gly130Arg in the Eukaryotic Translation Initiation Factor 2 Alpha Kinase 2 (EIF2AK2) gene, segregating with early-onset isolated generalized dystonia in five patients of a Taiwanese family. EIF2AK2 sequencing in 191 unrelated patients with unexplained dystonia yielded two unrelated Caucasian patients with an identical heterozygous c.388G>A, p.Gly130Arg variant, occurring de novo in one case, another patient carrying a different heterozygous variant, c.413G>C, p.Gly138Ala, and one last patient, born from consanguineous parents, carrying a third, homozygous variant c.95A>C, p.Asn32Thr. These three missense variants are absent from gnomAD, and are located in functional domains of the encoded protein. In three patients, additional neurological manifestations were present, including intellectual disability and spasticity. EIF2AK2 encodes a kinase (PKR) that phosphorylates the Eukaryotic Translation Initiation Factor 2 Alpha (eIF2α), which orchestrates the cellular stress response. Our expression studies showed abnormally enhanced activation of the cellular stress response, monitored by PKR-mediated phosphorylation of eIF2α, in fibroblasts from patients with EIF2AK2 variants. Intriguingly, PKR can also be regulated by PRKRA, the product of another gene causing monogenic dystonia. INTERPRETATION We identified EIF2AK2 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 eIF2α pathway in the pathogenesis of dystonia. This article is protected by copyright. All rights reserved.