Eukaryotic translation initiation factor 2-alpha kinases (EIF2AK) are serine–threonine kinases involved in integrated stress response, a cytoprotective pathway which ensures adaptation of mammalian cells to stress conditions. 1 Among the four members of this protein family, EIF2AK2, also known as Protein Kinase R, is activated by double-stranded RNA (primarily during viral infections), oxidative stress, endoplasmic reticulum (ER) stress, cytokines, and growth factors. 2 By phosphorylating Eukaryotic Translation Initiation Factor 2 Subunit 1 (EIF2S1) in response to cellular stressors, EIF2AK2 negatively regulates mRNA translation and protein synthesis and induces apoptosis. 1, 2 De novo missense variants in the EIF2AK2 gene were first linked to a complex neurological syndrome characterized by developmental delay, language impairment, various combinations of motor manifestations (including cerebellar, pyramidal, and dystonic features), and brain MRI abnormalities (encompassing dysmyelination, thin corpus callosum, and cerebral and/or vermian atrophy) in nine unrelated children in 2020. 3 Intriguingly, all individuals with EIF2AK2 variants exhibited neurological deterioration in the context of febrile illness or infection. 3 In 2021, Kuipers, Musacchio, and respective colleagues reported 13 individuals from six pedigrees carrying heterozygous (autosomal dominantly inherited or de novo) or homozygous EIF2AK2 missense variants which cause early-onset, mostly isolated, generalized dystonia likely through a gain-of-function mechanism. 4, 5 In order to replicate the association between EIF2AK2 mutations and isolated dystonia phenotypes, we retrieved our internal database of approximately 18,000 exomes (522 belonging to subjects recruited under the diagnostic category “dystonia”) and the 100,000 Genomes Project repository (1116 participants enrolled using the Human Phenotype Ontology term “dystonia”) searching for