2. Academic Validation
  3. EIF2AK2 Missense Variants Associated with Early Onset Generalized Dystonia

EIF2AK2 Missense Variants Associated with Early Onset Generalized Dystonia

  • Ann Neurol. 2021 Mar;89(3):485-497. doi: 10.1002/ana.25973.
Demy J S Kuipers 1,  Wim Mandemakers 1,  Chin-Song Lu 2 3,  Simone Olgiati 1,  Guido J Breedveld 1,  Christina Fevga 1,  Vera Tadic 4,  Miryam Carecchio 5 6,  Bradley Osterman 7,  Lena Sagi-Dain 8,  Yah-Huei Wu-Chou 9,  Chiung C Chen 3 10,  Hsiu-Chen Chang 2 3,  Shey-Lin Wu 11,  Tu-Hsueh Yeh 12 13,  Yi-Hsin Weng 3 10,  Antonio E Elia 14,  Celeste Panteghini 5,  Nicolas Marotta 15,  Martje G Pauly 4,  Andrea A Kühn 16,  Jens Volkmann 17,  Baiba Lace 18,  Inge A Meijer 19,  Krishna Kandaswamy 20,  Marialuisa Quadri 1 21,  Barbara Garavaglia 5,  Katja Lohmann 4,  Peter Bauer 20,  Niccolò E Mencacci 15,  Steven J Lubbe 15,  Christine Klein 4,  Aida M Bertoli-Avella 20,  Vincenzo Bonifati 1
Affiliations

Affiliations

  • 1 Department of Clinical Genetics, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands.
  • 2 Professor Lu Neurological Clinic, Taoyuan, Taiwan.
  • 3 Section of Movement Disorders, Department of Neurology and Neuroscience Research Center, Chang Gung Memorial Hospital, Taoyuan, Taiwan.
  • 4 Institute of Neurogenetics, University of Lübeck, Lübeck, Germany.
  • 5 Medical Genetics and Neurogenetics Unit, Fondazione IRCCS Istituto Neurologico C. Besta, Milan, Italy.
  • 6 Department of Neuroscience, University of Padua, Padua, Italy.
  • 7 Division of Child Neurology, Department of Pediatrics, Montreal Children's Hospital, McGill University Health Centre, Montreal, Quebec, Canada.
  • 8 Genetics Institute, Carmel Medical Center, Ruth and Bruce Rappaport Faculty of Medicine, Technion, Israel Institute of Technology, Haifa, Israel.
  • 9 Department of Medical Research, Chang Gung Memorial Hospital, Taoyuan, Taiwan.
  • 10 Department of Medicine, Chang Gung University, Taoyuan, Taiwan.
  • 11 Department Neurology, Changhua Christian Hospital, Chunghua, Taiwan.
  • 12 Department of Neurology, Taipei Medical University Hospital, Taipei, Taiwan.
  • 13 School of Medicine, Taipei Medical University, Taipei, Taiwan.
  • 14 Department of Clinical Neurosciences, Parkinson and Movement Disorders Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy.
  • 15 Ken and Ruth Davee Department of Neurology and Simpson Querry Center for Neurogenetics, Northwestern University, Feinberg School of Medicine, Chicago, IL, USA.
  • 16 Department of Neurology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität of Berlin and Humboldt, Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.
  • 17 Department of Neurology, University Hospital Würzburg, Würzburg, Germany.
  • 18 Centre Hospitalier Universitaire de Québec, Quebec City, Quebec, Canada.
  • 19 Department of Neurosciences and Pediatrics, Centre Hospitalier Universitaire Sainte-Justine, University of Montreal, Montreal, Quebec, Canada.
  • 20 Centogene AG, Rostock, Germany.
  • 21 Janssen Vaccines and Prevention, Leiden, the Netherlands.
PMID: 33236446 DOI: 10.1002/ana.25973
Abstract

Objective: The study was undertaken to identify a monogenic cause of early onset, generalized dystonia.

Methods: Methods consisted of genome-wide linkage analysis, exome and Sanger Sequencing, clinical neurological examination, brain magnetic resonance imaging, 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 5 patients of a Taiwanese family. EIF2AK2 Sequencing in 191 unrelated patients with unexplained dystonia yielded 2 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 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. EIF2AK2 encodes a kinase (protein kinase R [PKR]) that phosphorylates 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 (protein interferon-inducible double-stranded RNA-dependent protein kinase activator A), 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. ANN NEUROL 2021;89:485-497.

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