EIF2AK2 Missense Variants Associated with Early Onset Generalized Dystonia

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

Possible EIF2AK2‐Associated Stress‐Related Neurological Decompensation with Combined Dystonia and Striatal Lesions

“…Nevertheless, it is localized in the first dsRNA binding motif of the encoded protein, immediately adjacent to amino acid position-32 which is harbored in the same domain and in which two EIF2AK2 variants previously reported as disease-causing are locateda de-novo p.Asn32Ser 1 and a recessively inherited p. Asn32Thr. 2 This, in combination with its absence from healthy individuals in the GnomAD database and the highly suggestive phenotype of stress-associated neurological deterioration in our patient, is supportive of the p.Pro31Arg variant found in our case being pathogenic despite the in silico analyses predictions. The patient is currently 44 years old and her condition has remained static.…”

“…Pathogenic variants in EIF2AK2 have been reported in 24 individuals from 16 families in the literature to date, and all reported cases are summarized in Table S1. 1,2,5,6 Two broad phenotypes have been described. On the less severe end of the spectrum, patients The second phenotype represents a complex neurodevelopmental syndrome encompassing early childhood onset developmental delay combined with movement disorders, spasticity, and seizures in some.…”

“…Variants in EIF2AK2 have been recently associated with a spectrum of neurological disease encompassing early-onset isolated dystonia to childhood-onset developmental delay, fever-related neurological decompensation, movement disorders and leukodystrophy. 1,2 We describe a case with a novel EIF2AK2 variant presenting with childhood onset combined dystonia, feverrelated neurological deterioration and basal ganglia lesions.…”

A Recurrent EIF2AK2 Missense Variant Causes Autosomal‐Dominant Isolated Dystonia

“…The authors declared no conflict of interest. 1 Department of Neurology, University Hospital Würzburg, Würzburg, Germany…”

The importance of genetic testing for dystonia patients and translational research

“…Importantly, through international collaborations and swift searches through already existing WES/ WGS data of dystonia patients, 13 additional individuals with VPS16 disease-causing variants were identified (Steel et al 2020). Along the same lines, large and comprehensive genotype-phenotype data repositories offered and curated by diagnostic genetic testing companies are a powerful resource for identifying new disease genes or evaluating/confirming the clinical significance of the candidate genes or variants (Dulovic-Mahlow et al 2019;Abbasi-Moheb et al 2020;Kuipers et al 2020;Massadeh et al 2020). In turn, these research findings are promptly applied in diagnostic practice and sometimes fewer than 3 months since the initial report of a new disease gene are required for the given gene to become a part of commercial diagnostic gene panels (Lohmann and Klein 2014).…”