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A recurrent EIF2AK2 missense variant causes autosomal-dominant isolated dystonia.

Ann Neurol. 2021 Apr 18. doi: 10.1002/ana.26081. Epub ahead of print. PMID: 33866603.

Authors/Editors: Musacchio T, Zech M, Reich MM, Winkelmann J, Volkmann J.
Publication Date: 2021


We read with interest the article by Kuipers and colleagues1, reporting the identification of an EIF2AK2 c.388G>A (p.Gly130Arg) missense variant in 9 individuals with dystonia from 3 families. Although bioinformatics algorithms almost universally predicted a benign impact of the variant2, the authors demonstrated complete co-segregation of c.388G>A (p.Gly130Arg) in 7 affected subjects from the index family and its de-novo occurrence in another pedigree. Moreover, the authors were able to elucidate abnormally increased activation of EIF2AK2 in c.388G>A (p.Gly130Arg)-harboring patient cells, consistent with a gain-of-function effect. Notably, a set of de-novo EIF2AK2 missense variants affecting amino-acid positions other than glycine-130 have been described as causative for a neurodevelopmental syndrome with leukoencephalopathy, developmental delay, and episodic neurologic regression (Fig.1A)3. In an attempt to replicate the association between the EIF2AK2 c.388G>A (p.Gly130Arg) variant and dystonic presentations, we re analyzed whole-exome sequencing data from 953 patients with various forms of dystonia. 


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