De novo EIF2AK1 and EIF2AK2 Variants Are Associated with Developmental Delay, Leukoencephalopathy, and Neurologic Decompensation

D, Mao; Reuter, Chloe; Ruzhnikov, Maura R.Z.; Ae, Beck; Eg, Farrow; Lt, Emrick; Ja, Rosenfeld; Mackenzie, Katherine M.; Robak, Laurie; Wheeler, Matthew T.; Lc, Burrage; Jain, Mahim; P, Liu; Calame, Daniel G.; Küry, Sébastien; Sillesen, Martin; Schmitz-Abe, Klaus; Tonduti, Davide; Spaccini, Luigina; Iascone, Maria; Ca, Genetti; Koenig, MK; M, Graf; Tran, Alyssa A.; Alejandro, Mercedes E.; Lee, Byron; Thiffault, Isabelle; Agrawal, PB; Ja, Bernstein; Hj, Bellen; Ht, Chao

doi:10.1016/j.ajhg.2020.02.016

Cited by 40 publications

(50 citation statements)

References 48 publications

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“…In the same report, it was shown that the EIF2AK2 missense variants encode stable proteins, and the kinase activity of EIF2AK2 is reduced after poly(I:C) treatment in mammalian cell lines and proband‐derived fibroblasts 13 . Although the unaffected stability of the missense EIF2AK2 variants in unstressed cells is in line with our findings, we did not observe reduced kinase activity after poly(I:C) treatment.…”

Section: Discussionsupporting

confidence: 91%

“…Of note, the EIF2AK2 variants identified in this study and those reported in the previous publication 13 are not predicted to be functionally damaging by the majority of in silico prediction algorithms 17 . This phenomenon appears to be largely due to the lack of evolutionary conservation of the EIF2AK2 protein sequence 26,27 .…”

Section: Discussionsupporting

confidence: 46%

“…Recently, de novo missense variants in EIF2AK2 have independently been reported as the cause of a complex neurodevelopmental syndrome that appears to share phenotypic and pathogenic mechanisms with central nervous system hypomyelination/vanishing white matter disease 13 . In 8 patients reported with EIF2AK2 de novo missense variants, the phenotype was dominated by developmental delay, language and cognitive impairment, and white matter alterations.…”

Section: Discussionmentioning

confidence: 99%

“…In 8 patients reported with EIF2AK2 de novo missense variants, the phenotype was dominated by developmental delay, language and cognitive impairment, and white matter alterations. Ataxia, dysarthria, hypotonia, parkinsonism, and seizures were also present in some of them, and dystonia (additional details were not provided) was mentioned in 5 cases 13 . All those 8 patients exhibited neurological regression in the setting of febrile illness or infection.…”

Section: Discussionmentioning

confidence: 99%

“…However, a direct genetic involvement of key components of this pathway in dystonia have remained elusive so far. Very recently, de novo EIF2AK1 and EIF2AK2 missense variants were reported in children with developmental delay, leukoencephalopathy, and neurologic regression following febrile illness, with varying combinations of neurological manifestations, including dystonic features in some 13 . Here, we report the identification of EIF2AK2 variants implicated in the development of early onset generalized dystonia, with or without additional neurological disturbances, and inherited as an autosomal dominant or autosomal recessive trait, or occurring de novo.…”

mentioning

confidence: 85%

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EIF2AK2 Missense Variants Associated with Early Onset Generalized Dystonia

Kuipers

Mandemakers

et al. 2020

Annals of Neurology

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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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Section: Discussionsupporting

confidence: 91%