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

Abstract

Background Background: Variants in EIF2AK2 have been recently associated with a spectrum of neurological disease encompassing isolated dystonia to fever-related neurological decompensation, movement disorders and leukodystrophy. Case Case: A 32-year old patient presented with childhood-onset episodes of neurological decompensation after febrile illness, progressive anarthria, dystonia and spasticity. The T2/FLAIR MRI showed bilateral posterolateral putamen hyperintensities and white matter changes suggestive of leukodystrophy. Initial extensive metabolic workup and whole genome sequencing (WGS) was unremarkable. Re-analysis of the WGS data revealed a variant in exon 3 of the EIF2AK2 gene [(NM_001135651.3): c.92C > G (p.Pro31Arg)]. EIF2AK2-associated disorders should be incorporated into the differential diagnosis of the syndrome of fever-related neurological decompensation with movement disorders, especially in the presence of abnormal neuroimaging. Literature review Literature review: Disease-causing variants in EIF2AK2 have been reported in 24 individuals from 16 families in the literature to date. Two broad phenotypes have been described, including: (1) childhood-onset generalized dystonia and a normal brain MRI; and (2) early childhood-onset developmental delay combined with movement disorders, spasticity, and seizures in some. Notably, 92% of these patients have neurological deterioration after febrile illness or other physiological stress. Hypomyelination or delayed myelination and thin corpus callosum are seen in most patients and lower medullary lessions are common. Basal ganglia lesions have been reported previously in one case. Conclusions Conclusions: EIF2AK2-associated disorders should be incorporated into the differential diagnosis of the syndrome of fever-related neurological decompensation with movement disorders, especially in the presence of abnormal neuroimaging.

A Recurrent De Novo Variant in EIF2AK2 Causes a Hypomyelinating Leukodystrophy

“… 3 Variants in EIF2AK2 have likewise been identified in the molecular pathology of early-onset generalized dystonia (OMIM #619687), with either autosomal recessive or autosomal dominant inheritance, or occurring de novo . 6 - 9 In these cases, dystonia is seen isolated from other neurological features and the variants are found at distinct residues, although at least one variant has been reported as common between the two disorders. 3 , 6 We suggest that EIF2AK2-related disorders have a disease spectrum and that this spectrum might expand as more individuals with pathogenic variants in this gene are uncovered.…”

The integrated stress response pathway and neuromodulator signaling in the brain: lessons learned from dystonia

“…The convergent findings of ISR dysfunction across 3 forms of dystonia was pivotal to supporting a causal role for the ISR and led to the hypothesis that weakened ISR activation is a shared pathway mechanism for dystonia ( 5 ). A subsequent human genetic association of dystonia with mutations in the EIF2AK2 gene, which encodes the PKR kinase ( 23 – 27 ), further established the link between dystonia and the ISR. While a recent association of dystonia with mutation in the EIF4A2 gene ( 28 ) highlights the functional intersection between dystonia and the translational initiation process.…”

“… 32 ]). Human genes associated with effects on the ISR, or translational initiation, that present with clinical phenotypes of dystonia include PKR ( EIF2AK2 ) ( 23 – 27 ), EIF2B ( 42 , 95 ), ATF4 ( 5 ), EIF4A2 ( 28 ), and a range of tRNA synthetase genes associated with mitochondrial disorders ( 33 – 41 ) (e.g., AARS1 , AARS2 , CARS2 , EARS2 , WARS2 , TARS2 ). Activation of the ISR results in phosphorylation of the α subunit of eIF2 and reduces the rate of eIF2B-mediated GDP/GTP exchange of eIF2, preventing the formation of the ternary complex (TC) (GTP-eIF2-Met tRNA).…”

The apparent paradox of phenotypic diversity and shared mechanisms across dystonia syndromes

“…Of note, EIF2AK2 activity is regulated by the interferon-inducible double-stranded RNA-dependent protein kinase activator A, whose mutations cause a rare form of young onset parkinsonism-dystonia [49,50]. To further support the molecular link with stress response, fever-induced decompensation has recently been described in a patient carrying an EIF2AK2 novel variant [51,52].…”