A Recurrent EIF2AK2 Missense Variant Causes Autosomal‐Dominant Isolated Dystonia

Dystonia Linked to EIF4A2 Haploinsufficiency: A Disorder of Protein Translation Dysfunction

“…By molecular and clinical characterization of individuals with heterozygous EIF4A2 variants, we provide evidence for a previously unrecognized monogenic movement disorder. Our findings substantially broaden the clinical spectrum of EIF4A2 ‐associated neurodevelopmental disorders to include dystonia‐predominant manifestations, similar to observations in EIF2AK2 ‐related disease, another condition linked to the protein translation machinery, which is characterized by presentations of both intellectual developmental syndromes 16 and isolated dystonia 15,17 . Our patients′ phenotypes comprised dystonic features of variable severity, tremor, and jerky movements resembling myoclonus.…”

“…Our findings substantially broaden the clinical spectrum of EIF4A2-associated neurodevelopmental disorders to include dystoniapredominant manifestations, similar to observations in EIF2AK2-related disease, another condition linked to the protein translation machinery, which is characterized by presentations of both intellectual developmental syndromes 16 and isolated dystonia. 15,17 Our patients 0 phenotypes comprised dystonic features of variable severity, tremor, and jerky movements resembling myoclonus. The conditions bore some distinct similarities to presentations related to variants in ANO3 (dystonia 24; MIM: 615034) and KCTD17 (dystonia 26; MIM: 616398), with onset in adulthood or adolescence and leading involvement of the upper body (craniocervical region, arms).…”

“…15 Interestingly, the original descriptions of EIF2AK2-related disease were of individuals with neurodevelopmental phenotypes characterized by milestone delay and cognitive dysfunction, 16 followed by discovery of EIF2AK2 variants in patients with dystonia. 15,17 Recently, variants in another component of the protein synthetic pathway, eukaryotic translation initiation factor 4A isoform 2 (eIF4A2, encoded by EIF4A2), were found to lead to neurodevelopmental disorders with developmental delay, intellectual disability, and epilepsy. 18 Especially de novo missense and deletion mutations (besides biallelic variants in two recessive pedigrees) were described, many of which were demonstrated to induce heterozygous loss of eIF4A2 function.…”

“…Furthermore, two upstream regulators of eIF2α have been implicated in hereditary dystonia: biallelic variants in PRKRA cause dystonia 16 (MIM: 612067), 14 whereas dominant EIF2AK2 variants underlie dystonia 33 (MIM: 619687) 15 ; both diseases are thought to arise as a consequence of translation‐inhibition impairments 15 . Interestingly, the original descriptions of EIF2AK2 ‐related disease were of individuals with neurodevelopmental phenotypes characterized by milestone delay and cognitive dysfunction, 16 followed by discovery of EIF2AK2 variants in patients with dystonia 15,17 . Recently, variants in another component of the protein synthetic pathway, eukaryotic translation initiation factor 4A isoform 2 (eIF4A2, encoded by EIF4A2 ), were found to lead to neurodevelopmental disorders with developmental delay, intellectual disability, and epilepsy 18 .…”

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.…”