Childhood onset dystonia, chorea or related movement disorder

Gene: EIF2AK2

The rating of this gene has been updated following NHS Genomic Medicine Service approval.

Created: 19 Jun 2022, 11:23 p.m. | Last Modified: 19 Jun 2022, 11:23 p.m.

Panel Version: 1.237

Green List (high evidence)

10 individuals reported with complex neurological phenotype including ataxia and spasticity, as already noted.

Additional report in PMID 33236446 of same missense variant, p.Gly130Arg segregating with disease in 5 individuals from one family, and occurring de novo in another individual with prominent, early-onset dystonia. One more individual identified with a homozygous variant and dystonia. Some functional data to support variant pathogenicity. Three of the individuals had additional neurological features including ID.
PMID 33866603: further report of dystonia in a 3-generation family, same variant (p.Gly130Arg)

Created: 12 Jun 2021, 3:20 a.m. | Last Modified: 12 Jun 2021, 3:20 a.m.

Panel Version: 1.126

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Early onset dystonia

Publications

• 33236446
• 33866603

Green List (high evidence)

A further 6 families reported (PMID:33236446; 33866603) harbouring 3 different variants in this gene (including the first homozygous case). Clinical presentation was prominent in all cases for dystonia with onset in infancy or childhood, with subsequent generalisation. Additional clinical details are limited for the family described in PMID:33866603. However, in the remaining families detailed in PMID:33236446, 3 unrelated individuals additionally developed mild ID, spasticity, and brain MRI alterations; while the other 2 families (6 individuals) only had isolated dystonia.

Created: 28 Sep 2021, 3:57 p.m. | Last Modified: 28 Sep 2021, 3:57 p.m.

Panel Version: 1.157

Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.

Created: 3 Aug 2020, 4:36 p.m. | Last Modified: 3 Aug 2020, 4:36 p.m.

Panel Version: 1.8

Association with Developmental Delay, Leukoencephalopathy, and Neurologic Decompensation reported in both OMIM and G2P (probable).

PMID: 32197074 (2020) - Distinct de novo missense variants were identified in eight unrelated individuals who all share a notable phenotypic overlap of developmental delay, cognitive impairment, white matter alterations, dysarthria or lack of speech, and neurologic regression with febrile illness. Other variable features included hypotonia (7/8), hypertonia (7/8), ataxia (6/8), dystonia (5/8), tremor (3/8) and seizures (4/8). Functional data confirm reduced kinase activity compared to the wildtype protein product, and authors predict a dominant-negative effect.
Sources: Literature

Created: 3 Aug 2020, 4:35 p.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Leukoencephalopathy, developmental delay, and episodic neurologic regression syndrome, 618877

Publications

• 32197074
• 33236446
• 33866603