Early onset or syndromic epilepsy

Gene: ATP1A1

I don't know

Review and rating collated by Tracy Lester (Oxford Medical Genetics Laboratories Oxford University Hospitals NHS Foundation Trust, 2019_02_06) on behalf of Wessex and West Midlands GLH for GMS Neurology specialist test group, for Clinical Indication R59 'Early onset or syndromic epilepsy'. Review contributors: John Taylor and Helen Lord. Suggested gene rating: Green.

Created: 6 Aug 2019, 8:38 p.m. | Last Modified: 6 Aug 2019, 8:38 p.m.

Panel Version: 1.189

Green List (high evidence)

AD Familial hemiplegic migraine. Seizures are a less common feature according to OMIM. Marconi et al, 2003 - 2 Italian families with AD FHM, 1 large family had multiple affected over 6 generations - both had point mutations that segregate with disease and functional studies undertaken. All had similar clinical features - 5 patients had seizures. Spadaro et al, 2004 - Italian family (8 generations) - proband reported to have tonic-clonic seizures- in paper 5/8 had seizures. Riant et al, 2010 - pathogenic de novo variants found in 11/25 patients with sporadic hemiplegic migraine before 16 years. 5/11 seizures.

Created: 6 Aug 2019, 8:31 p.m. | Last Modified: 6 Aug 2019, 8:31 p.m.

Panel Version: 1.188

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Charcot-Marie-Tooth disease, axonal, type 2DD, 618036

Publications

• 30388404

Comment when marking as ready: Not associated with phenotype in OMIM or in Gen2Phen. Three heterozygous de novo variants reported in three unrelated cases manifesting with refractory seizures, severe hypomagnesemia and severe intellectual disability. Supportive in vitro studies were also presented.

Created: 18 Nov 2018, 10:35 p.m.

Green List (high evidence)

PMID: 30388404 reports on 3 subjects from 3 families with de novo pathogenic variants in ATP1A1. All 3 presented with similar phenotype consisting of hypomagnesemia, early onset refractory seizures as well as intellectual disability.

Alternative causes of hypomagnesemia with seizures (eg. due to TRPM6 mutations) were excluded while the phenotype of the 3 patients differed from similar disorder in that hypomagnesemia as well as seizures were not responsive to magnesium supplementation.

Three different missense variants are reported (L302R, G303R, M859R) all as de novo occurences and after confirmation of paternity.

Functional studies were suggestive of loss of the ATPase function, abnormal cation permeabilities as well as reduced level of expression (the latter was significant for at least for 2 of the 3 variants).

Mutations in ATP1A1 have also been reported in patients with Charcot-Marie-Tooth type 2 (CMT2DD - MIM: 618036) although the variants reported to date map seem to cluster within the helical linker region (residues 592 to 608). The young age of the patients with epilepsy and intellectual disability did not allow conclusions on eventual peripheral neuropathy in these individuals.

As a result this gene can be considered for inclusion in this panel as green (or amber).
Sources: Literature, Expert Review

Created: 16 Nov 2018, 8:53 p.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Phenotypes
Hypomagnesemia; Seizures; Intellectual disability

Publications

• 30388404