Early onset or syndromic epilepsy

Gene: ATP1A2

I don't know

Familial hemiplegic migraine not epilepsy or a seizure per se. PMID 29610157 provides a case with partial seizures. There have been reports of other cases where epilepsy was a feature reported in the literature, e.g. PMIDs 23918834, 24097848, 23838748

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
Alternating hemiplegia of childhood 1, 104290 ; Migraine familial basilar, 602481 ; Migraine, familial hemiplegic, 2, 602481

Publications

• 15159495

I don't know

As discussed with members of the GMS Neurology Specialist Test Group on the Webex call Thursday 8th August 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that there is sufficient evidence to rate this gene Green. Kept rating as Green.

Created: 15 Aug 2019, 10:04 a.m. | Last Modified: 15 Aug 2019, 10:04 a.m.

Panel Version: 1.228

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: Alison Callaway and John Taylor. Suggested gene rating: Amber.

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

Panel Version: 1.189

Comment on list classification: Updated rating from Amber to Green after discussion with Sarah Leigh; Sufficient cases from PMIDs:28058944, 18028407 and 12953268 of patients with familial hemiplegic migraine (FHM) also exhibiting seizures; PMID:28058944 (Prontera et al., 2018) calculate a co-occurrence of ~30%.

Created: 16 May 2019, 3:29 p.m.

PMID:28058944 (Prontera et al., 2018) performed a review of the comorbidities of familial/sporadic hemiplegic migraine with seizure/epilepsy in patients with CACNA1A, ATP1A2 or SCN1A mutations. For patients carrying ATP1A2 variants, 30.9% of migraine patients also had seizures 62/180 patients (the 180 patients covered 27 families).

Created: 16 May 2019, 3:02 p.m.

Vanmolkot et al., 2003 (PMID:12953268) describe novel variants in ATP1A2 in two families with FHM. The M731T variant was found in a family with pure FHM. The R689Q variant was identified in a family in which FHM and benign familial infantile convulsions partially cosegregate; all available affected family members with FHM, benign familial infantile convulsions, or both, carried the ATP1A2 mutation.

Created: 16 May 2019, 2:59 p.m.

PMID:18028407 (Deprez et al., 2008) found ATP1A2 variants in 2/20 families (p.Gly900Arg and p.Cys702Tyr). In the two families, 6 variant carriers had the combination of epilepsy and migraine, 2 had only epilepsy, and 6 had only migraine.

Created: 16 May 2019, 2:59 p.m.

Comment on phenotypes: OMIM reports Generalized tonic-clonic seizures in 50% patients with 'Alternating hemiplegia of childhood 1' (MIM:104290) but says seizures are less common in Migraine, familial basilar/Migraine, familial hemiplegic, 2 (OMIM:602481).

Created: 16 May 2019, 2:59 p.m.

PMID:29610157 (Ueda et al., 2018) report a 12 year old boy with a history of complex partial seizures, ADHD and fine motor difficulty. WES revealed a de novo missense variant in ATP1A2, and a maternally inherited POLG VUS. The authors hypothesize that the ATP1A2 variant contributed to the patient's phenotype.

Created: 16 May 2019, 2:58 p.m.

Comment on publications: PMID:9579893 (Terwindt et al., 1997) studied a large Dutch-Canadian family in which familial hemiplegic migraine (FHM) and a benign familial infantile epileptic syndrome concur and partially cosegregate. The genetic basis of the conditions was not finalised. Note that ATP1A2 is on chromosome 1q23.2.

Created: 16 May 2019, 2:54 p.m.

Green List (high evidence)

Currently on Amplexa CHE-113 epilepsy diagnostic panel

Created: 12 Feb 2019, 1:50 p.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Familial hemiplegic migraine; Epilepsy

Publications

• 18028407
• 9579893
• 12953268

Variants in this GENE are reported as part of current diagnostic practice

Green List (high evidence)

This publication says 30% of patients with ATP1A2 mutations and hemiplegic migraine have seizures, and OMIM says 50% of alternating hemiplegia patients have seizures. I think that makes it a common rather than rare feature of these disorders.

Created: 7 Aug 2018, 9:31 a.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Publications

• 28058944

Variants in this GENE are reported as part of current diagnostic practice

Comment on list classification: Associated with phenotype in OMIM, not in G2P. Seizures an uncommon feature of the phenotypes.

Created: 25 Jun 2018, 1:34 p.m.

Red List (low evidence)

Red List (low evidence)

Red List (low evidence)

Red List (low evidence)