Early onset or syndromic epilepsy
Gene: ATP1A2
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, 23838748Created: 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
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.
Currently on Amplexa CHE-113 epilepsy diagnostic panelCreated: 12 Feb 2019, 1:50 p.m.
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes
Familial hemiplegic migraine; Epilepsy
Publications
Variants in this GENE are reported as part of current diagnostic practice
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
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.
Gene: atp1a2 has been classified as Green List (High Evidence).
Source Wessex and West Midlands GLH was added to ATP1A2.
Source NHS GMS was added to ATP1A2.
Gene: atp1a2 has been classified as Green List (High Evidence).
Phenotypes for gene: ATP1A2 were changed from Alternating hemiplegia of childhood 1, 104290; Migraine, familial basilar, 602481; Migraine, familial hemiplegic, 2, 602481; benign familial infantile convulsions; epilepsy and migraine; occipitotemporal epilepsy; infantile epileptic syndrome to Alternating hemiplegia of childhood 1, 104290; Migraine, familial basilar, 602481; Migraine, familial hemiplegic, 2, 602481; benign familial infantile convulsions; epilepsy and migraine; occipitotemporal epilepsy; infantile epileptic syndrome
Phenotypes for gene: ATP1A2 were changed from Alternating hemiplegia of childhood 1 104290; Migraine, familial basilar 602481; Migraine, familial hemiplegic, 2 602481 to Alternating hemiplegia of childhood 1, 104290; Migraine, familial basilar, 602481; Migraine, familial hemiplegic, 2, 602481; benign familial infantile convulsions; epilepsy and migraine; occipitotemporal epilepsy; infantile epileptic syndrome
Publications for gene: ATP1A2 were set to 15159495; 29610157
Sarah Leigh: Comment on list classification
Gene: atp1a2 has been classified as Amber List (Moderate Evidence).
Gene: atp1a2 has been classified as Amber List (Moderate Evidence).
Phenotypes for gene: ATP1A2 were set to Alternating hemiplegia of childhood 1 104290; Migraine, familial basilar 602481; Migraine, familial hemiplegic, 2 602481
Publications for gene: ATP1A2 were set to 15159495; 29610157
Mode of inheritance for gene: ATP1A2 was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
ATP1A2 was added to Genetic Epilepsy Syndromes panel. Sources: Expert,Expert Review Red
ATP1A2 was created by Sarah Leigh