Early onset or syndromic epilepsy

Gene: ATP1A2

Green List (high evidence)

Comment on phenotypes: OMIM phenotype updated 2nd Sept 2026.

Created: 2 Sep 2026, 10:06 a.m. | Last Modified: 2 Sep 2026, 10:06 a.m.

Panel Version: 9.76

Comment on mode of inheritance: There are now at least 7 unrelated families reported in literature with biallelic ATP1A2 variants and the 'Fetal akinesia, respiratory insufficiency, microcephaly, polymicrogyria, and dysmorphic facies' syndrome. 2 unrelated individuals presented with epilepsy shortly after birth, and 2 further cases were reported with in-utero seizures. Hence, the mode of inheriatance should be changed from 'MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown' to 'BOTH monoallelic and biallelic, autosomal or pseudoautosomal' at the next update.

Created: 2 Sep 2026, 8:14 a.m. | Last Modified: 2 Sep 2026, 10:04 a.m.

Panel Version: 9.74

BIALLELIC CASES:
PMID: 28811059 Wilbur et al., 2017
Report of a boy who presented at age three months with epilepsy, nonepileptic paroxysmal events, and recurrent hemiplegia. WES identified ATP1A2 comp het variants (p.Arg548Cys) & (p.Arg1008Trp).

PMID: 31608932 Chatron et al., 2019
Report of four cases from 2 independent families with recessive lethal syndromic polymicrogyria. Examination revealed a common pattern associating meningeal arterial calcifications, necrotic and calcified areas in basal ganglia, dentato-olivary dysplasia and severe hypoplasia/agenesis of the pyramidal tracts. Probands from both families were homozygous for unique nonsense variants in ATP1A2.

PMID: 30690204 Monteiro et al., 2020
Report of three newborns from two unrelated families, who died neonatally, presenting in utero with an unusual form of fetal hydrops, seizures and polyhydramnios. At birth they had multiple joint contractures, microcephaly, malformations of cortical development, dysmorphic features and severe respiratory insufficiency. Biallelic LoF variants in ATP1A2 were found on WES.
P1 & P2 - affected sibs, male and female, Brazilian. Seizures developed soon after birth in P1, and in-utero seizures suspected by the mother in P2. P2 was homozygous for NM_000702: c.2104_2105delTG, p.(Cys702Serfs*12). P1 confirmed to be homozygous for the same variant with Sanger seq, unaffected parents were het.
P3 - Hispanic female neonate. Abnormal fetal movements noted, consistent with seizure activity. WES identified a homozygous ATP1A2 c.835del, p.(Arg279Glyfs*4) variant.

PMID: 37870493 Furukawa et al., 2023
Male individual born at 28 weeks, with respiratory distress and tonic seizures soon after birth. At 10 months presented with hypotonia, cryptorchidism, generalised tonic and facial clonic seizures, no eye contact or social responses. Brain MRI showed a markedly simplified gyral pattern. He was compound heterozygous for ATP1A2: c.1234C>T, p.Arg412* & ATP1A2: c.2288G>T, p.Arg763Leu - confirmed in trans.

PMID: 39046620 Hassani & Malekzadeh, 2024
Report of an Iranian consanguineous family with 2 newborn sibs affected by Fetal akinesia, respiratory insufficiency, microcephaly, polymicrogyria, and dysmorphic facies 'FARIMPD' syndrome. Both passed away within the first 24 hrs after birth. Homozygous c.1234C>T, p.Arg412* variant in ATP1A2 found by WES in the newborns.

PMID: 38549198 Burrill et al., 2024
Report of diamniotic twins, one of them affected. Fetal ultrasound and MRI of the affected twin demonstrated microcephaly, severe VM, compression of the corpus callosum, scalp and nuchal thickening, elongated ears, bilateral talipes, right-sided congenital diaphragmatic hernia (CDH), and loss of normal cerebral architecture. The proband passed away within the first hour of life due to respiratory compromise. Postmortem trio WES identified a homozygous ATP1A2 (c.2439+1G>A) variant as causal.

Created: 1 Sep 2026, 4:20 p.m. | Last Modified: 1 Sep 2026, 4:39 p.m.

Panel Version: 9.74

Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal

Phenotypes
Fetal akinesia, respiratory insufficiency, microcephaly, polymicrogyria, and dysmorphic facies, OMIM:619602; fetal akinesia, respiratory insufficiency, microcephaly, polymicrogyria, and dysmorphic facies, MONDO:0859204

Publications

• 28811059
• 31608932
• 30690204
• 37870493
• 38549198
• 39046620

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)