Early onset or syndromic epilepsy

Gene: ATP1A3

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)

Missense and inframe del/dup associated with disease. The precise mechanisms for these variants have yet to be determined, however, ATP1A3 dominant negative variants are thought to be associated with disease. See pubmed references.Assoc with AD CAPOS syndrome (cerebellar ataxia, areflexia, pes cavus, optic atrophy and sensorineural hearing loss), AD dystonia-12 and AD alternating hemiplegia of childhood 2 (AHC2). All 3 conditions share some clinical features - part of phenotypic spectrum. AHC2 - rare syndrome of infantile onset of episodic hemi-or quadriplegia - seizures reported as a feature by Heinzen et al, 2012. Rosewich et al, 2012 and Yang et al 2014 - some patients develop epilepsy/seizures - not all. Several papers reported multiple variants and some functional work has been done. Sasaki et al, 2014 - het E185K and het D801N variant in 12 (36%) and 10(30%) of 33 Japanese patients with AHC2 (11 other missense variants were detected in the other individuals). all de novo. E815K seemed to have a more severe disese course - neonatal onset and seizures, and only 2/10 D801N patients had seizures. The other 11 variants appeared to be more phenotypically similar to D801N although epilepsy was seen in some.

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 2, 614820; CAPOS syndrome,601338; Dystonia-12, 128235

Publications

• 25656163
• 24739246
• 29291920
• 30392841

Mode of pathogenicity
Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype -please provide details in the comments

Green List (high evidence)

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

Phenotypes
Alternating hemiplegia of childhood 2; Catastrophic epilepsy, unusual apnea spells, and postnatal microcephaly; Dystonia-12; CAPOS Syndrome (recurrent mutation)

Publications

• Heinzen et al (2012) Nature Genet 44(9): 1030-1035
• de Carvalho Aguiar et al (2004) Neuron 43: 169-175
• Demos et al (2014) Orphanet Journal of Rare Diseases 2014, 9:15

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

Green List (high evidence)

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

Phenotypes
Alternating hemiplegia of childhood 2; Catastrophic epilepsy, unusual apnea spells, and postnatal microcephaly; Dystonia-12; CAPOS Syndrome (recurrent mutation)

Publications

• Heinzen et al (2012) Nature Genet 44(9): 1030-1035
• de Carvalho Aguiar et al (2004) Neuron 43: 169-175
• Demos et al (2014) Orphanet Journal of Rare Diseases 2014, 9:15

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

Green List (high evidence)

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

Phenotypes
Alternating hemiplegia of childhood 2; Catastrophic epilepsy, unusual apnea spells, and postnatal microcephaly; Dystonia-12; CAPOS Syndrome (recurrent mutation)

Publications

• Heinzen et al (2012) Nature Genet 44(9): 1030-1035
• de Carvalho Aguiar et al (2004) Neuron 43: 169-175
• Demos et al (2014) Orphanet Journal of Rare Diseases 2014, 9:15

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

Green List (high evidence)

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

Phenotypes
Alternating hemiplegia of childhood 2; Catastrophic epilepsy, unusual apnea spells, and postnatal microcephaly; Dystonia-12; CAPOS Syndrome (recurrent mutation)

Publications

• Heinzen et al (2012) Nature Genet 44(9): 1030-1035
• de Carvalho Aguiar et al (2004) Neuron 43: 169-175
• Demos et al (2014) Orphanet Journal of Rare Diseases 2014, 9:15

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

Comment on mode of inheritance: Changed to not imprinted after checking imprinted gene list.

Created: 17 Dec 2015, 12:37 p.m.