Variants in the ATP1A3 Gene Mutations within Severe Apnea Starting in Early Infancy: An Observational Study of Two Cases with a Possible Relation to Epileptic Activity

Abstract

Mutations in the ATP1A3 gene are known to cause alternating hemiplegia of childhood (AHC) and rapid-onset dystonia parkinsonism (RDP). Both conditions are childhood-onset neurological disorders with distinct symptoms and different times of onset. ATP1A3 has also been associated with CAPOS syndrome (cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss). Within the various ATP1A3-related neurological syndromes, a specific genotype–phenotype correlation is starting to emerge. Several mutations such as the relatively common p.E815K pathogenic variant have been shown to strongly correlate with AHC, while others may cause both AHC and RDP. A significant subset of patients with AHC and RDP are reported to have epileptic seizures. Even though detailed clinical descriptions of seizures in childhood are rare, seizures involving apneic events seem to be frequent in ATP1A3-related neurological disorders. Here, we describe two children with unexplained severe apnea beginning around the first year of life and pathogenic variants in ATP1A3. We hypothesize that the symptoms are early-onset autonomic seizures related to the underlying pathogenic ATP1A3 variants.

Keywords

apnea - epilepsy genetics - autonomic seizures - developmental delay

Disclosure of Conflicts of Interest

None of the authors has any conflict of interest to disclose.

Ethical Publication Statement

We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.

• References

• 1 Dobretsov M, Stimers JR. Neuronal function and alpha3 isoform of the Na/K-ATPase. Front Biosci 2005; 10: 2373-2396
• 2 Sasaki M, Ishii A, Saito Y. , et al. Genotype-phenotype correlations in alternating hemiplegia of childhood. Neurology 2014; 82 (06) 482-490
• 3 Verret S, Steele JC. Alternating hemiplegia in childhood: a report of eight patients with complicated migraine beginning in infancy. Pediatrics 1971; 47 (04) 675-680
• 4 Bourgeois M, Aicardi J, Goutières F. Alternating hemiplegia of childhood. J Pediatr 1993; 122 (5 Pt 1): 673-679
• 5 Rosewich H, Thiele H, Ohlenbusch A. , et al. Heterozygous de-novo mutations in ATP1A3 in patients with alternating hemiplegia of childhood: a whole-exome sequencing gene-identification study. Lancet Neurol 2012; 11 (09) 764-773
• 6 Heinzen EL, Swoboda KJ, Hitomi Y. , et al; European Alternating Hemiplegia of Childhood (AHC) Genetics Consortium; Biobanca e Registro Clinico per l'Emiplegia Alternante (I.B.AHC) Consortium; European Network for Research on Alternating Hemiplegia (ENRAH) for Small and Medium-sized Enterpriese (SMEs) Consortium. De novo mutations in ATP1A3 cause alternating hemiplegia of childhood. Nat Genet 2012; 44 (09) 1030-1034
• 7 Heinzen EL, Arzimanoglou A, Brashear A. , et al; ATP1A3 Working Group. Distinct neurological disorders with ATP1A3 mutations. Lancet Neurol 2014; 13 (05) 503-514
• 8 Demos MK, van Karnebeek CD, Ross CJ. , et al; FORGE Canada Consortium. A novel recurrent mutation in ATP1A3 causes CAPOS syndrome. Orphanet J Rare Dis 2014; 9: 15
• 9 Nicolaides P, Appleton RE, Fryer A. Cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss (CAPOS): a new syndrome. J Med Genet 1996; 33 (05) 419-421
• 10 Roubergue A, Roze E, Vuillaumier-Barrot S. , et al. The multiple faces of the ATP1A3-related dystonic movement disorder. Mov Disord 2013; 28 (10) 1457-1459
• 11 Paciorkowski AR, McDaniel SS, Jansen LA. , et al. Novel mutations in ATP1A3 associated with catastrophic early life epilepsy, episodic prolonged apnea, and postnatal microcephaly. Epilepsia 2015; 56 (03) 422-430
• 12 Lek M, Karczewski KJ, Minikel EV. , et al; Exome Aggregation Consortium. Analysis of protein-coding genetic variation in 60,706 humans. Nature 2016; 536 (7616): 285-291
• 13 Yang X, Gao H, Zhang J. , et al. ATP1A3 mutations and genotype-phenotype correlation of alternating hemiplegia of childhood in Chinese patients. PLoS One 2014; 9 (05) e97274
• 14 Goldberg-Stern H, Aharoni S, Afawi Z. , et al. Broad phenotypic heterogeneity due to a novel SCN1A mutation in a family with genetic epilepsy with febrile seizures plus. J Child Neurol 2014; 29 (02) 221-226
• 15 Trump N, McTague A, Brittain H. , et al. Improving diagnosis and broadening the phenotypes in early-onset seizure and severe developmental delay disorders through gene panel analysis. J Med Genet 2016; 53 (05) 310-317