We describe the molecular basis of a distinctive syndrome characterized by infantile stress-induced episodic weakness, ataxia, and sensorineural hearing loss, with permanent areflexia and optic nerve pallor. Whole exome sequencing identified a deleterious heterozygous c.2452 G>A, p.(E818K) variant in the ATP1A3 gene and structural analysis predicted its protein-destabilizing effect. This variant has not been reported in context with rapid-onset dystonia parkinsonism and alternating hemiplegia of childhood, the 2 main diseases associated with ATP1A3. The clinical presentation in the family described here differs categorically from these diseases in age of onset, clinical course, cerebellar over extrapyramidal movement disorder predominance, and peripheral nervous system involvement. While this paper was in review, a highly resembling phenotype was reported in additional patients carrying the same c.2452 G>A variant. Our findings substantiate this variant as the cause of a unique inherited autosomal dominant neurologic syndrome that constitutes a third allelic disease of the ATP1A3 gene.
NicolaidesPAppletonREFryerA. Cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss (CAPOS): a new syndrome. J Med Genet. 1996;33:419–421.
2.
HudsonGAmati-BonneauPBlakelyEL. Mutation of OPA1 causes dominant optic atrophy with external ophthalmoplegia, ataxia, deafness and multiple mitochondrial DNA deletions: a novel disorder of mtDNA maintenance. Brain. 2008;131:329–337.
3.
Yu-Wai-ManPGriffithsPGGormanGS. Multi-system neurological disease is common in patients with OPA1 mutations. Brain. 2010;133:771–786.
4.
DemosMKvan KarnebeekCDRossCJ; FORGE Canada Consortium. A novel recurrent mutation in ATP1A3 causes CAPOS syndrome. Orphanet J Rare Dis. 2014128;9:15.
5.
HomerNMerrimanBNelsonSF. BFAST: an alignment tool for large scale genome resequencing. PLoS One. 20091111;4(11).
6.
LiHHandsakerBWysokerA. 1000 Genome Project Data Processing Subgroup. The Sequence Alignment/Map format and SAMtools. Bioinformatics. 2009815;25(16):2078–2079.
7.
HomerNNelsonSF. Improved variant discovery through local re-alignment of short-read next-generation sequencing data using SRMA. Genome Biol. 2010;11(10).
8.
DePristoMABanksEPoplinR. A framework for variation discovery and genotyping using next-generation DNA sequencing data. Nat Genet. 2011;43:491–498.
9.
NgPCHenikoffS. SIFT: Predicting amino acid changes that affect protein function. Nucleic Acids Res. 2003;31:3812–3814.
10.
OgawaHShinodaTCorneliusFToyoshimaC. Crystal structure of the sodium-potassium pump (Na+,K+-ATPase) with bound potassium and ouabain. Proc Natl Acad Sci USA. 2009;106:13742–13747.
SchymkowitzJBorgJStricherFNysRRousseauFSerranoL. The FoldX web server: an online force field. Nucleic Acids Res. 2005;33:W382–W388.
13.
ShinodaTOgawaHCorneliusFToyoshimaC. Crystal structure of the sodium-potassium pump at 2.4 Å resolution. Nature. 2009;459:446–450.
14.
SubramonySHSchottKRaikeRS. Novel CACNA1A mutation causes febrile episodic ataxia with interictal cerebellar deficits. Ann Neurol. 200312;54(6):725–731.
15.
CoeberghJAFransen van de PutteDESnoeckIN. A new variable phenotype in spinocerebellar ataxia 27 (SCA 27) caused by a deletion in the FGF14 gene. Eur J Paediatr Neurol. 20145;18(3):413–415.
16.
de CarvalhoAPSweadnerKJPennistonJT. Mutations in the Na+/K+-ATPase alpha3 gene ATP1A3 are associated with rapid-onset dystonia parkinsonism. Neuron. 2004;43:169–175.
17.
BrashearADobynsWBde CarvalhoAP. The phenotypic spectrum of rapid-onset dystonia-parkinsonism (RDP) and mutations in the ATP1A3 gene. Brain. 2007;130:828–835.
18.
BrashearAFarlowMRButlerIJKasarskisEJDobynsWB. Variable phenotype of rapid-onset dystonia-parkinsonism. Mov Disord. 1996;11:151–156.
19.
HeinzenELSwobodaKJHitomiY. (the European Alternating Hemiplegia of Childhood (AHC) Genetics Consortium, the Biobancae Registro Clinico per l’Emiplegia Alternante (I.B.AHC) Consortium, the 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;44:1030–1034.
20.
RosewichHThieleHOhlenbuschV. Heterozygous de-novo mutations in ATP1A3 in patients with alternating hemiplegia of childhood: a whole-exome sequencing gene-identification study. Lancet Neurol. 2012;11:764–773.
21.
BrashearAMinkJWHillD. ATP1A3 mutations in infants: a new rapid-onset dystonia–Parkinsonism phenotype characterized by motor delay and ataxia. Dev Med Child Neurol. 2012;54:1065–1067.
22.
BurnsJLandorfKBRyanMMCrosbieJOuvrierRA. Interventions for the prevention and treatment of pes cavus. Cochrane Database Syst Rev. 2007, Issue 4.
23.
DeAndradeMPYokoiFvan GroenTLingrelJBLiY. Characterization of Atp1a3 mutant mice as a model of rapid-onset dystonia with parkinsonism. Behav Brain Res. 2011;216:659–665.
24.
IkedaKSatakeSOnakaT. Enhanced inhibitory neurotransmission in the cerebellar cortex of Atp1a3-deficient heterozygous mice. J Physiol. 2013;591:3433–3449.
25.
KonishiTMendelsohnM. Effect of ouabain on cochlear potentials and endolymph composition in guinea pigs. Acta Otolaryngol.1970;69:192–199.
26.
McleanWJSmithKAGlowatzkiEPyottSJ. Distribution of the Na,K-ATPase α Subunit in the Rat Spiral Ganglion and Organ of Corti. J Assoc Res Otolaryngol. 2009;10:37–49.
27.
DobertsovMHastingsSLSimsTJStimersJRRomanovskyD. Stretch receptor-associated expression of alpha 3 isoform of the Na+, K+-ATPase in rat peripheral nervous system. Neuroscience2003;116:1069–1080.
28.
RoubergueARozeEVuillaumier-BarrotS. The multiple faces of the ATP1A3-related dystonic movement disorder. Mov Disord. 2013;28:1457–1459.
