Please use this identifier to cite or link to this item: http://hdl.handle.net/2440/103919
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dc.contributor.authorCorbett, M.en
dc.contributor.authorBellows, S.en
dc.contributor.authorLi, M.en
dc.contributor.authorCarroll, R.en
dc.contributor.authorMicallef, S.en
dc.contributor.authorCarvill, G.en
dc.contributor.authorMyers, C.en
dc.contributor.authorHowell, K.en
dc.contributor.authorMaljevic, S.en
dc.contributor.authorLerche, H.en
dc.contributor.authorGazina, E.en
dc.contributor.authorMefford, H.en
dc.contributor.authorBahlo, M.en
dc.contributor.authorBerkovic, S.en
dc.contributor.authorPetrou, S.en
dc.contributor.authorScheffer, I.en
dc.contributor.authorGecz, J.en
dc.date.issued2016en
dc.identifier.citationNeurology, 2016; 87(19):1975-1984en
dc.identifier.issn0028-3878en
dc.identifier.issn1526-632Xen
dc.identifier.urihttp://hdl.handle.net/2440/103919-
dc.description.abstractOBJECTIVE: To identify the genetic basis of a family segregating episodic ataxia, infantile seizures, and heterogeneous epilepsies and to study the phenotypic spectrum of KCNA2 mutations. METHODS: A family with 7 affected individuals over 3 generations underwent detailed phenotyping. Whole genome sequencing was performed on a mildly affected grandmother and her grandson with epileptic encephalopathy (EE). Segregating variants were filtered and prioritized based on functional annotations. The effects of the mutation on channel function were analyzed in vitro by voltage clamp assay and in silico by molecular modeling. KCNA2 was sequenced in 35 probands with heterogeneous phenotypes. RESULTS: The 7 family members had episodic ataxia (5), self-limited infantile seizures (5), evolving to genetic generalized epilepsy (4), focal seizures (2), and EE (1). They had a segregating novel mutation in the shaker type voltage-gated potassium channel KCNA2 (CCDS_827.1: c.765_773del; p.255_257del). A rare missense SCN2A (rs200884216) variant was also found in 2 affected siblings and their unaffected mother. The p.255_257del mutation caused dominant negative loss of channel function. Molecular modeling predicted repositioning of critical arginine residues in the voltage-sensing domain. KCNA2 sequencing revealed 1 de novo mutation (CCDS_827.1: c.890G>A; p.Arg297Gln) in a girl with EE, ataxia, and tremor. CONCLUSIONS: A KCNA2 mutation caused dominantly inherited episodic ataxia, mild infantile-onset seizures, and later generalized and focal epilepsies in the setting of normal intellect. This observation expands the KCNA2 phenotypic spectrum from EE often associated with chronic ataxia, reflecting the marked variation in severity observed in many ion channel disorders.en
dc.description.statementofresponsibilityMark A. Corbett, Susannah T. Bellows, Melody Li, Renée Carroll, Silvana Micallef, Gemma L. Carvill, Candace T. Myers, Katherine B. Howell, Snezana Maljevic, Holger Lerche, Elena V. Gazina, Heather C. Mefford, Melanie Bahlo, Samuel F. Berkovic, Steven Petrou, Ingrid E. Scheffer, Jozef Geczen
dc.language.isoenen
dc.publisherLIPPINCOTT WILLIAMS & WILKINSen
dc.rights© 2016 American Academy of Neurologyen
dc.subjectOocytes; Animals; Xenopus laevis; Humans; Epilepsy; Ataxia; Anticonvulsants; Cohort Studies; DNA Mutational Analysis; Pharmacogenetics; Membrane Potentials; Mutation; Models, Chemical; Aged; Middle Aged; Child; Child, Preschool; Infant; Family Health; Female; Male; Kv1.2 Potassium Channel; Young Adulten
dc.titleDominant KCNA2 mutation causes episodic ataxia and pharmacoresponsive epilepsyen
dc.typeJournal articleen
dc.identifier.rmid0030056722en
dc.identifier.doi10.1212/WNL.0000000000003309en
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/628952en
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/1054618en
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/1041920en
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/1002098en
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/1104831en
dc.identifier.pubid274631-
pubs.library.collectionMedicine publicationsen
pubs.library.teamDS14en
pubs.verification-statusVerifieden
pubs.publication-statusPublisheden
dc.identifier.orcidCorbett, M. [0000-0001-9298-3072]en
dc.identifier.orcidCarroll, R. [0000-0002-6979-3710]en
dc.identifier.orcidGecz, J. [0000-0002-7884-6861]en
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