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Novel mutations in ATP1A3 associated with catastrophic early life epilepsy, episodic prolonged apnea, and postnatal microcephaly
Author(s) -
Paciorkowski Alex R.,
McDaniel Sharon S.,
Jansen Laura A.,
Tully Hannah,
Tuttle Emily,
Ghoneim Dalia H.,
Tupal Srinivasan,
Gunter Sonya A.,
Vasta Valeria,
Zhang Qing,
Tran Thao,
Liu Yi B.,
Ozelius Laurie J.,
Brashear Allison,
Sweadner Kathleen J.,
Dobyns William B.,
Hahn Sihoun
Publication year - 2015
Publication title -
epilepsia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.687
H-Index - 191
eISSN - 1528-1167
pISSN - 0013-9580
DOI - 10.1111/epi.12914
Subject(s) - microcephaly , epilepsy , dystonia , apnea , medicine , encephalopathy , parkinsonism , endocrinology , pediatrics , neuroscience , psychology , disease , psychiatry
Summary Objective Mutations of ATP 1A3 have been associated with rapid onset dystonia‐parkinsonism and more recently with alternating hemiplegia of childhood. Here we report one child with catastrophic early life epilepsy and shortened survival, and another with epilepsy, episodic prolonged apnea, postnatal microcephaly, and severe developmental disability. Novel heterozygous mutations (p.Gly358Val and p.Ile363Asn) were identified in ATP 1A3 in these children. Methods Subjects underwent next‐generation sequencing under a research protocol. Clinical data were collected retrospectively. The biochemical effects of the mutations on ATP 1A3 protein function were investigated. Postmortem neuropathologic specimens from control and affected subjects were studied. Results The mutations localized to the P domain of the Na,K‐ ATP ase α3 protein, and resulted in significant reduction of Na,K‐ ATP ase activity in vitro. We demonstrate in both control human brain tissue and that from the subject with the p.Gly358Val mutation that ATP 1A3 immunofluorescence is prominently associated with interneurons in the cortex, which may provide some insight into the pathogenesis of the disease. Significance The findings indicate these mutations cause severe phenotypes of ATP 1A3 ‐related disorder spectrum that include catastrophic early life epilepsy, episodic apnea, and postnatal microcephaly.