Abstract
Introduction
Mutations of the ATP1A3 gene are associated with a wide spectrum of neurological disorders including rapid
onset dystonia-parkinsonism and alternating hemiplegia of childhood (AHC). The genotype-phenotype
correlations in these cases remain unclear however. We here report a pediatric case
of catastrophic early life epilepsy, respiratory failure, postnatal microcephaly,
and severe developmental disability associated with a novel heterozygous ATP1A3 mutation.
Subject
A boy with a normal birth to nonconsanguineous parents was transferred to the NICU
due to postnatal respiratory failure at 2 days. He showed extreme hypotonia, episodic
oculomotor abnormality and tachycardia, and frequent epileptic seizures. Mechanical
ventilation was required but his epileptic seizures were intractable to multiple antiepileptic
drugs, including extremely high doses of phenobarbital.
Methods and Results
Whole exome sequencing analysis of the case and his parents identified a de novo heterozygous
mutation in the ATP1A3 gene (c.2736_2738CTTdel, p.Phe913del).
Discussion
The Phe913 residue in the ATP1α3 protein that is deleted in our case is highly conserved
among vertebrates. Notably, an amino acid deletion in the same transmembrane domain
of this protein, p.Val919del, has been reported previously in typical AHC cases, suggesting
that p.Phe913del is a pathogenic mutation. Several reported cases with severe symptoms
and very early onset epilepsy harbor ATP1α3 mutations at structural positions in this
protein that differ from that of Phe913. Further functional studies are required to
clarify the relationship between the loss of Phe913 and the very distinct resulting
phenotype.
Keywords
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References
- Mutations in the Na+/K+-ATPase alpha3 gene ATP1A3 are associated with rapid-onset dystonia parkinsonism.Neuron. 2004; 43: 169-175
- Alternating hemiplegia in childhood: a report of eight patients with complicated migraine beginning in infancy.Pediatrics. 1971; 47: 675-680
- De novo mutations in ATP1A3 cause alternating hemiplegia of childhood.Nat Genet. 2012; 44: 1030-1034
- 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
- A novel recurrent mutation in ATP1A3 causes CAPOS syndrome.Orphanet J Rare Dis. 2014; 9: 15
- Relapsing encephalopathy with cerebellar ataxia related to an ATP1A3 mutation.Dev Med Child Neurol. 2015; 57: 1183-1186
- Novel mutations in ATP1A3 associated with catastrophic early life epilepsy, episodic prolonged apnea, and postnatal microcephaly.Epilepsia. 2015; 56: 422-430
- A PDE3A mutation in familial hypertension and brachydactyly syndrome.J Hum Genet. 2016; 61: 701-703
- Alternating Hemiplegia of Childhood: Retrospective Genetic Study and Genotype-Phenotype Correlations in 187 Subjects from the US AHCF Registry.PLoS ONE. 2015; 10e0127045
- Genotype-phenotype correlations in alternating hemiplegia of childhood.Neurology. 2014; 82: 482-490
- Identification of ATP1A3 Mutations by Exome Sequencing as the Cause of Alternating Hemiplegia of Childhood in Japanese Patients.PLOS ONE. 2013; 8: e56120
- ATP1A3-related epileptic encephalopathy responding to ketogenic diet.Brain Dev. 2018; 40: 433-438
- Early-onset encephalopathy with paroxysmal movement disorders and epileptic seizures without hemiplegic attacks: About three children with novel ATP1A3 mutations.Brain Dev. 2018; 40: 768-774
- Early Life Epilepsy and Episodic Apnea Revealing an ATP1A3 Mutation: Report of a Pediatric Case and Literature Review.Neuropediatrics. 2018; (in press)
Article info
Publication history
Published online: November 01, 2018
Accepted:
October 16,
2018
Received in revised form:
September 12,
2018
Received:
June 6,
2018
Identification
Copyright
© 2018 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.
