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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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.
