A case of early onset life-threatening epilepsy associated with a novel ATP1A3 gene variant

Naoko Ishihara, Hidehito Inagaki, Misa Miyake, Yoshiki Kawamura, Tetsushi Yoshikawa, Hiroki Kurahashi

Research output: Contribution to journalArticle

1 Citation (Scopus)

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.

Original languageEnglish
Pages (from-to)285-291
Number of pages7
JournalBrain and Development
Volume41
Issue number3
DOIs
Publication statusPublished - 01-03-2019

Fingerprint

Epilepsy
Mutation
Genes
Respiratory Insufficiency
Parents
Exome
Microcephaly
Developmental Disabilities
Muscle Hypotonia
Genetic Association Studies
Phenobarbital
Nervous System Diseases
Artificial Respiration
Tachycardia
Anticonvulsants
Vertebrates
Proteins
Parturition
Pediatrics
Phenotype

All Science Journal Classification (ASJC) codes

  • Pediatrics, Perinatology, and Child Health
  • Developmental Neuroscience
  • Clinical Neurology

Cite this

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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.",
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A case of early onset life-threatening epilepsy associated with a novel ATP1A3 gene variant. / Ishihara, Naoko; Inagaki, Hidehito; Miyake, Misa; Kawamura, Yoshiki; Yoshikawa, Tetsushi; Kurahashi, Hiroki.

In: Brain and Development, Vol. 41, No. 3, 01.03.2019, p. 285-291.

Research output: Contribution to journalArticle

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