title: Compound heterozygous BRAT1 mutations cause familial Ohtahara syndrome with hypertonia and microcephaly.
abstract: Homozygous frameshift BRAT1 mutations were found in patients with lethal neonatal rigidity and multifocal seizure syndrome (MIM# 614498). Here, we report on two siblings with compound heterozygous mutations in BRAT1. They had intractable seizures from neonatal period, dysmorphic features and hypertonia. Progressive microcephaly was also observed. Initial electroencephalogram showed a suppression-burst pattern, leading to a diagnosis of Ohtahara syndrome. They both died from pneumonia at 1 year and 3 months, respectively. Whole-exome sequencing of one patient revealed a compound heterozygous BRAT1 mutations (c.176T>C (p.Leu59Pro) and c.962_963del (p.Leu321Profs*81)). We are unable to obtain DNA from another patient. The p.Leu59Pro mutation occurred at an evolutionarily conserved amino acid in a CIDE-N (N-terminal of an cell death-inducing DFF45-like effector) domain, which has a regulatory role in the DNA fragmentation pathway of apoptosis. Our results further support that mutations of BRAT1 could lead to epileptic encephalopathy.
authors.affiliation: Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
authors.forename: Hirotomo
authors.initials: H
authors.lastname: Saitsu
authors.affiliation: Department of Neurology, Kanagawa Children's Medical Center, Yokohama, Japan.
authors.forename: Sumimasa
authors.initials: S
authors.lastname: Yamashita
authors.affiliation: Department of Pathology, Kanagawa Children's Medical Center, Yokohama, Japan.
authors.forename: Yukichi
authors.initials: Y
authors.lastname: Tanaka
authors.affiliation: Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Tsurusaki
authors.affiliation: Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
authors.forename: Mitsuko
authors.initials: M
authors.lastname: Nakashima
authors.affiliation: Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
authors.forename: Noriko
authors.initials: N
authors.lastname: Miyake
authors.affiliation: Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
authors.forename: Naomichi
authors.initials: N
authors.lastname: Matsumoto
mesh_terms: D004827:Epilepsy / Q000235:genetics* / Q000503:physiopathology; D005260:Female; D016368:Frameshift Mutation; D006579:Heterozygote; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D008831:Microcephaly / Q000235:genetics* / Q000401:mortality / Q000503:physiopathology; D009122:Muscle Hypertonia / Q000235:genetics* / Q000401:mortality / Q000503:physiopathology; D009687:Nuclear Proteins / Q000235:genetics*; D035781:Siblings
chemical_list: C573230:BRAT1 protein, human; D009687:Nuclear Proteins