title: BRAT1-associated neurodegeneration: Intra-familial phenotypic differences in siblings.
abstract: Recessive mutations in BRAT1 cause lethal neonatal rigidity and multifocal seizure syndrome, a phenotype characterized by neonatal microcephaly, hypertonia, and refractory epilepsy with premature death by age 2 years. Recently, attenuated disease variants have been described, suggesting that a wider clinical spectrum of BRAT1-associated neurodegeneration exists than was previously thought. Here, we report two affected siblings with compound heterozygous truncating mutations in BRAT1 and intra-familial phenotypic heterogeneity, with a less severe disease course in the female sibling. This phenotypic variability should be taken into account when treating patients with BRAT1-associated neurodegenerative disease. Mildly affected individuals with BRAT1 mutations show that BRAT1 must be considered as a cause in childhood refractory epilepsy and microcephaly with survival beyond infancy. © 2016 Wiley Periodicals, Inc.
authors.affiliation: Department of Neurology, Women's and Children's Health Network, Adelaide, South Australia, Australia.|School of Medicine, University of Adelaide, South Australia, Australia.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Smith
authors.affiliation: Department of Anatomical Pathology, SA Pathology, Adelaide, South Australia, Australia.
authors.forename: Jill
authors.initials: J
authors.lastname: Lipsett
authors.affiliation: Epilepsy Research Program, School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, South Australia, Australia.|Sansom Institute for Health Research, University of South Australia, Adelaide, South Australia, Australia.|Centre for Cancer Biology, University of South Australia, Adelaide, South Australia, Australia.
authors.forename: Leanne M
authors.initials: LM
authors.lastname: Dibbens
authors.affiliation: Epilepsy Research Program, School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, South Australia, Australia. sarah.heron@unisa.edu.au.|Sansom Institute for Health Research, University of South Australia, Adelaide, South Australia, Australia. sarah.heron@unisa.edu.au.|Centre for Cancer Biology, University of South Australia, Adelaide, South Australia, Australia. sarah.heron@unisa.edu.au.
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Heron
mesh_terms: D017668:Age of Onset; D000483:Alleles; D059472:Exome; D017809:Fatal Outcome; D005260:Female; D005808:Genes, Recessive; D056726:Genetic Association Studies; D056426:Genetic Loci; D005838:Genotype; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007223:Infant; D008297:Male; D009154:Mutation; D019636:Neurodegenerative Diseases / Q000175:diagnosis* / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D035781:Siblings
chemical_list: C573230:BRAT1 protein, human; D009687:Nuclear Proteins
keywords: BRAT1; microcephaly; multifocal seizures; neurodegeneration