BRAT1 mutations are associated with infantile epileptic encephalopathy, mitochondrial dysfunction, and survival into childhood.
We describe two siblings who were affected with early onset focal seizures, severe progressive postnatal microcephaly, muscular hypertonia, feeding problems and bouts of apnea, only minimal psychomotor development, as well as death in infancy and childhood. We identified compound heterozygous mutations in BRAT1 exons 5 (c.638_639insA) and 8 (c.1134+1G>A) in one affected child via next-generation sequencing of the disease-associated genome followed by phenotype-driven bioinformatic analysis. Sanger sequencing confirmed the presence of these mutations in both patients and a heterozygote status of the parents. Whereas the frameshift mutation (c.638_639insA) has been described in one family, the splice-site mutation (c.1134+1G>A) is novel. In contrast to all cases published so far, one of our patients showed a considerably milder clinical course with survival into childhood. Investigation of a skeletal muscle biopsy showed a severely reduced COX enzyme histochemical staining, indicating mitochondrial dysfunction. Our data expand the clinical and mutational spectrum of the BRAT1-associated phenotype. © 2016 Wiley Periodicals, Inc.
Institut für Medizinische Genetik und Humangenetik, Charité-Universitätsmedizin Berlin, Berlin, Germany.
Denise
D
Horn
Klinik für Pädiatrie m.S. Neurologie & NeuroCure Clinical Research Center, Charité-Universitätsmedizin Berlin, Berlin, Germany.
Bernhard
B
Weschke
Klinik für Pädiatrie m.S. Neurologie & NeuroCure Clinical Research Center, Charité-Universitätsmedizin Berlin, Berlin, Germany.
Ellen
E
Knierim
Institut für Medizinische Genetik und Humangenetik, Charité-Universitätsmedizin Berlin, Berlin, Germany.|Max-Planck-Institut für Molekulare Genetik, FG Development & Disease, Berlin, Germany.
Björn
B
Fischer-Zirnsak
Institut für Neuropathologie, Charité-Universitätsmedizin Berlin, Berlin, Germany.
Werner
W
Stenzel
Klinik für Pädiatrie m.S. Neurologie & NeuroCure Clinical Research Center, Charité-Universitätsmedizin Berlin, Berlin, Germany.
Markus
M
Schuelke
Institute of Bioorganic Chemistry, Polish Academy of Sciences, Poznan, Poland.|Labor Berlin-Charité Vivantes GmbH, Humangenetik, Berlin, Germany.
Tomasz
T
Zemojtel
D000483:Alleles; D019943:Amino Acid Substitution; D001921:Brain / Q000473:pathology; D002648:Child; D002675:Child, Preschool; D055028:Comparative Genomic Hybridization; D019295:Computational Biology / Q000379:methods; D004252:DNA Mutational Analysis; D004569:Electroencephalography; D004827:Epilepsy / Q000175:diagnosis* / Q000235:genetics*; D015870:Gene Expression; D056726:Genetic Association Studies; D005838:Genotype; D006801:Humans; D008279:Magnetic Resonance Imaging / Q000379:methods; D008297:Male; D008928:Mitochondria / Q000235:genetics* / Q000378:metabolism; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics*; D010641:Phenotype; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D014463:Ultrasonography
C573230:BRAT1 protein, human; D009687:Nuclear Proteins; D011451:Prostaglandin-Endoperoxide Synthases
BRAT1; apnea; muscular hypertonia; seizures