BRAT1 mutations are associated with infantile epileptic encephalopathy, mitochondrial dysfunction, and survival into childhood. Issue 9 (9th June 2016)

• Record Type: Journal Article
• Authors: Horn, Denise; Weschke, Bernhard; Knierim, Ellen; Fischer‐Zirnsak, Björn; Stenzel, Werner; Schuelke, Markus; Zemojtel, Tomasz
• Is Part Of: American journal of medical genetics. Volume 170:Issue 9(2016)
• Page Start: 2274
• Page End: 2281
• Publication Date: 2016-06-09
• Subjects: BRAT1 -- seizures -- apnea -- muscular hypertonia; Medical genetics -- Periodicals; 616.14205
• DOI: 10.1002/ajmg.a.37798
• Languages: English
• ISSNs: 1552-4825

Abstract

Abstract : 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.