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BRAT1 mutations are associated with infantile epileptic encephalopathy, mitochondrial dysfunction, and survival into

Denise Horn1, Bernhard Weschke2, Ellen Knierim2

  • 1Institut für Medizinische Genetik und Humangenetik, Charité-Universitätsmedizin Berlin, Berlin, Germany.

American Journal of Medical Genetics. Part A
|June 11, 2016
PubMed

Insights

Two siblings with early onset seizures and microcephaly had compound heterozygous mutations in BRAT1. This expands the known genetic causes and clinical spectrum of this severe neurodevelopmental disorder.

Area of Science:

  • Genetics
  • Neuroscience
  • Biochemistry

Background:

  • BRAT1 gene mutations are associated with severe early-onset neurodevelopmental disorders.
  • Previous cases highlight a uniformly severe clinical course with early mortality.

Observation:

  • Two siblings presented with early onset focal seizures, progressive microcephaly, hypotonia, feeding difficulties, apnea, and minimal psychomotor development.
  • Genetic analysis revealed compound heterozygous mutations in BRAT1 (c.638_639insA and c.1134+1G>A).
  • One patient exhibited a milder course, surviving into childhood, with evidence of mitochondrial dysfunction (reduced COX staining).

Findings:

  • Identification of compound heterozygous mutations in BRAT1, including a novel splice-site mutation (c.1134+1G>A).
  • The frameshift mutation (c.638_639insA) was previously reported in one family.
  • Clinical variability is demonstrated, with one patient showing prolonged survival.

Implications:

  • This study expands the known mutational spectrum of BRAT1-associated disorders.
  • The findings suggest potential genotype-phenotype correlations and highlight mitochondrial dysfunction in some cases.
  • Further research into BRAT1 function and associated pathomechanisms is warranted.

Keywords:
BRAT1apneamuscular hypertoniaseizures

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