Mitochondrial epileptic encephalopathy, 3-methylglutaconic aciduria and variable complex V deficiency associated with TIMM50 mutations

Clin Genet. 2017 May;91(5):690-696. doi: 10.1111/cge.12855. Epub 2016 Oct 12.


Mitochondrial encephalopathies are a heterogeneous group of disorders that, usually carry grave prognosis. Recently a homozygous mutation, Gly372Ser, in the TIMM50 gene, was reported in an abstract form, in three sibs who suffered from intractable epilepsy and developmental delay accompanied by 3-methylglutaconic aciduria. We now report on four patients from two unrelated families who presented with severe intellectual disability and seizure disorder, accompanied by slightly elevated lactate level, 3-methylglutaconic aciduria and variable deficiency of mitochondrial complex V. Using exome analysis we identified two homozygous missense mutations, Arg217Trp and Thr252Met, in the TIMM50 gene. The TIMM50 protein is a subunit of TIM23 complex, the mitochondrial import machinery. It serves as the major receptor in the intermembrane space, binding to proteins which cross the mitochondrial inner membrane on their way to the matrix. The mutations, which affected evolutionary conserved residues and segregated with the disease in the families, were neither present in large cohorts of control exome analyses nor in our ethnic specific exome cohort. Given the phenotypic similarity, we conclude that missense mutations in TIMM50 are likely manifesting by severe intellectual disability and epilepsy accompanied by 3-methylglutaconic aciduria and variable mitochondrial complex V deficiency. 3-methylglutaconic aciduria is emerging as an important biomarker for mitochondrial dysfunction, in particular for mitochondrial membrane defects.

Keywords: 3-methylglutaconic aciduria; TIMM50; epileptic encephalopathy; exome analysis; mitochondria.

Publication types

  • Case Reports

MeSH terms

  • Adenosine Triphosphatases / deficiency*
  • Adenosine Triphosphatases / genetics
  • Carrier Proteins / genetics
  • Child
  • Child, Preschool
  • Epilepsy / genetics*
  • Female
  • Humans
  • Infant
  • Male
  • Membrane Proteins / deficiency*
  • Membrane Proteins / genetics
  • Membrane Transport Proteins / genetics*
  • Metabolism, Inborn Errors / genetics*
  • Mitochondrial Encephalomyopathies / genetics*
  • Mitochondrial Precursor Protein Import Complex Proteins
  • Mitochondrial Proton-Translocating ATPases
  • Mutation
  • Polymorphism, Single Nucleotide
  • Pregnancy


  • Carrier Proteins
  • Membrane Proteins
  • Membrane Transport Proteins
  • Mitochondrial Precursor Protein Import Complex Proteins
  • TIMM50 protein, human
  • Adenosine Triphosphatases
  • Mitochondrial Proton-Translocating ATPases
  • oligomycin sensitivity-conferring protein

Supplementary concepts

  • 3-Methylglutaconic Aciduria
  • Mitochondrial encephalopathy