title: Mitochondrial epileptic encephalopathy, 3-methylglutaconic aciduria and variable complex V deficiency associated with TIMM50 mutations.
abstract: 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.
authors: Department of Pediatrics, Al-Makassed Islamic Hospital, Jerusalem, Israel.
authors: M A
authors: MA
authors: Shahrour
authors: Metabolic Disease Unit, Soroka Medical Center, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheba, Israel.
authors: O
authors: O
authors: Staretz-Chacham
authors: Department of Biochemistry & Molecular Biology, Tel Aviv University, Tel Aviv, Israel.
authors: D
authors: D
authors: Dayan
authors: Section of Human Biochemical Genetics, Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
authors: J
authors: J
authors: Stephen
authors: NIH Undiagnosed Diseases Program, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
authors: A
authors: A
authors: Weech
authors: Department of Pediatrics, Al-Makassed Islamic Hospital, Jerusalem, Israel.
authors: N
authors: N
authors: Damseh
authors: Department of Biochemistry & Molecular Biology, Tel Aviv University, Tel Aviv, Israel.|Section of Human Biochemical Genetics, Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.|Graduate Partnerships Program, Tel Aviv University, Tel Aviv, Israel, and the National Institutes of Health, Bethesda, MD, USA.
authors: H
authors: H
authors: Pri Chen
authors: Pediatric Neurology Unit, Hadassah, Hebrew University Medical Center Jerusalem, Jerusalem, Israel.
authors: S
authors: http://orcid.org/0000-0003-2878-1278
authors: S
authors: Edvardson
authors: Section of Human Biochemical Genetics, Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
authors: S
authors: S
authors: Mazaheri
authors: Monique and Jacques Roboh Department of Genetic Research, Hadassah, Hebrew University Medical Center Jerusalem, Jerusalem, Israel.
authors: A
authors: A
authors: Saada
authors: NIH Intramural Sequencing Center (NISC), National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
authors: Metabolic Disease Unit, Soroka Medical Center, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheba, Israel.
authors: E
authors: E
authors: Hershkovitz
authors: NIH Intramural Sequencing Center (NISC), National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
authors: A
authors: A
authors: Shaag
authors: Section of Human Biochemical Genetics, Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
authors: M
authors: M
authors: Huizing
authors: Department of Pediatrics, Al-Makassed Islamic Hospital, Jerusalem, Israel.
authors: B
authors: B
authors: Abu-Libdeh
authors: Section of Human Biochemical Genetics, Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.|NIH Undiagnosed Diseases Program, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
authors: W A
authors: WA
authors: Gahl
authors: Department of Biochemistry & Molecular Biology, Tel Aviv University, Tel Aviv, Israel.
authors: A
authors: A
authors: Azem
authors: Metabolic Disease Unit, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Tel-Hashomer, Israel.|Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel.
authors: Y
authors: Y
authors: Anikster
authors: NIH Undiagnosed Diseases Program, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.|Division of Medical Genomics, Inova Translational Medicine Institute, Fairfax, VA, USA.
authors: T
authors: T
authors: Vilboux
authors: NIH Intramural Sequencing Center (NISC), National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
authors: O
authors: O
authors: Elpeleg
authors: Section of Human Biochemical Genetics, Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.|NIH Undiagnosed Diseases Program, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
authors: M C
authors: http://orcid.org/0000-0003-1697-6959
authors: MC
authors: Malicdan
mesh_terms: D000251:Adenosine Triphosphatases / Q000172:deficiency* / Q000235:genetics; D002352:Carrier Proteins / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D004827:Epilepsy / Q000235:genetics*; D005260:Female; D006801:Humans; D007223:Infant; D008297:Male; D008565:Membrane Proteins / Q000172:deficiency* / Q000235:genetics; D026901:Membrane Transport Proteins / Q000235:genetics*; D008661:Metabolism, Inborn Errors / Q000235:genetics*; D017237:Mitochondrial Encephalomyopathies / Q000235:genetics*; D000090622:Mitochondrial Precursor Protein Import Complex Proteins; D025261:Mitochondrial Proton-Translocating ATPases; D009154:Mutation; D020641:Polymorphism, Single Nucleotide; D011247:Pregnancy
chemical_list: D002352:Carrier Proteins; D008565:Membrane Proteins; D026901:Membrane Transport Proteins; D000090622:Mitochondrial Precursor Protein Import Complex Proteins; C509348:TIMM50 protein, human; D000251:Adenosine Triphosphatases; D025261:Mitochondrial Proton-Translocating ATPases; C020439:oligomycin sensitivity-conferring protein
keywords: 3-methylglutaconic aciduria; TIMM50; epileptic encephalopathy; exome analysis; mitochondria