title: ATP synthase deficiency due to TMEM70 mutation leads to ultrastructural mitochondrial degeneration and is amenable to treatment.
abstract: TMEM70 is involved in the biogenesis of mitochondrial ATP synthase and mutations in the TMEM70 gene impair oxidative phosphorylation. Herein, we report on pathology and treatment of ATP synthase deficiency in four siblings. A consanguineous family of Roma (Gipsy) ethnic origin gave birth to 6 children of which 4 were affected presenting with dysmorphic features, failure to thrive, cardiomyopathy, metabolic crises, and 3-methylglutaconic aciduria as clinical symptoms. Genetic testing revealed a homozygous mutation (c.317-2A>G) in the TMEM70 gene. While light microscopy was unremarkable, ultrastructural investigation of muscle tissue revealed accumulation of swollen degenerated mitochondria with lipid crystalloid inclusions, cristae aggregation, and exocytosis of mitochondrial material. Biochemical analysis of mitochondrial complexes showed an almost complete ATP synthase deficiency. Despite harbouring the same mutation, the clinical outcome in the four siblings was different. Two children died within 60 h after birth; the other two had recurrent life-threatening metabolic crises but were successfully managed with supplementation of anaplerotic amino acids, lipids, and symptomatic treatment during metabolic crisis. In summary, TMEM70 mutations can cause distinct ultrastructural mitochondrial degeneration and almost complete deficiency of ATP synthase but are still amenable to treatment.
authors.affiliation: Edinger Institute, Institute of Neurology, Goethe University, 60528 Frankfurt am Main, Germany.
authors.forename: Anne K
authors.initials: AK
authors.lastname: Braczynski
authors.affiliation: Department of Neuropediatrics, Goethe University, 60590 Frankfurt am Main, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Vlaho
authors.affiliation: Edinger Institute, Institute of Neurology, Goethe University, 60528 Frankfurt am Main, Germany.
authors.forename: Klaus
authors.initials: K
authors.lastname: Müller
authors.affiliation: Functional Proteomics, SFB815 Core Unit, Faculty of Medicine, Goethe University, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany.
authors.forename: Ilka
authors.initials: I
authors.lastname: Wittig
authors.affiliation: Edinger Institute, Institute of Neurology, Goethe University, 60528 Frankfurt am Main, Germany ; Department of Neuropediatrics, Goethe University, 60590 Frankfurt am Main, Germany.
authors.forename: Anna-Eva
authors.initials: AE
authors.lastname: Blank
authors.affiliation: Edinger Institute, Institute of Neurology, Goethe University, 60528 Frankfurt am Main, Germany.
authors.forename: Dominique S
authors.initials: DS
authors.lastname: Tews
authors.affiliation: Edinger Institute, Institute of Neurology, Goethe University, 60528 Frankfurt am Main, Germany.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Drott
authors.affiliation: Medical Genetic Center, 80336 Munich, Germany.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Kleinle
authors.affiliation: Medical Genetic Center, 80336 Munich, Germany.
authors.forename: Angela
authors.initials: A
authors.lastname: Abicht
authors.affiliation: Medical Genetic Center, 80336 Munich, Germany ; Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, Tyne and Wear NE1 3BZ, UK.
authors.forename: Rita
authors.initials: R
authors.lastname: Horvath
authors.affiliation: Edinger Institute, Institute of Neurology, Goethe University, 60528 Frankfurt am Main, Germany.
authors.forename: Karl H
authors.initials: KH
authors.lastname: Plate
authors.affiliation: Department of Neuropathology, Charité, 10117 Berlin, Germany.
authors.forename: Werner
authors.initials: W
authors.lastname: Stenzel
authors.affiliation: Department of Neuropathology, Charité, 10117 Berlin, Germany ; Department of Neuropathology, University Hospital, Johannes Gutenberg University Mainz, 55131 Mainz, Germany.
authors.forename: Hans H
authors.initials: HH
authors.lastname: Goebel
authors.affiliation: Division of Clinical and Metabolic Genetics, The Hospital for Sick Children and University of Toronto, Toronto, ON, Canada M5G 1X8 ; Genetics and Genome Biology, Peter Gilgan Center for Research and Learning, Toronto, ON, Canada M5G 0A4.
authors.forename: Andreas
authors.initials: A
authors.lastname: Schulze
authors.affiliation: Edinger Institute, Institute of Neurology, Goethe University, 60528 Frankfurt am Main, Germany.
authors.forename: Patrick N
authors.initials: PN
authors.lastname: Harter
authors.affiliation: Department of Neuropediatrics, Goethe University, 60590 Frankfurt am Main, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Kieslich
authors.affiliation: Edinger Institute, Institute of Neurology, Goethe University, 60528 Frankfurt am Main, Germany.
authors.forename: Michel
authors.initials: M
authors.lastname: Mittelbronn
mesh_terms: D000293:Adolescent; D002648:Child; D003937:Diagnosis, Differential; D005260:Female; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008928:Mitochondria / Q000201:enzymology / Q000473:pathology* / Q000648:ultrastructure; D028361:Mitochondrial Diseases / Q000235:genetics* / Q000473:pathology* / Q000628:therapy; D024101:Mitochondrial Proteins / Q000235:genetics*; D025261:Mitochondrial Proton-Translocating ATPases / Q000172:deficiency* / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D016896:Treatment Outcome
chemical_list: D008565:Membrane Proteins; D024101:Mitochondrial Proteins; C533106:TMEM70 protein, human; D025261:Mitochondrial Proton-Translocating ATPases