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Mitochondrial encephalocardio-myopathy with early neonatal onset due to TMEM70 mutation
  1. Tomáš Honzík1,
  2. Markéta Tesařová1,
  3. Johannes A Mayr2,
  4. Hana Hansíková1,
  5. Pavel Ješina1,
  6. Olaf Bodamer2,
  7. Johannes Koch2,
  8. Martin Magner1,
  9. Peter Freisinger3,
  10. Martina Huemer4,
  11. Olga Kostková1,
  12. Rudy van Coster5,
  13. Stanislav Kmoch6,
  14. Josef Houštêk7,
  15. Wolfgang Sperl2,
  16. Jiří Zeman1
  1. 1Department of Pediatrics and Adolescent Medicine, First Faculty of Medicine, Charles University in Prague, Prague, Czech Republic
  2. 2Department of Pediatrics, Paracelsus Medical University, Salzburg, Austria
  3. 3Children's Hospital Schwabing, Technical University Munich, Munich, Germany
  4. 4Department of Pediatrics, Landeskrankenhaus Bregenz, Bregenz, Austria
  5. 5Department of Pediatrics, University Hospital Ghent, Ghent, Belgium
  6. 6Institute of Inherited Metabolic Disorders, First Faculty of Medicine, Charles University in Prague, Prague, Czech Republic
  7. 7Department of Bioenergetics, Institute of Physiology, Academy of Science of the Czech Republic, Prague, Czech Republic
  1. Correspondence to Professor Ji í Zeman, Department of Pediatrics and Adolescent Medicine, First Faculty of Medicine, Charles University in Prague, Ke Karlovu 2, 128 08 Prague 2, Czech Republic; jzem{at} or Professor Wolfgang Sperl, Department of Pediatrics, Paracelsus Medical University, Müllner Hauptstrasse 48, A-5020 Salzburg, Austria; w.sperl{at}


Objective Mitochondrial disturbances of energygenerating systems in childhood are a heterogeneous group of disorders. The aim of this multi-site survey was to characterise the natural course of a novel mitochondrial disease with ATP synthase deficiency and mutation in the TMEM70 gene.

Methods Retrospective clinical data and metabolic profiles were collected and evaluated in 25 patients (14 boys, 11 girls) from seven European countries with a c.317-2A→G mutation in the TMEM70 gene.

Results Severe muscular hypotonia (in 92% of newborns), apnoic spells (92%), hypertrophic cardiomyopathy (HCMP; 76%) and profound lactic acidosis (lactate 5–36 mmol/l; 92%) with hyperammonaemia (100–520 µmol/l; 86%) were present from birth. Ten patients died within the first 6 weeks of life. Most patients surviving the neonatal period had persisting muscular hypotonia and developed psychomotor delay. HCMP was non-progressive and even disappeared in some children. Hypospadia was present in 54% of the boys and cryptorchidism in 67%. Increased excretion of lactate and 3-methylglutaconic acid (3-MGC) was observed in all patients. In four surviving patients, life-threatening hyperammonaemia occurred during childhood, triggered by acute gastroenteritis and prolonged fasting.

Conclusions ATP synthase deficiency with mutation in TMEM70 should be considered in the diagnosis and management of critically ill neonates with early neonatal onset of muscular hypotonia, HCMP and hypospadias in boys accompanied by lactic acidosis, hyperammonaemia and 3-MGC-uria. However, phenotype severity may vary significantly. The disease occurs frequently in the Roma population and molecular-genetic analysis of the TMEM70 gene is sufficient for diagnosis without need of muscle biopsy in affected children.

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  • Funding This study was supported by grants from the Ministry of Health (IGA-NS 9759-4) and Ministry of Education, Youth and Sports of the Czech Republic (1M0520, AV0Z 50110509, MSM 0021620806) and Verein zur Pädiatrischen Forschung und Fortbildung, Salzburg OeNB Jubiläumsfonds 12568.

  • Competing interests None.

  • Ethics approval The study was approved by the Committees of Medical Ethics at all collaborating institutions.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Patient consent Parental consent obtained.