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Diagnosis of ‘possible’ mitochondrial disease: an existential crisis
  1. Sumit Parikh1,
  2. Amel Karaa2,
  3. Amy Goldstein3,4,
  4. Enrico Silvio Bertini5,
  5. Patrick F Chinnery6,
  6. John Christodoulou7,8,
  7. Bruce H Cohen9,10,
  8. Ryan L Davis11,12,
  9. Marni J Falk3,4,
  10. Carl Fratter13,14,
  11. Rita Horvath15,16,
  12. Mary Kay Koenig17,
  13. Michaelangelo Mancuso18,
  14. Shana McCormack3,4,
  15. Elizabeth M McCormick3,
  16. Robert McFarland19,
  17. Victoria Nesbitt19,20,
  18. Manuel Schiff21,
  19. Hannah Steele15,22,
  20. Silvia Stockler23,
  21. Carolyn Sue11,12,24,
  22. Mark Tarnopolsky25,
  23. David R Thorburn26,27,28,
  24. Jerry Vockley29,
  25. Shamima Rahman30,31
  1. 1Mitochondrial Medicine Center, Neurologic Institute, Cleveland Clinic, Cleveland, Ohio, USA
  2. 2Genetics Unit, Mitochondrial Disease Program, Massachusetts General Hospital, Boston, Massachusetts, USA
  3. 3Mitochondrial Medicine Frontier Program, Division of Human Genetics, Department of Pediatrics, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
  4. 4University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA
  5. 5Unit of Neuromuscular and Neurodegenerative Disorders, Bambino Gesu Children’s Hospital, IRCCS, Rome, Italy
  6. 6MRC Mitochondrial Biology Unit and Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK
  7. 7Neurodevelopmental Genomics Research Group, Murdoch Children’s Research Institute, Melbourne, Victoria, Australia
  8. 8Department of Paediatrics, Melbourne Medical School, University of Melbourne, Melbourne, Victoria, Australia
  9. 9Department of Pediatrics and Rebecca D. Considine Research Institute, Akron Children’s Hospital, Akron, Ohio, USA
  10. 10Northeast Ohio Medical University, Rootstown, Ohio, USA
  11. 11Northern Clinical School, University of Sydney, Sydney, New South Wales, Australia
  12. 12Department of Neurogenetics, Koling Institute, University of Sydney and Royal North Shore Hospital, Sydney, New South Wales, Australia
  13. 13NHS Specialized Services for Rare Mitochondrial Disorders of Adults and Children UK, Oxford, UK
  14. 14Oxford Medical Genetics Laboratories, Oxford University, Oxford, UK
  15. 15Wellcome Centre for Mitochondrial Research, Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK
  16. 16Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK
  17. 17Department of Pediatrics, Mitochondrial Center, University of Texas McGovern Medical School, Houston, Texas, USA
  18. 18Department of Experimental and Clinical Medicine, Neurological Institute, University of Pisa, Pisa, Italy
  19. 19Institute of Neurosciences, Wellcome Trust Centre for Mitochondrial Research, Newcastle University, Newcastle, UK
  20. 20NHS Highly Specialised Services for Rare Mitochondrial Disorders, Oxford University Hospitals, Oxford, UK
  21. 21Reference Center for Inborn Errors of Metabolism, Robert-Debré University Hospital, APHP, UMR1141, PROTECT, INSERM, Université Paris-Diderot, Paris, France
  22. 22Department of Neurology, Sunderland Royal Hospital, Sunderland, UK
  23. 23Department of Pediatrics, Division of Biochemical Diseases, University of British Columbia, Vancouver, Canada
  24. 24Department of Neurology, Royal North Shore Hospital, Sydney, NewSouth Wales, Australia
  25. 25Department of Pediatrics, Neuromuscular and Neurometabolic Clinic, McMaster University, Hamilton, Ontario, Canada
  26. 26Royal Children’s Hospital, Murdoch Childrens Research Institute, Melbourne, Victoria, Australia
  27. 27Victorian Clinical Genetics Services, Royal Children’s Hospital, Melbourne, Victoria, Australia
  28. 28Department of Paediatrics, University of Melbourne, Melbourne, Victoria, Australia
  29. 29Department of Pediatrics, University of Pittsburgh School of Medicine; Center for Rare Disease Therapy, Children’s Hospital of Pittsburgh, Pittsburgh, Pennsylvania, USA
  30. 30Mitochondrial Research Group, UCL Great Ormond Street Institute of Child Health, London, UK
  31. 31Metabolic Unit, Great Ormond Street Hospital NHS Foundation Trust, London, UK
  1. Correspondence to Dr Sumit Parikh, Mitochondrial Medicine Center, Neurologic Institute, Cleveland Clinic, Cleveland OH 44195, USA; parikhs{at}


Primary genetic mitochondrial diseases are often difficult to diagnose, and the term ‘possible’ mitochondrial disease is used frequently by clinicians when such a diagnosis is suspected. There are now many known phenocopies of mitochondrial disease. Advances in genomic testing have shown that some patients with a clinical phenotype and biochemical abnormalities suggesting mitochondrial disease may have other genetic disorders. In instances when a genetic diagnosis cannot be confirmed, a diagnosis of ‘possible’ mitochondrial disease may result in harm to patients and their families, creating anxiety, delaying appropriate diagnosis and leading to inappropriate management or care. A categorisation of ‘diagnosis uncertain’, together with a specific description of the metabolic or genetic abnormalities identified, is preferred when a mitochondrial disease cannot be genetically confirmed.

  • diagnosis
  • metabolic disorders
  • clinical genetics
  • evidence based practice

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  • SP and AK contributed equally.

  • Contributors SP, AK and AG conceived the presented idea and prepared a document outline including needed supplementary material. SP, AK, AG and SR developed and supervised the manuscript. SP, AK, AG, ESB, PFC, JC, BHC, RLD, MJF, CF, RH, MKK, MM, SM, EMM, RM, VN, MS, HS, SS, CS, MT, DRT, JV and SR commented on, approved and helped expand on the presented idea, drafted and revised portions of the manuscript including supplementary materials and commented on and approved the final draft.

  • Funding RH is a Wellcome Trust Investigator (109915/Z/15/Z), who receives support from the Wellcome Centre for Mitochondrial Research (203105/Z/16/Z), Medical Research Council (UK) (MR/N025431/1), the European Research Council (309548), the Wellcome Trust Pathfinder Scheme (201064/Z/16/Z) and the Newton Fund (UK/Turkey, MR/N027302/1). PFC is a Wellcome Trust Senior Fellow in Clinical Science (101876/Z/13/Z) and a UK NIHR Senior Investigator, who receives support from the Medical Research Council Mitochondrial Biology Unit (MC_UP_1501/2), the Medical Research Council (UK) Centre for Translational Muscle Disease (G0601943), EU FP7 TIRCON and the National Institute for Health Research (NIHR) Biomedical Research Centre based at Cambridge University Hospitals NHS Foundation Trust and the University of Cambridge. SR is supported by a Great Ormond Street Hospital Children’s Charity Research Leadership Award (V1260) and by research grant funding from the NIHR Great Ormond Street Hospital Biomedical Research Centre and the Lily Foundation. ESB, SR and MR are members of the European Reference Network for Rare Hereditary Metabolic Disorders (METABERN)—Project ID No 739543. MetabERN is partly cofunded by the European Union in the framework of the Third Health Programme ‘ERN-2016—Framework Partnership Agreement 2017-2021’. MM is supported by research grants from Telethon and MITOCON Italian patients’ association (grants GSP09004 and GSP16001).

  • Competing interests None declared.

  • Patient consent Not required.

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