Diagnosis of 'possible' mitochondrial disease: an existential crisis

Sumit Parikh^#¹, Amel Karaa^#², Amy Goldstein^{3

4}, Enrico Silvio Bertini⁵, Patrick F Chinnery⁶, John Christodoulou^{7

8}, Bruce H Cohen^{9

10}, Ryan L Davis^{11

12}, Marni J Falk^{3

4}, Carl Fratter^{13

14}, Rita Horvath^{15

16}, Mary Kay Koenig¹⁷, Michaelangelo Mancuso¹⁸, Shana McCormack^{3

4}, Elizabeth M McCormick³, Robert McFarland¹⁹, Victoria Nesbitt^{19

20}, Manuel Schiff²¹, Hannah Steele^{15

22}, Silvia Stockler²³, Carolyn Sue^{11

12

24}, Mark Tarnopolsky²⁵, David R Thorburn^{26

27

28}, Jerry Vockley²⁹, Shamima Rahman^{30

31}

Affiliations

¹ Mitochondrial Medicine Center, Neurologic Institute, Cleveland Clinic, Cleveland, Ohio, USA.
² Genetics Unit, Mitochondrial Disease Program, Massachusetts General Hospital, Boston, Massachusetts, USA.
³ Mitochondrial Medicine Frontier Program, Division of Human Genetics, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
⁴ University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA.
⁵ Unit of Neuromuscular and Neurodegenerative Disorders, Bambino Gesu Children's Hospital, IRCCS, Rome, Italy.
⁶ MRC Mitochondrial Biology Unit and Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK.
⁷ Neurodevelopmental Genomics Research Group, Murdoch Children's Research Institute, Melbourne, Victoria, Australia.
⁸ Department of Paediatrics, Melbourne Medical School, University of Melbourne, Melbourne, Victoria, Australia.
⁹ Department of Pediatrics and Rebecca D. Considine Research Institute, Akron Children's Hospital, Akron, Ohio, USA.
¹⁰ Northeast Ohio Medical University, Rootstown, Ohio, USA.
¹¹ Northern Clinical School, University of Sydney, Sydney, New South Wales, Australia.
¹² Department of Neurogenetics, Koling Institute, University of Sydney and Royal North Shore Hospital, Sydney, New South Wales, Australia.
¹³ NHS Specialized Services for Rare Mitochondrial Disorders of Adults and Children UK, Oxford, UK.
¹⁴ Oxford Medical Genetics Laboratories, Oxford University, Oxford, UK.
¹⁵ Wellcome Centre for Mitochondrial Research, Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK.
¹⁶ Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK.
¹⁷ Department of Pediatrics, Mitochondrial Center, University of Texas McGovern Medical School, Houston, Texas, USA.
¹⁸ Department of Experimental and Clinical Medicine, Neurological Institute, University of Pisa, Pisa, Italy.
¹⁹ Institute of Neurosciences, Wellcome Trust Centre for Mitochondrial Research, Newcastle University, Newcastle, UK.
²⁰ NHS Highly Specialised Services for Rare Mitochondrial Disorders, Oxford University Hospitals, Oxford, UK.
²¹ Reference Center for Inborn Errors of Metabolism, Robert-Debré University Hospital, APHP, UMR1141, PROTECT, INSERM, Université Paris-Diderot, Paris, France.
²² Department of Neurology, Sunderland Royal Hospital, Sunderland, UK.
²³ Department of Pediatrics, Division of Biochemical Diseases, University of British Columbia, Vancouver, Canada.
²⁴ Department of Neurology, Royal North Shore Hospital, Sydney, NewSouth Wales, Australia.
²⁵ Department of Pediatrics, Neuromuscular and Neurometabolic Clinic, McMaster University, Hamilton, Ontario, Canada.
²⁶ Royal Children's Hospital, Murdoch Childrens Research Institute, Melbourne, Victoria, Australia.
²⁷ Victorian Clinical Genetics Services, Royal Children's Hospital, Melbourne, Victoria, Australia.
²⁸ Department of Paediatrics, University of Melbourne, Melbourne, Victoria, Australia.
²⁹ Department of Pediatrics, University of Pittsburgh School of Medicine; Center for Rare Disease Therapy, Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania, USA.
³⁰ Mitochondrial Research Group, UCL Great Ormond Street Institute of Child Health, London, UK.
³¹ Metabolic Unit, Great Ormond Street Hospital NHS Foundation Trust, London, UK.

^# Contributed equally.

PMID: 30683676
DOI: 10.1136/jmedgenet-2018-105800

Review

Diagnosis of 'possible' mitochondrial disease: an existential crisis

Sumit Parikh et al. J Med Genet. 2019 Mar.

. 2019 Mar;56(3):123-130.

doi: 10.1136/jmedgenet-2018-105800. Epub 2019 Jan 25.

Authors

Affiliations

¹ Mitochondrial Medicine Center, Neurologic Institute, Cleveland Clinic, Cleveland, Ohio, USA.
² Genetics Unit, Mitochondrial Disease Program, Massachusetts General Hospital, Boston, Massachusetts, USA.
³ Mitochondrial Medicine Frontier Program, Division of Human Genetics, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
⁴ University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA.
⁵ Unit of Neuromuscular and Neurodegenerative Disorders, Bambino Gesu Children's Hospital, IRCCS, Rome, Italy.
⁶ MRC Mitochondrial Biology Unit and Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK.
⁷ Neurodevelopmental Genomics Research Group, Murdoch Children's Research Institute, Melbourne, Victoria, Australia.
⁸ Department of Paediatrics, Melbourne Medical School, University of Melbourne, Melbourne, Victoria, Australia.
⁹ Department of Pediatrics and Rebecca D. Considine Research Institute, Akron Children's Hospital, Akron, Ohio, USA.
¹⁰ Northeast Ohio Medical University, Rootstown, Ohio, USA.
¹¹ Northern Clinical School, University of Sydney, Sydney, New South Wales, Australia.
¹² Department of Neurogenetics, Koling Institute, University of Sydney and Royal North Shore Hospital, Sydney, New South Wales, Australia.
¹³ NHS Specialized Services for Rare Mitochondrial Disorders of Adults and Children UK, Oxford, UK.
¹⁴ Oxford Medical Genetics Laboratories, Oxford University, Oxford, UK.
¹⁵ Wellcome Centre for Mitochondrial Research, Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK.
¹⁶ Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK.
¹⁷ Department of Pediatrics, Mitochondrial Center, University of Texas McGovern Medical School, Houston, Texas, USA.
¹⁸ Department of Experimental and Clinical Medicine, Neurological Institute, University of Pisa, Pisa, Italy.
¹⁹ Institute of Neurosciences, Wellcome Trust Centre for Mitochondrial Research, Newcastle University, Newcastle, UK.
²⁰ NHS Highly Specialised Services for Rare Mitochondrial Disorders, Oxford University Hospitals, Oxford, UK.
²¹ Reference Center for Inborn Errors of Metabolism, Robert-Debré University Hospital, APHP, UMR1141, PROTECT, INSERM, Université Paris-Diderot, Paris, France.
²² Department of Neurology, Sunderland Royal Hospital, Sunderland, UK.
²³ Department of Pediatrics, Division of Biochemical Diseases, University of British Columbia, Vancouver, Canada.
²⁴ Department of Neurology, Royal North Shore Hospital, Sydney, NewSouth Wales, Australia.
²⁵ Department of Pediatrics, Neuromuscular and Neurometabolic Clinic, McMaster University, Hamilton, Ontario, Canada.
²⁶ Royal Children's Hospital, Murdoch Childrens Research Institute, Melbourne, Victoria, Australia.
²⁷ Victorian Clinical Genetics Services, Royal Children's Hospital, Melbourne, Victoria, Australia.
²⁸ Department of Paediatrics, University of Melbourne, Melbourne, Victoria, Australia.
²⁹ Department of Pediatrics, University of Pittsburgh School of Medicine; Center for Rare Disease Therapy, Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania, USA.
³⁰ Mitochondrial Research Group, UCL Great Ormond Street Institute of Child Health, London, UK.
³¹ Metabolic Unit, Great Ormond Street Hospital NHS Foundation Trust, London, UK.

^# Contributed equally.

PMID: 30683676
DOI: 10.1136/jmedgenet-2018-105800

Abstract

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.

Keywords: clinical genetics; diagnosis; evidence based practice; metabolic disorders.

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Conflict of interest statement

Competing interests: None declared.

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Diagnosis of 'possible' mitochondrial disease: an existential crisis

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Diagnosis of 'possible' mitochondrial disease: an existential crisis

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