European Journal of Pediatrics

, Volume 178, Issue 1, pp 21–32 | Cite as

Diagnosis, management, and follow-up of mitochondrial disorders in childhood: a personalized medicine in the new era of genome sequence

  • Margarida Paiva CoelhoEmail author
  • Esmeralda Martins
  • Laura Vilarinho


Primary mitochondrial disorders are highly variable in clinical presentation, biochemistry, and molecular etiology. Mitochondrial disorders can be caused by genetic defects in the mitochondrial, in nuclear genome, or in the interplay between the two genomes. Biochemical screening tests may be inconclusive or misleading since patients, with confirmed mitochondrial disorders specially in pediatric age, may exhibit normal routine biochemistry, muscle histology, or enzymatic analysis of the mitochondrial respiratory chain. Diagnosis is often challenging even with combination of multiple criteria (clinical, biochemical, histological, and functional), as innumerous conditions cause secondary mitochondrial dysfunction. Nowadays, a definite diagnosis is only possible by genetic confirmation since no single score system is satisfactorily accurate, being sensitive but not specific.

Conclusion: Awareness between physicians is of major importance considering that clinical suspicion may not be obvious regarding the heterogenicity in presentation and biochemical features of mitochondrial disorders. In this review, we provide information on diagnosis approach to patients suspected for mitochondrial disorders as well as management on chronic and acute settings. Follow-up should provide comprehensive information on patient’s status, since intervention on these diseases is mostly supportive and prognosis is variable and sometimes unpredictable.

What is Known:

Mitochondrial disorders are heterogenous and may present at any age, with any symptoms and any type of inheritance.

Mitochondrial disorders may be due to pathogenic variants in mitochondrial DNA (mtDNA) or nuclear genes (nDNA).

What is New:

Since no single score system is satisfactorily accurate, a definite diagnosis is only possible with genetic studies with gene panels proving to be a cost-effective approach.

Clinical and biochemical features of patients without a confirmed diagnosis must be reviewed and other diagnosis must be considered. A wider genetic approach may be applied (WES or WGS).


Mitochondria Mitochondrial disease mtDNA Respiratory chain deficiency Genetic diagnosis 



Adenosine triphosphate


Deoxyribonucleic acid


Leber hereditary optic neuropathy


Mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes


Myoclonic epilepsy with red ragged fibers


Magnetic resonance imaging


Mitochondrial DNA


Neuropathy with ataxia and retinitis pigmentosa


Nuclear DNA


Oxidative phosphorylation


Progressive external ophthalmoplegia


Red ragged fiber


Whole exome sequence


Whole genome sequence


Authors’ Contributions

Margarida Paiva Coelho: review of literature and article drafting

Esmeralda Martins: critical manuscript review

Laura Vilarinho: critical manuscript review

Funding information

The customized gene panel referred in this paper was supported by FCT (PTDC/DTP-PIC/2220/2014) and NORTE2020 (NORTE-01-0246-FEDER-000014).

Compliance with ethical standards

This article does not contain any studies with human participants or animals performed by any of the authors.

Conflict of interests

The authors declare that they have no conflict of interest.


  1. 1.
    Alston CL, Rocha MC, Lax NZ, Turnbull DM, Taylor RW (2017) The genetics and pathology of mitochondrial disease. J Pathol 241:236–250. CrossRefGoogle Scholar
  2. 2.
    Bernier FP, Boneh A, Dennett X, Chow CW, Cleary MA, Thorburn DR (2002) Diagnostic criteria for respiratory chain disorders in adults and children. Neurology 59:1406–1411. CrossRefGoogle Scholar
  3. 3.
    Blau N, Duran M, Gibson KM, Dionisi Vici C (2014) Physician’s guide to the diagnosis, treatment, and follow-up of inherited metabolic diseases. Springer Berlin Heidelberg, BerlinCrossRefGoogle Scholar
  4. 4.
    Bourgeois JM, Tarnopolsky MA (2004) Pathology of skeletal muscle in mitochondrial disorders. Mitochondrion 4:441–452. CrossRefGoogle Scholar
  5. 5.
    Calvo SE, Compton AG, Hershman SG, Lim SC, Lieber S, Tucker EJ, Laskowski A, Garone C, Liu S, Jaffe DB, Christodoulou J, Fletcher JM, Bruno DL (2012) Molecular diagnosis of infantile mitochondrial disease with targeted next-generation sequencing. Sci Transl Med 4:1–28. CrossRefGoogle Scholar
  6. 6.
    Caracausi M, Ghini V, Locatelli C, Mericio M, Piovesan A, Antonaros F, Pelleri MC, Vitale L, Vacca RA, Bedetti F, Mimmi MC, Luchinat C, Turano P, Strippoli P, Cocchi G (2018) Plasma and urinary metabolomic profiles of Down syndrome correlate with alteration of mitochondrial metabolism. Sci Rep 8:1–16. CrossRefGoogle Scholar
  7. 7.
    Carroll CJ, Brilhante V, Suomalainen A (2014) Next-generation sequencing for mitochondrial disorders. Br J Pharmacol 171:1837–1853. CrossRefGoogle Scholar
  8. 8.
    Challa S, Kanikannan MA, Murthy JM, Bhoompally VR, Surath M (2004) Diagnosis of mitochondrial diseases: clinical and histological study of sixty patients with ragged red fibers. Neurol India 52:353–358Google Scholar
  9. 9.
    Chi C-S (2015) Diagnostic approach in infants and children with mitochondrial diseases. Pediatr Neonatol 56:7–18. CrossRefGoogle Scholar
  10. 10.
    Chow J, Rahman J, Achermann JC, Dattani MT, Rahman S (2017) Mitochondrial disease and endocrine dysfunction. Nat Rev Endocrinol 13:92–104. CrossRefGoogle Scholar
  11. 11.
    Clinical Molecular Genetics Society (2008) Practice guidelines for the molecular diagnosis of mitochondrial diseases. Available online:
  12. 12.
    Debray FG, Lambert M, Allard P, Mitchell GA (2010) Low citrulline in leigh disease: still a biomarker of maternally inherited leigh syndrome. J Child Neurol 25:1000–1002. CrossRefGoogle Scholar
  13. 13.
    Demine S, Reddy N, Renard P, Raes M, Arnould T (2014) Unraveling biochemical pathways affected by mitochondrial dysfunctions using metabolomic approaches. Metabolites 4:831–878. CrossRefGoogle Scholar
  14. 14.
    DiMauro S, Schon EA (2003) Mitochondrial respiratory-chain diseases. N Engl J Med 348:2656–2668. CrossRefGoogle Scholar
  15. 15.
    Emma F, Montini G, Parikh SM, Salviati L (2016) Mitochondrial dysfunction in inherited renal disease and acute kidney injury. Nat Rev Nephrol 12:267–280. CrossRefGoogle Scholar
  16. 16.
    Enns GM, Cohen BH (2017) Clinical trials in mitochondrial disease. J Inborn Errors Metab Screen 5:232640981773301. CrossRefGoogle Scholar
  17. 17.
    Feichtinger RG, Sperl W, Bauer JW, Kofler B (2014) Mitochondrial dysfunction: a neglected component of skin diseases. Exp Dermatol 23:607–614. CrossRefGoogle Scholar
  18. 18.
    Finsterer J, Bindu PS (2015) Therapeutic strategies for mitochondrial disorders. Pediatr Neurol 52:302–313. CrossRefGoogle Scholar
  19. 19.
    Finsterer J, Segall L (2010) Drugs interfering with mitochondrial disorders. Drug Chem Toxicol 33:138–151. CrossRefGoogle Scholar
  20. 20.
    Finsterer J, Zarrouk Mahjoub S (2012) Mitochondrial toxicity of antiepileptic drugs and their tolerability in mitochondrial disorders. Expert Opin Drug Metab Toxicol 8:71–79. CrossRefGoogle Scholar
  21. 21.
    Grady JP, Campbell G, Ratnaike T, Blakely EL, Falkous G, Nesbitt V, Schaefer AM, Mcnally RJ, Gorman GS, Taylor RW, Turnbull DM, Mcfarland R (2014) Disease progression in patients with single, large-scale mitochondrial DNA deletions. Brain 137:323–334. CrossRefGoogle Scholar
  22. 22.
    Kohda M, Tokuzawa Y, Kishita Y, Nyuzuki H, Moriyama Y, Mizuno Y, Hirata T, Yatsuka Y, Yamashita-Sugahara Y, Nakachi Y, Kato H, Okuda A, Tamaru S, Borna NN, Banshoya K, Aigaki T, Sato-Miyata Y, Ohnuma K, Suzuki T, Nagao A, Maehata H, Matsuda F, Higasa K, Nagasaki M, Yasuda J, Yamamoto M, Fushimi T, Shimura M, Kaiho-Ichimoto K, Harashima H, Yamazaki T, Mori M, Murayama K, Ohtake A, Okazaki Y (2016) A comprehensive genomic analysis reveals the genetic landscape of mitochondrial respiratory chain complex deficiencies. PLoS Genet 12:1–31. CrossRefGoogle Scholar
  23. 23.
    Lamari F, Saudubray J-M, Mitchell GA (2016) Inborn metabolic diseases, 6th edn. Springer Berlin Heidelberg, BerlinGoogle Scholar
  24. 24.
    Legati A, Reyes A, Nasca A, Invernizzi F, Lamantea E, Tiranti V, Garavaglia B, Lamperti C, Ardissone A, Moroni I, Robinson A, Ghezzi D, Zeviani M (2016) New genes and pathomechanisms in mitochondrial disorders unraveled by NGS technologies. Biochim Biophys Acta Bioenerg 1857:1326–1335. CrossRefGoogle Scholar
  25. 25.
    Liang C, Ahmad K, Sue CM (2014) The broadening spectrum of mitochondrial disease: shifts in the diagnostic paradigm. Biochim Biophys Acta Gen Subj 1840:1360–1367. CrossRefGoogle Scholar
  26. 26.
    Liu JJ, Ghosh S, Kovalik JP, Ching J, Choi HW, Tavintharan S, Ong CN, Sum CF, Summers SA, Tai ES, Lim SC (2017) Profiling of plasma metabolites suggests altered mitochondrial fuel usage and remodeling of sphingolipid metabolism in individuals with type 2 diabetes and kidney disease. Kidney Int Reports 2:470–480. CrossRefGoogle Scholar
  27. 27.
    McCormick E, Place E, Falk MJ (2013) Molecular genetic testing for mitochondrial disease: from one generation to the next. Neurotherapeutics 10:251–261. CrossRefGoogle Scholar
  28. 28.
    Montero R, Yubero D, Villarroya J, Henares D, Jou C, Rodríguez MA, Ramos F, Nascimento A, Ortez CI, Campistol J, Perez-due B (2016) GDF-15 is elevated in children with mitochondrial diseases and is induced by mitochondrial dysfunction. 1–15.
  29. 29.
    Niezgoda J, Morgan PG (2013) Anesthetic considerations in patients with mitochondrial defects. Paediatr Anaesth 23:785–793. CrossRefGoogle Scholar
  30. 30.
    Nogueira C, Almeida LS, Nesti C, Pezzini I, Videira A, Vilarinho L, Santorelli FM (2014) Syndromes associated with mitochondrial DNA depletion. Ital J Pediatr 40:1–10. CrossRefGoogle Scholar
  31. 31.
    Ohtake A, Murayama K, Mori M, Harashima H, Yamazaki T, Tamaru S, Yamashita Y, Kishita Y, Nakachi Y, Kohda M, Tokuzawa Y, Mizuno Y, Moriyama Y, Kato H, Okazaki Y (2014) Diagnosis and molecular basis of mitochondrial respiratory chain disorders: exome sequencing for disease gene identification. Biochim Biophys Acta Gen Subj 1840:1355–1359. CrossRefGoogle Scholar
  32. 32.
    Parikh S, Goldstein A, Koenig MK, Scaglia F, Enns GM, Saneto R, Anselm I, Cohen BH, Falk MJ, Greene C, Gropman AL, Haas R, Hirano M, Morgan P, Sims K, Tarnopolsky M, Van Hove JLK, Wolfe L, DiMauro S (2015) Diagnosis and management of mitochondrial disease: a consensus statement from the Mitochondrial Medicine Society. Genet Med 17:689–701. CrossRefGoogle Scholar
  33. 33.
    Parikh S, Goldstein A, Karaa A, Koenig MK, Anselm I, Brunel-Guitton C, Christodoulou J, Cohen BH, Dimmock D, Enns GM, Falk MJ, Feigenbaum A, Frye RE, Ganesh J, Griesemer D, Haas R, Horvath R, Korson M, Kruer MC, Mancuso M, McCormack S, Raboisson MJ, Reimschisel T, Salvarinova R, Saneto RP, Scaglia F, Shoffner J, Stacpoole PW, Sue CM, Tarnopolsky M, Van Karnebeek C, Wolfe LA, Cunningham ZZ, Rahman S, Chinnery PF (2017) Patient care standards for primary mitochondrial disease: a consensus statement from the Mitochondrial Medicine Society. Genet Med 19.
  34. 34.
    Rahman S, Wolf NI (2017) Diagnostic Workup of Patients with Mitochondrial Diseases. In: Hoffmann G, Zschocke J, Nyhan W (eds) Inherited Metabolic Diseases. Springer, BerlinGoogle Scholar
  35. 35.
    Salway JG (2017) Metabolism at a glance, 4th edn. Wiley-Blackwell Publishing, OxfordGoogle Scholar
  36. 36.
    Shaham O, Slate NG, Goldberger O, Xu Q, Ramanathan A, Souza AL, Clish CB, Sims KB, Mootha VK (2010) A plasma signature of human mitochondrial disease revealed through metabolic profiling of spent media from cultured muscle cells. Proc Natl Acad Sci 107:1571–1575. CrossRefGoogle Scholar
  37. 37.
    Taylor RW, Turnbull DM (2005) Mitochondrial DNA mutations in human disease. Nat Rev Genet 6:389–402. CrossRefGoogle Scholar
  38. 38.
    Vilarinho L (2000) Genética Mitocondrial Humana (Doctoral dissertation), Universidade do PortoGoogle Scholar
  39. 39.
    Vilarinho L, Santorelli FM, Cardoso ML, Coelho T, Guimarães A, Coutinho P (1998) Mitochondrial DNA analysis in ocular myopathy. Eur Neurol 39:148–153. CrossRefGoogle Scholar
  40. 40.
    Vilarinho L, Santorelli FM, Coelho I, Rodrigues L, Maia M, Barata I, Cabral P, Dionísio A, Costa A, Guimarães A, Dimauro S (1999) The mitochondrial DNA A3243G mutation in Portugal: clinical and molecular studies in 5 families. J Neurol Sci 163:168–174. CrossRefGoogle Scholar
  41. 41.
    Viscomi C, Bottani E, Zeviani M (2015) Emerging concepts in the therapy of mitochondrial disease. Biochim Biophys Acta Bioenerg 1847:544–557. CrossRefGoogle Scholar
  42. 42.
    Wolf NI, Smeitink JAM (2002) Mitochondrial disorders: a proposal for consensus diagnostic criteria in infants and children. Neurology 59:1402–1405. CrossRefGoogle Scholar
  43. 43.
    Wong LJ (2013) Next generation molecular diagnosis of mitochondrial disorders. Mitochondrion 13:379–387. CrossRefGoogle Scholar
  44. 44.
    Wortmann SB, Mayr JA, Nuoffer JM, Prokisch H, Sperl W (2017) A guideline for the diagnosis of pediatric mitochondrial disease: the value of muscle and skin biopsies in the genetics era. Neuropediatrics 48:309–314. CrossRefGoogle Scholar
  45. 45.
    Zhang H, Wang F, Xiao H, Yao Y (2018) The ratio of urinary α1-microglobulin to microalbumin can be used as a diagnostic criterion for tubuloproteinuria. Intractable Rare Dis Res 7:46–50. CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Pediatrics Department, Centro Materno Infantil do NorteCentro Hospitalar do PortoPortoPortugal
  2. 2.Reference Center for Inherited Metabolic DisordersCentro Hospitalar do PortoPortoPortugal
  3. 3.Newborn Screening, Metabolism and Genetics Unit, Human Genetics DepartmentNational Institute of Health Dr. Ricardo JorgePortoPortugal

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