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

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Abstract

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).

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Abbreviations

ATP:

Adenosine triphosphate

DNA:

Deoxyribonucleic acid

LHON:

Leber hereditary optic neuropathy

MELAS:

Mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes

MERRF:

Myoclonic epilepsy with red ragged fibers

MRI:

Magnetic resonance imaging

mtDNA:

Mitochondrial DNA

NARP:

Neuropathy with ataxia and retinitis pigmentosa

nDNA:

Nuclear DNA

OXPHOS:

Oxidative phosphorylation

PEO:

Progressive external ophthalmoplegia

RRF:

Red ragged fiber

WES:

Whole exome sequence

WGS:

Whole genome sequence

References

  1. Alston CL, Rocha MC, Lax NZ, Turnbull DM, Taylor RW (2017) The genetics and pathology of mitochondrial disease. J Pathol 241:236–250. https://doi.org/10.1002/path.4809

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1212/01.WNL.0000033795.17156.00

    Article  CAS  PubMed  Google Scholar 

  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, Berlin

    Book  Google Scholar 

  4. Bourgeois JM, Tarnopolsky MA (2004) Pathology of skeletal muscle in mitochondrial disorders. Mitochondrion 4:441–452. https://doi.org/10.1016/j.mito.2004.07.036

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1126/scitranslmed.3003310.Molecular

    Article  Google Scholar 

  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. https://doi.org/10.1038/s41598-018-20834-y

    Article  CAS  Google Scholar 

  7. Carroll CJ, Brilhante V, Suomalainen A (2014) Next-generation sequencing for mitochondrial disorders. Br J Pharmacol 171:1837–1853. https://doi.org/10.1111/bph.12469

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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 52:353–358

    PubMed  Google Scholar 

  9. Chi C-S (2015) Diagnostic approach in infants and children with mitochondrial diseases. Pediatr Neonatol 56:7–18. https://doi.org/10.1016/j.pedneo.2014.03.009

    Article  PubMed  Google Scholar 

  10. Chow J, Rahman J, Achermann JC, Dattani MT, Rahman S (2017) Mitochondrial disease and endocrine dysfunction. Nat Rev Endocrinol 13:92–104. https://doi.org/10.1038/nrendo.2016.151

    Article  CAS  PubMed  Google Scholar 

  11. Clinical Molecular Genetics Society (2008) Practice guidelines for the molecular diagnosis of mitochondrial diseases. Available online: http://www.acgs.uk.com/media/774659/mito_2008.pdf

  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. https://doi.org/10.1177/0883073809351983

    Article  PubMed  Google Scholar 

  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. https://doi.org/10.3390/metabo4030831

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. DiMauro S, Schon EA (2003) Mitochondrial respiratory-chain diseases. N Engl J Med 348:2656–2668. https://doi.org/10.1056/NEJMra022567

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1038/nrneph.2015.214

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Enns GM, Cohen BH (2017) Clinical trials in mitochondrial disease. J Inborn Errors Metab Screen 5:232640981773301. https://doi.org/10.1177/2326409817733013

    Article  Google Scholar 

  17. Feichtinger RG, Sperl W, Bauer JW, Kofler B (2014) Mitochondrial dysfunction: a neglected component of skin diseases. Exp Dermatol 23:607–614. https://doi.org/10.1111/exd.12484

    Article  CAS  PubMed  Google Scholar 

  18. Finsterer J, Bindu PS (2015) Therapeutic strategies for mitochondrial disorders. Pediatr Neurol 52:302–313. https://doi.org/10.1016/j.pediatrneurol.2014.06.023

    Article  PubMed  Google Scholar 

  19. Finsterer J, Segall L (2010) Drugs interfering with mitochondrial disorders. Drug Chem Toxicol 33:138–151. https://doi.org/10.3109/01480540903207076

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1517/17425255.2012.644535

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1093/brain/awt321

    Article  PubMed  Google Scholar 

  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. https://doi.org/10.1371/journal.pgen.1005679

    Article  CAS  Google Scholar 

  23. Lamari F, Saudubray J-M, Mitchell GA (2016) Inborn metabolic diseases, 6th edn. Springer Berlin Heidelberg, Berlin

    Google Scholar 

  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. https://doi.org/10.1016/j.bbabio.2016.02.022

    Article  CAS  Google Scholar 

  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. https://doi.org/10.1016/j.bbagen.2013.10.040

    Article  CAS  Google Scholar 

  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. https://doi.org/10.1016/j.ekir.2016.12.003

    Article  Google Scholar 

  27. McCormick E, Place E, Falk MJ (2013) Molecular genetic testing for mitochondrial disease: from one generation to the next. Neurotherapeutics 10:251–261. https://doi.org/10.1007/s13311-012-0174-1

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1371/journal.pone.0148709

  29. Niezgoda J, Morgan PG (2013) Anesthetic considerations in patients with mitochondrial defects. Paediatr Anaesth 23:785–793. https://doi.org/10.1111/pan.12158

    Article  PubMed  PubMed Central  Google Scholar 

  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. https://doi.org/10.1186/1824-7288-40-34

    Article  CAS  Google Scholar 

  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. https://doi.org/10.1016/j.bbagen.2014.01.025

    Article  CAS  Google Scholar 

  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. https://doi.org/10.1038/gim.2014.177

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1038/gim.2017.107

  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, Berlin

  35. Salway JG (2017) Metabolism at a glance, 4th edn. Wiley-Blackwell Publishing, Oxford

  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. https://doi.org/10.1073/pnas.0906039107

    Article  PubMed  PubMed Central  Google Scholar 

  37. Taylor RW, Turnbull DM (2005) Mitochondrial DNA mutations in human disease. Nat Rev Genet 6:389–402. https://doi.org/10.1038/nrg1606

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Vilarinho L (2000) Genética Mitocondrial Humana (Doctoral dissertation), Universidade do Porto

  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. https://doi.org/10.1159/000007925

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1016/S0022-510X(99)00030-1

    Article  CAS  PubMed  Google Scholar 

  41. Viscomi C, Bottani E, Zeviani M (2015) Emerging concepts in the therapy of mitochondrial disease. Biochim Biophys Acta Bioenerg 1847:544–557. https://doi.org/10.1016/j.bbabio.2015.03.001

    Article  CAS  Google Scholar 

  42. Wolf NI, Smeitink JAM (2002) Mitochondrial disorders: a proposal for consensus diagnostic criteria in infants and children. Neurology 59:1402–1405. https://doi.org/10.1212/01.WNL.0000031795.91814.D8

    Article  PubMed  Google Scholar 

  43. Wong LJ (2013) Next generation molecular diagnosis of mitochondrial disorders. Mitochondrion 13:379–387. https://doi.org/10.1016/j.mito.2013.02.001

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1055/s-0037-1603776

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.5582/irdr.2017.01079

    Article  PubMed  PubMed Central  Google Scholar 

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Funding

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

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Authors and Affiliations

  1. Pediatrics Department, Centro Materno Infantil do Norte, Centro Hospitalar do Porto, Largo da Maternidade, S/N, 4450, Porto, Portugal

    Margarida Paiva Coelho

  2. Reference Center for Inherited Metabolic Disorders, Centro Hospitalar do Porto, Porto, Portugal

    Esmeralda Martins

  3. Newborn Screening, Metabolism and Genetics Unit, Human Genetics Department, National Institute of Health Dr. Ricardo Jorge, Porto, Portugal

    Laura Vilarinho

Authors
  1. Margarida Paiva Coelho
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  2. Esmeralda Martins
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  3. Laura Vilarinho
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Contributions

Margarida Paiva Coelho: review of literature and article drafting

Esmeralda Martins: critical manuscript review

Laura Vilarinho: critical manuscript review

Corresponding author

Correspondence to Margarida Paiva Coelho.

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

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The authors declare that they have no conflict of interest.

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Communicated by Peter de Winter

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Paiva Coelho, M., Martins, E. & Vilarinho, L. Diagnosis, management, and follow-up of mitochondrial disorders in childhood: a personalized medicine in the new era of genome sequence. Eur J Pediatr 178, 21–32 (2019). https://doi.org/10.1007/s00431-018-3292-x

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  • DOI: https://doi.org/10.1007/s00431-018-3292-x

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