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

  • Margarida Paiva Coelho
  • Esmeralda Martins
  • Laura Vilarinho
Review

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).

Keywords

Mitochondria Mitochondrial disease mtDNA Respiratory chain deficiency Genetic diagnosis 

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

Notes

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.

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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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