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Review Article

Natural history of mitochondrial disorders: a systematic review

Nandaki Keshavan, Shamima Rahman
Essays In Biochemistry Jul 06, 2018, EBC20170108; DOI: 10.1042/EBC20170108
Nandaki Keshavan
Mitochondrial Research Group, UCL Great Ormond Street Institute of Child Health
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Shamima Rahman
Mitochondrial Research Group, UCL Great Ormond Street Institute of Child HealthMetabolic Unit, Great Ormond Street Hospital for Children NHS Foundation Trust, London, U.K.
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  • For correspondence: shamima.rahman@ucl.ac.uk
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Abstract

The natural history of a disease defines the age of onset, presenting features, clinical phenotype, morbidity and mortality outcomes of disease that is unmodified by treatments. A clear understanding of the natural history of mitochondrial disorders is essential for establishing genotype-phenotype–prognosis correlations. We performed a systematic review of the reported natural history of mitochondrial disease by searching the literature for all published natural history studies containing at least 20 individuals. We defined a phenotype as ‘common’ if it was observed in ≥30% of cases in a study, thereby highlighting common and uncommon phenotypes for each disorder. Thirty-seven natural history studies were identified encompassing 29 mitochondrial disease entities. Fifty-nine percent of disorders had an onset before 18 months and 81% before 18 years. Most disorders had multisystemic involvement and most often affected were the central nervous system, eyes, gastrointestinal system, skeletal muscle, auditory system and the heart. Less frequent involvement was seen for respiratory, renal, endocrine, hepatic, haematological and genitourinary systems. Elevated lactate was the most frequent biochemical abnormality, seen in 72% of disorders. Age of death was <1 y in 13% of disorders, <5 y in 57% and <10 y in 74%. Disorders with high mortality rates were generally associated with earlier deaths. The most robust indicators of poor prognosis were early presentation of disease and truncating mutations. A thorough knowledge of natural history has helped to redefine diagnostic criteria for classical clinical syndromes and to establish a clinical baseline for comparison in single-arm clinical trials of novel therapies.

  • Mitochondrial disease
  • Natural history
  • Outcomes
  • Phenotype
  • Survival
  • Abbreviations

    LHON,
    Leber hereditary optic neuropathy;
    MCHS,
    myocerebrohepatopathy spectrum;
    MELAS,
    mitochondrial encephalomyopathy with lactic acidosis and stroke-like episode;
    MIDD,
    maternally inherited diabetes and deafness;
    MitoNET,
    German Network for Mitochondrial disorders;
    OXPHOS,
    oxidative phosphorylation;
    SLSMD,
    single large-scale mitochondrial DNA deletion
    • © 2018 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society
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    Natural history of mitochondrial disorders: a systematic review
    Nandaki Keshavan, Shamima Rahman
    Essays In Biochemistry Jul 2018, EBC20170108; DOI: 10.1042/EBC20170108
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    Natural history of mitochondrial disorders: a systematic review
    Nandaki Keshavan, Shamima Rahman
    Essays In Biochemistry Jul 2018, EBC20170108; DOI: 10.1042/EBC20170108

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    Keywords

    Mitochondrial disease
    Natural history
    Outcomes
    Phenotype
    Survival

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