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.
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July 2018
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Cover Image
Cover Image
Mitochondria are unique organelles under the dual genetic control executed by nuclear DNA and their own genome, mitochondrial DNA. Every cell contains a population of mitochondria and multiple copies of mtDNA, carrying wild type or mutated variants (heteroplasmy). The genetic variability together with the complex regulation of multiple metabolic pathways operating in mitochondria are responsible for phenotypic variability, schematically represented in the cover image. In this issue of Essays in Biochemistry, we illustrate the biological pathways operating in mitochondria and the pathomechanisms leading to disease. We also provide an overview of the current advances in the approach to diagnosis, design of new therapies, and development of clinical trials. Image kindly provided by Caterina Garone (MRC Mitochondrial Biology Unit).
Review Article|
July 06 2018
Natural history of mitochondrial disorders: a systematic review
Nandaki Keshavan;
Nandaki Keshavan
1Mitochondrial Research Group, UCL Great Ormond Street Institute of Child Health
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Shamima Rahman
1Mitochondrial Research Group, UCL Great Ormond Street Institute of Child Health
2Metabolic Unit, Great Ormond Street Hospital for Children NHS Foundation Trust, London, U.K.
Correspondence: Shamima Rahman (shamima.rahman@ucl.ac.uk)
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Publisher: Portland Press Ltd
Received:
March 31 2018
Revision Received:
May 09 2018
Accepted:
May 15 2018
Online ISSN: 1744-1358
Print ISSN: 0071-1365
© 2018 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society
2018
Essays Biochem (2018) 62 (3): 423–442.
Article history
Received:
March 31 2018
Revision Received:
May 09 2018
Accepted:
May 15 2018
Citation
Caterina Garone, Michal Minczuk, Nandaki Keshavan, Shamima Rahman; Natural history of mitochondrial disorders: a systematic review. Essays Biochem 20 July 2018; 62 (3): 423–442. doi: https://doi.org/10.1042/EBC20170108
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