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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