Large-scale mitochondrial DNA deletions are one of the most common causes of mitochondrial disease. The presentation varies greatly and understanding of the disease course has remained unclear. This large study of 80 patients with disease onset in childhood provides a detailed and improved insight into the characteristic symptoms, signs and course of the disease. It demonstrates that a broad spectrum of age-dependent multi-organ involvement is frequent. The findings will be of help in identifying affected patients and point to the importance of coordinated multidisciplinary follow up. (By Mr. Kristoffer Björkman, https://jmg.bmj.com/content/early/2021/12/05/jmedgenet-2021-108006 )