mtDNA heteroplasmy level and copy number in mitochondrial disease

Several members of the WCMR team were involved in a study published earlier this month in EMBO Molecular Medicine, a peer-reviewed scientific journal dedicated to translational research. The list of authors includes a number of researchers, clinicians, nurses, clinical scientists and biostatisticians, highlighting the importance of a multidisciplinary team approach to understanding mitochondrial disease and ultimately improving the lives of patients.

The study looked at the overall health impact, or disease burden, of mitochondrial disease associated with a particular genetic change found in the mitochondrial DNA (m.3243A>G). This is the most common genetic change (mutation) seen in our cohort of patients but can affect people in many different ways, with a vast range of clinical symptoms reported. One of the major challenges with any mitochondrial disease, but especially mitochondrial disease associated with the m.3243A>G mutation, is providing patients with accurate advice on their possible disease burden and how this could change over time. This is thought to be linked to the level of mutation found in the patient’s tissues, referred to as the mutation load, with higher mutation loads often associated with more severe disease. However, this is complicated by variation in the mutation load between commonly sampled patient tissues, which can make the prognosis more uncertain. To address this, the team looked at the level of m.3243A>G mutation in over 200 patients. They compared mutation load in three commonly sampled tissues – blood, urine and skeletal muscle – and compared these to disease burden, providing a model that can be used to predict the likely course of disease.

There were many interesting findings from the study, including the observation that m.3243A>G mutation load in urine is highly variable and can be influenced by the sex of the patient, with about 20% lower mutation level seen in females compared to males. The study also confirmed the observation that m.3243A>G mutation load decreases in blood over time in the majority of patients, but despite this, mutation load in blood (when adjusted for the age of the patient) is better at predicting disease burden than mutation load in urine. Taken together, these findings allow a more accurate mutation load to be determined by adjusting for both sex and age, and the team have developed a web-based tool that can do just that ( This is available for clinicians and will help support the management of their patients.

Dr Sarah Pickett, a Wellcome Research Career Re-entry fellow and joint first author on the paper, said “Interpretation of m.3243A>G mutation levels in blood has previously been difficult because levels decrease over the lifetime of an individual. Clinicians will now be able to use our web-based tool to adjust these levels for the age of patients, giving a better understanding of likely disease burden.”

The overall conclusion of the study was that some of the variation in disease severity seen in patients with the m.3243A>G mutation can be partly explained by mutation load and age. Importantly, age-adjusted blood mutation load appears to be a reliable indicator of disease progression, and has the benefit of being a convenient sample to collect within a clinical setting.  However further studies are necessary to determine what other factors influence disease progression.

To read the full paper click here