WBC heteroplasmy and m.3243A>G-related mitochondrial disease
Research type
Research Study
Full title
Predicting the progression of m.3243A>G-related mitochondrial disease using white blood cell heteroplasmy
IRAS ID
252716
Contact name
Sarah Pickett
Contact email
Sponsor organisation
The Newcastle upon Tyne Hospitals NHS Foundation Trust
Duration of Study in the UK
2 years, 0 months, 1 days
Research summary
This study, supported by the Wellcome Centre for Mitochondrial Research (WCMR), seeks to understand the distribution of mitochondrial DNA mutations within white blood cell (WBCs) subtypes in order to better predict the progression of mitochondrial disease. This study will focus on patients with mitochondrial disease caused by the m.3243A>G mutation. Blood samples will be obtained from participants and their white blood cells sorted into homogeneous populations. The mtDNA mutation load of each of these populations will be analysed to determine whether there are differences in the mtDNA mutation load between WBC sub-types. The results of this study, if relevant, will be added to disease progression algorithms previously developed within the group.
The m.3243 A>G mtDNA mutation is the most common genetic cause of mitochondrial disease. The clinical presentation associated with this mutation is extremely varied and exemplifies the complex relationship between genotype and phenotype. This is further complicated by the multi-copy nature of mtDNA which enables both wild-type and mutated copies of mtDNA to be present in the same cell, the ratio of which is termed heteroplasmy. Although it has long been established that the heteroplasmy of the m.3243A>G mutation declines in blood as individuals age, the reasons behind this decline are unclear. However, recent work by the WCMR has shown that even though there is a decline in heteroplasmy with age, blood heteroplasmy is the best predictor of disease progression, although combined with age only has a predictive value of 27%.1 Being able to predict disease is clinically important since this will allow tailored treatment for patients, for example early use of diet to prevent diabetes, use of cardio protective drugs and the early introduction of anticonvulsants.
One way to potentially improve the predictive power of total blood heteroplasmy in m.3243A>G patients is to investigate the heteroplasmy of the subtypes of cells which make up the WBC population within a blood sample. Preliminary data has shown that the different WBCs (T-cells, B-cells etc) each have different levels of contribution to the overall WBC heteroplasmy level. This study aims to investigate heteroplasmy in WBC subtypes to elucidate which particular blood cell is most suitable for predicting patient progression.
REC name
London - West London & GTAC Research Ethics Committee
REC reference
19/LO/0117
Date of REC Opinion
4 Jan 2019
REC opinion
Favourable Opinion