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mtDNA heteroplasmy level and copy number indicate disease burden in m.3243A > G mitochondrial disease


Mitochondrial disease associated with the pathogenic m.3243A>G variant is a common, clinically heterogeneous, neurogenetic disorder. Using multiple linear regression and linear mixed modelling, we evaluated which commonly assayed tissue (blood N=231, urine N=235, skeletal muscle N=77) represents the m.3243A>G mutation load and mitochondrial DNA (mtDNA) copy number most strongly associated with disease burden and progression. m.3243A>G levels are correlated in blood, muscle and urine (R-2=0.61-0.73). Blood heteroplasmy declines by similar to 2.3%/year; we have extended previously published methodology to adjust for age. In urine, males have higher mtDNA copy number and similar to 20% higher m.3243A>G mutation load; we present formulas to adjust for this. Blood is the most highly correlated mutation measure for disease burden and progression in m.3243A>G-harbouring individuals; increasing age and heteroplasmy contribute (R-2=0.27, P<0.001). In muscle, heteroplasmy, age and mtDNA copy number explain a higher proportion of variability in disease burden (R-2=0.40, P<0.001), although activity level and disease severity are likely to affect copy number. Whilst our data indicate that age-corrected blood m.3243A>G heteroplasmy is the most convenient and reliable measure for routine clinical assessment, additional factors such as mtDNA copy number may also influence disease severity.

Type Journal
ISBN 1757-4676
Authors Grady, J. P.; Pickett, S. J.; Ng, Y. S.; Alston, C. L.; Blakely, E. L.; Hardy, S. A.; Feeney, C. L.; Bright, A. A.; Schaefer, A. M.; Gorman, G. S.; McNally, R. J. Q.; Taylor, R. W.; Turnbull, D. M.; McFarland, R.
Publisher Name EMBO Molecular Medicine
Published Date 2018-06-01
Published Volume 10
Published Issue 6
Status Published in-print
DOI UNSP e8262 10.15252/emmm.201708262
URL link to publisher's version <Go to ISI>://WOS:000434413000001