mt <scp>DNA</scp> heteroplasmy level and copy number indicate disease burden in m.3243A&gt;G mitochondrial disease

TLDR

Mitochondrial disease associated with the pathogenic m.3243A>G variant is a common, clinically heterogeneous, neurogenetic disorder. The study evaluated, using multiple linear regression and linear mixed‑modeling, which tissue—blood, urine, or skeletal muscle—provides the m.3243A>G mutation load and mtDNA copy number most strongly linked to disease burden and progression. The authors applied these statistical models to blood, urine, and muscle samples, adjusted for age, and derived urine‑specific formulas to account for sex‑related differences in mtDNA copy number and mutation load. Age‑corrected blood m.3243A>G heteroplasmy emerged as the most convenient and reliable predictor of disease burden and progression, while muscle heteroplasmy, age, and mtDNA copy number explain greater variability and urine shows sex‑related differences.

Abstract

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 (R2 = 0.61-0.73). Blood heteroplasmy declines by ~2.3%/year; we have extended previously published methodology to adjust for age. In urine, males have higher mtDNA copy number and ~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 (R2 = 0.27, P < 0.001). In muscle, heteroplasmy, age and mtDNA copy number explain a higher proportion of variability in disease burden (R2 = 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.