Longitudinal changes of mtDNA A3243G mutation load and level of functioning in MELAS

Abstract

Mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS), one of the most common mitochondrial multisystemic diseases, is most commonly associated with an A-to-G transition at nucleotide position 3243 (A3243G) in mitochondrial DNA. We studied 34 individuals harboring the A3243G mutation for up to 7 years; 17 had the full MELAS phenotype and 17 who were classified as "carrier relatives" because they were either asymptomatic or had some symptoms suggestive of mitochondrial disease but no seizures or strokes. Using the sensitive real-time polymerase chain reaction to quantify the A3243G mutation, we confirmed that the percent mutation decreases progressively in DNA isolated from blood: the average percent decrease was 0.5% per year for fully symptomatic patients and 0.2% per year for oligosymptomatic carrier relatives. We also correlated mutant loads with functional status estimated by the Karnofksky score: even though the mutation load decreases, the level of functioning worsens in fully symptomatic patients, whereas the level of functioning of carrier relatives remains largely unchanged. This study suggests that A3243G mutant load in DNA isolated from blood is neither useful for prognosis nor for functional assessment.

Figure 1

A. Change in heteroplasmy among fully symptomatic MELAS patients. B. Change in heteroplasmy among carrier relatives. The dashed lines are individual heteroplasmy paths from 17 fully symptomatic MELAS patients (Figure 1A) or 17 carrier relatives (Figure 1B). The circles are the actual measured heteroplasmy levels. The solid line indicates how the percentage of heteroplasmy changes with follow-up year on average and is estimated from a linear mixed model. The coefficient of determination is calculated based on Nagelkerke, NJD [1991]. Coefficient of determination R² = 0.86 (Figure 1A) and 0.91 (Figure 1B)

Figure 1

A. Change in heteroplasmy among fully symptomatic MELAS patients. B. Change in heteroplasmy among carrier relatives. The dashed lines are individual heteroplasmy paths from 17 fully symptomatic MELAS patients (Figure 1A) or 17 carrier relatives (Figure 1B). The circles are the actual measured heteroplasmy levels. The solid line indicates how the percentage of heteroplasmy changes with follow-up year on average and is estimated from a linear mixed model. The coefficient of determination is calculated based on Nagelkerke, NJD [1991]. Coefficient of determination R² = 0.86 (Figure 1A) and 0.91 (Figure 1B)