Résumé :
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Communication n° 479. The A3243G and A8344G mutations in tRNA Leu (UUR) and tRNA Lys genes are heteroplasmic mutations of mitochondrial DNA, which recurrents in mitochondrial disorders, but also in their asymptomatic maternal relatives. The aim of our study was to investigate the relationship between tissue mutation repartition and disease phenotype and severity. We measured mutation loads in blood (B), urinary (U), mouth (Mo), hair (H) cells and in muscle (Mu) and searched for differences that might be of practical use in prognosis and diagnosis Forty eight independent occurrences of the A3243G (n=43) and A8344G (n=5) diagnosed in our laboratory were included (183 samples from 70 mutation carriers). A3243G was quantified by PCR-DGGE and radio-labelled PCR-RFLP integration, using a heteroplasmic standardized reference material .Disease severity was estimated according to age at first event, CNS injury and number of affected organs. Statistical analysis was performed with the non parametric Mann-Whitney and Spearman tests MELAS and MERRF mutation loads were always higher in symptomatic (S) patients than in non symptomatic (NS) carriers. However there inter-tissue distribution patterns were different. A3243G mutation load in S-subjects was always higher in muscle and urine than in other tissues with a wide overlap zone (Mu: 0.61Æ 0.15, U: 0.61Æ 0.25; Mo 0.45Æ0.16, H: 0.45Æ0.19 and B 0.34 Æ0.14) More severe phenotypes had significantly higher A3243G mutation load in urine and muscle. At the opposite, A8344G has similar proportion in every tissue (0.67 Æ 0.14 to 0.79 Æ 0.10) and in S-patients, a high threshold seems necessary to the presence of symptoms. A3243G mutation has very heterogeneous distribution and urine appears the best non-invasive sample for its diagnosis. Considerable overlap between mutation load in S and NS individuals with A3243G makes prognosis uncertain. A8344G has a more homogeneous distribution and a straightforward relationship between mutation load and disease severity.
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