Importance of searching for associated mitochondrial DNA alterations in patients with multiple deletions

Multiple mitochondrial DNA (mtDNA) deletions have been reported in patients with autosomal dominant and recessive disorders. We studied several affect ed and one non-affected individuals belonging to a pedigree in which the in heritance of the pathological trait was compatible with an autosomique domi nant transmission. Affected members had late-onset multisystem disorders wi th multiple mtDNA deletions in skeletal muscle. But this family presented a striking difference from previously described cases, because none of the p atients had progressive external ophthalmoplegia (PEO). We also studied one young boy with a no contributary family history. He had a cerebellar ataxi a with PEO and multiple mtDNA deletions in muscle. Molecular analysis revea led that in the first family, repeated sequences were present at the breakp oint junctions, whereas such motifs were not found in the young patient's c ase. In the first family, we evidenced mtDNA point mutations in clones cont aining breakpoint junctions and a 9-bp motif triplication in the intergenic COII/tRNA(Lys) region, whereas this sequence is repeated twice in the wild type mtDNA. Our results suggest that multiple deletions observed in the tw o pedigrees result from different molecular mechanisms and point out the ro le of repeated sequences in the first pedigree. No mtDNA repair system has been described in mammals so far, but the molecular abnormalities found in the first family suggest that a defect in an mtDNA repair system, homologou s to the E. coil MutHLS pathway, could be responsible for such a phenotype.