Late-onset mitochondrial DNA depletion: DNA copy number, multiple deletions, and compensation

Through a report of 4 late-onset cases with mitochondrial DNA (mtDNA) deple tion, we address the specificity of the clinical entities associated with a very low residual amount of mtDNA Three of the patients met the diagnostic criteria of Kearns Sayre syndrome, which has never been associated with mt DNA depletion. The fourth patient had an isolated skeletal myopathy. Delete d mtDNA molecules were found by long-range polymerase chain reaction (PCR) only in the Kearns Sayre syndromes, which strengthens the clinical differen ces between the two types of patients. Ad patients had extremely low residu al amounts of mtDNA as shown by Southern blot analysis. Using an original m ethod based on competitive PCR, we were able to measure the number of mtDNA copies per diploid genome. These results demonstrated the severity of the depletion in the patients by comparison not only to normal controls but als o to patients with mtDNA disorders. Despite the severity of the depletion, in situ hybridization using two mtDNA transcripts revealed a normal steady- state level of transcription. Such compensation provides clues to the strik ing contrast between the severity of mtDNA depletion and the late onset and slowly progressive disease.