VARIATION IN MITOCHONDRIAL-DNA LEVELS IN MUSCLE FROM NORMAL CONTROLS - IS DEPLETION OF MTDNA IN PATIENTS WITH MITOCHONDRIAL MYOPATHY A DISTINCT CLINICAL SYNDROME

Recent studies have identified a group of patients with cytochrome oxi dase (COX) deficiency presenting in infancy associated with a deficien cy of mtDNA in muscle or other affected tissue (Moraes et al 1991). We used a navel approach to compare the level of mitochondrial (mtDNA) c ompared to nuclear DNA in skeletal muscle from a group of patients and controls, based on dot blots that were hybridized with a mtDNA probe labelled with S-35[dCTP] and a reference nuclear DNA probe labelled wi th [P-32]dCTP. The ratio of mtDNA to nuclear DNA varied in samples fro m different muscles of the same individual. Secondly, fetal muscle had very low levels of mtDNA compared to nuclear DNA, and data from older controls (cross-sectional rather than sequential) suggest that this i ncreases rapidly over the first 3 months after birth and thereafter mo re slowly. Four patients with COX deficiency had levels of mtDNA that were below the age-specific range defined by 'normal' quadriceps muscl e. The clinical features of two of these patients were similar to earl ier case reports of mtDNA depletion. Tn three patients the clinical co urse was relatively benign compared to cases that have previously been described. Levels of mtDNA in skeletal muscle from some patients with other farms of muscle disease were also found to be low, suggesting t hat mtDNA depletion, possibly related to depletion of mitochondria, ma y be a relatively non-specific response of muscle to various pathologi cal processes. However, there does appear to be a distinctive group of young patients with reduced cytochrome oxidase activity in muscle, in whom marked mtDNA depletion reflects the primary defect.