Biochemical analysis of individual MRC complex activities13 of individual S1 muscle homogenate showed that cIV activity, normalized to citrate synthase (CS), was 20% of the mean normal value in muscle and 61% in fibroblasts. A partial decrease in complex II activity (cII/CS) was also noted in muscle (44%) and fibroblasts (58%); however, spectrophotometric succinate dehydrogenase (SDH) activity was normal in both tissues and the histochemical SDH reaction in muscle was also normal (Figures S1C and S1D). The SDH reaction in the individual S2 muscle biopsy was normal as well (Figures S1E and S1F). Biochemical assay of individual S2 muscle homogenate revealed marked increase of CS activity in muscle homogenate, resulting in reduced values of all the respiratory chain activities when normalized to CS. Nevertheless, cIV/CS showed the most severe defect in muscle (3% of the controls’ mean). Additionally, a partial decrease of cII/CS and cIV/CS activities was detected in fibroblasts. Histochemical and biochemical analyses of a muscle biopsy from individual S3 performed at age 10 years showed profound COX deficiency, with a residual cIV/CS activity of 5% of the controls’ mean (Figures S2A and S2B, Table 2); fibroblasts were not available for further study. In muscle and fibroblasts obtained from individual S4 at 5 years, a severe decrease in cIV/CS activity (8% and 25%, respectively) was found. Individual S6 muscle biopsy taken at 2 years showed diffuse reduction of COX histochemical activity (Figures S2C and S2D), and spectrophotometric analysis of respiratory chain enzymes showed isolated cIV/CS defect (36% of the control mean). Furthermore, the histochemical reaction to COX was dramatically decreased in S6 fibroblasts (Figure 2E) compared to a control cell line (Figure 2F). A summary of the MRC activities is provided in Table 2 for all cases with the exception of individual S5 who did not undergo investigative muscle or skin biopsies.