Regionalized Pathology Correlates with Augmentation of mtDNA Copy Numbers in a Patient with Myoclonic Epilepsy with Ragged-Red Fibers (MERRF-Syndrome)

Human patients with myoclonic epilepsy with ragged-red fibers (MERRF) suffer from regionalized pathology caused by a mutation in the mitochondrial DNA (m.8344A→G). In MERRF-syndrome brain and skeletal muscles are predominantly affected, despite mtDNA being present in any tissue. In the past such tissue-specificity could not be explained by varying mtDNA mutation loads. In search for a region-specific pathology in human individuals we determined the mtDNA/nDNA ratios along with the mutation loads in 43 different post mortem tissue samples of a 16-year-old female MERRF patient and in four previously healthy victims of motor vehicle accidents. In brain and muscle we further determined the quantity of mitochondrial proteins (COX subunits II and IV), transcription factors (NRF1 and TFAM), and VDAC1 (Porin) as a marker for the mitochondrial mass. In the patient the mutation loads varied merely between 89–100%. However, mtDNA copy numbers were increased 3–7 fold in predominantly affected brain areas (e.g. hippocampus, cortex and putamen) and in skeletal muscle. Similar increases were absent in unaffected tissues (e.g. heart, lung, kidney, liver, and gastrointestinal organs). Such mtDNA copy number increase was not paralleled by an augmentation of mitochondrial mass in some investigated tissues, predominantly in the most affected tissue regions of the brain. We thus conclude that “futile” stimulation of mtDNA replication per se or a secondary failure to increase the mitochondrial mass may contribute to the regionalized pathology seen in MERRF-syndrome

Detection of both isotypes of complement C4, C4A and C4B, in normal human glomeruli

Detection of both isotypes of complement C4, C4A and C4B, in normal human glomeruli. Monoclonal antibodies reactive against the complement C4A and C4B isotypic components were used in an immunoper-oxidase technique for the histological study of normal human renal tissue. Prominent staining with both antibodies was seen in the mesan-gial areas of all normal kidney sections investigated. Occasional staining of arteriolar walls of the same tissues, however, was also observed. In contrast, no mesangial staining was seen using monoclonal antibodies reactive against other ‘early’ complement components, such as Clq and C3. Specificity of the glomerular staining with the anti-C4 reagents was demonstrated in two patients possessing only the C4A serum component but lacking genetically the C4B locus products. As would be predicted, glomerular staining with the anti-C4A reagent, but not anti-C4B, was clearly demonstrable. It is concluded that both isotypes of complement C4 are present in normal human glomeruli and thus might be operative for normal mesangial function