Clinical and pathologic features of focal segmental glomerulosclerosis with mitochondrial tRNA(Leu(UUR)) gene mutation

Background. Several families have been described in which an A to G transit ion mutation at position 3243 (A3243G) of the mitochondrial DNA (mtDNA) is associated with focal and segmental glomerulosclerosis (FSGS). However, the prevalence, clinical features, and pathophysiology of FSGS carrying mtDNA mutations are largely undefined. Methods. Among 11 biopsy-proven primary FSGS patients of unknown etiology, we examined seven FSGS patients to determine whether any of the clinical an d pathological features of FSGS were associated with an A3243G mtDNA mutati on. In four subjects in whom the A3243G mtDNA mutation was discovered in bl ood leukocytes, as well as in urine sediments, we retrospectively reviewed the medical records and re-evaluated the renal biopsy specimen using light and electron microscopy. We further screened the patient's family members f or the presence and degree of heteroplasmy for this mtDNA mutation and obta ined medical histories that were consistent with mitochondrial cytopathy. Results. The four individuals identified with the A3243G mtDNA mutation wer e female. Proteinuria was diagnosed in these individuals during a routine a nnual health checkup in their teenage years. None of the patients showed an y symptoms related to mitochondrial myopathy, encephalopathy, lactic acidos is, and stroke-like episode, whereas diabetes mellitus in two of the patien ts and a hearing disturbance in one patient became manifest within a 3- to 13-year follow-up period. Strict maternal transmitted inheritance was confi rmed by pedigree studies in all of these patients. Steroid therapy was inef fective in all four patients. In two of these patients, renal function decl ined slowly to end-stage renal failure. Histologic examination of biopsy sp ecimens revealed that glomeruli were not hypertrophied, while electron micr oscopic examination identified severely damaged, multinucleated podocytes c ontaining extremely dysmorphic abnormal mitochondria in all patients. Conclusions. FSGS may belong to the spectrum of renal involvement in A3243G mtDNA mutation in humans. Severely injured podocytic changes containing ab normal mitochondria may explain the pathogenesis of FSGS in association wit h the A3243G mtDNA mutation.