O. Hotta et al., Clinical and pathologic features of focal segmental glomerulosclerosis with mitochondrial tRNA(Leu(UUR)) gene mutation, KIDNEY INT, 59(4), 2001, pp. 1236-1243
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.