A Case of Mitochondrial Cytopathy with a Typical Point Mutation for MELAS, Presenting with Severe Focal-Segmental Glomerulosclerosis as MainClinical Manifesta tion

Abstract

A 27-year-old female with short stature and mild hearing loss was diagnosed as having focal-segmental glomerulosclerosis by renal biopsy at our hospital. One year later she developed progressive renal dysfunction and cardiac failure and was admitted again to our hospital for evaluation. Though her only neurological disorder was mild hearing loss, her short stature and elevated lactate and pyruvate values in cerebrospinal fluid suggested mitochondrial cytopathy. A muscle biopsy specimen of the left biceps brachii, using modified Gomori trichrome stain, showed a typical image of ragged-red fibers, and an increased number of giant mitochondria with paracrystalline inclusions were visible by electron microscopy. Mitochondrial DNA from the skeletal muscle showed an A-to-G transition at 3243 of transfer RNA^Leu(UUR), the common point mutation for mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes. These data confirmed the diagnosis of atypical mitochondrial cytopathy with renal and heart involvement. Mitochondrial cytopathies are often associated with hypertrophic cardiomyopathy but rarely with renal disease. Among the few reported cases with associated renal disease, most included renal tubular disorders; few cases with focal glomerular sclerosis are known. The present case of atypical mitochondrial cytopathy was characterized by a unique clinical course and rare complications with focal-segmental glomerulosclerosis.

The Spectrum of Systemic Involvement in Adults Presenting with Renal Lesion and Mitochondrial tRNA(Leu) Gene Mutation

“…All of them experienced deafness, and diabetes mellitus was consistently found. Pooling our data with previous series in adults with kidney involvement, 20 of 24 patients suffered hearing loss (4,(13)(14)(15)(16)(17). In all but one of our patients, deafness predated renal involvement with an interval ranging from 3 to 22 yr.…”

“…Diabetes mellitus was diagnosed in 12 of the 15 adult patients previously studied (4,(13)(14)(15)(16)(17). In our series, all the patients developed type 2 diabetes between 17 and 46 yr of age.…”

“…However, some families predominantly express diabetes and deafness (9 -10), while some individuals present with cardiomyopathy (11) or chronic progressive external ophthalmoplegia (12). Last, focal and segmental glomerulosclerosis (FSGS) was found in adult patients carrying the A3243G mutation (4,(13)(14)(15)(16)(17).…”

An Autopsy Case of Mitochondrial Encephalomyopathy with Lactic Acidosis and Stroke-like Episodes Syndrome with Chronic Renal Failure.

“…While renal tubular dysfunction is generally associated with a large deletion in mtDNAor rarely with duplication (2-7, 13-15), all the reported cases involving glomerular lesions were associated with the adenine to guanine transition at position 3243 of the mitochondrial tRNAleu gene (7-ll, 13, 17-19). The 3243 mutation was originally detected in MELASsyndrome (20), and recently the same mutation has been found in some patients with non-MELAS-associated phenotypes including PEO (progressive external ophthalmoplegia), maternally inherited diabetes mellitus, sensorineunal hearing loss, hypertrophic cardiomyopathy, and hereditary glomerulopathy (21)(22)(23)(24)(25)(26)(27). Some types of glomerulonephritis, such as focal segmental glomerulosclerosis, should be seen as a phenotypic expression of this mutation.…”

Glomerulopathy in MELAS syndrome

“…More recently glomerular disease with nephrotic syndrome has been described in a few patients having an A to G transition at position 3,243 in mitochondrial DNAencoding tRNA (Leu) (10)(11)(12)(13)(14). This mutation is known to be associated in most cases with MELAS(myopathy, encephalopathy, lactic acidosis and stroke-like episodes), one of the major clinical entities of mitochondrial encephalomyopathies.…”