A point mutation of mitochondrial DNA at nucleotide position 3243 has been shown to cause mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS) (1). This mutation, however, is also found in maternally inherited diabetes and deafness (MIDD) (2), which accounts for ∼1% of the diabetic population in Japan (3). The same point mutation of mitochondrial DNA causes a wide range of symptoms that have been suggested to be due to the difference in the degree of heteroplasmy; thus, the proportion of the mutant mitochondrial DNA is divergent among different tissues (4). Little evidence, however, is available due to difficulty in obtaining viable samples from active lesions associated with complications causing symptoms. In a diabetic patient with MELAS and severe gastrointestinal disease, including functional ileus, duodenal ulcer, and acute gastric mucosal lesions, which were resistant to treatment, we had a rare opportunity to investigate the degree of heteroplasmy of the 3243 mutation in a biopsy specimen of gastric mucosa, tissue with a major lesion that causes gastrointestinal complications, compared with peripheral white blood cells.

A 21-year-old woman had diabetes (HbA1c 7.3%), bilateral hearing loss, muscle weakness, and several stroke-like episodes with high serum lactate and pyruvate levels (lactate 7.4 mmol/l and pyruvate 261 μmol/l). Neurological findings showed bilateral sensory hearing loss, bilateral external ophthalmoplegia and droopy eyelids, muscle weakness (proximal > distal), and cerebellar ataxia. Magnetic resonance imaging scans showed cerebellar atrophy and mild cerebral atrophy. Her mother, grandmother, and mother’s brother also had hearing loss, but there was no obvious family history of diabetes. She also had functional ileus, duodenal ulcer, and acute gastric mucosal lesions, which were resistant to treatment. She was diagnosed as having MELAS with diabetes and gastrointestinal disease. DNA extracted from peripheral blood cells from the patient, her mother, and her elder sister was positive for the 3243 mutation. The proportion of the mutated allele in the proband (39%) was much higher than that in her sister (19%) and mother (10%). We also analyzed mitochondrial DNA of biopsy specimens of her gastric mucosa, which exhibited a higher proportion (57%) of the mutated allele than her peripheral white blood cells (39%), suggesting that her gastrointestinal complications were attributable to a high proportion of the mitochondrial variant in the gastrointestinal tract.

A high degree of mutated mitochondria in the gastrointestinal tract was previously reported in a case without typical clinical features of MELAS but with diabetes and gastrointestinal symptoms (5). There was 70% heteroplasmy of the mutation in his gastrointestinal tract, while that in peripheral white blood cells was 37% (5). Taking these findings together, it is likely that gastrointestinal symptoms in patients with the 3243 mutation, with either MELAS or MIDD, correlate with the degree of heteroplasmy in the gastrointestinal tract. These observations provide further evidence that the clinical diversity of symptoms related to mitochondrial 3243 mutation may be due to diversity in the proportion of the mutation in each organ.

1
Kari M, Jacca SM, Seija U, Anne MR: Epidemiology of A3243G, the mutation for mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS): prevalence of the mutation in adult population.
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van-den-Oueland JM, Lemkes HH, Trembath RC, Ross R, Velho G, Massen JA: Maternally inherited diabetes and deafness is a distinct subtype of diabetes and associates with a single point mutation in the mitochondrial tRNALeu (UUR) gene.
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Matsuo O, Ikuya N, Yuichi G: Single muscle fiber analysis in patients with 3243 mutation in mitochondrial DNA: comparison with the phenotype and the proportion of mutant gene.
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