ClinVar

Shin et al. (2000) studied a 60-year-old Japanese man who for 10 years had had manifestations of dilated cardiomyopathy. His mother and younger brother were similarly affected. Endomyocardial biopsy demonstrated marked loss or disruption of sarcomeres and massive accumulation of mitochondria of various sizes. In the tRNA of both brothers, a G-to-A transition was found at position 12192 in the MTTH gene. The mutation was located 2 bp from the 3-prime end of the T-psi-C loop of the tRNA. Because the mutation added an A:T basepair and shortened the loop itself, it was thought to affect mitochondrial function.

Searching for the same mutation, Shin et al. (2000) screened 126 patients with hypertrophic cardiomyopathy, 55 patients with dilated cardiomyopathy, and 168 control subjects without cardiac disease. They identified 4 additional patients with the 12192G-A substitution. One had hypertrophic cardiomyopathy and the mother had cardiomyopathy. The second had asymptomatic hypertrophic cardiomyopathy; the third had dilated cardiomyopathy with frequent premature ventricular contractions; and the fourth had dilated cardiomyopathy with heart failure. No control subjects had the mutation. All 5 subjects with the 12192G-A mutation showed homoplasmy. In addition, they shared an A-to-T substitution at position 16318 in the D-loop, which was not detected in other patients with cardiomyopathy or in subjects without cardiomyopathy. These findings strongly supported the close evolutionary relationship of the 2 mtDNA changes in these patients, as well as a single origin of the 12192G-A mutation. All 5 patients reported by Shin et al. (2000) showed no evidence of neurologic abnormalities or of diabetes.

Mimaki et al. (2003) reported a male patient with cardiomyopathy and Leber hereditary optic neuropathy (LHON; 535000) who had the 12192G-A mutation as well as the 11778G-A mutation in the ND4 gene (516003.0001), which is one of the most common mutations found in LHON patients. Because no case of LHON presenting with cardiomyopathy had previously been reported, the findings suggested that this was an instance of double pathogenic mitochondrial DNA mutations associated either synergistically or concomitantly with 2 different clinical manifestations.