In 1 of 5 MERRF (545000) patients who did not have the 8344A-G mutation, Silvestri et al. (1992) identified an 8356T-C transition in the MTTK gene. The patient was a 36-year-old woman with a history of myoclonic epilepsy, generalized seizures, ataxia, myopathy, and hearing loss that started at age 30 years. Laboratory studies showed a moderate increase in serum creatine kinase and lactic acidosis. Muscle biopsy showed abundant ragged-red fibers. Family history was suggestive of maternal inheritance: the patient's mother and 1 of her 2 sisters had similar symptoms and, in addition, features of hyperthyroidism; muscle biopsy showed ragged-red fibers in both. They died at ages 52 and 25, respectively. Another sister had hearing loss but refused examination. Two maternal uncles were moderately affected; 1 had seizures and the other had hearing loss. The mutation disrupted a highly conserved basepair in the T-psi-C tem. (Transfer RNA has a cloverleaf configuration with 4 major arms. Three of the arms consist of basepaired stems and unpaired loops. Whereas the anticodon arm is so named because it contains the anticodon triplet in the center of the loop and the D arm is named for its content of the base dihydrouridine, the T-psi-C arm is named for the presence of a triplet of nucleotides in which psi stands for pseudouridine, one of the unusual bases in tRNA.) The mutant mtDNA population was essentially homoplasmic in muscle but was heteroplasmic in blood (47%). The mutation was not found in 20 patients with other mitochondrial diseases or in 25 controls.
Zeviani et al. (1993) described a point mutation in mtDNA in several members of 3 generations of a Sardinian kindred with a maternally inherited syndrome characterized by features of both MERRF and MELAS (540000). A single, heteroplasmic T-to-C transition at nucleotide 8356 was identified. The mutation was in the region of the tRNA-lys gene corresponding to the T-psi-C stem. The relative amount of mutant mtDNA in muscle correlated with the severity of the clinical presentation. Clinical features included myoclonic epilepsy, neural deafness, ataxia, and stroke-like episodes.
Nakamura et al. (2010) reported a family in which 4 members carried both the 8356T-C mutation and a 3243A-G transition in the MTTL1 gene (590050.0001), which is usually associated with MELAS syndrome. The female proband and her cousin had MERRF, a deceased aunt had a MERRF/MELAS overlap syndrome, and the mother of the proband was asymptomatic. Genetic analysis showed that the double mutations were heteroplasmic in blood of the proband and her cousin but at low levels in her asymptomatic mother. In muscle tissue of the proband and her deceased aunt, the proportion of the 3243A-G mutation was higher than in blood, and the 8356T-C mutation was homoplasmic. Nakamura et al. (2010) hypothesized that the phenotype in affected individuals began with MERRF and evolved into MELAS later in life.
