MT-TA

Inheritance Pattern: Mitochondrial

Disease ID:MONDO:0044970

Submitter: ClinGen

The relationship between *MT-TA* and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of March 4, 2024. The *MT-TA* gene encodes the mitochondrial tRNA for alanine. Defects of this tRNA lead to impaired mitochondrial translation, with decreased synthesis of mtDNA-encoded subunits of oxidative phosphorylation (OXPHOS) complexes I, III, IV, and V, resulting in impaired OXPHOS enzyme activities. *MT-TA* was first reported in relation to maternally inherited primary mitochondrial disease in 2001 (PMID: 11715067), in a patient with myopathy, sensorineural hearing loss, migraines, and impaired glucose tolerance. A wide spectrum of associated features has been reported over time. While various names have been given to the constellation of features seen in those with *MT-TA*-related disease, pathogenic variants in this gene cause a primary mitochondrial disease. Therefore, the *MT-TA* phenotype has been lumped into one disease entity according to the ClinGen Lumping and Splitting Framework. Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included six unique variants (m.5591G>A, m.5610G>A, m.5631G>A, m.5613T>C, m.5636T>C, m.5650G>A) in eight probands across seven publications (PMIDs: 11715067, 17825557, 14569122, 27014581, 20813205, 25873012, 16476954). Single fiber testing further supported the pathogenicity of several of these variants (PMIDs: 16476954, 25873012, 20813205, 27014581, 14569122, 17825557). Age of onset in affected individuals ranged from late childhood/teens to 60s, and all reported individuals were alive at the time of report. Features in affected individuals included myopathy (weakness, exercise intolerance), ptosis, ophthalmoplegia, lipomas, and hearing loss. Muscle biopsies showed ragged red fibers and COX-negative fibers, as well as respiratory chain enzyme deficiencies. Heteroplasmy levels in affected individuals tended to be highest in muscle when multiple tissues were assessed and were variable in other tissues when tested. The mechanism of disease appears to be loss of function. This gene-disease association is further supported by a known biochemical function shared with other genes associated with primary mitochondrial disease, animal models, and rescue in animal models by heteroplasmy shift (PMIDs: 33340416, 27626666, 30250142, 34050192). In summary, there is definitive evidence to support the relationship between *MT-TA* and primary mitochondrial disease. This relationship has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on March 4, 2024 (SOP Version 10).