MT-TM

Inheritance Pattern: Mitochondrial

Disease ID:MONDO:0044970

Submitter: ClinGen

The relationship between *MT-TM* and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of December 19, 2022. The *MT-TM* gene encodes the mitochondrial tRNA for methionine, which is located from m.4402-4469 on the heavy strand of the mitochondrial DNA (mtDNA). Defects of this tRNA lead to impaired mitochondrial translation, which leads to decreased synthesis of mtDNA-encoded subunits of oxidative phosphorylation (OXPHOS) complexes I, III, IV, and V, resulting in impaired OXPHOS enzyme activities. While various names have been given to the constellation of features seen in those with *MT-TM*-related disorders, pathogenic variants in this gene cause a primary mitochondrial disease. Therefore, the *MT-TM* phenotype has been lumped into one disease entity according to the ClinGen Lumping and Splitting Framework. *MT-TM* was first reported to be associated with maternally inherited primary mitochondrial disease in 1998 (PMID: 9633749). The condition was first described in a 10-year-old girl with exercise intolerance, myopathy, and short stature with mildly elevated serum lactate. Subsequent publications have shown a consistent phenotype involving a mitochondrial myopathy (typically childhood onset) with elevated lactate. Chronic external progressive ophthalmoplegia (CPEO) is not common but has been reported. Basal ganglia lesions and Leigh syndrome spectrum/mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) overlap have also been reported in one patient. Retinitis pigmentosa has also been reported. Muscle biopsy often shows classic findings of mitochondrial myopathy with COX-negative and ragged red (or blue) fibers. Combined OXPHOS deficiencies in muscle are also observed (PMIDs: 24711008, 25468263). Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included 7 unique missense variants including one recurrent variant, m.4450G>A. These variants were generally present at high levels of heteroplasmy in muscle tissue and at lower to undetectable levels in other tissues such as blood, saliva, buccal tissue, urine, and fibroblasts, highlighting the diagnostic importance of muscle biopsy in *MT-TM*-related primary mitochondrial disease. Of note, affected individuals with mitochondrial myopathy have been reported with heteroplasmy levels as low as 30% in muscle tissue (PMID: 31488384). Single fiber studies were performed in several individuals with results supporting variant pathogenicity. Some publications did not include details on single fiber studies such as the number of fibers tested and statistical significance values, therefore this GCEP opted to exclude these studies from scoring (PMID: 29174468). One case was excluded from scoring as two rare mtDNA variants (one in *MT-TM* and one in *MT-CO3*) co-segregated with manifestations (PMID: 19460300) and single fiber studies could not differentiate the causal variant. Another case was excluded because no nuclear DNA testing was performed to investigate an isolated complex IV deficiency in this case (PMID: 23463613). In summary, this curation included 8 probands across 8 publications from 1998-2019 (PMIDs: 9633749, 24711008, 25468263, 30739820, 11335700, 31488384, 31022467, 29174468). This gene-disease association is also supported by functional implication given protein interaction with the multitude of other mitochondrial translation proteins linked to primary mitochondrial disease (PMID: 30030363). Subsequent analyses on the m.4409T>C variant in E. coli showed reduced aminoacylation of tRNA by human methionine aminoacyl synthetase and structural deficits in mt-tRNA Met impacting mitochondrial translation (PMID: 18835817). Of note, while one case was not considered in this curation given the individual had splenic lymphoma and no signs of mitochondrial myopathy, this GCEP elected to score cybrid studies performed in this publication as functional evidence supporting the deleterious effect of the m.4450G>A variant (PMID: 9452079). In summary, there is definitive evidence to support this gene-disease relationship, including that more than three years have elapsed since the first proposal of the association. No convincing evidence has emerged that contradicts the gene-disease relationship. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on December 19, 2022 (SOP Version 9).