Submission Details

The relationship between MT-TE and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of March 20, 2023. The MT-TE gene encodes the mitochondrial tRNA for glutamic acid, which is located from m. 14674 – 14742 on the reverse 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.

MT-TE was first reported in relation to maternally-inherited primary mitochondrial disease in 1994 (PMID: 8155739), in two individuals with mitochondrial myopathy that were subsequently described as having reversible infantile respiratory chain deficiency (RIRCD, PMID: 19720722). 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-TE-related disease, pathogenic variants in this gene cause a primary mitochondrial disease. Therefore, the MT-TE 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 nine unique variants (m.14674T>C, m.14674T>G, m.14680C>A, m.14685G>A, m.14709T>C, m.14710G>A, m.14723T>C, m.14724G>A, m.14739G>A) in 17 probands across 13 publications (PMIDs: 8155739, 21194154, 17715279, 23334599, 7726155, 7726154, 9353617, 15048886, 15670724, 23847141, 23334599, 17266923, 17056256). Single fiber testing further supported the pathogenicity of several of these variants (PMIDs: 23334599, 7726154, 15670724, 23334599, 17266923, 17056256). Age of onset in affected individuals varied from birth to 30s. Clinical features in affected individuals included (benign) infantile reversible COX deficiency myopathy (also referred to RIRCD); chronic external progressive ophthalmoplegia (CPEO), mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS)/Leigh syndrome spectrum overlap, myoclonic epilepsy and ragged red fibers (MERRF); pigmentary retinopathy, migraines, myopathy, diabetes, pulmonary hypertension, ataxia, neuropathy, global developmental delay, dysarthria, and hearing loss. Brain imaging was variable. Muscle biopsies showed ragged red fibers, COX-negative fibers, and decreased respiratory chain enzyme activities in some cases, although activities were normal in other individuals. Metabolic screening labs showed variable results. Heteroplasmy levels in affected individuals were 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 and functional alteration in patient cells and cybrids (PMIDs: 33340416, 7726155, 21194154).

In summary, there is definitive evidence to support the relationship between MT-TE 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 20, 2023 (SOP Version 9).