MT-TH

Inheritance Pattern: Mitochondrial

Disease ID:MONDO:0010790

Submitter: Orphanet

Inheritance Pattern: Mitochondrial

Disease ID:MONDO:0044970

Submitter: ClinGen

The relationship between *MT-TH* and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of November 7, 2022. The *MT-TH* gene encodes the mitochondrial transfer RNA (tRNA) for histidine, which is located from m. 12138 – 12206 on the heavy strand of 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-TH* was first reported in relation to maternally inherited primary mitochondrial disease in 2003 in an individual with pigmentary retinopathy and sensorineural deafness (PMID: 12682337). While various names have been given to the constellation of features seen in those with *MT-TH*-related disease, pathogenic variants in this gene cause a primary mitochondrial disease. Therefore, the *MT-TH* phenotype has been lumped into one disease entity according to the ClinGen Lumping and Splitting Framework. Evidence supporting the gene-disease relationship between *MT-TH* and primary mitochondrial disease includes case-level data and experimental data. This curation includes six variants (m.12146A>G, m.12147G>A, m.12158A>G, m.12183G>A, m.12201T>C, m.12206C>T) observed in seven probands in seven publications (PMIDs: 12682337, 14967777, 15111688, 21704194, 21931169, 23696415, 35092007). Segregation evidence is scored as case-level data according to the criteria established by the Mitochondrial Disease Gene Curation Expert Panel. Age of onset in affected individuals varied from adolescence to the 40s. Clinical features included stroke-like episodes, seizures, myoclonus, ataxia, optic atrophy, retinal dystrophy, cataracts, hearing loss, hypogonadism, and mood disorder. Cerebellar vermis hypoplasia and signal changes in the basal ganglia, dentate nuclei, temporal lobes, and occipital lobes were seen on brain imaging. Tissue biopsies identified ragged red fibers and COX-negative fibers. Lab values showed increased blood and cerebrospinal fluid lactate. Decreased activities of complexes I and IV were variably seen in muscle. Heteroplasmy levels of the variants in affected individuals ranged from 81% to homoplasmic in muscle, 33-87% in urine, 1-60% in blood, and undetectable to homoplasmic in fibroblasts. Single fiber testing, cybrid analysis, and Northern blot analysis further supported variant pathogenicity. This gene-disease relationship is also supported by known biochemical function and functional alteration in patient and non-patient cells (in vitro functional assays demonstrated reduced rates of mitochondrial translation as a result of variants in *MT-TH*; PMID: 24920829, 21704194). 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. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on November 7, 2022 (SOP Version 9).