P.079 MT-TA: A mitochondrial genome cause of developmental and epileptic encephalopathy

Background: MT-TA (OMIM 590000), one of 22 mitochondrial transfer-RNA (mt-tRNA) genes, encodes the mt-tRNA for alanine. Pathogenic variants in mt-tRNA genes affect the translation of respiratory chain complexes I, III, and IV; which leads to mitochondrial dysfunction and a clinically variable phenotype. MT-TA pathogenic variants have been described in only seven patients, all of whom had isolated myopathy Methods: Case report. Results: Our patient initially presented with drug-resistant West syndrome, later evolving towards a Lennox Gastaut phenotype. Although she had hypotonia, serum creatine kinase and electromyography were normal. Brain-MRI showed bilateral symmetric hypointense T1, hyperintense T2-fluid-attenuated-inversion-recovery and restricted-diffusion signal changes in the dentate nuclei. Mitochondrial genome testing identified a previously published pathogenic variant in MT-TA (m.5591G>A) with 14% blood heteroplasmy and 16% urine heteroplasmy. The variant was absent in serum sampled from the patient’s mother Conclusions: Our case extends the phenotypic spectrum of MT-TA variants to include developmental and epileptic encephalopathy, in the apparent absence of muscle disease. We hypothesize that our patient may have the greatest degree of heteroplasmy in brain tissue; however, animal models and induced pluripotent stem cell (iPSC) models are needed to identify the precise mechanism by which MT-TA dysfunction results in variable phenotypes with variable degrees of heteroplasmy.