Novel MTO1 Mutations Associated with an Intrafamilial Phenotypic Variability

Background Mitochondrial diseases are a group of rare inborn metabolic disorders with multi-systemic manifestations. MTO1 gene mutations are associated with MTO1 (Mitochondrial tRNA Translation Optimization 1) protein deficiency, a mitochondrial disorder, which commonly presents with lactic acidosis and hypertrophic cardiomyopathy. Case presentation The authors describe two siblings with mitochondrial cytopathy and distinct outcomes. The index case, a female born in 1989, presented hypotonia and lactic acidosis since birth. She developed a severe myoclonic encephalopathy, movement disorder and psychomotor and growth delay. Respiratory chain enzyme complex measurement in muscle revealed a partial deficiency of complex III and IV. Throughout the years she had multiple decompensations with severe acidemia and died at age of 16, due to a respiratory infection. She never presented cardiac alterations. The younger sibling, a male born in 2002, had a less severe clinical presentation. He presented hypotonia and lactic acidosis at birth. Metabolic study performed in the first days of life revealed elevated plasma alanine and hyperlactacidemia. At 8 months of age a partial deficiency of complex IV was reported. He had a mild persistent hyperlactacidemia, psychomotor development delay, generalized hypotonia, dilated cardiomyopathy and epilepsy. In 2017, at 15 years of age, a genetic study confirmed the mitochondrial disease with identification of two MTO1 likely pathogenic variants [c.413delT (p.M138Sfs*6) / c.1450C > T (p.R484W)]. Currently, he is clinically stable, maintaining a multidisciplinary follow up. The same genotype was confirmed in his sister’s stored DNA. Conclusions With this case, report the authors emphasize mitochondrial diseases' phenotypic heterogeneity, even in the same family, and the significance of the new genetic diagnostic techniques. The authors also report a novel MTO1 likely pathogenic variant not described to date.