Novel MTO1 mutations associated with an intrafamilial phenotypic variability

Abstract

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.