The genotypic and phenotypic spectrum of MTO1 deficiency.

James J O’byrne ,Michael Champion,Robert Mcfarland,Robert W Taylor,Rita Horvath,Charu Deshpande,Ali Dursun,Saikat Santra,Aisha Ghani,Teck Wah Ting,Johannes A Mayr,Ron A Wevers,Richard J Rodenburg,Tobias B Haack,Wyeth W Wasserman,Ian Garber,Ivo Barić,Peter Freisinger,Saskia B Wortmann,Urania Kotzaeridou,Ralf A Husain,Holger Prokisch,Ramona Salvarinova,Colin J.d Ross ,Rıza Köksal Özgül ,Leo A J Kluijtmans ,Maja Tarailo‐Graovac ,Jan A.m Smeitink ,Michaela Brunner‐Krainz ,Andrew A M Morris ,Mark A Tarnopolsky ,Udo F H Engelke ,Clara Van Karnebeek

doi:10.1016/j.ymgme.2017.11.003

Abstract

BackgroundMitochondrial diseases, a group of multi-systemic disorders often characterized by tissue-specific phenotypes, are usually progressive and fatal disorders resulting from defects in oxidative phosphorylation. MTO1 (Mitochondrial tRNA Translation Optimization 1), an evolutionarily conserved protein expressed in high-energy demand tissues has been linked to human early-onset combined oxidative phosphorylation deficiency associated with hypertrophic cardiomyopathy, often referred to as combined oxidative phosphorylation deficiency-10 (COXPD10).Material and methodsThirty five cases of MTO1 deficiency were identified and reviewed through international collaboration. The cases of two female siblings, who presented at 1 and 2 years of life with seizures, global developmental delay, hypotonia, elevated lactate and complex I and IV deficiency on muscle biopsy but without cardiomyopathy, are presented in detail.ResultsFor the description of phenotypic features, the denominator varies as the literature was insufficient to allow for complete ascertainment of all data for the 35 cases. An extensive review of all known MTO1 deficiency cases revealed the most common features at presentation to be lactic acidosis (LA) (21/34; 62% cases) and hypertrophic cardiomyopathy (15/34; 44% cases). Eventually lactic acidosis and hypertrophic cardiomyopathy are described in 35/35 (100%) and 27/34 (79%) of patients with MTO1 deficiency, respectively; with global developmental delay/intellectual disability present in 28/29 (97%), feeding difficulties in 17/35 (49%), failure to thrive in 12/35 (34%), seizures in 12/35 (34%), optic atrophy in 11/21 (52%) and ataxia in 7/34 (21%). There are 19 different pathogenic MTO1 variants identified in these 35 cases: one splice-site, 3 frameshift and 15 missense variants. None have bi-allelic variants that completely inactivate MTO1; however, patients where one variant is truncating (i.e. frameshift) while the second one is a missense appear to have a more severe, even fatal, phenotype. These data suggest that complete loss of MTO1 is not viable. A ketogenic diet may have exerted a favourable effect on seizures in 2/5 patients.ConclusionMTO1 deficiency is lethal in some but not all cases, and a genotype-phenotype relation is suggested. Aside from lactic acidosis and cardiomyopathy, developmental delay and other phenotypic features affecting multiple organ systems are often present in these patients, suggesting a broader spectrum than hitherto reported. The diagnosis should be suspected on clinical features and the presence of markers of mitochondrial dysfunction in body fluids, especially low residual complex I, III and IV activity in muscle. Molecular confirmation is required and targeted genomic testing may be the most efficient approach. Although subjective clinical improvement was observed in a small number of patients on therapies such as ketogenic diet and dichloroacetate, no evidence-based effective therapy exists.

Highlights

Mitochondrial diseases encompass a broad range of disorders that may result from pathogenic mutations of mitochondrial DNA or the nuclear genome and affect all ages in a mono- or multisystemic manner with an estimated prevalence of ~ 1:5,000 [1,2]
A novel form of mitochondrial disease caused by mutations in MTO1, encoding the mitochondrial tRNA translation optimization 1 (MTO1) protein (OMIM#614667) was first described in 2012 in 2 Italian siblings, born of unrelated parents, presenting soon after birth with lactic acidosis, severe hypoglycaemia and fatal infantile hypertrophic cardiomyopathy [6,7]
The current series of 35 cases with bi-allelic mutations in MTO1, which encodes a ubiquitously expressed enzyme necessary for optimization of mtDNA-dependent protein synthesis, is to our knowledge the largest to date. Review of their clinical features confirmed as hallmarks of this primary mitochondrial disease developmental/ cognitive impairment, lactic acidosis and complex IV deficiency ( ± other deficiencies) in muscle

Summary

Introduction

Mitochondrial diseases encompass a broad range of disorders that may result from pathogenic mutations of mitochondrial DNA or the nuclear genome and affect all ages in a mono- or multisystemic manner with an estimated prevalence of ~ 1:5,000 [1,2]. A novel form of mitochondrial disease caused by mutations in MTO1, encoding the mitochondrial tRNA translation optimization 1 (MTO1) protein (OMIM#614667) was first described in 2012 in 2 Italian siblings, born of unrelated parents, presenting soon after birth with lactic acidosis, severe hypoglycaemia and fatal infantile hypertrophic cardiomyopathy [6,7]. MTO1 is one of two subunits of an enzyme that catalyzes the 5-carboxymethylaminomethylation of the wobble uridine base in the mitochondrial tRNAs specific to leucine, tryptophan, glutamine, glutamic acid and lysine [8,9,10] This posttranscriptional modification is critical to the accuracy and efficiency of mtDNA translation. None have bi-allelic variants that completely inactivate MTO1; patients where one variant is truncating (i.e. frameshift) while the second one is a missense appear to have a more severe, even fatal, phenotype These data suggest that complete loss of MTO1 is not viable. Subjective clinical improvement was observed in a small number of patients on therapies such as ketogenic diet and dichloroacetate, no evidencebased effective therapy exists

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