The genotypic and phenotypic spectrum of MTO1 deficiency

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.

Phenotypic variability of MTO1-deficiency

“…We read with interest the article by O'Byrne et al about the presentation of 2 and review of 35 patients with MTO1-deficiency [1] . We have the following comments and concerns.…”

“…Patient-1 had febrile seizures since age 2.5y and absence seizures since age 3.5y [1] . Which antiepileptic drugs (AEDs) were administered during the course?…”

“…Particularly valproic acid may exhibit severe side effects in patients with a mitochondrial disorder (MID) and may even cause death, particularly in patients carrying POLG1 mutations [3] . Seizures were refractory to treatment at age 11y [1] . Was refractoriness attributable to the mitochondrion-toxic effect of the applied AEDs?…”

“…At age 11y patient-1 developed multiple, transient T2-hyperintensities within the peduncles, basal ganglia, and the cortex [1] . Were these imaging abnormalities stroke-like lesions, the morphological equivalent of stroke-like episodes (SLEs)?…”

“…One of the dominant phenotypic features seems to be hypertrophic cardiomyopathy and arrhythmias ( Table 1 ) [1] . How many of the analysed patients developed heart failure or systolic dysfunction and required cardiac therapy?…”