The genotypic and phenotypic spectrum of MTO1 deficiency.

TitleThe genotypic and phenotypic spectrum of MTO1 deficiency.
Publication TypeJournal Article
Year of Publication2018
AuthorsO'Byrne JJ, Tarailo-Graovac M, Ghani A, Champion M, Deshpande C, Dursun A, Ozgul RK, Freisinger P, Garber I, Haack TB, Horvath R, Barić I, Husain RA, Kluijtmans LAJ, Kotzaeridou U, Morris AA, Ross CJ, Santra S, Smeitink J, Tarnopolsky M, Wortmann SB, Mayr JA, Brunner-Krainz M, Prokisch H, Wasserman WW, Wevers RA, Engelke UF, Rodenburg RJ, Ting TWah, McFarland R, Taylor RW, Salvarinova R, van Karnebeek CDM
JournalMol Genet Metab
Volume123
Issue1
Pagination28-42
Date Published01/2018
ISSN1096-7206
Abstract

BACKGROUND: Mitochondrial 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 METHODS: Thirty five cases of MTO1 deficiency were identified and reviewed through international collaboration. The cases of two female siblings, who presented at 1 and 2years 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.

RESULTS: For 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.

CONCLUSION: MTO1 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.

DOI10.1016/j.ymgme.2017.11.003
Alternate JournalMol. Genet. Metab.
PubMed ID29331171
PubMed Central IDPMC5780301
Grant List / / Wellcome Trust / United Kingdom
301221 / / CIHR / Canada
203105/Z/16/Z / / Wellcome Trust / United Kingdom
G0800674 / / Medical Research Council / United Kingdom