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Mol Genet Metab. 2018 Jan;123(1):28-42. doi: 10.1016/j.ymgme.2017.11.003. Epub 2017 Nov 15.

The genotypic and phenotypic spectrum of MTO1 deficiency.

Author information

1
Division of Biochemical Diseases, Department of Pediatrics, BC Children's Hospital, BC Children's Hospital Research Institute, University of British Columbia, Vancouver, Canada.
2
Centre for Molecular Medicine and Therapeutics, Vancouver, BC, Canada; BC Children's Hospital Research Institute, University of British Columbia, Vancouver, Canada; Department of Medical Genetics, University of British Columbia, Vancouver, Canada; Institute of Physiology and Biochemistry, Faculty of Biology, The University of Belgrade, Belgrade, Serbia.
3
Department of Inherited Metabolic Disease, Guy's and St Thomas' NHS Foundation Trusts, Evelina London Children's Hospital, London, UK.
4
Clinical Genetics Unit, Guys and St Thomas' NHS Foundation Trust, London, UK.
5
Hacettepe University, Faculty of Medicine, Institute of Child Health, Department of Pediatric Metabolism, Ankara, Turkey.
6
Department of Pediatrics, Klinikum Reutlingen, Reutlingen, Germany.
7
BC Children's Hospital Research Institute, University of British Columbia, Vancouver, Canada.
8
Institute of Human Genetics, Technische Universität München, Munich, Germany; Institute of Medical Genetics and Applied Genomics, University of Tuebingen, Tuebingen, Germany.
9
John Walton Muscular Dystrophy Research Centre, Wellcome Trust Centre for Mitochondrial Research, Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK.
10
University Hospital Center Zagreb & School of Medicine, University of Zagreb, Croatia.
11
Centre for Inborn Metabolic Disorders, Department of Neuropediatrics, Jena University Hospital, Jena, Germany.
12
Department of Laboratory Medicine, Translational Metabolic Laboratory, Radboud University Medical Center, Nijmegen, The Netherlands.
13
Department of General Pediatrics, Division of Neuropediatrics and Metabolic Medicine, University Hospital Heidelberg, Heidelberg, Germany.
14
Willink Biochemical Genetics Unit, Manchester Centre for Genomic Medicine, Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK.
15
Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, BC, Canada.
16
Department of Clinical Inherited Metabolic Disorders, Birmingham Children's Hospital, Steelhouse Lane, Birmingham, UK.
17
Radboud Center for Mitochondrial Medicine, Radboud University Medical Center, Nijmegen, The Netherlands.
18
Department of Pediatrics, Division of Neuromuscular and Neurometabolic Diseases, McMaster University Medical Centre, Hamilton, ON, Canada.
19
Institute of Human Genetics, Technische Universität München, Munich, Germany; Institute of Human Genetics, Helmholtz Zentrum Munich, Neuherberg, Germany; Department of Pediatrics, Salzburger Landeskliniken (SALK), Paracelsus Medical University (PMU), Salzburg, Austria.
20
Department of Pediatrics, Salzburger Landeskliniken (SALK), Paracelsus Medical University (PMU), Salzburg, Austria.
21
Department of Pediatrics, Medical University Graz, Graz, Austria.
22
Institute of Human Genetics, Technische Universität München, Munich, Germany; Institute of Human Genetics, Helmholtz Zentrum Munich, Neuherberg, Germany.
23
Centre for Molecular Medicine and Therapeutics, Vancouver, BC, Canada; BC Children's Hospital Research Institute, University of British Columbia, Vancouver, Canada; Department of Medical Genetics, University of British Columbia, Vancouver, Canada.
24
Genetics Service, Department of Pediatrics, KK Women's and Children's Hospital, Singapore.
25
Wellcome Centre for Mitochondrial Research, Institute of Neuroscience, Newcastle University, Newcastle upon Tyne, UK.
26
Division of Biochemical Diseases, Department of Pediatrics, BC Children's Hospital, BC Children's Hospital Research Institute, University of British Columbia, Vancouver, Canada; BC Children's Hospital Research Institute, University of British Columbia, Vancouver, Canada; Department of Pediatrics, University of British Columbia, Vancouver, BC, Canada.
27
Department of Pediatrics, University of British Columbia, Vancouver, BC, Canada; Centre for Molecular Medicine and Therapeutics, Vancouver, BC, Canada; BC Children's Hospital Research Institute, University of British Columbia, Vancouver, Canada; Departments of Pediatrics and Clinical Genetics, Academic Medical Center, Amsterdam, The Netherlands. Electronic address: cvankarnebeek@cw.bc.ca.

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.

KEYWORDS:

Cardiomyopathy; Ketogenic diet; Lactic acidosis; Mitochondrial disease; Mitochondrial translation optimization 1; Oxidative Phosphorylation Defect

PMID:
29331171
PMCID:
PMC5780301
DOI:
10.1016/j.ymgme.2017.11.003
[Indexed for MEDLINE]
Free PMC Article

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