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Chien Y.-H.,National Taiwan University Hospital | Abdenur J.E.,CHOC Childrens | Baronio F.,University of Bologna | Bannick A.A.,Detroit Medical Center | And 36 more authors.
Orphanet Journal of Rare Diseases

Background: This paper summarizes the results of a group effort to bring together the worldwide available data on patients who are either homozygotes or compound heterozygotes for mutations in MAT1A. MAT1A encodes the subunit that forms two methionine adenosyltransferase isoenzymes, tetrameric MAT I and dimeric MAT III, that catalyze the conversion of methionine and ATP to S-adenosylmethionine (AdoMet). Subnormal MAT I/III activity leads to hypermethioninemia. Individuals, with hypermethioninemia due to one of the MAT1A mutations that in heterozygotes cause relatively mild and clinically benign hypermethioninemia are currently often being flagged in screening programs measuring methionine elevation to identify newborns with defective cystathionine β-synthase activity. Homozygotes or compound heterozygotes for MAT1A mutations are less frequent. Some but not all, such individuals have manifested demyelination or other CNS abnormalities. Purpose of the study: The goals of the present effort have been to determine the frequency of such abnormalities, to find how best to predict whether they will occur, and to evaluate the outcomes of the variety of treatment regimens that have been used. Data have been gathered for 64 patients, of whom 32 have some evidence of CNS abnormalities (based mainly on MRI findings), and 32 do not have such evidence. Results and Discussion: The results show that mean plasma methionine concentrations provide the best indication of the group into which a given patient will fall: those with means of 800 μM or higher usually have evidence of CNS abnormalities, whereas those with lower means usually do not. Data are reported for individual patients for MAT1A genotypes, plasma methionine, total homocysteine (tHcy), and AdoMet concentrations, liver function studies, results of 15 pregnancies, and the outcomes of dietary methionine restriction and/or AdoMet supplementation. Possible pathophysiological mechanisms that might contribute to CNS damage are discussed, and tentative suggestions are put forth as to optimal management. © 2015 Chien et al. Source

Rooijers K.,Netherlands Cancer Institute | Loayza-Puch F.,Netherlands Cancer Institute | Nijtmans L.G.,Nijmegen Center for Mitochondrial Disorders | Agami R.,Netherlands Cancer Institute | Agami R.,Rotterdam University
Nature Communications

Mitochondria are essential cellular organelles for generation of energy and their dysfunction may cause diabetes, Parkinson's disease and multi-systemic failure marked by failure to thrive, gastrointestinal problems, lactic acidosis and early lethality. Disease-associated mitochondrial mutations often affect components of the mitochondrial translation machinery. Here we perform ribosome profiling to measure mitochondrial translation at nucleotide resolution. Using a protocol optimized for the retrieval of mitochondrial ribosome protected fragments (RPFs) we show that the size distribution of wild-type mitochondrial RPFs follows a bimodal distribution peaking at 27 and 33 nucleotides, which is distinct from the 30-nucleotide peak of nuclear RPFs. Their cross-correlation suggests generation of mitochondrial RPFs during ribosome progression. In contrast, RPFs from patient-derived mitochondria mutated in tRNA-Tryptophan are centered on tryptophan codons and reduced downstream, indicating ribosome stalling. Intriguingly, long RPFs are enriched in mutated mitochondria, suggesting they characterize stalled ribosomes. Our findings provide the first model for translation in wild-type and disease-triggering mitochondria. © 2013 Macmillan Publishers Limited. Source

Cabrera-Orefice A.,National Autonomous University of Mexico | Ibarra-Garcia-Padilla R.,National Autonomous University of Mexico | Maldonado-Guzman R.,National Autonomous University of Mexico | Guerrero-Castillo S.,Nijmegen Center for Mitochondrial Disorders | And 5 more authors.
Journal of Bioenergetics and Biomembranes

It is proposed that the Saccharomyces cerevisiae the Mitochondrial Unselective Channel (ScMUC) is tightly regulated constituting a physiological uncoupling system that prevents overproduction of reactive oxygen species (ROS). Mg2+, Ca2+ or phosphate (Pi) close ScMUC, while ATP or a high rate of oxygen consumption open it. We assessed ScMUC activity by measuring in isolated mitochondria the respiratory control, transmembrane potential (ΔΨ), swelling and production of ROS. At increasing [Pi], less [Ca2+] and/or [Mg2+] were needed to close ScMUC or increase ATP synthesis. The Ca2+-mediated closure of ScMUC was prevented by high [ATP] while the Mg2+ or Pi effect was not. When Ca2+ and Mg2+ were alternatively added or chelated, ScMUC opened and closed reversibly. Different effects of Ca2+ vs Mg2+ effects were probably due to mitochondrial Mg2+ uptake. Our results suggest that ScMUC activity is dynamically controlled by both the ATP/Pi ratio and divalent cation fluctuations. It is proposed that the reversible opening/closing of ScMUC leads to physiological uncoupling and a consequent decrease in ROS production. © 2015, Springer Science+Business Media New York. Source

de Laat P.,Nijmegen Center for Mitochondrial Disorders | Fleuren L.H.J.,Nijmegen Center for Mitochondrial Disorders | Bekker M.N.,RadboudUMC | Smeitink J.A.M.,Nijmegen Center for Mitochondrial Disorders | Janssen M.C.H.,Nijmegen Center for Mitochondrial Disorders

Introduction: The mitochondrial DNA m.3243A. > G mutation is the most prevalent mutation causing mitochondrial disease in adult patients. Aside from some case reports, there are no studies on obstetric complications in a cohort of m.3243A > G carriers. We aimed to identify the prevalence of obstetric complications in a cohort of women carrying the m.3243A > G mutation. Methods: All female carriers of the m.3243A > G mutation known from our previous national inventory were sent a questionnaire regarding their obstetric history. Data were compared to national references. Data from the national inventory, including NMDAS (disease severity) scores and heteroplasmy levels in urinary epithelial cells (UEC) were used to stratify women. Results: Sixty women participated, the mean age was 47 years (range 20-70), mean NMDAS was 14.6 (range 0-46), and mean heteroplasmy percentage in UEC was 19.9% (range 5-85%). Ninety-eight pregnancies in 46 women were reported. Twenty-three (25.3%) had a premature delivery and five of them (5.5%) had a gestation of ≤ 32 weeks and eleven of the women (12%) suffered from preeclampsia. No different heteroplasmy level was found in the women with preeclampsia. Nine pregnancies (11%) were complicated by gestational diabetes. Discussion: Obstetric complications occur frequently in carriers of the m.3243A > G mutation. Proper guidance during pregnancies and early detection of possible obstetric complications are needed. As techniques to prevent transmission of mitochondrial mutations are studied it is important to know the possible complications patients may experience from the ensuing pregnancy. © 2015 Elsevier B.V. and Mitochondria Research Society. Source

McCann B.J.,Nijmegen Center for Mitochondrial Disorders | McCann B.J.,TU Darmstadt | Tuppen H.A.L.,Northumbria University | Kusters B.,RadboudUMC | And 6 more authors.
Neuromuscular Disorders

We present a Dutch family with a novel disease-causing mutation in the mitochondrial tRNASer(UCN) gene, m.7507A>G. The index patient died during the neonatal period due to cardio-respiratory failure and fatal lactic acidosis. A second patient, his cousin, has severe hearing loss necessitating cochlear implants and progressive exercise intolerance. Laboratory investigations of both patients revealed combined deficiencies of the enzyme complexes of the mitochondrial respiratory chain in several tissues. Reduced levels of fully assembled complexes I and IV in fibroblasts by BN-PAGE associated with (near) homoplasmic levels of the m.7507A>G mutation in several tissues and a severe reduction in the steady-state level of mt-tRNASer(UCN) in fibroblasts were observed. The novel mitochondrial DNA mutation was shown to segregate with disease; several healthy maternal family members showed high heteroplasmy levels (up to 76 ± 4% in blood and 68 ± 4% in fibroblasts) which did not lead to any alterations in the activities of the enzyme complexes of the respiratory chain in fibroblasts or clinical signs and symptoms. We hereby conclude that the m.7507A>G mutation causes a heterogeneous clinical phenotype and is only pathogenic at very high levels of mtDNA heteroplasmy. © 2014 Elsevier B.V. Source

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