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respiratory chain complex disorders

Kazumasa Fuwa, Mitsuru Kubota, Masami Kanno, Hiroshi Miyabayashi, Ken Kawabata, Keiichi Kanno, Masaki Shimizu
Diagnosis of mitochondrial respiratory chain disorder (MRCD) is often difficult. Its pathogenesis is still unclear. We diagnosed MRCD by measuring the activity of the mitochondrial respiratory chain enzyme, and the patient also had hemophagocytic lymphohistiocytosis (HLH). A preterm female infant was born at 34 weeks of gestation. On day 6, HLH was revealed by bone marrow aspiration. She died on day 10 due to uncontrollable HLH. An autopsy was performed, and we measured the activity of the mitochondrial respiratory chain enzyme in the liver, muscle, and heart...
2016: Case Reports in Pediatrics
Meredith Meyer, Attila D Kovács, David A Pearce
Infantile CLN1 disease, also known as infantile neuronal ceroid lipofuscinosis, is a fatal childhood neurodegenerative disorder caused by mutations in the CLN1 gene. CLN1 encodes a soluble lysosomal enzyme, palmitoyl protein thioesterase 1 (PPT1), and it is still unclear why neurons are selectively vulnerable to the loss of PPT1 enzyme activity in infantile CLN1 disease. To examine the effects of PPT1 deficiency on several well-defined neuronal signaling and cell death pathways, different toxic insults were applied in cerebellar granule neuron cultures prepared from wild type (WT) and palmitoyl protein thioesterase 1-deficient (Ppt1 (-/-) ) mice, a model of infantile CLN1 disease...
October 8, 2016: Metabolic Brain Disease
Łukasz P Zieliński, Anthony C Smith, Alexander G Smith, Alan J Robinson
Mitochondrial respiratory chain dysfunction causes a variety of life-threatening diseases affecting about 1 in 4300 adults. These diseases are genetically heterogeneous, but have the same outcome; reduced activity of mitochondrial respiratory chain complexes causing decreased ATP production and potentially toxic accumulation of metabolites. Severity and tissue specificity of these effects varies between patients by unknown mechanisms and treatment options are limited. So far most research has focused on the complexes themselves, and the impact on overall cellular metabolism is largely unclear...
September 30, 2016: Mitochondrion
Monika Oláhová, Kyle Thompson, Steven A Hardy, Inês A Barbosa, Arnaud Besse, Maria-Eleni Anagnostou, Kathryn White, Tracey Davey, Michael A Simpson, Michael Champion, Greg Enns, Susan Schelley, Robert N Lightowlers, Zofia M A Chrzanowska-Lightowlers, Robert McFarland, Charu Deshpande, Penelope E Bonnen, Robert W Taylor
Mitochondrial diseases collectively represent one of the most heterogeneous group of metabolic disorders. Symptoms can manifest at any age, presenting with isolated or multiple-organ involvement. Advances in next-generation sequencing strategies have greatly enhanced the diagnosis of patients with mitochondrial disease, particularly where a mitochondrial aetiology is strongly suspected yet OXPHOS activities in biopsied tissue samples appear normal. We used whole exome sequencing (WES) to identify the molecular basis of an early-onset mitochondrial syndrome-pathogenic biallelic variants in the HTRA2 gene, encoding a mitochondria-localised serine protease-in five subjects from two unrelated families characterised by seizures, neutropenia, hypotonia and cardio-respiratory problems...
September 30, 2016: Journal of Inherited Metabolic Disease
Mohammad Mehdi Heidari, Mehri Khatami, Amirhossein Danafar, Tahere Dianat, Ghazaleh Farahmand, Ali Reza Talebi
BACKGROUND: Several recent studies have shown that mitochondrial DNA mutations lead to major disabilities and premature death in carriers. More than 150 mutations in human mitochondrial DNA (mtDNA) genes have been associated with a wide spectrum of disorders. Varicocele, one of the causes of infertility in men wherein abnormal inflexion and distension of veins of the pampiniform plexus is observed within spermatic cord, can increase reactive oxygen species (ROS) production in semen and cause oxidative stress and sperm dysfunction in patients...
October 2016: International Journal of Fertility & Sterility
Carolina Courage, Christopher B Jackson, Dagmar Hahn, Liliya Euro, Jean-Marc Nuoffer, Sabina Gallati, André Schaller
Isolated defects of the mitochondrial respiratory complex II (succinate dehydrogenase, SDH) are rare, accounting for approximately 2% of all respiratory chain deficiency diagnoses. Here, we report clinical and molecular investigations of three family members with a heterozygous mutation in the large flavoprotein subunit SDHA previously described to cause complex II deficiency. The index patient presented with bilateral optic atrophy and ocular movement disorder, a progressive polyneuropathy, psychiatric involvement, and cardiomyopathy...
September 28, 2016: American Journal of Medical Genetics. Part A
Caterina Garone, Juliana Gurgel-Giannetti, Simone Sanna-Cherchi, Sindu Krishna, Ali Naini, Catarina M Quinzii, Michio Hirano
SUCLA2 defects have been associated with mitochondrial DNA (mtDNA) depletion and the triad of hypotonia, dystonia/Leigh-like syndrome, and deafness. A 9-year-old Brazilian boy of consanguineous parents presented with psychomotor delay, deafness, myopathy, ataxia, and chorea. Despite the prominent movement disorder, brain magnetic resonance imaging (MRI) was normal while (1)H-magnetic resonance spectroscopy (MRS) showed lactate peaks in the cerebral cortex and lateral ventricles. Decreased biochemical activities of mitochondrial respiratory chain enzymes containing mtDNA-encoded subunits and mtDNA depletion were observed in muscle and fibroblasts...
September 20, 2016: Journal of Child Neurology
Laura Bianciardi, Valentina Imperatore, Erika Fernandez-Vizarra, Angela Lopomo, Micol Falabella, Simone Furini, Paolo Galluzzi, Salvatore Grosso, Massimo Zeviani, Alessandra Renieri, Francesca Mari, Elisa Frullanti
We report here the case of a young male who started to show verbal fluency disturbance, clumsiness and gait anomalies at the age of 3.5years and presented bilateral striatal necrosis. Clinically, the diagnosis was compatible with Leigh syndrome but the underlying molecular defect remained elusive even after exome analysis using autosomal/X-linked recessive or de novo models. Dosage of respiratory chain activity on fibroblasts, but not in muscle, underlined a deficit in complex I. Re-analysis of heterozygous probably pathogenic variants, inherited from one healthy parent, identified the p...
September 3, 2016: Molecular Genetics and Metabolism
Gabriele Giachin, Romain Bouverot, Samira Acajjaoui, Serena Pantalone, Montserrat Soler-López
Neurons are extremely energy demanding cells and highly dependent on the mitochondrial oxidative phosphorylation (OXPHOS) system. Mitochondria generate the energetic potential via the respiratory complexes I to IV, which constitute the electron transport chain (ETC), together with complex V. These redox reactions release energy in the form of ATP and also generate reactive oxygen species (ROS) that are involved in cell signaling but can eventually lead to oxidative stress. Complex I (CI or NADH:ubiquinone oxidoreductase) is the largest ETC enzyme, containing 44 subunits and the main contributor to ROS production...
2016: Frontiers in Molecular Biosciences
Renata Oliveira, Ewen W Sommerville, Kyle Thompson, Joana Nunes, Angela Pyle, Manuela Grazina, Patrick F Chinnery, Luísa Diogo, Paula Garcia, Robert W Taylor
Mitochondrial translation defects are important causes of early onset mitochondrial disease. Although the biochemical (combined respiratory chain deficiency) signature and neuroimaging are usually distinctive, they are not diagnostic as the genetic origin of mitochondrial translation defects is heterogeneous. We report a female child, born at term to non-consanguineous parents, who exhibited global hypotonia, failure to thrive, persistent and progressive hyperlactacidaemia with lactic acidosis, liver dysfunction and encephalopathy and died at the age of 5 months...
August 30, 2016: JIMD Reports
Josef Finsterer, Marlies Frank
There are indications that preexisting mitochondrial disorders or beta-oxidation defects predispose for propofol infusion syndrome. This review aimed at investigating if propofol infusion syndrome occurs exclusively in patients with mitochondrial disorder and if propofol can unmask a mitochondrial disorder. Propofol infusion syndrome has been reported in genetically confirmed mitochondrial disorder patients. In addition, muscle biopsy of patients with propofol infusion syndrome revealed complex IV or complex II deficiency...
November 2016: Journal of Child Neurology
Daniel A Lichtenstein, Andrew W Crispin, Anoop K Sendamarai, Dean R Campagna, Klaus Schmitz-Abe, Cristovao M Sousa, Martin D Kafina, Paul J Schmidt, Charlotte M Niemeyer, John Porter, Alison May, Mrinal M Patnaik, Matthew M Heeney, Alec Kimmelman, Sylvia S Bottomley, Barry H Paw, Kyriacos Markianos, Mark D Fleming
The congenital sideroblastic anemias (CSAs) are a heterogeneous group of inherited blood disorders characterized by pathological mitochondrial iron deposition in erythroid precursors. Each known cause has been attributed to a mutation in a protein associated with heme biosynthesis, iron-sulfur cluster biogenesis, mitochondrial translation, or a component of the mitochondrial respiratory chain. Here, we describe a recurring mutation, c.276_278del, p.F93del, in NDUFB11, a mitochondrial respiratory complex I-associated protein encoded on the X chromosome, in 5 males with a variably syndromic, normocytic CSA...
October 13, 2016: Blood
Michael Nafisinia, Yiran Guo, Xiao Dang, Jiankang Li, Yulan Chen, Jianguo Zhang, Nicole J Lake, Wendy A Gold, Lisa G Riley, David R Thorburn, Brendan Keating, Xun Xu, Hakon Hakonarson, John Christodoulou
Leigh syndrome is a subacute necrotising encephalomyopathy proven by post-mortem analysis of brain tissue showing spongiform lesions with vacuolation of the neuropil followed by demyelination, gliosis and capillary proliferation caused by mutations in one of over 75 different genes, including nuclear- and mitochondrial-encoded genes, most of which are associated with mitochondrial respiratory chain function. In this study, we report a patient with suspected Leigh syndrome presenting with seizures, ptosis, scoliosis, dystonia, symmetrical putaminal abnormalities and a lactate peak on brain MRS, but showing normal MRC enzymology in muscle and liver, thereby complicating the diagnosis...
June 26, 2016: JIMD Reports
Lina Ghaloul-Gonzalez, Amy Goldstein, Catherine Walsh Vockley, Steven F Dobrowolski, Amy Biery, Afifa Irani, Jordan Ibarra, D Holmes Morton, Al-Walid Mohsen, Jerry Vockley
The Old Order Amish populations in the US are one of the Plain People groups and are descendants of the Swiss Anabaptist immigrants who came to North America in the early eighteenth century. They live in numerous small endogamous demes that have resulted in reduced genetic diversity along with a high prevalence of specific genetic disorders, many of them autosomal recessive. Mitochondrial respiratory chain deficiencies arising from mitochondrial or nuclear DNA mutations have not previously been reported in the Plain populations...
August 2016: Molecular Genetics and Metabolism
Alessia Nasca, Andrea Legati, Enrico Baruffini, Cecilia Nolli, Isabella Moroni, Anna Ardissone, Paola Goffrini, Daniele Ghezzi
Mitochondria are highly dynamic organelles, undergoing continuous fission and fusion, and mitochondrial dynamics is important for several cellular functions. DNM1L is the most important mediator of mitochondrial fission, with a role also in peroxisome division. Few reports of patients with genetic defects in DNM1L have been published, most of them describing de novo dominant mutations. We identified compound heterozygous DNM1L variants in two brothers presenting with an infantile slowly progressive neurological impairment...
September 2016: Human Mutation
Amanda Smith, Skye McBride, Julien L Marcadier, Jean Michaud, Osama Y Al-Dirbashi, Jeremy Schwartzentruber, Chandree L Beaulieu, Sherri L Katz, Jacek Majewski, Dennis E Bulman, Michael T Geraghty, Mary-Ellen Harper, Pranesh Chakraborty, Matthew A Lines
Mutations of the mitochondrial citrate carrier (CIC) SLC25A1 cause combined D-2- and L-2-hydroxyglutaric aciduria (DL-2HGA; OMIM #615182), a neurometabolic disorder characterized by developmental delay, hypotonia, and seizures. Here, we describe the female child of consanguineous parents who presented neonatally with lactic acidosis, periventricular frontal lobe cysts, facial dysmorphism, recurrent apneic episodes, and deficient complex IV (cytochrome c oxidase) activity in skeletal muscle. Exome sequencing revealed a homozygous SLC25A1 missense mutation [NM_005984...
June 16, 2016: JIMD Reports
Yuya Hashimura, Ichiro Morioka, Chieko Hisamatsu, Naoki Yokoyama, Mariko Taniguchi-Ikeda, Hiroshi Yokozaki, Kei Murayama, Akira Ohtake, Kyoko Itoh, Yasuhiro Takeshima, Kazumoto Iijima
A female infant born at 36 weeks gestational age with birthweight 2135 g, and who developed respiratory disorder, hyperlactacidemia and hypertrophic cardiomyopathy after birth, was admitted to hospital at 3 days of age. After admission, bilious emesis, abdominal distention, and passage disorder of the gastrointestinal tract were resistant to various drugs. Exploratory laparotomy was performed at 93 days of age, but no organic lesions were identified and normal Meissner/Auerbach nerve plexus was confirmed, which led to a clinical diagnosis of chronic intestinal pseudo-obstruction (CIPO)...
July 2016: Pediatrics International: Official Journal of the Japan Pediatric Society
Tuva Barøy, Christeen Ramane J Pedurupillay, Yngve T Bliksrud, Magnhild Rasmussen, Asbjørn Holmgren, Magnus D Vigeland, Timothy Hughes, Maaike Brink, Richard Rodenburg, Bård Nedregaard, Petter Strømme, Eirik Frengen, Doriana Misceo
Mitochondrial DNA depletion syndromes (MTDPS) represent a clinically and genetically heterogeneous group of autosomal recessive disorders, caused by mutations in genes involved in maintenance of mitochondrial DNA (mtDNA). Biallelic mutations in FBXL4 were recently described to cause encephalomyopathic MTDPS13. The syndrome has infantile onset and presents with hypotonia, feeding difficulties, a pattern of mild facial dysmorphisms, global developmental delay and brain atrophy. Laboratory investigations reveal elevated blood lactate levels, unspecific mitochondrial respiratory chain (MRC) enzyme deficiencies and mtDNA depletion...
May 13, 2016: European Journal of Medical Genetics
Laurent Béghin, Stéphanie Coopman, Manuel Schiff, Joseph Vamecq, Karine Mention-Mulliez, Régis Hankard, Jean-Marie Cuisset, Hélène Ogier, Frédéric Gottrand F, Dries Dobbelaere
BACKGROUND & AIMS: Mitochondrial OXPHOS disorders (MODs) affect one or several complexes of respiratory chain oxidative phosphorylation. An increased fat/low-carbohydrate ratio of the diet was recommended for treating MODs without, however, evaluating its potential benefits through changes in the respective contributions of cell pathways (glycolysis, fatty acid oxidation) initiating energy production. Therefore, the objective of the present work was to compare Resting Energy Expenditure (REE) under basal diet (BD) and challenging diet (CD) in which fat on sugar content ratio was doubled...
April 8, 2016: Clinical Nutrition: Official Journal of the European Society of Parenteral and Enteral Nutrition
Metodi D Metodiev, Kyle Thompson, Charlotte L Alston, Andrew A M Morris, Langping He, Zarah Assouline, Marlène Rio, Nadia Bahi-Buisson, Angela Pyle, Helen Griffin, Stefan Siira, Aleksandra Filipovska, Arnold Munnich, Patrick F Chinnery, Robert McFarland, Agnès Rötig, Robert W Taylor
Mitochondrial disorders are clinically and genetically diverse, with mutations in mitochondrial or nuclear genes able to cause defects in mitochondrial gene expression. Recently, mutations in several genes encoding factors involved in mt-tRNA processing have been identified to cause mitochondrial disease. Using whole-exome sequencing, we identified mutations in TRMT10C (encoding the mitochondrial RNase P protein 1 [MRPP1]) in two unrelated individuals who presented at birth with lactic acidosis, hypotonia, feeding difficulties, and deafness...
May 5, 2016: American Journal of Human Genetics
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