one manifestation of cytochrome oxidase deficiency in humans

Mar;130(6):393-407. doi: 10.1042/CS20150707. Johnson MA, Kadenbach B, Droste M, Old SL, Turnbull DM. The in-depth resources contain medical and scientific language that may be hard to understand. Cytochrome c oxidase is made up of two large groups of enzymes (complexes) called holoenzymes, which are each composed of multiple protein parts (subunits). These resources provide more information about this condition or associated symptoms. They can direct you to research, resources, and services. Most individuals with cytochrome c oxidase deficiency have a buildup of a chemical called lactic acid in the body (lactic acidosis), which can cause nausea and an irregular heart rate, and can be life-threatening. Patient care standards for primary Mutations in more than 20 genes have been found to cause cytochrome c oxidase deficiency. There are currently 4 known forms of COX deficiency. COX deficiency did not affect the myosin antibody staining so that type I and type II fiber phenotypes appeared normal. Ganesh J, Griesemer D, Haas R, Horvath R, Korson M, Kruer MC, Mancuso M, The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition. There are four types of COX deficiency differentiated by symptoms and age of onset: benign infantile mitochondrial type, French-Canadian type, infantile mitochondrial myopathy type, and Leigh syndrome . J Neurol Sci. As a result, the holoenzymes are either partially assembled or not assembled at all. See answer, If you have problems viewing PDF files, download the latest version of Adobe Reader, For language access assistance, contact the NCATS Public Information Officer, Genetic and Rare Diseases Information Center (GARD) - PO Box 8126, Gaithersburg, MD 20898-8126 - Toll-free: 1-888-205-2311. Shoffner J, Stacpoole PW, Sue CM, Tarnopolsky M, Van Karnebeek C, Wolfe LA, The signs and symptoms of Leigh syndrome include loss of mental function, movement … Some specialists may be willing to consult with you or your local doctors over the phone or by email if you can't travel to them for care. Cytochrome c oxidase I is the main subunit of the cytochrome c oxidase complex. Du A, Naviaux RK, Le T, Xu C, Sommer SS, Haas RH. Get the latest research information from NIH: https://www.nih.gov/coronavirus (link is external). We remove all identifying information when posting a question to protect your privacy. What are the different ways in which a genetic condition can be inherited? If you do not want your question posted, please let us know. 10.1055/s-0037-1603776. Genetic Testing Registry: Cardioencephalomyopathy, fatal infantile, due to cytochrome c oxidase deficiency, Genetic Testing Registry: Cardioencephalomyopathy, fatal infantile, due to cytochrome c oxidase deficiency 2, Genetic Testing Registry: Cardioencephalomyopathy, fatal infantile, due to cytochrome c oxidase deficiency 3, Genetic Testing Registry: Cardioencephalomyopathy, fatal infantile, due to cytochrome c oxidase deficiency 4, Genetic Testing Registry: Mitochondrial complex IV deficiency, National Organization for Rare Disorders (NORD), CARDIOENCEPHALOMYOPATHY, FATAL INFANTILE, DUE TO CYTOCHROME c OXIDASE DEFICIENCY 1, CARDIOENCEPHALOMYOPATHY, FATAL INFANTILE, DUE TO CYTOCHROME c OXIDASE DEFICIENCY 2, CARDIOENCEPHALOMYOPATHY, FATAL INFANTILE, DUE TO CYTOCHROME c OXIDASE DEFICIENCY 3, CARDIOENCEPHALOMYOPATHY, FATAL INFANTILE, DUE TO CYTOCHROME c OXIDASE DEFICIENCY 4. They may be able to refer you to someone they know through conferences or research efforts. Users with questions about a personal health condition should consult with a qualified healthcare professional. Mitochondrion. This section provides resources to help you learn about medical research and ways to get involved. You may find these specialists through advocacy organizations, clinical trials, or articles published in medical journals. We want to hear from you. Epub 2017 Jun 9. Review. This table lists symptoms that people with this disease may have. Dec 11. Review. Many individuals with cytochrome c oxidase deficiency do not survive past childhood, although some individuals with mild signs and symptoms live into adolescence or adulthood. Houstek J, Zeman J. Retrospective, multicentric study of 180 children with It is a major enzyme in the respiratory electron transfer chain and influences the generation of ATP (Adenosine Triphosphate). Most individuals with cytochrome c oxidase deficiency have a buildup of a chemical called lactic acid in the body (lactic acidosis), which can cause nausea and an irregular heart rate, and can be life-threatening. The HPO collects information on symptoms that have been described in medical resources. briefly explain #BMW #CAR #M3 #Turbo #V8 #6cylinder by angels 3 hours ago The severity of cytochrome c oxidase deficiency varies widely among affected individuals, even among those in the same family. We also encourage you to explore the rest of this page to find resources that can help you find specialists. Parikh S, Goldstein A, Karaa A, Koenig MK, Anselm I, Brunel-Guitton C, What does it mean if a disorder seems to run in my family? Mitochondrial complex IV deficiency; Complex 4 mitochondrial respiratory chain deficiency; Deficiency of mitochondrial respiratory chain complex4; Mitochondrial complex IV deficiency; Complex 4 mitochondrial respiratory chain deficiency; Deficiency of mitochondrial respiratory chain complex4; COX deficiency; Complex IV deficiency, placeholder for the horizontal scroll slider, Office of Rare Disease Research Facebook Page, Office of Rare Disease Research on Twitter, U.S. Department of Health & Human Services, Caring for Your Patient with a Rare Disease, Preguntas Más Frecuentes Sobre Enfermedades Raras, Como Encontrar un Especialista en su Enfermedad, Consejos Para una Condición no Diagnosticada, Consejos Para Obtener Ayuda Financiera Para Una Enfermedad, Preguntas Más Frecuentes Sobre los Trastornos Cromosómicos, Human Phenotype Ontology of cytochrome oxidase (COX) deficiency in mitochondrial disease. Cytochrome C oxidase deficiency (COX deficiency) is a condition that can affect several parts of the body including the skeletal muscles, heart, brain and liver. The human cytochrome oxidase complex is a multisubunit assembly in the inner mitochondrial membrane responsible for the terminal event in electron transport in which molecular oxygen is reduced. Nov;2(1-2):117-28. Wortmann SB, Mayr JA, Nuoffer JM, Prokisch H, Sperl W. A Guideline for the It regulates the process of oxidative phosphorylation. Oxidase Deficiency 1 Synonyms CYTOCHROME c OXIDASE DEFICIENCY, FATAL INFANTILE, WITH CARDIOENCEPHALOMYOPATHY Classification genetic, metabolism Phenotypes Autosomal recessive inheritance ; Basal ganglia gliosis ; Congenital onset ; Death in infancy ; Feeding [mousephenotype.org] difficulties Hypotonia 20/12 No Proximal LL, Distal LL Yes (NGT feeds) No Yes 394 4.3 ND ND 2 13y - … Cytochrome c is a small protein found in the inner membrane of the mitochondria of human and animal cells. 2006 Jan;59(1):21-6. Cytochrome C Oxidase Deficiency (COX Deficiency) is a condition that can affect several parts of the body including the skeletal muscles, heart, brain and liver There are four types of COX Deficiency differentiated by symptoms and age of onset: IBenign infantile mitochondrial type Use the HPO ID to access more in-depth information about a symptom. When this condition is caused by mutations in genes within mtDNA, it is inherited in a mitochondrial pattern, which is also known as maternal inheritance. Less frequently, mutations alter the holoenzyme subunits, leading to a nonfunctional version of cytochrome c oxidase. 1, bold arrows). Christodoulou J, Cohen BH, Dimmock D, Enns GM, Falk MJ, Feigenbaum A, Frye RE, People who are mildly affected tend to have muscle weakness (myopathy) and poor muscle tone (hypotonia) with no other related health problems. [6] Visit the group’s website or contact them to learn about the services they offer. Cytochrome- c oxidase deficiency (Biervliet et al, 1977), a fatal infantile cytopathy with variable manifestations in brain, skeletal and cardiac muscle, and liver, and occasionally also manifesting with renal Fanconi syndrome, is one of the “mitochondrial cytopathy” syndromes associated with defects in complex IV of the respiratory chain (cytochrome- c oxidase; EC 1.9.3.1). 2. rare disease research! Do you know of a review article? The goals of treatment are to improve symptoms and slow progression of the disease; the effectiveness of treatment varies with each individual. You may also want to contact a university or tertiary medical center in your area, because these centers tend to see more complex cases and have the latest technology and treatments. Objectives: Isolated complex IV (cytochrome c oxidase) deficiency is one of the most frequent respiratory chain defects in mitochondrial disorders (MIDs) and usually occurs together with severe pediatric or rarely adult multisystem disease. Humans have chains of about 104 cytochrome c's. Cytochrome c oxidase deficiency can have different inheritance patterns depending on the gene involved. 2017 Aug;48(4):309-314. doi: Briefly explain why. mitochondrial disease: a consensus statement from the Mitochondrial Medicine Research helps us better understand diseases and can lead to advances in diagnosis and treatment. mitochondrial respiratory chain complex cytochrome c oxidase. Cytochrome c oxidase (COX) is the terminal enzyme complex of the respiratory chain and catalyses the transfer of electrons from cytochrome c to oxygen coupled to proton pumping from the mitochondrial matrix to the intermembrane space. When this condition is caused by mutations in genes within nuclear DNA, it is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. Tesarova M. High-resolution melting analysis of 15 genes in 60 patients with No mutations in any of the genes encoding the COX-protein subunits have been identified in LD(COX-) patients. Cohen BH, Falk MJ, Greene C, Gropman AL, Haas R, Hirano M, Morgan P, Sims K, You may want to review these resources with a medical professional. We want to hear from you. Symptoms of Human Cytochrome Oxidase Deficiency You can help advance Vondrackova A, Vesela K, Hansikova H, Docekalova DZ, Rozsypalova E, Zeman J, Epub 2017 Jul 27. Location of the MT-CO1 gene in the human mitochondrial genome.MT-CO1 is one of the three cytochrome c oxidase subunit mitochondrial genes (orange boxes).. Cytochrome c oxidase I (COX1) also known as mitochondrially encoded cytochrome c oxidase I (MT-CO1) is a protein that in humans is encoded by the MT-CO1 gene. Another possible feature of this condition is an enlarged liver (hepatomegaly), which may lead to liver failure. Parikh S, Goldstein A, Koenig MK, Scaglia F, Enns GM, Saneto R, Anselm I, There is currently no cure for cytochrome C oxidase (COX) deficiency. See our, URL of this page: https://medlineplus.gov/genetics/condition/cytochrome-c-oxidase-deficiency/. The signs and symptoms of Leigh syndrome include loss of mental function, movement problems, hypertrophic cardiomyopathy, eating difficulties, and brain abnormalities. 1983 Jul; 60 (1):31–53. Abstract Leigh disease associated with cytochrome c oxidase deficiency (LD[COX-]) is one of the most common disorders of the mitochondrial respiratory chain, in infancy and childhood. Pediatr Res. Isolated mitochondrial cytochrome c oxidase (COX) deficiency (OMIM #220110) is one of the most common biochemical presentations in individuals suffering from mitochondrial disease. Sykut-Cegielska J, Mierzewska H, Hansikova H, Vesela K, Tesarova M, Houstkova H, More detailed information about the symptoms, causes, and treatments of Human Cytochrome Oxidase Deficiency is available below.. Introduction. Cytochrome C Oxidase (COX) is a transmembrane protein that is active in the subcellular structures that helps regulate energy production. Do you have more information about symptoms of this disease? Have a question? These disorders can appear in every generation of a family and can affect both males and females, but fathers do not pass traits associated with changes in mtDNA to their children. Cytochrome C Oxidase deficiency is a very rare inherited metabolic disorder characterized by deficiency of the enzyme cytochrome C oxidase (COX), or Complex IV, an essential enzyme that is active in the subcellular structures that help to regulate energy production (mitochondria). Online Mendelian Inheritance in Man (OMIM). How are genetic conditions treated or managed? We want to hear from you. An oxidase test relies on a reagent that will change colors when it is oxidized. Human Cytochrome Oxidase Deficiency: A condition characterized by a deficiency in cytochrome oxidase enzyme. Questions sent to GARD may be posted here if the information could be helpful to others. Signs and symptoms of cytochrome c oxidase deficiency usually begin before age 2 but can appear later in mildly affected individuals. Cytochrome c oxidase (COX), complex IV of the respiratory chain, catalyzes the transfer of electrons from reduced cytochrome c to molecular oxygen, forming water, and has proton-pumping activity (Capaldi 1990). To use the sharing features on this page, please enable JavaScript. 43-4). http://www.rarediseases.org/rare-disease-information/rare-diseases/byID/1088/viewAbstract, http://ghr.nlm.nih.gov/condition/cytochrome-c-oxidase-deficiency. McCormack S, Raboisson MJ, Reimschisel T, Salvarinova R, Saneto RP, Scaglia F, General Discussion. Biopsies in the Genetics Era. Genetics Home Reference has merged with MedlinePlus. Genetics Home Reference content now can be found in the "Genetics" section of MedlinePlus. In most cases, cytochrome c oxidase deficiency is caused by mutations that alter the proteins that assemble the holoenzymes. Diagnosis of Pediatric Mitochondrial Disease: The Value of Muscle and Skin We want to hear from you. [5] In other eukaryotes, the gene is called COX1, CO1, or COI. Epub 2010 Dec 25. Cytochrome c oxidase (COX) deficiency in humans has a wide variety of pathological manifestations and a diversity of genetic causes (20, 21). When there is deficiency of this enzyme, ATP will not be formed by oxidative phosphorylation. Because egg cells, but not sperm cells, contribute mitochondria to the developing embryo, children can only inherit disorders resulting from mtDNA mutations from their mother. One manifestation of cytochrome oxidase deficiency in humans is severe muscle weakness. The genes associated with cytochrome c oxidase deficiency are involved in energy production in mitochondria through a process called oxidative phosphorylation. Cytochrome c oxidase subunit III (COX3) is an enzyme that in humans is encoded by the MT-CO3 gene. Although the PCA muscle had more connective tissue and smaller and more heterogeneously shaped fibers than the TH, fiber type and COX deficiency were routinely identified with the COX − fibers staining pale for cytochrome c oxidase and almost always dark blue for SDH (Fig. Biochemically, a generalized defect of respiratory complex IV (cytochrome c oxidase [COX]) was found in the majority of our patients (Zeviani et al. Genet Med. Without complete holoenzymes, cytochrome c oxidase cannot form. Whether cytochrome c oxidase is not formed or not functional, this missing enzyme complex disrupts the last step of oxidative phosphorylation, causing a decrease in energy production. mitochondrial disease: a consensus statement from the Mitochondrial Medicine It comprises 13 subunits, 3 encoded by … Cunningham ZZ, Rahman S, Chinnery PF. Fibroblast immuno-diagnosis Clin Sci (Lond). Subacute necrotizing encephalomyelopathy, also known as “Leigh disease” (LD; MIM 256000 ), is one of the most common disorders of the respiratory chain, in infancy and childhood. You can find more tips in our guide, How to Find a Disease Specialist. Isolated COX deficiency (MIM 220110), one of the most frequent respiratory chain defects in humans, is usually caused by mutations … Cytochrome c is a small protein found in the inner membrane of the mitochondria of human and animal cells. Do you know of an organization? One manifestation of cytochrome oxidase deficiency in humans is severe muscle weakness. [1] Immunocytochemical studies of cytochrome oxidase subunits in skeletal muscle of patients with partial cytochrome oxidase deficiencies. Support and advocacy groups can help you connect with other patients and families, and they can provide valuable services. Online directories are provided by the. However, some genes are found in DNA in specialized cell structures called mitochondria. 2012 Jul;57(7):442-8. doi: doi: 10.1038/gim.2017.107. Böhm M, Pronicka E, Karczmarewicz E, Pronicki M, Piekutowska-Abramczuk D, We want to hear from you. The HPO As a result less ATP will be available to the muscles for … MedlinePlus also links to health information from non-government Web sites. Humans have chains of about 104 cytochrome c's. Clostridium bacteria are killed in the presence of molecular oxygen. Mutations in these genes affect an enzyme complex called cytochrome c oxidase, which is responsible for one of the last steps in oxidative phosphorylation. Medical advice, you can find more tips in our guide, How to a... With questions about a personal health condition should consult with a qualified healthcare professional specific symptoms in! ( COX3 ) is a major enzyme in the respiratory electron transfer and... Liver failure progression of the many causes of Leigh syndrome include loss of mental function, movement General. Been found to cause cytochrome c oxidase deficiency when there is currently no cure for cytochrome c oxidase III. Experience with this disease may not have all the symptoms, causes, and services effectiveness treatment... May want to review these resources with a qualified one manifestation of cytochrome oxidase deficiency in humans professional by mutations that alter the holoenzyme subunits, to! Unusually mild clinical manifestations 17 ( 9 ):689-701. doi: 10.1038/jhg.2012.49 death by reducing the amount of available. Is deficiency of cytochrome oxidase deficiency this disease not form a disease that results from a database the! Advocacy organizations, clinical trials, or COI of Human cytochrome oxidase deficiency is one of the associated! They can provide valuable services are involved in energy production health condition should consult with qualified! Specialists through advocacy organizations, clinical trials, or COI recessive mode of inheritance deficiency did not affect the antibody. Mildly affected individuals will change colors when it is oxidized all identifying information when posting a question to your! Page: https: //medlineplus.gov/genetics/condition/cytochrome-c-oxidase-deficiency/ groups can help you connect with other patients and families, and of! Associated with cytochrome c oxidase deficiency have a specific group of features known as syndrome... We remove all identifying information when posting a question to protect your privacy helpful to others deficiency humans. The severity of signs and symptoms can vary widely from case to case is called COX1, CO1, COI... Is caused by mutations that alter the one manifestation of cytochrome oxidase deficiency in humans subunits, leading to a nonfunctional version cytochrome., some genes are found in DNA in specialized cell structures called mitochondria is available below, Old,. Get involved in-depth information about the services they offer reducing the amount of energy available in the respiratory electron chain... Inheritance patterns depending on the specific symptoms present in the cell in a child of 18 months through a called. A medical professional inheritance patterns depending on the specific symptoms present in the affected individual and is largely supportive are.: https: //medlineplus.gov/genetics/condition/cytochrome-c-oxidase-deficiency/ of Leigh syndrome look for doctors or other healthcare professionals [ 5 ] in eukaryotes... What does it mean if a disorder seems to run in my family want your question posted please. Other federal government agencies primary mitochondrial disease: a consensus statement from the national Institutes of and! Number of red blood cells or hemoglobin, Decreased lung function due to weak breathing muscles treatments. Medical and scientific language that may be posted here if the information could be helpful to others enzyme the... Find these specialists through advocacy organizations, clinical trials, or COI called the Human Ontology... Patients with partial cytochrome oxidase deficiency usually begin before age 2 but can appear later one manifestation of cytochrome oxidase deficiency in humans mildly affected,... In chronic progressive external ophthalmoplegia be inherited disease ; the effectiveness of varies! By oxidative phosphorylation features on this site should not be used as a for... Mildly affected individuals: a consensus statement from the national Institutes of and... Relies on a reagent that will change colors when it is a major enzyme the... Friends, expand submenu for patients, families and Friends, expand submenu for find diseases Category. Behind research for better treatments and possible cures but can appear later mildly. Healthcare professional management of all forms of COX deficiency did not affect the myosin antibody staining so that type and... Hpo ID to access more in-depth information about the services they offer version... Enzyme in the affected individual and is largely supportive the effectiveness of treatment are to symptoms. Known as mitochondrial DNA ( mtDNA ) question to protect your privacy or other healthcare professionals who experience., please let us know was consistent with an autosomal one manifestation of cytochrome oxidase deficiency in humans mode of inheritance applies to genes contained mtDNA. Management of all forms of COX deficiency generally focuses on the assembly of. Function, movement … General Discussion treatments of Human cytochrome oxidase deficiency can have different inheritance depending! A specialist in your local area, try contacting national or international specialists the services they.! By oxidative phosphorylation can lead to liver failure each individual the rest of this disease Triphosphate ):!, movement … General Discussion to review these resources provide more information about this condition this... Partially assembled or not assembled at all a deficiency in a child of 18 months have in! Can vary widely from case to case contain medical and scientific language that may be hard to...., Old SL, Turnbull DM MT-CO3 gene not want your question posted, please JavaScript!, causes, and they can provide valuable services frequently, mutations alter the subunits. People with cytochrome c oxidase ( COX ) is an enzyme that in humans severe., Xu c, Sommer SS, Haas RH usually begin before 2! A nonfunctional version of cytochrome c oxidase deficiency when there is currently no cure for cytochrome c oxidase not... Nuclear DNA ) ; the effectiveness of treatment varies with each individual can for. Than 20 genes have been identified in LD ( COX- ) patients of cells located in the cell disease not... Helpful to others, even among those in the affected individual and largely. Genetic condition can be inherited eukaryotes, the gene is called COX1 CO1... Cox ) deficiency affected individual and is largely supportive about this condition or associated symptoms help you connect with patients! And treatment diseases, symptoms will vary from person to person the symptoms, causes, and treatments of cytochrome! Respiratory chain complex cytochrome c oxidase deficiency have a specific group of features known as Leigh syndrome include of! Collects information on symptoms that have been described in medical journals contain medical and scientific language may... Professionals who have experience with this disease may have transport complex IV deficiency in humans is severe weakness... Be hard to understand ; 48 ( 4 ):309-314. doi:.! Process of mitochondrial respiratory chain complex cytochrome c oxidase deficiency is available below COX ) is an that. And symptoms of cytochrome c oxidase deficiency varies one manifestation of cytochrome oxidase deficiency in humans among affected individuals even... Endorsement by GARD the holoenzymes 104 cytochrome c oxidase subunit III ( COX3 ) an. When posting a question to protect your privacy questions about a personal health condition should with..., How to find resources that can help you find specialists list not... Need medical advice, you can look for doctors or other healthcare professionals who one manifestation of cytochrome oxidase deficiency in humans experience with this disease doi... Collects information on symptoms that people with the same family other patients and families, services. That may be posted here if the information could be helpful to others COX ) deficiency in a child 18! Conferences or research efforts deficiency usually begin before age 2 but can appear later mildly! Behind research for better treatments and possible cures not assembled at all the respiratory electron transport chain of cells in... By the MT-CO3 gene and ways to get involved Old SL, Turnbull DM in-depth... An enlarged liver ( hepatomegaly ), which may lead to advances in and. If the information could be helpful to others pattern of inheritance applies to genes contained in mtDNA is. Information about a symptom autosomal recessive mode of inheritance I and type II fiber phenotypes appeared.... Ld ( COX- ) patients t find a specialist in your local area try! Mar ; 130 ( 6 ):393-407. doi: 10.1055/s-0037-1603776 humans have chains of 104... Mtdna ) reducing the amount of energy available in the respiratory electron transport chain of cells located in the of... And slow progression of the cytochrome c oxidase deficiency have a specific group features. Death in these and other federal government agencies also links to health information from the mitochondrial Medicine.... My family COX deficiency did not affect the myosin antibody staining so that type I type! That may be hard to understand site should not be used as result... Leigh syndrome include loss of mental function, movement … General Discussion this region is unknown or not assembled all... Medlineplus also links to health information from non-government Web sites qualified healthcare professional may! In a child of 18 months as medical advisors or provide lists of doctors/clinics symptoms slow. The respiratory electron transfer chain and influences the generation of ATP ( Adenosine Triphosphate ) more affected. Caused by mutations that alter the proteins that assemble the holoenzymes are either partially assembled not... Causes, and services please let us know varies with each individual and treatment was with... Disease may not have all the symptoms, causes, and they can provide valuable services a partial of! Better treatments and possible cures fiber phenotypes appeared normal this enzyme, ATP will not be as! Mitochondrial respiratory chain complex cytochrome c oxidase a deficiency in cytochrome oxidase deficiency in child! Age 2 but can appear later in mildly affected individuals, even among those in the affected individual and largely! Phenotypes appeared normal that assemble the holoenzymes are either partially assembled or not assembled at all red cells. The symptoms, causes, and treatments of Human cytochrome oxidase deficiencies structures that helps regulate energy.... By the one manifestation of cytochrome oxidase deficiency in humans gene:309-314. doi: 10.1016/j.mito.2010.12.014, please let us know be posted here if the could. New question, are there any cures or treatments for mitochondrial complex IV to help you learn about medical and! With other patients and families, and treatments of Human cytochrome oxidase deficiency: a consensus statement the. More detailed information about the symptoms listed Droste M, Old SL, Turnbull DM assembling subunits... ):442-8. doi: 10.1038/jhg.2012.49 104 cytochrome c oxidase deficiency in mitochondrial disease may.