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User:Eteceterally/Mitochondrial Genetic Disorders


Brain MRIs of stroke-like lesions typical of MELAS, a mitochondrial disorder.

Mitochondrial genetic disorders are chronic inherited diseases characterized by defective mitochondria. The inheritance of mitochondrial disorders mainly follows an autosomal recessive pattern, with other variations such as maternal uniparental inheritance, X-linked recessive inheritance and autosomal dominant inheritance[1].

Mitochondrial dysfunction results in insufficient production of energy for normal bodily functions, with debilitating symptoms ranging from muscle weakness to learning disabilities[2]. Patients with mitochondrial genetic disorder suffer from continuous disease development and worsening symptoms over time.

A variety of tests are used to diagnose mitochondrial disorders, including but not limited to: lactate and pyruvate level measurements[3], DNA testing[4], tissue testing etc[5]. Current technology provides limited support in the areas of treatment and management, in vitro fertilization (IVF) mitochondria transfer and gene therapy treatment are the most effective solutions available to date[6][7].

Inheritance

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Maternal Inheritance

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Harmful mutations from within the mitochondrial genome are solely inherited from the mother. Mitochondria are heteroplasmic, meaning there are multiple variations of mitochondrial genomes available in human tissue[8]. In healthy individuals, harmful mutations in a small fraction of mitochondria are compensated by the abundance of functional mitochondria. Essentially, the human body can tolerate up to a certain level of mitochondrial dysfunction[9]. A person suffers from maternally inherited mitochondrial disorder when the level of dysfunctional mitochondria passes that threshold.

The process by which maternal mitochondria are inherited are structured to limit the amount of defective mitochondria that gets passed on to children. During the formation of a zygote, mitochondria are segregated to allow only a small portion of mitochondria to be shared with progeny. As the zygote reaches its multicellular stage (up to 128 cells), only around 3 cells will constitute the formation of the offspring, while the rest are needed to form the extraembryonic tissue for the developing fetus. This process of mitochondrial selection creates a bottleneck sampling effect[10], the probability of a large portion of dysfunctional mitochondria getting inherited is very small. As such, mitochondrial diseases are quite rare, with an incidence of only 1 out of 5000 people[11].

Other forms of Inheritance

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Mutations in mitochondrial DNA (mtDNA) are not solely responsible for all forms of mitochondrial dysfunction. The mitochondria imports many proteins coded for by nuclear DNA (nDNA), defect-causing mutations in these proteins are also common. Conditions caused by mutations in nDNA are inherited through either autosomal recessive, autosomal dominant, or X-linked patterns[12].

When the disease is inherited in an autosomal recessive fashion, possession of two copies of the mutated gene would trigger the condition to develop[13]. Mitochondrial disorders inherited in this pattern usually result from consanguineous descent.

Autosomal dominant mitochondrial disorders only require one copy of the mutated gene to bring about the conditions[14]. Examples of this inheritance pattern are not uncommon, and usually caused by either sporadic de novo mutations or have late-presenting symptoms.

For mitochondrial conditions inherited in an X-linked manner, the affected genes are located on the X chromosome. If the mother is a carrier for an X-linked recessive disease, all female offspring would be carriers and all male offspring would be affected[15]. Pyruvate dehydrogenase complex deficiency (E1 alpha), is an example of an X-linked recessive mitochondrial disorder.

Disease Mechanism

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The general principle behind all forms of genetic mitochondrial disorder is inadequate oxygen phosphorylation (OXPHOS). OXPHOS subunits, also known as electron transport chain enzymes, are essential in generating adenosine triphosphate (ATP) by creating a proton motive force via protein complexes I through V (CI - CV). The proteins generate a proton gradient within the intermembrane space of mitochondria, and the efflux of protons creates an electrochemical gradient essential for ATP synthesis. Disruption of the OXPHOS process results in a decreased ability to produce ATP, which is the body’s main source of energy, with consequences ranging from cell injury to possibly apoptosis[16]. The genetic coding for these complexes are expressed in complicated patterns involving both nDNA and mtDNA[17], with the exception of CII (which is coded by nDNA only)[18]. At the moment, a couple of disease-causing genetic mutations have been identified. The classical form of disease-causing mutation are mutations that directly cause impairments in an OXPHOS subunit. Other forms of disease-causing defects include altered mtDNA maintenance and defects in mitochondrial transcription and translation factors[19].  

Pathophysiology

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There are many mitochondrial disease-causing genes that target either one or more of the OXPHOS subunits located within the mitochondria. Each of these genes interact with the structure and function of the OXPHOS units in varying manners. As such, it is challenging to identify the specific phenotypes caused by a mutated gene.

Genes associated with CI Deficiency

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CI (NADH ubiquinone oxidoreductase) is in charge of translocating protons from the mitochondrial matrix into the intermembrane space. It does so by isolating protons from NADH and attaching it to water-soluble ubiquinone (UQ), which then diffuses into the intermembrane space.

Isolated CI deficiency appears in nearly one-third of all mitochondrial disorders. A large percentage of cases still lack proper diagnosis due to the complexity of the large enzyme and its dual genetic origin. The diagnosis of CI deficiency disorders include Leigh syndrome (LS), neonatal cardiomyopathy with lactic acidosis, fatal infantile lactic acidosis (FILA), macrocystic leukoencephalopathy, and isolated myopathy[20].

 
Diagram indicating different genes associated to mitochondrial disorders.

ACAD9

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ACAD9 is a frequent mutation associated with the reduction in CI assembly and activity. Patients exhibit infantile hypertrophic cardiomyopathy, encephalopathy, and lactic acidosis. Other clinical features include severe neonatal symptoms including liver and kidney damage. Riboflavin is usually prescribed to temporarily alleviate symptoms for patients, although surviving patients often develop delayed-onset neurologic or muscular symptoms[21].

NUBPL/lnd1

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Nucleotide-binding protein like (NUBPL) specifically inserts essential Fe-S centers into CI. Patients with compound heterozygous mutations in NUBPL are usually diagnosed with mitochondrial encephalopathy and CI deficiency[22].

Genes associated with CII Deficiency

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CII acts to deliver electrons into the quinone pool, which is responsible for regulating electron transport. CII contains four protein subunits: succinate dehydrogenase (SDHA), succinate dehydrogenase iron-sulfur subunit (SDHB), succinate dehydrogenase complex subunit C (SDHC) and succinate dehydrogenase complex subunit D (SDHD). CII does not transport protons into the intermembrane space, hence has less involvement in the generation of the electrochemical gradient.

Isolated examples of defect-causing CII deficiency genes are observed in less than 10% of OXPHOS defective cases[23]. CII deficiency is generally classified into two clinical presentations: mitochondrial encephalomyopathy and familial paragangliomas[24]. The former is characterized by prevalence of LS, including other symptoms such as encephalopathy and isolated cardiomyopathy. The pathophysiology behind the latter, the induction of CII-associated paragangliomas, remains unknown.

SDHAF1

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SDHAF1 is a protein associated with the incorporation of Fe-S centers into SDHB. Mutations in this area are shown to lead to reduced CII activity. To date, no mutations in SDHAF1 are present in people with paragangliomas[25].

SDHAF2

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SDHAF2 is a chaperone responsible for regulating the refolding of SDHA for flavination. A missense mutation in SDHAF2 has been identified to show association to the expression of head and neck paragangliomas[26].

Genes associated with CIII Deficiency

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The CIII protein extracts protons from the quinone pool generated by CII, translocating the protons into the intermembrane space.

CIII deficiency is rare in comparison to CI and CIV deficiencies. Disease-causing genes mainly compose of recessively inherited mutations in nDNA that affect structural subunits and assembly factors. Clinical presentations for these mutations are diverse[27].

BCS1L

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All mutations of the BCS1L gene are highly associated with isolated CIII deficiency and reduced incorporation of Fe-S centers into CIII. BCS1L mutations can cause a diverse range of syndromes such as GRACILE syndrome, Björnstad syndrome, as well as other nonsense mutations and variants in splice sites[28].

Genes associated with CIV Deficiency

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CIV (or COX) is the terminal oxidase of the ETC. Its functions include the translocation of protons into the intermembrane layer, and the reduction of oxygen to form water.

During infancy, the most severe clinical manifestation of CIV deficiency is LS. There are very few defect-causing mutations relating to the structural components of CIV, indicating that most mutations in this area are not suitable for extrauterine life. Instead, most disease-causing genes are associated with the incorporation of CIV prosthetic groups[29].

SCO1 and SCO2

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Both SCO1 and SCO2 promote incorporation of copper ions in catalytic sites CuB and CuA of CIV subunit MTCO1 and MTCO2, thus inhibiting normal CIV function. Infants found with defective SCO1 and SCO2 are usually diagnosed with fatal encephalomyopathy[30][31].

Genes associated with CV Deficiency

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CV, more commonly known as ATP synthase, uses energy generated by the proton gradient to convert inorganic phosphate and ADP into energy-storing ATP.

ATP-synthase deficiency due to nDNA mutations is often manifested through neonatal-onset hypotonia and hypertrophic cardiomyopathy[32]. Two disease-causing mtDNA mutations have also been identified[33].

TMEM70

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The prevalent TMEM70 mutation is a homozygous A-to-G transition in intron 2. The mutation results in unconventional splicing and the confusion of mRNA processing of the CV protein. Clinical severity varies, possibly due to variations between individuals in RNA decay systems. The most frequent symptoms include respiratory distress, cardiomyopathy, and delays in psychomotor functions[34].

MT-ATP6 and MT-ATP8

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MT-ATP6 and MT-ATP8 are the only two mtDNA mutations found to be correlated to ATP-synthase deficiency. Heteroplasmic missense mutations in MT-ATP6 are associated with adult-onset NARP (neuropathy, ataxia, and retinitis pigmentosa) and LS[35]. Conversely, the main clinical phenotype of MT-ATP8 mutations is hypertrophic cardiomyopathy[36].

Diagnosis

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Biochemical Testing in Blood and Spinal Fluid

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Initial mitochondrial disorder testing usually involves measurement of lactate and pyruvate levels in plasma and cerebrospinal fluid (CSF). Typical signs of mitochondrial disorder is the underutilization of pyruvate in the mitochondria, resulting in insufficient ATP synthesis[37]. Lactate levels rise as a product of increased anaerobic respiration. However, lactate measurements are limited by sampling errors and handling issues. In a properly collected sample, an elevated plasma lactate level (>3 mmol/l) suggests potential mitochondrial dysfunction or organic acidemias and metabolic errors present in other diseases[38]. For patients with associated neurological symptoms, elevated CSF lactate levels is a useful indicator of mitochondrial disease[39].

Pyruvate level measurements are more catered towards defects involving enzymes closely involved in pyruvate metabolism, such as pyruvate dehydrogenase and pyruvate carboxylase. The instability of pyruvate compounds acts as the main limitation of this method alongside other sampling and collection errors[40].

Amino acid analysis in blood or spinal fluid is commonly used to evaluate the possibility for mitochondrial disease. Defective mitochondria often induce altered redox reactions, leading to elevations in several amino acids including alanine, glycine, proline, and threonine[41]. Elevations in urinary organic acids, creatine phosphokinase and uric acid are also good measures for diagnosing mitochondrial disorders[42].

DNA Testing

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Developments in DNA sequencing allows for more DNA-testing options to be performed on mitochondrial disorders. Effective mtDNA coding and heteroplasmy analysis can now be performed in blood. Patients with low heteroplasmy of 5 ~ 10% are more prone to mitochondrial disorders[43]. Advent technology such as massive-parallel and next-generation sequencing proved useful for detecting mtDNA deletion or duplication syndromes, while other options such as single gene testing on nDNA, and the recently more prevalent whole exome sequencing are also available[44].

Biochemical Testing of Tissue

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Tissue testing for mitochondrial diseases are most often conducted on muscle tissue. Muscle biopsies allow for detection of mtDNA mutations in specific tissues as well as the presence of low heteroplasmy levels. Biopsies also often help validate the significance of unknown variants found in other tests.

Muscle histology analysis routinely includes light microscopy detecting structural changes, histochemical stains for the evaluation of specific enzymes, and examination of muscle ultrastructure via an electron microscope[45].

Treatment and Management

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Currently there are no known cures for mitochondrial genetic disorders. However scientists are looking into methods that alleviate the symptoms of the disease.

Gene therapy treatment is an experimental method currently running on mice which tries to eliminate the damaged defect-causing mtDNA[46]. This technique is also known as mitochondrially targeted zinc finger nuclease (mtZFN). It recognizes and eliminates mutated mitochondrial DNA by comparing differences in DNA sequences between healthy and mutated DNA.

Alternatively, in vitro fertilisation (IVF) transfer of mitochondria is a technique that removes affected mitochondria from an embryo and replaces them with healthy mitochondria[47]. Therefore, mitochondrial disorder must be identified prenatally for IVF transfer to be successful.

Sources

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  1. ^ Chinnery, Patrick F. (November 2002). "Inheritance of mitochondrial disorders". 2 (1–2): 149–155. doi:10.1016/S1567-7249(02)00046-6. {{cite journal}}: Cite journal requires |journal= (help)
  2. ^ Scott, Iain; Logan, David C., "Mitochondrial Dynamics: The Control of Mitochondrial Shape, Size, Number, Motility, and Cellular Inheritance", Plant Mitochondria, John Wiley & Sons, Inc., pp. 1–35, ISBN 978-0-470-98659-2, retrieved 2020-04-07
  3. ^ Koenig, MK (May 2008). "Presentation and diagnosis of mitochondrial disorders in children". Pediatric neurology. 38 (5): 305–13. doi:10.1016/j.pediatrneurol.2007.12.001. PMID 18410845. Retrieved 10 April 2020.
  4. ^ McCormick, E; Place, E; Falk, MJ (April 2013). "Molecular genetic testing for mitochondrial disease: from one generation to the next". Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics. 10 (2): 251–61. doi:10.1007/s13311-012-0174-1. PMID 23269497. Retrieved 10 April 2020.
  5. ^ Rodenburg, RJ (April 2011). "Biochemical diagnosis of mitochondrial disorders". Journal of inherited metabolic disease. 34 (2): 283–92. doi:10.1007/s10545-010-9081-y. PMID 20440652. Retrieved 6 April 2020.
  6. ^ Tanaka, Masashi; Borgeld, Harm-Jan; Zhang, Jin; Muramatsu, Shin-ichi; Gong, Jian-Sheng; Yoneda, Makoto; Maruyama, Wakako; Naoi, Makoto; Ibi, Tohru; Sahashi, Ko; Shamoto, Masayo; Fuku, Noriyuki; Kurata, Miyuki; Yamada, Yoshiji; Nishizawa, Kumi; Akao, Yukihiro; Ohishi, Nobuko; Miyabayashi, Shigeaki; Umemoto, Hiraku; Muramatsu, Tatsuo; Furukawa, Koichi; Kikuchi, Akihiko; Nakano, Imaharu; Ozawa, Keiya; Yagi, Kunio (2002). "Gene therapy for mitochondrial disease by delivering restriction endonuclease SmaI into mitochondria". Journal of Biomedical Science. 9 (6 Pt 1): 534–541. doi:10.1159/000064726. ISSN 1021-7770. Retrieved 16 April 2020.
  7. ^ Saxena, N; Taneja, N; Shome, P; Mani, S (2017). "Mitochondrial Donation: A Boon or Curse for the Treatment of Incurable Mitochondrial Diseases". Journal of human reproductive sciences. 11 (1): 3–9. doi:10.4103/jhrs.JHRS_54_17. PMID 29681709. Retrieved 16 April 2020.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  8. ^ Wallace, DC; Chalkia, D (1 November 2013). "Mitochondrial DNA genetics and the heteroplasmy conundrum in evolution and disease". Cold Spring Harbor perspectives in biology. 5 (11): a021220. doi:10.1101/cshperspect.a021220. PMID 24186072. {{cite journal}}: |access-date= requires |url= (help)
  9. ^ Rossignol, Rodrigue; Faustin, Benjamin; Rocher, Christophe; Malgat, Monique; Mazat, Jean-Pierre; Letellier, Thierry (2003-03-15). "Mitochondrial threshold effects". The Biochemical Journal. 370 (Pt 3): 751–762. doi:10.1042/BJ20021594. ISSN 0264-6021. PMC 1223225. PMID 12467494.
  10. ^ Zhang, Haixin; Burr, Stephen P.; Chinnery, Patrick F. (07 20, 2018). "The mitochondrial DNA genetic bottleneck: inheritance and beyond". Essays in Biochemistry. 62 (3): 225–234. doi:10.1042/EBC20170096. ISSN 1744-1358. PMID 29880721. {{cite journal}}: Check date values in: |date= (help)
  11. ^ Ng, YS; Turnbull, DM (January 2016). "Mitochondrial disease: genetics and management". Journal of neurology. 263 (1): 179–91. doi:10.1007/s00415-015-7884-3. PMID 26315846. {{cite journal}}: |access-date= requires |url= (help)
  12. ^ Boles, Richard; Mason, Terri. "Inheritance and Genetics". UMDF. Retrieved 7 April 2020.
  13. ^ Boles, Richard; Mason, Terri. "Inheritance and Genetics". UMDF. Retrieved 7 April 2020.
  14. ^ Boles, Richard; Mason, Terri. "Inheritance and Genetics". UMDF. Retrieved 7 April 2020.
  15. ^ Boles, Richard; Mason, Terri. "Inheritance and Genetics". UMDF. Retrieved 7 April 2020.
  16. ^ Yadav, N; Kumar, S; Marlowe, T; Chaudhary, A K; Kumar, R; Wang, J; O'Malley, J; Boland, P M; Jayanthi, S; Kumar, T K S; Yadava, N; Chandra, D (5 November 2015). "Oxidative phosphorylation-dependent regulation of cancer cell apoptosis in response to anticancer agents". Cell Death & Disease. 6 (11): e1969–e1969. doi:10.1038/cddis.2015.305. {{cite journal}}: |access-date= requires |url= (help)
  17. ^ Falk, MJ; Sondheimer, N (December 2010). "Mitochondrial genetic diseases". Current opinion in pediatrics. 22 (6): 711–6. doi:10.1097/MOP.0b013e3283402e21. PMID 21045694. {{cite journal}}: |access-date= requires |url= (help)
  18. ^ Reinecke, Fimmie; Smeitink, Jan A.M.; van der Westhuizen, Francois H. (December 2009). "OXPHOS gene expression and control in mitochondrial disorders". Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease. 1792 (12): 1113–1121. doi:10.1016/j.bbadis.2009.04.003. {{cite journal}}: |access-date= requires |url= (help)
  19. ^ Thornton, B; Cohen, B; Copeland, W; Maria, BL (September 2014). "Mitochondrial disease: clinical aspects, molecular mechanisms, translational science, and clinical frontiers". Journal of child neurology. 29 (9): 1179–207. doi:10.1177/0883073814537379. PMID 24916430. {{cite journal}}: |access-date= requires |url= (help)
  20. ^ Chinnery, Patrick F. "Mitochondrial Disorders Overview". NCBI. Retrieved 10 April 2020.
  21. ^ Ghezzi, D; Zeviani, M (20 July 2018). "Human diseases associated with defects in assembly of OXPHOS complexes". Essays in biochemistry. 62 (3): 271–286. doi:10.1042/EBC20170099. PMID 30030362. {{cite journal}}: |access-date= requires |url= (help)
  22. ^ Wydro, M. M.; Balk, J. (4 July 2013). "Insights into the pathogenic character of a common NUBPL branch-site mutation associated with mitochondrial disease and complex I deficiency using a yeast model". Disease Models & Mechanisms. 6 (5): 1279–1284. doi:10.1242/dmm.012682. Retrieved 6 April 2020.
  23. ^ Ghezzi, D; Zeviani, M (20 July 2018). "Human diseases associated with defects in assembly of OXPHOS complexes". Essays in biochemistry. 62 (3): 271–286. doi:10.1042/EBC20170099. PMID 30030362. {{cite journal}}: |access-date= requires |url= (help)
  24. ^ Jain-Ghai, S; Cameron, JM; Al Maawali, A; Blaser, S; MacKay, N; Robinson, B; Raiman, J (February 2013). "Complex II deficiency--a case report and review of the literature". American journal of medical genetics. Part A. 161A (2): 285–94. doi:10.1002/ajmg.a.35714. PMID 23322652. {{cite journal}}: |access-date= requires |url= (help)
  25. ^ Ohlenbusch, Andreas; Edvardson, Simon; Skorpen, Johannes; Bjornstad, Alf; Saada, Ann; Elpeleg, Orly; Gärtner, Jutta; Brockmann, Knut (2012). "Leukoencephalopathy with accumulated succinate is indicative of SDHAF1 related complex II deficiency". Orphanet Journal of Rare Diseases. 7 (1): 69. doi:10.1186/1750-1172-7-69. Retrieved 7 April 2020.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  26. ^ "UniProtKB - Q9NX18 (SDHF2_HUMAN)". UniProt. Retrieved 1 April 2020.
  27. ^ Ghezzi, D; Zeviani, M (20 July 2018). "Human diseases associated with defects in assembly of OXPHOS complexes". Essays in biochemistry. 62 (3): 271–286. doi:10.1042/EBC20170099. PMID 30030362. {{cite journal}}: |access-date= requires |url= (help)
  28. ^ Tegelberg, Saara; Tomašić, Nikica; Kallijärvi, Jukka; Purhonen, Janne; Elmér, Eskil; Lindberg, Eva; Nord, David Gisselsson; Soller, Maria; Lesko, Nicole; Wedell, Anna; Bruhn, Helene; Freyer, Christoph; Stranneheim, Henrik; Wibom, Rolf; Nennesmo, Inger; Wredenberg, Anna; Eklund, Erik A.; Fellman, Vineta (20 April 2017). "Respiratory chain complex III deficiency due to mutated BCS1L: a novel phenotype with encephalomyopathy, partially phenocopied in a Bcs1l mutant mouse model". Orphanet Journal of Rare Diseases. 12 (1). doi:10.1186/s13023-017-0624-2. Retrieved 6 April 2020.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  29. ^ Ghezzi, D; Zeviani, M (20 July 2018). "Human diseases associated with defects in assembly of OXPHOS complexes". Essays in biochemistry. 62 (3): 271–286. doi:10.1042/EBC20170099. PMID 30030362. {{cite journal}}: |access-date= requires |url= (help)
  30. ^ Valnot, I; Osmond, S; Gigarel, N; Mehaye, B; Amiel, J; Cormier-Daire, V; Munnich, A; Bonnefont, JP; Rustin, P; Rötig, A (November 2000). "Mutations of the SCO1 gene in mitochondrial cytochrome c oxidase deficiency with neonatal-onset hepatic failure and encephalopathy". American journal of human genetics. 67 (5): 1104–9. doi:10.1016/S0002-9297(07)62940-1. PMID 11013136. {{cite journal}}: |access-date= requires |url= (help)
  31. ^ Bourens, M; Boulet, A; Leary, SC; Barrientos, A (1 June 2014). "Human COX20 cooperates with SCO1 and SCO2 to mature COX2 and promote the assembly of cytochrome c oxidase". Human molecular genetics. 23 (11): 2901–13. doi:10.1093/hmg/ddu003. PMID 24403053. Retrieved 9 April 2020.
  32. ^ Dautant, A; Meier, T; Hahn, A; Tribouillard-Tanvier, D; di Rago, JP; Kucharczyk, R (2018). "ATP Synthase Diseases of Mitochondrial Genetic Origin". Frontiers in physiology. 9: 329. doi:10.3389/fphys.2018.00329. PMID 29670542. {{cite journal}}: |access-date= requires |url= (help)CS1 maint: unflagged free DOI (link)
  33. ^ Mayr, J. A.; Havlickova, V.; Zimmermann, F.; Magler, I.; Kaplanova, V.; Jesina, P.; Pecinova, A.; Nuskova, H.; Koch, J.; Sperl, W.; Houstek, J. (21 June 2010). "Mitochondrial ATP synthase deficiency due to a mutation in the ATP5E gene for the F1   subunit". Human Molecular Genetics. 19 (17): 3430–3439. doi:10.1093/hmg/ddq254. Retrieved 6 April 2020. {{cite journal}}: no-break space character in |title= at position 86 (help)
  34. ^ Braczynski, Anne K.; Vlaho, Stefan; Müller, Klaus; Wittig, Ilka; Blank, Anna-Eva; Tews, Dominique S.; Drott, Ulrich; Kleinle, Stephanie; Abicht, Angela; Horvath, Rita; Plate, Karl H.; Stenzel, Werner; Goebel, Hans H.; Schulze, Andreas; Harter, Patrick N.; Kieslich, Matthias; Mittelbronn, Michel (2015). "ATP Synthase Deficiency due to TMEM70 Mutation Leads to Ultrastructural Mitochondrial Degeneration and Is Amenable to Treatment". BioMed Research International. 2015: 1–10. doi:10.1155/2015/462592. Retrieved 6 April 2020.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  35. ^ Dautant, Alain; Meier, Thomas; Hahn, Alexander; Tribouillard-Tanvier, Déborah; di Rago, Jean-Paul; Kucharczyk, Roza (4 April 2018). "ATP Synthase Diseases of Mitochondrial Genetic Origin". Frontiers in Physiology. 9. doi:10.3389/fphys.2018.00329. {{cite journal}}: |access-date= requires |url= (help)CS1 maint: unflagged free DOI (link)
  36. ^ Ghezzi, D; Zeviani, M (20 July 2018). "Human diseases associated with defects in assembly of OXPHOS complexes". Essays in biochemistry. 62 (3): 271–286. doi:10.1042/EBC20170099. PMID 30030362. {{cite journal}}: |access-date= requires |url= (help)
  37. ^ Mitochondrial Medicine Society's Committee on, Diagnosis.; Haas, RH; Parikh, S; Falk, MJ; Saneto, RP; Wolf, NI; Darin, N; Wong, LJ; Cohen, BH; Naviaux, RK (May 2008). "The in-depth evaluation of suspected mitochondrial disease". Molecular genetics and metabolism. 94 (1): 16–37. doi:10.1016/j.ymgme.2007.11.018. PMID 18243024. {{cite journal}}: |access-date= requires |url= (help)
  38. ^ Joost, K.; Rodenburg, R.J.; Piirsoo, A.; van den Heuvel, L.; Žordania, R.; Põder, H.; Talvik, I.; Kilk, K.; Soomets, U.; Õunap, K. (2012). "A Diagnostic Algorithm for Mitochondrial Disorders in Estonian Children". Molecular Syndromology. doi:10.1159/000341375. {{cite journal}}: |access-date= requires |url= (help); C1 control character in |last5= at position 1 (help)
  39. ^ Koenig, MK (May 2008). "Presentation and diagnosis of mitochondrial disorders in children". Pediatric neurology. 38 (5): 305–13. doi:10.1016/j.pediatrneurol.2007.12.001. PMID 18410845. Retrieved 10 April 2020.
  40. ^ Parikh, S; Goldstein, A; Koenig, MK; Scaglia, F; Enns, GM; Saneto, R; Anselm, I; Cohen, BH; Falk, MJ; Greene, C; Gropman, AL; Haas, R; Hirano, M; Morgan, P; Sims, K; Tarnopolsky, M; Van Hove, JL; Wolfe, L; DiMauro, S (September 2015). "Diagnosis and management of mitochondrial disease: a consensus statement from the Mitochondrial Medicine Society". Genetics in medicine : official journal of the American College of Medical Genetics. 17 (9): 689–701. doi:10.1038/gim.2014.177. PMID 25503498. Retrieved 10 April 2020.
  41. ^ Parikh, S; Goldstein, A; Koenig, MK; Scaglia, F; Enns, GM; Saneto, R; Anselm, I; Cohen, BH; Falk, MJ; Greene, C; Gropman, AL; Haas, R; Hirano, M; Morgan, P; Sims, K; Tarnopolsky, M; Van Hove, JL; Wolfe, L; DiMauro, S (September 2015). "Diagnosis and management of mitochondrial disease: a consensus statement from the Mitochondrial Medicine Society". Genetics in medicine : official journal of the American College of Medical Genetics. 17 (9): 689–701. doi:10.1038/gim.2014.177. PMID 25503498. Retrieved 10 April 2020.
  42. ^ Parikh, S; Goldstein, A; Koenig, MK; Scaglia, F; Enns, GM; Saneto, R; Anselm, I; Cohen, BH; Falk, MJ; Greene, C; Gropman, AL; Haas, R; Hirano, M; Morgan, P; Sims, K; Tarnopolsky, M; Van Hove, JL; Wolfe, L; DiMauro, S (September 2015). "Diagnosis and management of mitochondrial disease: a consensus statement from the Mitochondrial Medicine Society". Genetics in medicine : official journal of the American College of Medical Genetics. 17 (9): 689–701. doi:10.1038/gim.2014.177. PMID 25503498. Retrieved 10 April 2020.
  43. ^ McCormick, E; Place, E; Falk, MJ (April 2013). "Molecular genetic testing for mitochondrial disease: from one generation to the next". Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics. 10 (2): 251–61. doi:10.1007/s13311-012-0174-1. PMID 23269497. Retrieved 10 April 2020.
  44. ^ McCormick, E; Place, E; Falk, MJ (April 2013). "Molecular genetic testing for mitochondrial disease: from one generation to the next". Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics. 10 (2): 251–61. doi:10.1007/s13311-012-0174-1. PMID 23269497. Retrieved 10 April 2020.
  45. ^ Rodenburg, RJ (April 2011). "Biochemical diagnosis of mitochondrial disorders". Journal of inherited metabolic disease. 34 (2): 283–92. doi:10.1007/s10545-010-9081-y. PMID 20440652. Retrieved 6 April 2020.
  46. ^ Tanaka, Masashi; Borgeld, Harm-Jan; Zhang, Jin; Muramatsu, Shin-ichi; Gong, Jian-Sheng; Yoneda, Makoto; Maruyama, Wakako; Naoi, Makoto; Ibi, Tohru; Sahashi, Ko; Shamoto, Masayo; Fuku, Noriyuki; Kurata, Miyuki; Yamada, Yoshiji; Nishizawa, Kumi; Akao, Yukihiro; Ohishi, Nobuko; Miyabayashi, Shigeaki; Umemoto, Hiraku; Muramatsu, Tatsuo; Furukawa, Koichi; Kikuchi, Akihiko; Nakano, Imaharu; Ozawa, Keiya; Yagi, Kunio (2002). "Gene therapy for mitochondrial disease by delivering restriction endonuclease SmaI into mitochondria". Journal of Biomedical Science. 9 (6 Pt 1): 534–541. doi:10.1159/000064726. ISSN 1021-7770. Retrieved 16 April 2020.
  47. ^ Saxena, N; Taneja, N; Shome, P; Mani, S (2017). "Mitochondrial Donation: A Boon or Curse for the Treatment of Incurable Mitochondrial Diseases". Journal of human reproductive sciences. 11 (1): 3–9. doi:10.4103/jhrs.JHRS_54_17. PMID 29681709. Retrieved 16 April 2020.{{cite journal}}: CS1 maint: unflagged free DOI (link)
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