The Power of a Name – Comment HERE

As the acronym MELAS suggests, this disease is characterized by mitochondrial encephalomyopathy, lactic acidosis, and stroke-like symptoms. At the first Child Neurological Society meeting, mitochondrial encephalomyopathy was introduced as “a group of neuromuscular disorders with defects in the oxidative pathways of energy production.” Mitochondrial encephalomyopathies are divided into three distinct clinical subgroups: (1) mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS); (2) myoclonus epilepsy associated with ragged-red fibers (MERRF); and (3) chronic progressive external ophthalmoplegia. An A-to-G transition mutation at nucleotide pair 3,243 in the dihydrouridine loop of mitochondrial tRNALeu(UUR) that is specific to patients with MELAS (Goto, Nonaka, and Horai 1990).

MELAS is defined as a distinctive syndrome that can be differentiated from two other clinical disorders that are also associated with mitochondrial myopathy and cerebral disease. The other defining feature of this disease includes ragged red fibers in skeletal muscle, short stature, seizures, and hemiparesis, hemianopia, or cortical blindness (Pavlakis et al. 1984). Like other mitochondrial defects, this syndrome targets organ systems with high metabolic activity, including the nervous and cardiovascular systems, and clinical onset typically occurs in early adulthood (before the age of 40) and symptoms can appear after a seemingly normal childhood with development attributable to cumulative effects of chronic lactic acidosis

MELAS is one of the most common mitochondrial diseases, with an estimated incidence of 1 in 4000.(El-Hattab et al. 2015) The clinical constellation of mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome was first characterized in a report on two patients with the clinical presentations described in the name. In other patients reported in the literature, ragged red muscle fibers suggested an abnormality of the electron transport system, but at this time, the precise biochemical disorders in these three clinical syndromes remained to be elucidated.

The ragged red fibers derive their name from the appearance of the degenerating granular fibers after they have been stained with the modified Gomori trichrome stain. The red staining represents growing mitochondrial elements, and the presence of these ragged red fibers suggests an abnormality of the electron transport system since these findings are regularly seen in documented biochemical deficiencies involving the respiratory chain (Pavlakis et al. 1984)

MELAS is a mitochondrial inherited genetic disorder, although it may result from a sporadic mutation with no family history. Mitochondrial genetic disorders are the result of mutations causing impaired mitochondrial function, including oxidative phosphorylation and energy production. In MELAS, mutations in tRNA are believed to cause impairment of protein assembly into respiratory chain complexes. Many different transfer RNA (tRNA) mutations can cause MELAS. The most common mutation is in the MTTL1 mitochondrial gene. A single base pair mutation, m.3243A>G, is found in 80% patients, and a second common mutation, m.3271T>C, is found in 10%. (El-Hattab et al. 2015).

Although the clinical features are relatively distinctive, the biochemical abnormalities reported so far have not been uniform across cases, therefore implying a syndrome. Most of the current diagnostic criteria on the mitochondrial disease was developed prior to the identification of molecular genetic knowledge. Muscle biopsy was the gold standard for obtaining an accurate diagnosis of mitochondrial diseases. Now, the diagnosis of MELAS is often confirmed by the presence of RRF on succinate dehydrogenase histochemical stain, as a result of diseased mitochondrial aggregates in the subsarcolemmal areas of muscle fibers.

The research indicates that when the mitochondria cause defects in OXPHOS, increasing production of reactive oxygen species (ROS), this triggers the activation of the cell death pathway. Autophagy inpatient-specific induced pluripotent stem (iPS) from fibroblasts of patients with MELAS had well-characterized mitochondrial DNA mutations and distinct OXPHOS defects. An increase in autophagy was observed when compared with its normal counterpart, whereas mitophagy is very scarce contributing to decreased cellular viability.

There is currently no cure for MELAS. Symptoms of seizures are combatted with anti-epileptic medications. Vitamins such as coenzyme Q10 or L-carnitine are thought to help increase energy production by mitochondria and may slow the effects of the disease. There are ongoing MELAS phase I and II trials of Idebenone, a synthetic coenzyme Q10, which has been shown to improve neurological function in other mitochondrial disorders (Scaglia, Identifier: NCT00887562). L-arginine has been shown to attenuate the severity of symptoms when used in acute attacks and decrease the frequency of episodes. L-citrulline is also believed to be beneficial in recovery reduction of stroke risk. This relationship is theorized to be due to the correction of nitric oxide deficiency in MELAS patients, as arginine and citrulline are precursors to nitric oxide production.(El-Hattab et al. 2015)

12 thoughts on “The Power of a Name – Comment HERE

  1. Hi Alyssa! I really enjoyed reading your theme pages. They were well-organized and had lots of great information. My question to you is, given what we have been able to accomplish with gene therapies including CRISPR, do you think it is a possibility that we could prevent cases of MELAS in the near future? Thanks!

    Katy Mayer
    Muhlenberg 2018

    1. Hi Katy! Thank you for your comment!

      With no cure at the present time, transmission prevention (primarily by the mother, although you can check out recent research on my primer page where mitochondrial mutations can perhaps be transmitted paternally), is the only available option for decreasing the disease incidence of MELAS. Although it seems intuitive, CRISPR/Cas9 is not an effective treatment for mitochondrial disorders, however, there are other therapies that have been somewhat effective in the literature.

      Mitochondrial replacement therapy (MRT) is another technique that uses an enucleated donor embryo as a cytoplasmic environment for the nuclei of parent germ cells. This prevents the transmission of mitochondria from the maternal parent cells and has the potential to prevent transmission in patients with higher mutant mitochondrial loads. Naturally, this method is subject to many ethical concerns because of a donor embryo that is used to transplant the patient’s nuclear DNA. These therapies have ultimately been approved in the United Kingdom and recently declared ethically permissible by the FDA. MRT is the “slippery slope” argument and the fear of playing God by changing heritable genetic information of an individual, and critics assert that altering genetic information is unethical.
      Many mitochondrial disease patients with mtDNA mutations possess both normal and mutant mtDNA in an individual cell, termed heteroplasmy (Yahata et al. 2017). Therefore, CRISPR/Cas9 offers the “promise” of reducing the mutation load, which could subsequently reduce symptoms and the burden of disease (Fogleman et al. 2016). CRISPR/Cas9 has the ability to avoid ethical concerns seen with MRT since it does not require a donor form of genetic material. However, CRISPR/Cas9 has the potential to alter DNA locations other than the target, which if not controlled properly, could result in inactivation of essential genes, activation of pro-oncotic genes, or rearrangement of chromosomes (“International Summit on Human Gene Editing: A Global Discussion 2015). Another challenge is that it can be hard to import guide RNA component into mitochondria (Patananan et al. 2016).

      While CRISPR/Cas9 has proven to be efficient in nuclear DNA, and other than one controversial study (Jo, 2015), there is little evidence for application to mtDNA. This is because the RNA species cannot cross the mitochondrial membrane, and there have been no reports of a successful application of this technique to correct mtDNA mutations since (Craven et al. 2017). Most scientists would agree that mitochondria cannot take up the guide RNAs necessary for this technique.

      Since mitochondrial defects can be due to just mtDNA mutations or a combination of mtDNA and nuclear DNA mutations, the benefit of these treatments is hard to gauge. These authors agree that the procedure is worth pursuing if it can improve lives, even if only helping a small number of people (Fogleman et al. 2016), although you would have to make that decision for yourself as a provider.

      TALEN-mediated shift of mitochondrial DNA heteroplasmy in MELAS-iPSCs with m.13513G> was performed with mitochondrial disease patient-specific generated with induced pluripotent stem cells (MiPSCs) with a high proportion of m.3243A>G mtDNA mutations. Mitochondrial-targeted transcription activator-like effector nucleases (mitoTALENs) were generated that successfully eliminated the m.3243A>G mutation in MiPSCs. And off-target mutagenesis was not detected in the targeted MiPSC clones. This technology affords patient-specific pluripotent stem cells that retain the contents of the patient’s cells, including mtDNA, which is especially important, since as discussed above, mitochondrial mutations often display heteroplasmy (Yahata et al. 2017).

      One recent and revolutionary mtDNA approach that has been successfully utilized programmable nuclease therapy approach used mitochondrially targeted zinc-finger nucleases (mtZFN) delivered by adeno-associated virus to eliminate specific mutant mtDNA across the heart. mtZFN, recognizes and eliminates mutant mitochondrial DNA based on the DNA sequence differences between healthy and mutant mitochondrial DNA, leading to a decrease in the mitochondrial mutation burden and improved mitochondrial function. This indicates that programmable nucleases have potential with regards to the treatment of heteroplasmic mitochondrial diseases (Gammage et al. 2018). This treatment still poses issues, however, since the genes encoding the genome editors were introduced by viruses, a type of gene therapy that has not proven to be as applicable in the clinic.


      Jo A., Ham S., Lee G.H., Lee Y.Y.-S.Y.-I., Kim S., Lee Y.Y.-S.Y.-I., (2015) Efficient mitochondrial genome editing by CRISPR/Cas9. Biomed. Res. Int. 2015, 1–10doi:10.1155/2015/30571

      Craven, Lyndsey, Charlotte L. Alston, Robert W. Taylor, and Doug M. Turnbull. 2017. “Recent Advances in Mitochondrial Disease.” Annual Review of Genomics and Human Genetics 18 (1): 257–75.

      Fogleman, Sarah, Casey Santana, Casey Bishop, Alyssa Miller, and David G Capco. 2016. “CRISPR/Cas9 and Mitochondrial Gene Replacement Therapy: Promising Techniques and Ethical Considerations.” American Journal of Stem Cells 5 (2): 39–52.

      Gammage, Payam A., Carlo Viscomi, Marie-Lune Simard, Ana S. H. Costa, Edoardo Gaude, Christopher A. Powell, Lindsey Van Haute, et al. 2018. “Genome Editing in Mitochondria Corrects a Pathogenic MtDNA Mutation in Vivo.” Nature Medicine 24 (11): 1691.

      “International Summit on Human Gene Editing: A Global Discussion | The National Academies Press.” n.d. Accessed May 11, 2019.

      Patananan, Alexander N., Ting-Hsiang Wu, Pei-Yu Chiou, and Michael A. Teitell. 2016. “Modifying the Mitochondrial Genome.” Cell Metabolism 23 (5): 785–96.

      Yahata, Naoki, Yuji Matsumoto, Minoru Omi, Naoki Yamamoto, and Ryuji Hata. 2017. “TALEN-Mediated Shift of Mitochondrial DNA Heteroplasmy in MELAS-IPSCs with m.13513G>A Mutation.” Scientific Reports 7 (1): 15557.

  2. What is life expectancy for someone with MELAS? If the onset occurs at a younger age, does this affect the outcome?

    1. Hi Mama!! Happy Mother’s Day!! (Tehe)

      The 3243A>G mtDNA mutation constitutes the most common cause of mitochondrial disease in adults. Researchers suggest that patients carrying this mutation may have lesser symptoms and a normal life span. (Windpessl, Müller, and Wallner 2014).

      There is conflicting information, since another source argues that the prognosis for MELAS is poor. This reports that the age of death is between 10 to 35 years, although some patients may live longer. Life is largely prolonged through the use of palliative care and symptom management. Prognosis is a result of body degeneration due to progressive dementia, muscle weakness, or complications from other affected organs such as heart or kidneys (Koo et. al., 1993).

      A retrospective study of 22 consecutive patients with mitochondrial disease and the A3243G mutation of mtDNA at the Chang Gung Memorial Hospital between 1988 and 2009 showed that seizures and status epilepticus were the most important predictive values for a poor outcome in patients with the mtA3243G mutation. The age of onset and organ involvement did not significantly influence prognosis (Liu et al. 2012).

      In one report, a cohort study, which is a longitudinal study that samples a group of sharing a defining characteristic and performing a cross-section at intervals through time. This included 85 matrilineal relatives from 35 families. The average life expectancy was observed to be around 16.9 years after the onset of symptoms (Kaufmann, 2011).


      Betty Koo, et. al.; Mitochondrial encephalomyopathy, lactic acidosis, stroke-like episodes (MELAS): clinical, radiological, pathological, and genetic observations. ; Annals of Neurology ; 1993 ; 34(1) ; 25-32

      Liu, Chi-Hung, Chien-Hung Chang, Hung-Chou Kuo, Long-Sun Ro, Chia-Wei Liou, Yau-Huei Wei, and Chin-Chang Huang. 2012. “Prognosis of Symptomatic Patients with the A3243G Mutation of Mitochondrial DNA.” Journal of the Formosan Medical Association 111 (9): 489–94.

      “Natural History of MELAS Associated with Mitochondrial DNA m.3243A>G Genotype | Neurology.” n.d. Accessed May 11, 2019.

      Windpessl, Martin, Petra Müller, and Manfred Wallner. 2014. “Truth Is a Daughter of Time: A Case of MELAS Diagnosed 25 Years after Initial Manifestation.” Oxford Medical Case Reports 2014 (2): 24–25.

  3. Very interesting article, Alyssa. Very well researched and explained in clear understandable terms, though a lot of it was beyond my personal full comprehension. I have a question about whether and how often this affects children. I believe you state that the symptoms often first appear in early adulthood. Are there any indications prior to symptoms emerging? Also, it seems the symptoms may be caused by excessive lactic acidosis. Would it be possible to identify MELAS before symptoms appear and find a way to prevent the harm to the cells? Are there any early indicators of these mutations and defects? Could this be something all children are screened for?
    Thank you

    1. Hello, Esther! Thank you for reading and replying to my blog!

      The most common early symptoms include seizures, recurrent headaches, loss of appetite and vomiting. In the early developmental years, children may be shorter in stature and difficulty tolerating exercise may be early indicators of a mitochondrial disorder (“MELAS Syndrome,” NORD).

      As you pointed out, people with MELAS syndrome have an accumulation of lactic acid in the blood (lactic acidosis), that leads to symptoms such as vomiting, abdominal pain, fatigue, muscle weakness and difficulty breathing. The accumulation of lactic acid has been noted in the spinal fluid and in the brain, however, this cannot be determined using a simple diagnostic test. In some cases, affected individuals will experience a slow deterioration of intellectual function (dementia), and/or a diminished ability to communicate by speech, writing, and/or signs (aphasia).

      Both normal and mutated mtDNA can exist in the same cell, a situation known as heteroplasmy. The number of defective mitochondria may be out-numbered by the number of normal mitochondria. Symptoms may not appear in any given generation until the mutation affects a significant proportion of mtDNA. The uneven distribution of normal and mutant mtDNA in different tissues can affect different organs in members of the same family. This can result in a variety of symptoms in affected family members.
      Stroke-like episodes with temporary muscle weakness on one side of the body (hemiparesis) may also occur which can lead to altered consciousness, vision and hearing loss, loss of motor skills and intellectual disability.

      There are currently, over 30 pathogenic variants in mitochondrial DNA (mtDNA) are reported to cause MELAS. The diagnostic criteria includes (1) a stroke-like episode prior to age 40 years; (2) seizures and/or dementia, constituting encephalopathy, and (3) lactic acidosis and/or ragged-red fibers on muscle biopssy (Sunde et al. 2016). A muscle biopsy would show Ragged red fibers (RRFs) with the modified Gomori trichrome stain where the muscle fibers become irregular (“MELAS – GeneReviews®).

      Given the maternal inheritance of mtDNA mutations, family planning is an important consideration for reproductive choices. It is almost certain that all children of an affected female will inherit the mutation in mtDNA, but this mutation can present at unpredictable levels of heteroplasmy, thus presenting at various severities. If there is a known mitochondrial disorder in the family of sufficient severity impairment of quality of life or functional status, testing can be used, although genetic testing for mitochondrial disorders is considered investigational when the criteria for medical necessity are not met, since there is insufficient evidence to support a conclusion concerning the health outcomes or benefits associated with this procedure (“Genetic Testing for Mitochondrial Disorders,”). Molecular genetic testing approaches include of gene-targeted testing which is single-gene testing, concurrent or serial single-gene testing, multigene panel, or comprehensive genomic testing (“MELAS – GeneReviews®).


      “MELAS – GeneReviews® – NCBI Bookshelf.” n.d. Accessed April 12, 2019.h ttps://

      “MELAS Syndrome.” n.d. NORD (National Organization for Rare Disorders) (blog). Accessed May 11, 2019.

      Sunde, Kiri, Patrick R. Blackburn, Anvir Cheema, Jennifer Gass, Jessica Jackson, Sarah Macklin, and Paldeep S. Atwal. 2016. “Case Report: 5year Follow-up of Adult Late-Onset Mitochondrial Encephalomyopathy with Lactic Acid and Stroke-like Episodes (MELAS).” Molecular Genetics and Metabolism Reports 9 (December): 94–97.

  4. Since MELAS is mainly diagnosed using histological tests and basic genetic assays, do you know of any more rigorous diagnostic methods that are being studied? Since MELAS is not extremely well characterized (based on my impression), it would be interesting to see if there could be ways to better distinguish between MELAS and other conditions like cerebral disease and mitochondrial myopathy. It would seem to me that there should be a lot more going on in the cells than meets the eye (literally), and transcriptomic/genomic/metabolomic tests may be better able to differentiate between the conditions, as well as getting a better picture of what other effects MELAS may have.

    1. Hi Brock 😊

      There are actually reports of a noninvasive diagnosis of the 3243A>G mitochondrial DNA mutation using urinary epithelial cells as early as the year 2004. The routine diagnosis of the 3243A>G mutation in blood remains difficult, as mutation levels are known to decrease in this tissue over time, while in some patients it may be absent altogether (McDonnell et al. 2004). The ability to test the urine epithelial cells can be explained by the fact that muscle and the CNS are both postmitotic and are commonly affected tissues in patients with the 3243A>G mutation. The mesodermal layer also gives rise to the urogenital system with the exception of the bladder, and therefore the urinary epithelia, which are derived from the endodermal germ layer.

      Newer testing methodologies allow for more accurate detection of low heteroplasmy in blood. The newest technologies use massive parallel or next-generation sequencing (NGS) which are the new gold standard for mtDNA genome sequencing. These yield improved reliability and sensitivity of mtDNA genome analyses, revealing significant information for point mutations, low-level heteroplasmy, and deletions. This provides just a single test that is able to accurately diagnose mtDNA disorders. Some companies do offer panels with a small number of targeted genes. Whole-exome sequencing became clinically available in 201 1 (Parikh et al. 2015).

      When the phenotype of MELAS is indistinguishable from many other inherited disorders characterized by seizures and weakness, genomic testing is currently the best option. Exome sequencing is most commonly utilized, and genome sequencing is also a possibility El-Hattab, Almannai, and Scaglia 1993). A clinically relevant differentiating feature of MELAS from other mitochondrial disorders are the recurrent stroke-like episodes. MELAS can be discriminated from an ischemic stroke using three-dimensional pseudo-continuous arterial spin labelling (3D pCASL). Mechanistically they differ in the fact that MELAS is caused by energy failure from defective oxidative metabolic pathways of energy production. Therefore, the whole-brain 3D pCASL technique is useful in differentiating MELAS from ischemic stroke when clinical symptoms and conventional MRI manifestations appear to be identical (Li et al. 2017).

      Notably, two morphologic abnormalities found on muscle biopsy can distinguish MELAS from other mitochondrial diseases: the large proportion of ragged-red fibers (RRF) with normal muscle cytochrome c oxidase (COX) activity and the presence of strongly succinate dehydrogenase-reactive blood vessels (SSV). Most MELAS patients have normal or increased COX activity. This is likely because the the mtDNA mutation is insufficient to impair COX activity. The presence of SSV in muscle biopsy can help to confirm the MELAS diagnosis, especially in patients without RRF in their muscle biopsy, but should not be used as an exclusion criterion for MELAS, due to a lower frequency of this presentation. Current diagnostic strategies involving molecular analysis of tRNALeu(UUR) gene should not be the only criteria for diagnosing MELAS and can be supplemented with tests as described above (Lorenzoni et al. 2009).


      Li, Rui, Hua-feng Xiao, Jin-hao Lyu, Danny J.J. Wang, Lin Ma, and Xin Lou. 2017. “Differential Diagnosis of Mitochondrial Encephalopathy with Lactic Acidosis and Stroke-like Episodes (MELAS) and Ischemic Stroke Using 3D Pseudocontinuous Arterial Spin Labeling: Differential Diagnosis of MELAS.” Journal of Magnetic Resonance Imaging 45 (1): 199–206.

      Lorenzoni, Paulo José, Rosana H. Scola, Cláudia S. Kamoi Kay, Raquel C. Arndt, Aline A. Freund, Isac Bruck, Mara Lúcia S. F. Santos, and Lineu C. Werneck. 2009. “MELAS: Clinical Features, Muscle Biopsy and Molecular Genetics.” Arquivos de Neuro-Psiquiatria 67 (3A): 668–76.

      McDonnell, Martina T., Andrew M. Schaefer, Emma L. Blakely, Robert McFarland, Patrick F. Chinnery, Douglass M. Turnbull, and Robert W. Taylor. 2004. “Noninvasive Diagnosis of the 3243A>G Mitochondrial DNA Mutation Using Urinary Epithelial Cells.” European Journal of Human Genetics 12 (9): 778.

      Parikh, Sumit, Amy Goldstein, Mary Kay Koenig, Fernando Scaglia, Gregory M. Enns, Russell Saneto, Irina Anselm, et al. 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.

  5. Hi Alyssa,
    Great job summarizing a complicated topic! I was surprised to see that this syndrome is commonly first encountered in adulthood. Based on your research, could you paint a basic picture of what the diagnostic process may look like? Specifically (and to make answering this easier for you), (a) in what setting are most diagnoses made – is the patient mostly doing okay but with vague complaints, are they critically ill with severe lactic acidosis, are they encephalopathic to the point that they are unresponsive/globally confused? and (b) is this the kind of rare syndrome that would take several visits to diagnose, or do you think there are unique signs/enough awareness that a physician could pick up on this at the first visit?

  6. MELAS is caused primarily by mutations in mitochondrial DNA. Technology has now allowed a child to be born with three parents: genomic DNA from two parents and mitochondrial DNA from a third. This allows parents to avoid their child inheriting a mitochondrial disease. With improved reproductive technology, family planning, and careful carrier screening on the part of parents, do you think in the future we will see a decrease in the incidence of MELAS? What factors might contribute to whether we see this change (societal, fiscal, etc.)? Where will this leave MELAS research for cases that have mutations in nuclear DNA?

  7. Very interesting research. However, I would like to know that since the disease is a mitochondrial genetic disorder is it disproportionally weighted towards an increase in diagnosis in female vs. males. Since it is the mother’s mitochondria that are past to the embryo during inheritance.

    1. Hi Paul! Thanks for the question!

      I came across an interesting article titled “The costs of being male: are there sex-specific effects of uniparental mitochondrial inheritance?” A maternal inheritance of mitochondrial DNA prevents the mixing of genomes from different individuals, thus limiting the opportunity for the spread of selfish genes that may be detrimental. The authors addressed the question, will maternal inheritance of the mitochondria, and the resultant female-specific adaptation of the mtDNA genome, result in a higher incidence of mitochondrial diseases that are male-biased in their prevalence or severity?

      Due to the absence of selection for their mtDNA, the authors wondered if males are more prone to suffer from mitochondrial diseases owing to mutations in mtDNA. Leber’s hereditary optic neuropathy (LHON) is one example with a male dominant presence of this disease. About 10% of women carrying the mutated mtDNA variant develop symptoms linked to the disease, while 50% of males do develop symptoms. However, there is data on sex-specific occurrence or severity for MELAS.

      The authors hypothesize that since mtDNA-encoded gene products have been fine-tuned in females due to their selection, it is possible that male mitochondria will be less adapted to cope with higher metabolic demands, particularly in tissues with high oxygen demands. This could potentially make males more susceptible to mitochondrial damage than females (which could help explain the longevity gap). Again, empirical evidence for strong sex-biased effects of mtDNA is scarce (Beekman, Dowling, and Aanen 2014).

      Nevertheless, as reported by the National Organization for Rare Disorders MELAS is a disorder that affects males and females in equal numbers (“MELAS Syndrome” NORD).


      Beekman, Madeleine, Damian K. Dowling, and Duur K. Aanen. 2014. “The Costs of Being Male: Are There Sex-Specific Effects of Uniparental Mitochondrial Inheritance?” Philosophical Transactions of the Royal Society B: Biological Sciences 369 (1646).

      “MELAS Syndrome.” n.d. NORD (National Organization for Rare Disorders) (blog). Accessed May 11, 2019.

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