Course:MEDG550/Student Activities/Mitochondrial DNA Depletion Syndrome

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Figure 1: Representation of mitochondria and mtDNA

Mitochondrial DNA Depletion Syndrome (MDDS) is the term for a group of rare disorders that decrease the amount of energy made by certain tissues in the body[1]. The tissues most commonly affected by this disease are the muscles, liver, intestines, and brain[2]. The symptoms of MDDS range from mild to severe and are dependent on which tissues are affected. Although there is no treatment for MDDS, there are options for managing symptoms.


MDDS is caused by a reduced amount of mitochondrial DNA (mtDNA) in certain tissues.


Figure 2: Representation of animal cell with labeled organelles. A mitochondrion is seen in the upper portion of the image.

Within each cell of the body there are small, distinct components that work together to keep the cell functioning.[3] These components are called organelles, like the mitochondria. Each organelle has a specific task; mitochondria's task is to make energy to power the cell, which in turn powers the systems beyond[3]. Mitochondria are regulated by the two kinds of DNA. Most DNA is in the nucleus, called nuclear DNA, and there is some DNA within the mitochondria itself, called mtDNA[3]. DNA acts as a master code for building everything within a cell and in turn, the human body. The code is made of four individual building blocks, or nucleotides, called adenine (A), cytosine (C), guanine (G), and thymine (T)[3].

Parts of nuclear and mitochondrial DNA can be translated into proteins. Proteins are small units of matter that carry out tasks to support organelles and keep the body functioning. The sections of DNA that code for proteins are called genes[3]. When certain genes in the nuclear or mtDNA are disrupted or missing, it can decrease the amount of mitochondrial nucleotides (A, T, G, or C) produced[2]. This prevents the mitochondria from making enough proteins, which means the organelle cannot function properly. Because mitochondria are the powerhouse of the cell[4], when it is not working it means the cell will not have enough energy. When enough cells fail to produce enough energy, it leads to a weakening of surrounding tissues and causes the MDDS diagnosis. There are tests that can measure how much of each mitochondrial nucleotide (A, T, G, and C) are made, which can tell if a person has MDDS[5].

Inheritance Pattern

Figure 3: Visual representation of autosomal recessive and autosomal dominant inheritance patterns.

The majority of MDDS conditions are inherited in an autosomal recessive manner[6]. Every individual has two sets of each gene, having received one copy of their genes from each parent (see Figure 3). At conception, the sperm and egg contain a randomly selected half of parental DNA that come together, creating a full set of DNA for the embryo. This means that both parents must carry at least one copy of the disease-causing gene for a child to be affected. Male children and female children are equally likely to be affected. The chance of having an affected child will be 1 in 4, or 25%[7].

Note: Each pregnancy will have a 1/4 chance of being affected, regardless of if a previous child is affected or not. This is because each pregnancy is the result of a new sperm and new egg, which each have a 50% chance of passing along their affected gene.

Several MDDS conditions are inherited in an autosomal dominant manner[6]. This means that one copy of the disease-causing gene will cause a person to have symptoms. This also affects males and females equally.

Not all mitochondrial diseases are inherited in the autosomal recessive/dominant manner[2][6]. Some instead come from errors in the genes contained within the mtDNA. mtDNA is only inherited from the maternal side (mother, birth parent, egg donor, etc.), and will not match Figure 3.


Symptoms generally begin shortly after birth or in childhood, but some will manifest later in life[6]. The symptoms a person with MDDS will experience, and when they appear, will depend on the specific gene variant they have[1]. A healthcare provider will be able to identify symptoms that are relevant to the condition and discuss treatment options. They generally affect the brain and nervous system, muscles, liver, and digestive system[2]. The intensity of symptoms can range from mild to severe, and will also be dependent on the gene.

Symptoms range from mild to severe, and vary from person to person[8]. Common symptoms can include:

  • Seizures
  • Hearing loss
  • Hypotonia (muscle weakness)
  • Shortness of breath
  • Fatigue
  • Ataxia (lack of muscle control, difficulty with movement)
  • Developmental delay
  • Liver failure

For more specific symptoms, see Patient Resources in Table 1.


MDDS is usually diagnosed through genetic testing[9]. To get genetic testing, a patient may first have a physical, metabolic (how the body uses energy), or a neurological exam[10]. Other testing, such as a muscle biopsy or blood test, may also be done before genetic testing. This is because there are other conditions with similar symptoms to MDDS that will need to be ruled out before genetic testing[10]. A family history may be taken to see if anyone else in the family may be affected or needs testing.

Types of MDDS and Associated Genes

There are currently several genes identified that predict MDDS, and each are associated with different symptoms[8]. For people with MDDS, one of their genes has a change within its DNA that keeps it from working properly. These changes result in what is called a genetic variant[11]. Some variants cause disease, and those variants are called pathogenic[11]. However, changes in genes are normal and some variants do not cause any illnesses. These are referred to as benign[11]. If a person is undergoing testing, they may also have a result that is not clearly benign or pathogenic. These results will be labeled VUS, or variant of unknown significance[11]. The different kinds of MDDS generally fall into five categories based on the tissues they affect.

Categories of MDDS

mtDNA Depletion Syndrome Primarily Affected Tissues Associated Genes[8][12] Patient Resources
Neurogastrointestinal Nervous system and digestive system TYMP with encephalomyopathic type)
Hepatocerebral Liver and nervous system DGUOK, MPV17, POLG, C10ORF2 (Focuses on MPV17)
Myopathic Muscular system TK2 (TK2)
Cardiomyopathic Cardiovascular (heart muscle) SLC25A4 (Mitochondrial myopathies)
Encephalomyopathic Brain, nervous system, and muscular system SUCLA2, SUCLG1, RRM2B, TYMP on SUCLG1)

Table 1: Summary of mitochondrial DNA depletion syndrome categories and associated genes. Each link describes the symptoms a patient may experience.

Management of MDDS

As of 2022, there are no cures for MDDS[13]. The treatments for a patient will be tailored to the specific symptoms they experience (Table 1). Management will continue throughout a person's life. This will also be tailored to the patient's needs, but could include visits with their physician, a neurologist, gastroenterologist, cardiologist, and/or an endocrinologist[8].

Social Considerations

A genetic diagnosis of MDDS may bring relief, especially if a person has been sick for a long time[14]. A diagnosis can help families plan future pregnancies or connect with a community of peers. Unfortunately, the diagnosis can also bring up complicated emotions. Family members who test negative may feel a kind of "survivor's guilt," and there can be anxiety around how MDDS will change a person's life.[15] It is normal for genetic test results, positive or negative, to result in a wide range of emotions[16]. If these emotions are distressing, counselling or connecting to a support system (see Patient Resources) is strongly encouraged.

Patient Resources

Resources for patients with MDDS are grouped with resources for patients with other mitochondrial disorders. Below is a list of websites, podcasts, and groups that may help people with MDDS connect to a community, access advocates, and share their stories.




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  1. 1.0 1.1 Nogueira, Celia (April 2014). "Syndromes associated with mitochondrial DNA depletion". Italian Journal of Pediatrics. 40. doi: Check |doi= value (help).
  2. 2.0 2.1 2.2 2.3 Basel, Donald (03/01/2020). "Mitochondrial DNA Depletion Syndromes". Clinics in Perinatology. 47: 123–141, . Check date values in: |date= (help)CS1 maint: extra punctuation (link)
  3. 3.0 3.1 3.2 3.3 3.4 Johnson, George B. (2012). The Living World 7th Edition. New York, NY: McGrawl Hill. pp. 16, 84, 57–58, 236–238, . ISBN 978–0–07–802417–7 Check |isbn= value: invalid character (help).CS1 maint: extra punctuation (link)
  4. Siekevitz, Philip (July 1957). "Powerhouse of the Cell". Scientific American. 197: 131–144 – via JSTOR.
  5. "Mitochondrial DNA Depletion Syndrome Panel". Blueprint Genetics. Retrieved 14/01/2023. Check date values in: |access-date= (help)
  6. 6.0 6.1 6.2 6.3 Suomalainen, Anu; Isohanni, Pirjo (July 2010). "Mitochondrial DNA depletion syndromes – Many genes, common mechanisms". Neuromuscular Disorders. 20: 429–437. doi: Check |doi= value (help).
  7. Hartl, Daniel; Jones, Elizabeth (2006). Essential Genetics: A Genomics Perspective. Sadbury, MA: Jones and Bartlett Publishers. pp. 77–79. ISBN 978-0-7637-3527-2.
  8. 8.0 8.1 8.2 8.3 El-Hattab, Ayman W.; Scaglia, Fernando (April 2013). "Mitochondrial DNA Depletion Syndromes: Review and Updates of Genetic Basis, Manifestations, and Therapeutic Options". Neurotherapeutics. 10: 186–198. doi:10.1007/s13311-013-0177-6.
  9. Dimmock, David (2010). "Quantitative Evaluation of the Mitochondrial DNA Depletion Syndrome". Clinical Chemistry. 56: 1119–1127. line feed character in |title= at position 49 (help)
  10. 10.0 10.1 Goldstein, Amy; Falk, Marni (31/01/2019). "Mitochondrial DNA Deletion Syndromes". National Library of Medicine. Retrieved 14/01/2023. Check date values in: |access-date=, |date= (help)
  11. 11.0 11.1 11.2 11.3 Richards, Sue (01/11/2015). "Standards and Guidelines for the Interpretation of Sequence Variants: A Joint Consensus Recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology". Genetic Medicine. 14: 405–424. doi:10.1038/gim.2015.30. Check date values in: |date= (help)
  12. Kniffin, Carol (09/06/2013). "MITOCHONDRIAL DNA DEPLETION SYNDROME 12B (CARDIOMYOPATHIC TYPE), AUTOSOMAL RECESSIVE; MTDPS12B". OMIM. Check date values in: |date= (help)
  13. Carlo, Viscomi (June–July 2015). "Emerging concepts in the therapy of mitochondrial disease". Biochimica et Biophysica Acta (BBA) - Bioenergetics. 1847: 544–557.
  14. Bauskis, Alicia (June 2022). "The diagnostic odyssey: insights from parents of children living with an undiagnosed condition". Orphanet Journal of Rare Diseases volume. 17. doi: Check |doi= value (help).
  15. Domchek; Jameson; Miesfeldt (05/04/2015). "The Practice of Genetics in Clinical Medicine". Check date values in: |date= (help)
  16. McCormick, Cara Zayac (22/11/2022). "Investigating Psychological Impact after Receiving Genetic Risk Results—A Survey of Participants in a Population Genomic Screening Program". Journal of Personalized Medicine. 12. doi: Check |doi= value (help). Check date values in: |date= (help)