Mitochondrial DNA Depletion Syndrome

From UBC Wiki
Representation of mitochondrial DNA within a cell.

Mitochondrial DNA Depletion Syndrome (MDDS) is the term for a group of rare disorders that decrease the amount of energy produced by certain tissues. The tissues most commonly affected by this disease are the muscles, liver, intestines, and brain. The symptoms a person will experience is variable, depending on which tissues are affected and how much DNA is missing from those tissues. Although there is no treatment for MDDS, genetic testing can help manage symptoms.

Cause

Eukaryotic animal cell representation featuring organelles. Mitochondria can be seen in the upper left hand portion of the image.

MDDS is caused by a reduced amount of mitochondrial DNA (mtDNA) that leads to insufficient energy production for the surrounding tissues. Without energy, these tissues become weak and lead to disorder.

Background

Within each cell of the body there are small, distinct components that work together to keep the cell functioning. These components are called organelles, and each organelle has a specific task. The mitochondria's task is to make energy to power the cell, which in turn powers the system beyond. Mitochondria are regulated by two kinds of DNA: DNA within the nucleus called nuclear DNA, and DNA within the mitochondria itself called mtDNA. 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). Parts of the DNA code can be translated into proteins, which are small units of matter that carry out tasks to support organelles and keep the cell and body functioning. The sections of DNA that code for proteins are called genes. 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. This prevents the mitochondria from functioning properly, and will lead to less energy within the cell. When this leads to a weakening of surrounding tissues, it is called MDDS. 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.

Inheritance Pattern

The majority of MDDS conditions are inherited in an autosomal recessive manner. Every individual has two sets of each gene, having received one copy of their genes from each parent. 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, and it will affect males and females equally. The chance of having an affected child will be 1 in 4.

Several MDDS conditions are inherited in an autosomal dominant manner. 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. 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 the inheritance will look different. You can learn more about mitochondrial inheritance here at this link.

Visual representation of autosomal recessive and autosomal dominant inheritance patterns.

Types of MDDS and Associated Genes

There are currently 15 genes identified that predict MDDS, and each are associated with different symptoms.

mtDNA Depletion Syndromes Associated Genes
Neurogastrointestinal MTDPS1, MTDPS4B
Hepatocerebral MTDPS3, MTDPS4A, MTDPS15
Myopathic MTDPS2, MTDPS11
Cardiomyopathic MTDPS10, MTDPS12A, MTDPS12B
Encephalomyopathic MTDPS5, MTDPS8A, MTDPS9, MTDPS13, MTDPS14

Symptoms

Symptoms generally begin shortly after birth or in childhood, but some will manifest later in life. The symptoms of MDDS a person experiences will depend on which of their tissues are lacking mtDNA. The specific tissues affected are, in turn, determined by the gene that is disrupted or missing. Below are symptoms common across multiple forms of MDDS:

  • Failure to Thrive
  • Hearing Loss

Clinical Management

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Social Considerations

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Resources for Patients

Resources for patients with MDDS are grouped together 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 and share their stories.

Websites

Socials

Media

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