Wellcome Trust Centre For Mitochondrial Research

Mitochondrial DNA depletion syndrome (MDDS)

Mitochondrial DNA Depletion Syndrome (MDDS)

It is important that mitochondrial DNA (mtDNA) is correctly maintained to allow the mitochondria to function. Problems with mtDNA maintenance can reduce the amount and quality of the mtDNA, which can lead to impaired energy production. This can cause a particular type of mitochondrial disease known as mitochondrial DNA depletion syndrome (MDDS). The term depletion refers to the markedly decreased amount of mitochondrial DNA found in muscle, liver and brain tissues in these disorders.

Who does MDDS affect?

Mitochondrial DNA depletion syndromes can affect both children and adults. The early-onset form affecting infants and children is most severe and often fatal in early life. The late-onset form that affects adults is less severe and disease progression is often slower.

How many people does MDDS affect?

Mitochondrial DNA depletion syndromes are extremely rare. For example, there are thought to be <100 cases of mitochondrial DNA depletion syndrome associated with the TK2 mutation throughout the world. The prevalence is even lower for mitochondrial DNA depletion syndromes associated with mutations in other genes.

What are the clinical features of MDDS?

Mitochondrial DNA depletion syndromes are associated with many clinical features, some of which can be fatal in childhood. The type and severity of symptoms will often depend on the particular gene that is affected. In some cases, the main clinical feature is progressive muscle weakness, which can make breathing difficult and lead to respiratory failure. The other cases the brain may be affected causing seizures, stroke-like episodes, movement disorders or developmental delay. Other parts of the body commonly affected include the liver, kidney and gastrointestinal tract and hearing loss is also a feature of some gene mutations.

What are the causes of MDDS?

Mitochondrial DNA depletion syndromes are caused by genetic errors (mutations) in genes found within the nuclear DNA. These mutations affect genes that have an essential role in the replication and maintenance of mtDNA.

Genes known to be associated with MDDS disease include TK2, POLG, RRM2B, SUCLA2, SUCLG1, DGOUK, MPV17, TYMP and C10orf2.

How is MDDS inherited?

In order to develop a Mitochondrial DNA depletion syndrome you need to have two copies of the faulty gene. Typically, each parent carries one copy of the faulty gene but they do not show signs or symptoms of the condition because they also have a second normal copy of the gene, which is sufficient to maintain health. This inheritance is known as autosomal recessive and there is a 1 in 4 chance of these parents having an affected child who inherits both copies of the faulty gene (one from each parent).

It is also possible for a gene to spontaneously mutate, which if combined with one parent passing on a faulty gene, may also cause disease.

Are there any treatments for MDDS?

Treatment usually focuses on managing the symptoms and providing supportive care. There is an experimental treatment in development that may benefit some patients with mitochondrial DNA depletion syndrome. This is known as nucleoside bypass therapy.

What is nucleoside bypass therapy?

There are four chemical ‘building blocks’ needed to maintain mtDNA, collectively known as deoxynucleoside triphosphates (dNTPs). If the body is unable to produce these dNTPs due to a mutation in one of the many genes that are needed to make them, this can result in mitochondrial DNA depletion syndrome. It may be possible to ‘bypass’ this shortage of dNTPs by providing deoxynucleosides, or similar building blocks known as deoxynucleotides, to some patients with mitochondrial DNA depletion syndrome as an oral medication. This may restore the supply of dNTPs required for mtDNA maintenance, which could improve some of the clinical symptoms associated with the condition.

Is nucleoside bypass therapy being used?

Based on preclinical research, nucleoside bypass therapy is being used for a small number of patients in both Europe and America on compassionate grounds. These patients have mitochondrial DNA depletion syndrome associated with the TK2 mutation, which mainly affects muscle.

Will nucleoside bypass therapy be suitable for all mitochondrial DNA depletion syndromes?

It is unclear at this stage whether nucleoside bypass therapy could be used for mitochondrial DNA depletion syndromes caused by mutations in genes other than TK2. Further preclinical studies are required to determine whether the therapy can be used to treat all mitochondrial DNA depletion syndromes.

Can MDDS be prevented?

If the genetic mistakes are present, then there is nothing that can be taken during pregnancy or given to the infant that will prevent MDDS occurring.

However, once a genetic mistake has been identified, there are reproductive options that can be offered to prevent MDDS in the next pregnancy. For people living in the UK, reproductive advice can be discussed with the doctors at any of the 3 highly specialised mitochondrial disease centres in Newcastle, London and Oxford.

One reproductive option is prenatal testing. This form of prevention is only suitable for those people who would consider termination and would usually be done after 10-12 weeks of the pregnancy by chorionic villus biopsy. The gene is examined in DNA from the biopsy to see which copies have been inherited. If both faulty copies have been inherited, then termination of the pregnancy is offered.

Another reproductive option is preimplantation genetic diagnosis (PGD). This is an IVF-based technique that involves examining the gene in DNA taken from early embryos grown in the lab to see which copies have been inherited. The aim is to identify an embryo that does not carry the genetic mistakes that cause MDDS. If such an embryo is identified, it can be transferred to the womb to try and establish a pregnancy.