Thymidine Kinase 2 Deficiency

What else is it called?

  • TK2 deficiency

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What causes it?

Thymidine Kinase 2 Deficiency [TK2 Deficiency] is an autosomal recessive condition which can result in a lack of mitochondrial DNA [mtDNA] replication. The TK2 gene provides instructions for the production of the enzyme mitochondrial thymidine kinase. The mitochondria are commonly referred to as the energy production centre of the cell, as this is where energy is produced for the cells of the body. A mutation to the TK2 gene means that the enzyme can only work partially, or it may not be able to function at all due to the impact this has on its production, this leads to an imbalance in the nucleotide pool, nucleotides are building blocks of DNA and RNA and they are used to replicate mtDNA. Ultimately, this gene mutation can lead to a total lack of energy production in tissues in the body, the impact can be worse in cells that require high amounts of energy such as skeletal muscles and in heart muscles.

Sadly, there can be many severe health consequences due to this condition. Please see the signs and symptoms section for more information on this.

How common is it?

TK2 Deficiency is an extremely rare condition. To date, there have been more than 50 individuals diagnosed with this condition worldwide, the exact number is unknown. Due to the rarity of this condition, it is unclear whether it is more common amongst males or females or amongst specific ethnicities.

What are the signs and symptoms?

Signs and symptoms appear in a spectrum of severity in infancy, childhood, adolescence or adulthood; earlier onset typically appears with a more rapid progression. Due to the condition’s genetic variability, it may be a challenge when diagnosing. Some of the signs and symptoms of this condition are as follows.

Infant/childhood symptoms:

The first signs which may become apparent are a loss of breath at times such as when climbing stairs or doing a mildly straining task which would usually be relatively easy, this may then progress on towards:

  • Respiratory muscle weakness
  • Loss of motor function
  • Spinal muscular weakness
  • Progressive muscle weakness
  • Hearing loss
  • Problems with swallowing and chewing
  • Increased risk of seizures
  • Poor reflexes
  • Slow mental development

When TK2 Deficiency presents in late childhood, children may also show signs of droopy eyelids and an inability to move their eyebrows and eyelids. Sadly, for this subgroup TK2 Deficiency can sometimes be more severe and fatal due to rapidly progressive myopathy and the loss of motor function which can ultimately lead to death due to respiratory failure or respiratory complications.

Adult symptoms:

  • Muscle weakness such as facial
  • Dysphagia
  • Difficulty walking
  • Slowed mental development
  • Low muscle tone [hypotonia]
  • Trouble breathing
  • Increased risk of seizures and other neurological disfunctions

How is it diagnosed?

The current way to diagnose this condition is through genetic testing, this will involve taking a swab from the inside of your cheek or other area to test your genes for the genetic mutation. This will be discussed with you by your health care professional. This condition may also be diagnosed by a muscle biopsy to check for the condition. This involves taking a small samples of muscle tissue for testing fibres, what enzymes are present and to measure mtDNA levels in the muscle. This may be a slightly painful procedure; however, this is a very accurate way to diagnose this condition. Blood tests will be used to check for elevated creatine kinase and lactate levels which are common with muscular wastage.

TK2 Deficiency may be misdiagnosed as it resembles several other diseases such as spinal muscular atrophy, Pompe disease, Sengers syndrome, Prader-Willi syndrome, limb-girdle muscular dystrophy, facioscapulohumeral dystrophy, congenital myasthenic syndrome, congenital myopathies, mitochondrial myopathy and other mitochondrial depletion syndromes.

Diagnosis can take a long time; this is due to the rarity of the condition and similarity it has to other conditions such as spinal muscular atrophy, Pompe disease, Sengers syndrome, Prader-Willi syndrome, limb-girdle muscular dystrophy, fascioscapulohumeral dystrophy, congenital myasthenic syndrome, congenital myopathies, mitochondrial myopathy and other mitochondrial depletion syndromes.

Can it be treated?

Currently, there is no approved therapies for this condition. Treatment is usually aimed at managing symptoms as they present, although research does persist in this area.

MT1621 is a new oral therapy that is currently in production and is going through further clinical trials, previous trials have looked promising with no reports of unexpected safety issues. This new therapy aims to restore the fidelity of mitochondria function for mtDNA replication and cellular energy production. Previous studies into this has shown promise in slowing or reversing TK2 Deficiency. For more information on this therapy treatment, please contact Metabolic support UK.

You will be treated by a multidisciplinary team of specialists which will help you manage the symptoms, this may include physiotherapists for treatment of muscular symptoms, neurologists, speech and language therapists and more. This will be discussed with you on diagnosis.

Do my family need to be tested?

TK2 Deficiency can only be passed on to a child if both parents have a copy of the faulty gene. This is called autosomal recessive inheritance. A person who has a copy of the faulty gene is known as a carrier.

If both parents are carriers, their child has a one in four (25%) chance of inheriting the disorder, and a one in two chance (50%) of being a carrier. This is the same for each child the parents have.

If the child only inherits one copy of the faulty gene, they will be a carrier but will not have the disorder. In some rare cases, TK2 Deficiency carriers have had mild symptoms of the disorder for which they carry the faulty gene.

Once you are diagnosed, you can speak to a genetic counsellor. They can explain how you may have inherited. They can also tell you about genetic testing for the rest of your family. They can provide advice and support if you go on to have children of your own.

Relevant Organisations

References

References are available on request. Please contact Helen Morris by phoning 0845 241 2173 or emailing helen@metabolicsupportuk.org [Resource Library No: TPPN32].

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