Learn The BasicsThymidine Kinase 2 deficiency (TK2d) is an ultra-rare, inherited mitochondrial disorder caused by a genetic mutation in the TK2 gene and mainly characterized by progressive muscle weakness.
Genetic basis of TK2d
The TK2 gene is found in the long arm of chromosome 16 and contains the information necessary to make the TK2 enzyme.
This enzyme works inside the mitochondria, the energy-producing centers of cells. The mitochondria have their own DNA, which is essential for their normal functioning. TK2 is involved in the production and maintenance of mitochondrial DNA by recycling the building blocks of mitochondrial DNA, called nucleotides, to make new mitochondrial DNA.
More than 30 pathogenic mutations have been identified in the TK2 gene, which are associated with TK2d. The majority of these mutations result in a change in a single amino acid in the gene that codes for the TK2 enzyme. These small changes can alter the function of the enzyme.
All mutations in the TK2 gene reduce the activity of the TK2 enzyme.
Consequences of the genetic mutations
When the activity of the TK enzyme is reduced due to a mutation in the TK2 gene, the recycling of mitochondrial DNA is impaired. This, in turn, leads to a shortage of available nucleotides for the repair and production of mitochondrial DNA, leading to mitochondrial DNA depletion or a reduction in the amount of mitochondrial DNA.
Without enough mitochondrial DNA, the mitochondria cannot function properly and produce the amount of energy required by cells.
Since muscle cells have particularly high energy demands to function, one of the main symptoms of TK2d is muscle weakness.
Some cells have as low as 5% of normal mitochondrial DNA, while others can have up to 60% of normal, but no one knows the reason for this.
Inheritance pattern
TK2d is inherited in an autosomal recessive pattern. This means that a person must inherit a recessive copy of the TK2 gene from each parent to have TK2d.
Family history and risk
A person who carries a recessive copy of the TK2 gene has a 50% chance of passing that it to each child and a 50% chance of passing on the healthy copy.
When two carriers have a child together, there is a 25% chance the child will inherit both defective copies of the TK2 gene and therefore develop TK2d.
The same couple has a 50% chance of having a child who is also a carrier of TK2d – inheriting a faulty copy of the gene from one parent and a healthy copy from the other.
Finally, the same couple has a 25% chance of each passing a healthy copy of the TK2 gene to their child, resulting in an unaffected child who is also not a carrier.
Since the TK2 gene is situated on an autosomal chromosome, meaning not on a sex-determining chromosome like X or Y, both boys and girls have an equal risk of inheriting the disease from carrier parents.