TK2d Basics

There are three main types of thymidine kinase 2 deficiency (TK2d), an ultra-rare genetic disease that primarily affects the muscles.

The types are categorized based on when the symptoms appear. They are early- or infantile-onset TK2d, childhood-onset TK2d and late-onset TK2d.

Early-onset TK2d

In early-onset TK2d, which is the most severe form of the disease, symptoms usually appear before age 1. They may include profound limb weakness and difficulty swallowing and breathing due to weakened throat and respiratory muscles.

Other symptoms may also include seizures, heart and kidney problems and multiple bone fractures.

Early onset TK2d progresses rapidly, with symptoms worsening over time. Most patients never learn how to walk, and those who do may lose this ability soon after they learn it. Most patients eventually require ventilatory support for breathing.

Patients with early-onset TK2d usually have a prognosis of one to two years after symptom onset, primarily due to respiratory failure.

Childhood-onset TK2d

Childhood-onset TK2d can begin anywhere between the ages of 1 and 12 and usually progresses more slowly than early-onset TK2d. 

Patients with this type of disease also experience weakness in the muscles of the arms and legs as well as those used for breathing and swallowing.

Other symptoms of childhood-onset TK2d may include difficulty moving or the inability to move the eyes, drooping eyelids and hearing loss.

Most children with this type of disease require a wheelchair for mobility by the age of 10, and many also need respiratory support with a ventilator as the muscles used for breathing weaken over time.

Most patients with this type of disease live more than 13 years after the symptoms first appear, and the cause of death is typically respiratory failure.

Late-onset TK2d

Late-onset TK2d is rarer than early-onset or childhood-onset TK2d and progresses more slowly.

Disease symptoms usually appear after the age of 12 and, like childhood-onset TK2d, include muscle weakness, difficulty swallowing, inability to move the eyes, droopy eyelids and hearing loss, as well as difficulty talking.

Patients may maintain the ability to walk, although they usually require mobility aids. 

As the disease progresses, most patients require ventilatory support for breathing. Patients with this type of disease usually live for 20 to 30 years after the symptoms first appear, with respiratory failure being the primary cause of death.

What causes each type of TK2d?

All types of TK2d are caused by mutations in the TK2 gene, but some specific mutations have been found only in certain forms of the disease, suggesting that these genetic differences may affect the timing and severity of symptoms.

For example, only patients with late-onset TK2d are homozygous for the p.Lys202del mutation, meaning they have this kind of mutation on both chromosomes. 

Patients with this type of disease also show multiple mitochondrial DNA deletions or fragments missing in their mitochondrial DNA.

Finally, the p.Arg130Trp mutation is associated with the most severe form of early-onset TK2d, with brain and spinal cord involvement likely during the first months of life.