Thymidine kinase 2 deficiency (TK2d) is an incredibly rare disease, but it's also a devastating one. It's caused by a genetic mutation in the TK2 gene that leads to a decrease in your body's mitochondrial DNA production.
Mitochondria generate energy that power your cells. When they are damaged, your muscles and organs can't function properly.
"In the case of TK2d, an enzyme called thymidine kinase can't do its job, which is to repair the DNA inside your mitochondria," says Angela Lek, PhD, chief research officer of the Muscular Dystrophy Association. Over time, this causes progressive muscle weakness that can lead to trouble eating and breathing, and, ultimately, death.
Thankfully, advances in both diagnoses and therapy mean more people can get the treatment that they need, and improve their prognoses, Lek says. Here's a look at the latest breakthroughs in the field – and why they may be game changers for people who live with TK2d.
A New, Groundbreaking Treatment
Kygevvi, a medicine to treat TK2d, was approved by the FDA in November 2025. It's the first ever drug for the condition. It combines two medications, doxecitine and doxribtimine.
TK2d was first identified in 2001, but for almost a quarter century, there weren't any treatments available for it. Health care professionals could only recommend supportive care, such as physical, occupational, and speech therapy, and, eventually, as symptoms got worse, feeding and breathing tubes.
In 2012, Michio Hirano, MD, a neurologist at Columbia University Medical Center in New York City, developed a mouse model to better understand TK2d and explore potential treatments. He had a hunch that the use of deoxynucleosides – the traditional building blocks for mitochondrial DNA – could help treat the condition.
His gut instinct was right. In 2014, he published a paper that showed the therapy was safe and effective in mice. Hirano was able to petition the FDA to allow him to use two deoxynucleosides, doxecitine and doxribtimine, for compassionate use in people with the condition.
Since then, clinical trials for the medication, now known as Kygevvi, have shown that in people whose symptoms started at age 12 or younger, the treatment may reduce the risk of death by more than 90%. About three-fourths of those receiving the treatment regain at least one lost motor skill. Some were able to reduce, or even stop, the use of a ventilator to help them breathe.
"Up until now, patients and their families were told that there was nothing that could be done to stop the progression of TK2d," says Lek. "Now we can offer them some hope."
The drug is only FDA-approved for people whose TK2d symptoms began in infancy or childhood. But researchers are also now studying it in people diagnosed with late-onset TK2d. "It appears to have benefits for this group of patients too, although we don't know if results will be as dramatic as for those whose symptoms started earlier," says Cristina Dominguez-Gonzalez, MD, PhD, a neurologist and mitochondrial researcher at the Hospital 12 de Octubre in Madrid, Spain.
Kygevvi right now is only approved for use in the United States. But people who live in other countries may be able to get access to the drug as part of a compassionate use program, says Dominguez-Gonzalez.
A Promise in Gene Therapy
Gene therapy is when doctors fix a defective gene or replace it with a healthy one as a way to fight disease. It's being studied for everything from cancer to cystic fibrosis to heart disease. It's also being researched for TK2d.
In recent studies, doctors use a virus known as an adenovirus to deliver a healthy TK2d gene copy into the cells of mice with the disease. Research showed that it significantly improved how long mice lived. On average, their life expectancy rose from just about two weeks to three months. When researchers added Kygevvi to the mix, the results were even more dramatic: The mice lived 481 days, or 16 months, on average.
The next step is to get a drug company on board, to test this combination in humans. "We have to tread very carefully with gene therapy, as it has its risks," says Hirano. "But we remain hopeful that this could be the wave of the future."
The Potential for a Faster Diagnosis
Since TK2d is so rare, most doctors have never seen it in their practice. But symptoms in both infantile-onset and childhood-onset TK2d are so dramatic that most pediatricians will refer people fairly quickly to a neurologist, says Austin Larson, MD, a geneticist who specializes in mitochondrial disorders at Children's Hospital Colorado in Aurora. But even then, time may be spent ruling out other neuromuscular conditions like spinal muscular atrophy (SMA) or other mitochondrial diseases.
The fastest and most effective way to diagnose TK2d is to go straight to genetic testing, says Larson. "Over the last several years, whole-genome sequencing has become more widely available," he explains. "This means providers can now diagnose TK2d and other super-rare conditions, even if they've never personally encountered it before. That's important, because the earlier we intervene in a patient's disease process, the better their prognosis."
It's important to ask for whole genome sequencing, says Larson. Other genetic tests may miss it because they don't cover mitochondrial-related genes like the TK2 gene.
Better Diagnosis and Treatment for Adults
Adult-onset TK2d, which makes up about 20% of all cases, often goes undiagnosed or misdiagnosed, since symptoms tend to be milder than those of the other forms, says Hirano. "We think there are adults out there who have it who don't know about it," he explains. One study found that people with adult-onset TK2d can go over 17 years without the proper diagnosis.
One country that has been able to diagnose adults quickly and efficiently is Spain. "We've identified about patients with adult-onset disease since the first clinical cases were diagnosed around 2001," says Dominguez-Gonzalez.
Spain created national reference centers for neuromuscular disorders in 2015. People who show any signs of neuromuscular disease, including symptoms of adult-onset TK2d like limb muscle weakness or upper eyelid drooping, are referred to these centers. Doctors there are more likely to order tests that could help to diagnose TK2d, such as muscle biopsies, and ultimately, genetic testing.
Adult TK2d patients in Spain are also often offered Kygevvi, even though the drug hasn't been technically approved for them. They can often access it either through a clinical trial or through their country's compassionate drug use program, says Dominguez-Gonzalez.
Her team is also studying certain biomarkers that are often elevated in people with TK2d, like growth differentiation factor 15 (GDF-15). "We monitor levels while patients are on drug therapy, to help us assess their response to treatment," she explains. "It's part of our ultimate goal, to make treatment accessible to every single patient who has TK2d."