Thymidine kinase 2 deficiency (TK2d) is an incredibly rare mitochondrial disease that affects fewer than one in every 500,000 people. It causes muscle weakness that, over time, causes you to lose the ability to walk, breathe, or eat on your own.
Most people who have TK2d develop signs of it in infancy or childhood, although some will only show symptoms in adulthood. An early start of the disease often means a worse prognosis.
Up until now, the only treatment available has been supportive care like physical therapy, wheelchairs, and feeding and breathing tubes. But in November 2025, a new drug, Kygevvi, received FDA approval for patients who began to show symptoms by the age of 12.
Michio Hirano, MD, chief of the Division of Neuromuscular Medicine at Columbia University Medical Center in New York City, is one of the world's leading experts on mitochondrial diseases such as TK2d. He has studied the condition for more than two decades and was one of the first doctors to treat patients with Kygevvi. Here, he provides his insights as to what it's like to live with TK2d and how new treatments improve the outlook for those diagnosed with the condition.
What do you say when you meet with a patient who has been newly diagnosed with TK2d?
Since TK2d is so uncommon, I've only seen about 35 patients in all my years of practice. At our mitochondrial center at Columbia, we currently treat 27 patients. They run the spectrum from very young infants to adults. They come from all over the world, including South Korea, Romania, and South America.
In my first meeting with a new patient with TK2d, I explain that the condition is caused by a genetic mutation in the TK2 gene that causes muscle weakness. It's due to decreased production of mitochondria, which provide the energy to power our cells.
There are three types of TK2d: infant onset, childhood onset, and adult onset. While there's no cure, there is a new treatment available to anyone whose symptoms began before the age of 12. We want to get as many of our patients as possible started on this medication.
What is the new drug recently approved to treat TK2d, and why has it been so significant?
Kygevvi has been a true game changer for people diagnosed with either infantile or childhood-onset TK2d. It combines two drugs – doxecitine and doxribtimine – that are an important part of your DNA. They help to restore your cells' mitochondrial function.
Our research shows that Kygevvi can reduce the risk of death by 95%. We also found that about two-thirds of treated patients regained some sort of milestone, and some were even able to come off of ventilators and feeding tubes.
We treated our first patient with Kygevvi in 2012. He was just 17 months old, and so weak that he could not lift his arms or legs off of the exam table. Soon after, we had to place breathing and feeding tubes. The drug was still investigational, but we were able to give it to him as part of the FDA's Compassionate Use program.
Today, he's alive and thriving. While he is still on a ventilator, he's able to come off of it during the day so that he can attend school. He's learned to read and write and has made friends. His progress has been beyond my wildest dreams. It's extremely gratifying to see that this medication has had such a positive, dramatic effect on my patients' lives.
What do patients need to know before they start Kygevvi?
Kygevvi was just approved in November 2025, so it won't become widely available until early 2026. Some centers, like mine, were part of the clinical trials, so many of our TK2d patients have started the medication already.
Kygevvi comes as a powder that's dissolved in water before you take it. It's taken three times a day with food. The main side effect is diarrhea. This usually can be managed with an over-the-counter medication such as loperamide (Imodium). It can also sometimes elevate your liver enzymes. But for most patients, the benefits outweigh the side effects.
What is one of the biggest challenges when it comes to TK2d?
Getting a timely diagnosis. Most doctors aren't familiar with the condition, so it may take time for a patient to get diagnosed. The first clue is usually a muscle biopsy, which can reveal mitochondrial alterations that are confirmed with genetic testing.
Usually, infants and young children are diagnosed fairly quickly, since their symptoms are often very dramatic. But someone with adult-onset TK2d may go months, or even years, since symptoms are more subtle. We suspect there are even adults with the condition today who will never get a diagnosis.
Hopefully, as genetic testing becomes more widely available, this will become less of a challenge. The faster we can get a patient diagnosed, the faster we can move to treatment.
Who are some other specialists who may be in the lives of someone who has TK2d?
When it comes to TK2d, it really does take a village. Patients require an entire medical team to manage the muscle weakness that affects everything from movement to eating to breathing.
The quarterback is usually a neurologist like me. But patients also need to see a pulmonologist, or lung doctor, to manage any respiratory complications such as pneumonia. They may require speech therapy, to help manage problems swallowing. If they require a feeding tube, they will need to see a GI specialist. Most patients also need physical and speech therapy, to help slow down muscle weakness and encourage them to speak and swallow.
Since patients come to see us from all over the country, and even the world, we work with them to find a team of specialists in their area who can provide all of these services.
What advice would you give to a patient recently diagnosed with TK2d, as well as their family?
Seek treatment as soon as possible. We have found that Kygevvi is very effective when it's given early in the course of the disease. The drug is only FDA-approved for patients diagnosed with infantile or childhood TK2d. But patients with adult-onset disease should talk to their medical team about the drug as well. Researchers are studying Kygevvi in adult-onset patients, and we have found that they also show some gradual improvement.
It is also important for patients and their families to have realistic expectations about treatment. I do explain that the majority of patients do see some sort of functional improvement in basic motor skills like the ability to sit independently, control their head, walk, or even climb up stairs. We see the most improvement in our younger patients, and our older ones tend to show more stabilization. It doesn't mean that you or your child will be able to come off ventilators or feeding tubes, for example. But most patients do benefit.
What are your thoughts on the long-term outlook for TK2d?
Right now, Kygevvi is the only drug being studied for TK2d. I'm very optimistic that it will improve the prognosis for patients, as well as their overall quality of life. I'm also hopeful that it will prove effective for adult-onset TK2d, too.
The other promising treatment for TK2d is gene therapy. It's still very early: My laboratory is studying it in a mouse model. But our preliminary research suggests that it may be remarkably effective when it's combined with Kygevvi. We still have a long road ahead, but I'm cautiously optimistic. It's an exciting time to be studying mitochondrial diseases like TK2d.