Thymidine Kinase 2 Deficiency (TK2d)

Thymidine Kinase 2 Deficiency, usually referred to as TK2d, is a genetic, progressive form of mitochondrial disease that primarily causes significant muscle weakness and, in some cases, respiratory difficulties. While not all individuals experience breathing issues, the condition mainly affects the proximal muscles – those closest to the centre of the body – which mostly impacts eating, swallowing, speaking, breathing and overall mobility.

TK2d can affect people of any age, with symptoms and progression often varying amongst individuals. Those affected experience significant challenges with mobility, breathing, swallowing, speech and energy levels, as well as the emotional, social and financial pressures that come with managing a long-term, life-limiting condition.

What is TK2d?

TK2d is an ultra-rare type of mitochondrial disease. It’s classed as a primary mitochondrial myopathy (PMM), meaning it presents predominantly as progressive and severe muscle weakness (myopathy) and low muscle tone (hypotonia).

There are three main subtypes of TK2d:

• Early-onset TK2d begins before the age of 2 years. This subtype of the disease is typically the most severe, with a median survival of about one year from first symptoms.
• Childhood-onset TK2d begins between the ages of 2 and 12. Most individuals with this subtype of TK2d survive more than 13 years after the first emergence of disease symptoms.
• Late-onset TK2d begins after 12 years of age. In general, individuals with this subtype of TK2d may be expected to live 23 years after disease onset.

It’s possible that a person first experiences symptoms as an infant or child but doesn’t get diagnosed until after the age of 12. This is still considered ‘early-onset’.

It’s difficult to accurately estimate the prevalence of TK2d as it’s a relatively newly characterised disease and not widely known. However, estimates suggest a worldwide prevalence of less than 1.64 cases per 1 million people.

What are the symptoms of TK2d?

Thymidine Kinase 2 Deficiency can develop in various ways and affect different parts of the body. Symptoms can differ from person to person and present at any age from infancy up until adulthood.

Patients with TK2d typically experience progressive proximal muscle weakness, which is a root cause of most symptoms, including the loss of motor skills and respiratory difficulties. Eventually, patients may lose the ability to walk, eat and breathe independently.

TK2d can affect the body in any of the following ways:

Eyes

• Droopy eyelids (ptosis).
• Impaired eye movements (ophthalmoparesis).

Lungs

• Difficulty breathing.

Nervous system

• Fatigue.
• Developmental delays/missed milestones (younger patients).

Muscles

• Muscle weakness.
• Low muscle tone.
• Difficulty walking and talking.
• Facial weakness.

Gastrointestinal

• Difficulty chewing and swallowing.

Symptoms can progress slowly or quickly, depending on the patient and age of onset. Early-onset TK2d is often more severe and progresses faster, whereas a later onset of the disease usually means it’s less severe and progresses more slowly.

TK2d aff­ects nearly all aspects of life. Children aren’t able to achieve normal developmental motor milestones, or lose those already gained, while adults lose their functional independence as they develop problems with breathing, eating and walking.

However, although these symptoms may seem overwhelming, they can be managed with support from a dedicated healthcare team, practical strategies and a variety of resources.

What causes TK2d?

TK2d is caused by a mutation in the thymidine kinase 2 nuclear gene – hence the name. TK2 gene mutations reduce the amount and quality of mitochondrial DNA (mtDNA) within cells, leading to insufficient energy production and improper function of muscles and organs. Our mitochondria are the energy-producing structures in our cells.

The condition is inherited in an autosomal recessive manner, meaning both parents pass a mutated TK2 gene to their child. However, not all children whose parents are carriers of the mutated TK2 gene will develop TK2d; each child has a 25% chance of having the disease.

How do you get a diagnosis of Thymidine Kinase 2 Deficiency?

TK2d diagnosis can be challenging due to variable symptoms that overlap with similar diseases. Those include muscular dystrophy, Pompe disease, spinal muscular atrophy (SMA) type 1 or 2, congenital myopathies and others.

For some, it takes less than a year to get a TK2d genetic diagnosis after symptoms first appear. However, for most, the journey can take several years. Delayed diagnosis can be due to a number of factors, including lack of awareness from healthcare professionals, misdiagnosis or geographical barriers.

Multiple consultations with different specialists, especially neurologists, are often part of the diagnostic journey for those affected by Thymidine Kinase 2 Deficiency.

Only certain genetic tests can definitively confirm a diagnosis of TK2d. For suspected TK2d, different genetic testing options are available, such as whole genome sequencing, whole exome sequencing, single gene testing and multigene panels that include the TK2 gene.

Other tests are often ordered for patients who show symptoms of TK2d, including:

• Brain magnetic resonance imaging (MRI).
• Electromyography (EMG) test.
• Muscle biopsy.

An early, accurate diagnosis of this type of mitochondrial myopathy is important to inform best supportive care and potential involvement in clinical trials.

Are there any treatments for TK2d?

There are currently no NHS-approved therapies for Thymidine Kinase 2 Deficiency, and treatment primarily consists of supportive care that requires the involvement of a multidisciplinary healthcare team. This will typically consist of a cardiologist, neurologist, geneticist and GP along with other allied health professionals.

Treatments are being investigated currently and some patients are able to receive a nucleoside therapy on a compassionate use basis through their UK clinician. This treatment is likely to be reviewed by NICE in 2026. The Lily Foundation are named stakeholders in this process and will be called upon during the committee meeting to represent the lived experiences of those with TK2d and the impact the condition has, as well as show the impact of treatment on health-related quality of life.

Is there any research underway into TK2d?

The Lily Foundation is part of a global TK2d Steering Committee, which brings together patient advocates from around the world to advise on patient impact, education and future publications.

Earlier this year, our Head of Patient Programmes, Katie, presented new research at the European Paediatric Neurology Society (EPNS) conference in Munich. The findings came from the Assessment of TK2d Patient Perspectives (ATP) study, a global project shaped by both clinicians and patients looking at the real-life impact of TK2d on those living with the condition and caregivers, which captured the heavy physical and emotional burden faced by people of all ages living with the condition.

What support is available for TK2d patients?

The NHS Highly Specialised Services for Mitochondrial Disorders are available across the UK, offering expert support with diagnosis, ongoing monitoring and management of symptoms. Families can also access NHS genetic counselling to better understand inheritance and make informed decisions about family planning.

At The Lily Foundation, we know that a TK2d diagnosis can be overwhelming. That’s why we’re here to provide practical guidance, emotional support and patient advocacy – helping families feel less alone and more empowered in navigating life with the condition. Alongside this, we fund vital research aimed at unlocking new treatments for the future.

And finally, a caregiver resource for those directly affected by TK2d has been put together by the TK2d Steering Committee.

Whether you or a loved one have just received a diagnosis, or have been living with TK2d for some time, our mitochondrial disease Q&A section is a useful place to find answers and further information.