POLG-related mitochondrial disease

POLG disease, also known as POLG syndrome, is a form of mitochondrial disease caused by changes in a gene called POLG. This gene helps the body maintain mitochondrial DNA, which is vital for our cells to produce energy. When the gene doesn’t work as it should, the body can’t make mitochondrial DNA as well as normal. As a result, cells can’t make enough energy to support the organs that rely heavily on it, such as the brain, liver, nerves and muscles.

This type of mitochondrial disorder can appear at any age. In infants and young children, it may present as a severe form known as Alpers syndrome, while in teenagers and adults it often develops more gradually and affects different parts of the body.

What is POLG syndrome?

POLG-related disease is a spectrum of conditions, meaning that symptoms and progression can vary widely. In some people it can lead to seizures and liver problems early in life, whilst others experience difficulties with co-ordination, nerve function or muscle strength later on.

All forms of this mitochondrial disease share the same underlying problem: the POLG gene is unable to correctly repair and copy mitochondrial DNA, which reduces the amount of energy available to the body’s cells.

Childhood presentation (Alpers syndrome)

Alpers syndrome is rare. It’s one of the most severe childhood forms of POLG disease and typical features include:

• Seizures that are difficult to control.
• Developmental regression or loss of previously acquired skills.
• Liver problems, which can be serious.
• Progressive decline requiring specialist medical care.

Teen and adult presentation

Symptoms can begin during adolescence or adulthood. Common features include:

• Problems with balance and co-ordination.
• Numbness, tingling or weakness caused by nerve involvement.
• Muscle fatigue or loss of strength.
• Seizures or headaches.
• Liver involvement (in a small proportion of cases).

Some individuals also present with specific clinical patterns such as MEMSA (myoclonic epilepsy, myopathy and sensory ataxia) and SANDO (sensory ataxic neuropathy, dysarthria and ophthalmoparesis), which fall within the broader spectrum of POLG-related disease.

Later adult-onset presentation (usually age 40+)

• Muscle symptoms including muscle fatigue and weakness and droopy eyelids with difficulty moving the eyes (CPEO).
• Some individuals have movement problems similar to Parkinson’s disease.

The course of the condition is variable. Some individuals remain stable for long periods, whilst others notice gradual change over time.

What are the symptoms of POLG disease?

Because POLG can affect several organs, symptoms differ from person to person. They may include:

• Difficulties with balance and walking.
• Numbness, tingling or pain in the hands and feet.
• Muscle weakness and tiredness.
• Vision or eye movement problems.
• Liver problems.

Not everyone will experience all these features.

What causes POLG syndrome?

Most cases of POLG-related mitochondrial disease follow an autosomal recessive pattern, meaning a person must inherit two changed copies of the gene, one from each parent. Less commonly, the condition can be autosomal dominant, where a single altered copy is enough to cause the disease.

How do you get a diagnosis of POLG disease?

Diagnosis of POLG usually involves a combination of medical assessment and laboratory testing. This may include:

• Genetic testing to identify changes in the POLG gene.
• Blood tests, including checks of liver function.
• Brain imaging or nerve studies, where indicated.
• Occasionally, a muscle or nerve biopsy, if recommended by a specialist.

Are there any treatments for POLG disease?

Like all forms of mitochondrial disease, there’s currently no cure for POLG-related disease. Treatment focuses on managing symptoms, supporting energy levels and protecting affected organs. Care is personalised and may include:

• Seizure management under the guidance of a neurologist.
• Physiotherapy and occupational therapy to support movement and independence.
• Regular monitoring of liver and neurological function.
• Pain and neuropathy management.
• Nutritional advice and fatigue management.

Important safety note: The medicine sodium valproate can cause serious liver injury in people with certain POLG changes and is generally not recommended unless specifically advised by a specialist. You can read more about which drugs are considered safe for mitochondrial disease patients on the drug information page of our website, but you should always discuss any new medication with your healthcare team.

Is there any ongoing research into POLG-related diseases?

Researchers are working to better understand POLG syndrome and to find possible new treatments.

A company called Pretzel Therapeutics have recently shared promising early laboratory findings. Their research focuses on developing a new type of medicine designed to help the POLG protein work more effectively, supporting the mitochondria’s ability to produce energy.

These studies have so far been carried out only in cells and animal models, but they represent an important early step towards future treatment development. While further research is needed to show whether this approach is safe and effective for people, it marks growing scientific attention and investment in POLG-related conditions.

We also have a close working partnership with The POLG Foundation, a charity founded by Prince Frederik of Luxembourg and his family after his diagnosis of POLG syndrome back in 2016. Frederik tragically passed away in March 2025, but the foundation continues to support research into effective treatments and a cure for POLG-related mitochondrial disorders.

What support is available for POLG patients?

In the UK, expert care for POLG disease and all forms of mitochondrial disease is available through the NHS Highly Specialised Services for Rare Mitochondrial Disorders.

Here at The Lily Foundation, we recognise how challenging a diagnosis of POLG-related disease can be, both physically and emotionally. We’re here to provide practical information, emotional support and advocacy for patients and their families.

If you or someone you love has a diagnosis of POLG-related mitochondrial disease, please head over to our mitochondrial disease Q&A page for more information, or contact our support team to connect with others who understand.