POLG mitochondrial disease is a spectrum of inherited disorders from mutations in the POLG gene. This gene provides instructions for a protein essential for mitochondria, our cellular power plants, to function. Faults in this gene disrupt the cellular energy supply, leading to a wide array of health issues that can appear from infancy to late adulthood with varying severity.
The Role of the POLG Gene and Mitochondria
Mitochondria, our cellular power plants, convert food energy into a usable form called ATP. They rely on their own genetic instructions, mitochondrial DNA (mtDNA). The POLG gene produces an enzyme, polymerase gamma, which is responsible for copying and repairing the mtDNA.
When the POLG gene has mutations, the polymerase gamma enzyme becomes faulty. This prevents it from replicating mtDNA efficiently, causing the amount of mtDNA to decrease (depletion) or accumulate errors. This damage leads to a significant energy shortage inside the cell.
The energy deficit is most pronounced in organs with high energy demands, like the brain, muscles, and liver, which is why symptoms are often neurological, muscular, and liver-related. The inheritance pattern is autosomal recessive, meaning an individual must inherit two mutated gene copies—one from each parent—to develop the disease.
Associated Clinical Syndromes and Symptoms
The clinical presentation of POLG-related disorders is broad, with symptoms influenced by gene mutations and age of onset. The conditions are grouped into several overlapping clinical syndromes that exist on a spectrum, and an individual may have features of more than one.
Alpers-Huttenlocher syndrome begins in infancy or early childhood. It is marked by difficult-to-control seizures, loss of developmental milestones, and progressive liver disease that can lead to liver failure. Onset is common between ages two and four, with a second peak in late adolescence.
Progressive External Ophthalmoplegia (PEO) appears in adulthood and involves the muscles controlling the eyes and eyelids. Individuals experience drooping eyelids (ptosis) and reduced eye movement (ophthalmoplegia). This can be accompanied by widespread muscle weakness in the limbs.
The Ataxia Neuropathy Spectrum (ANS) can emerge from adolescence to adulthood and is characterized by ataxia and neuropathy. Ataxia is a lack of voluntary muscle coordination, causing problems with balance and walking. Neuropathy is nerve damage that causes weakness, numbness, and pain, often in the hands and feet.
The Diagnostic Journey
Diagnosing a POLG-related disorder is a multi-step process. It begins with a physician assessing the patient’s symptoms and family medical history to guide subsequent testing.
Biochemical tests, such as measuring lactate and pyruvate levels, may be ordered. Elevated levels can indicate a problem with mitochondrial energy production. These tests can suggest a mitochondrial disease but are not specific to POLG disorders and serve as supportive evidence.
Imaging and functional tests provide more information. A magnetic resonance imaging (MRI) scan of the brain can reveal damage patterns associated with certain POLG syndromes. A muscle biopsy, where a muscle sample is examined for signs of mitochondrial dysfunction, may also be performed.
The conclusive step is genetic testing. Sequencing the POLG gene is the only way to definitively confirm a diagnosis by identifying the specific disease-causing mutations.
Current Management Strategies
With no cure available, treatment for POLG mitochondrial disease focuses on managing symptoms and providing supportive care. Management is individualized to the specific needs of each person. A multidisciplinary team of specialists, including neurologists, geneticists, and physical therapists, is often involved.
Supportive therapies are a large part of the management plan. Physical, occupational, and speech therapy can help maintain mobility and manage muscle weakness. Some patients are prescribed a “mitochondrial cocktail,” a combination of vitamins and cofactors, though its effectiveness varies.
Treatment also involves addressing specific symptoms as they arise. Anti-epileptic medications are used to control seizures, a common feature of severe POLG disorders. Liver dysfunction is monitored closely, and liver failure may require transplantation.
Avoiding certain harmful medications is a key part of management. The anti-seizure medication sodium valproate (valproic acid or Depakote) is strictly contraindicated for individuals with POLG mutations. This drug can cause or accelerate severe liver failure in this population, so educating patients and providers about this risk is a priority.