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POLG gene
Reviewed by Medicinsk Expert•Last updated: 2026-10-22•Gene

POLG gene

The POLG gene provides instructions for the catalytic subunit of polymerase gamma, the only enzyme responsible for replicating DNA within mitochondria.

Normal Function

The POLG gene provides instructions for the alpha subunit of a protein called polymerase gamma (pol γ). This protein functions within mitochondria, the structures that convert food into energy via oxidative phosphorylation. Pol γ is the only DNA polymerase active in mitochondria and is essential for replicating mitochondrial DNA (mtDNA) and performing DNA repair.

Health Conditions Related to Genetic Changes

Variants in the POLG gene cause a group of conditions known as POLG-related disorders. These conditions often involve mtDNA depletion (a reduction in the number of mtDNA copies) or large deletions of mtDNA, which impair oxidative phosphorylation and reduce cellular energy.

Alpers-Huttenlocher syndrome

This condition is characterized by seizures, psychomotor regression, and liver disease. Liver disease can be exacerbated by valproic acid. The most common variant, Ala467Thr, blocks the alpha subunit from attaching to the beta subunits, reducing DNA synthesis efficiency.

Ataxia neuropathy spectrum

This spectrum includes conditions formerly known as MIRAS and SANDO. It is characterized by problems with coordination and balance (ataxia) and nerve function disturbances (neuropathy).

Childhood myocerebrohepatopathy spectrum (MCHS)

MCHS is a disorder affecting the muscles (myo-), brain (cerebro-), and liver (hepato-). Variants in the POLG gene reduce the activity of pol γ, leading to mtDNA depletion in these tissues.

Myoclonic epilepsy myopathy sensory ataxia (MEMSA)

MEMSA is characterized by recurrent seizures (epilepsy), muscle weakness (myopathy), and problems with coordination and balance (ataxia).

Progressive external ophthalmoplegia

This condition weakens the muscles controlling eye movement and causes drooping eyelids (ptosis). Unlike other POLG-related disorders, this condition is often associated with large deletions of mtDNA in muscle tissue rather than overall mtDNA depletion.

Other Conditions

The POLG gene is also associated with Mitochondrial neurogastrointestinal encephalopathy disease and Leigh syndrome.

Frequently Asked Questions

If a young patient presents with unexplained, drug‑resistant seizures, psychomotor regression, or chronic liver dysfunction, especially if there is a family history of mitochondrial disease, a POLG mutation should be considered. A targeted POLG sequencing panel or whole‑exome sequencing is the standard diagnostic approach.
Valproic acid can precipitate severe liver failure in POLG mutation carriers. It is contraindicated in these patients. Alternatives such as levetiracetam, lamotrigine, or topiramate are preferred for seizure control, and liver function should be monitored closely if valproic acid is unavoidable.
Current research includes trials of nucleoside analogues (e.g., deoxythymidine) to support mtDNA replication, as well as gene‑replacement strategies in preclinical models. Patients can be screened for participation in international registries or clinical trials through specialized mitochondrial disease centers.
lpers‑Huttenlocher typically presents in infancy or early childhood with seizures, psychomotor regression, and progressive liver failure, often requiring liver transplantation. The ataxia‑neuropathy spectrum (e.g., MIRAS, SANDO) usually manifests later with progressive ataxia, peripheral neuropathy, and myopathy, and treatment focuses on supportive care, physical therapy, and avoiding hepatotoxic drugs.
Source: MedlinePlus, National Library of Medicine

MedlinePlus brings together authoritative health information from the National Library of Medicine (NLM), the National Institutes of Health (NIH), and other government agencies and health-related organizations.

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