POLG-related epilepsy occurs within a spectrum of mitochondrial disorders caused by pathogenic variants in POLG, the gene encoding mitochondrial DNA polymerase gamma. Epilepsy can be a major feature, particularly in Alpers-Huttenlocher syndrome and other early-onset POLG phenotypes.
Why POLG matters in epilepsy
POLG disease is one of the most important genetic diagnoses to recognise before using valproate.
Valproic acid and sodium valproate can cause severe or fatal liver failure in people with POLG-related disease and should be avoided.
Clinical spectrum
POLG-related disorders range from severe childhood-onset encephalopathy to later-onset epilepsy, ataxia, neuropathy, ophthalmoplegia and multisystem mitochondrial disease.
Age at onset and severity vary widely.
Alpers-Huttenlocher syndrome
Alpers-Huttenlocher syndrome is a severe childhood-onset POLG disorder characterised by developmental regression, refractory epilepsy and progressive liver dysfunction.
Seizures may precede obvious hepatic abnormalities.
Seizure types
Focal seizures are common, particularly occipital seizures, but myoclonic, bilateral tonic-clonic and status epilepticus can also occur.
Epilepsia partialis continua may develop in severe disease.
Visual symptoms
Occipital seizure activity can cause visual hallucinations, cortical visual loss or other visual disturbances.
These can be confused with migraine or stroke-like symptoms.
EEG
EEG may show posterior-predominant epileptiform abnormalities, multifocal discharges and progressive slowing.
EEG findings evolve with disease progression.
MRI
MRI may show occipital cortical abnormalities, thalamic or cerebellar involvement and progressive cerebral atrophy.
Imaging can change over time.
Valproate warning
Valproate should be avoided in POLG-related disorders.
GeneReviews explicitly advises avoiding valproic acid and sodium divalproex because of the risk of severe hepatotoxicity.
Other antiseizure medicines
No antiseizure medicine has been proven uniquely effective for POLG epilepsy.
Treatment is individualised by an experienced neurologist, while considering mitochondrial toxicity and liver function.
Status epilepticus
Refractory status epilepticus is a major complication in severe POLG disease.
Management often requires intensive-care treatment and specialist mitochondrial input.
Liver disease
Liver dysfunction may be subtle before catastrophic deterioration.
Normal liver tests at one point do not make valproate safe if POLG disease is suspected.
When to suspect POLG
Clues include early childhood refractory epilepsy, occipital seizures, developmental regression, ataxia, neuropathy, ophthalmoplegia, unexplained liver dysfunction or a family history consistent with mitochondrial disease.
Genetic testing
Diagnosis requires molecular testing of POLG.
Depending on phenotype, biallelic or dominant pathogenic variants may be relevant.
Inheritance
Many severe childhood phenotypes are autosomal recessive.
Some later-onset progressive external ophthalmoplegia phenotypes can be autosomal dominant.
Worldwide access
Rapid molecular diagnosis matters because it can immediately change medication safety.
Where genetic testing is delayed, clinical suspicion alone should prompt caution with valproate.
The central point
POLG is one of the clearest examples of a genetic diagnosis changing medication safety: valproate can be dangerous and should be avoided when POLG disease is known or strongly suspected.
Related reading
Mitochondrial Epilepsy →
Genetic Testing in Epilepsy →
Sources
Medical note: valproate should be avoided in POLG-related disease because of serious hepatotoxicity risk.
Evidence checked: September 2026.