POLG

POLG refers to the gene that encodes the catalytic subunit of mitochondrial DNA polymerase gamma, the enzyme responsible for replicating and repairing mitochondrial DNA. It is encoded in the nucleus and imported into mitochondria, where it forms a holoenzyme with the accessory subunit POLG2. The polymerase possesses 3' to 5' exonuclease proofreading and works with the mitochondrial DNA template to maintain mtDNA copy number and integrity.

Mutations in POLG cause a group of mitochondrial diseases known as POLG-related disorders, with a spectrum from infantile to adult onset. Most conditions follow autosomal recessive inheritance, though dominant POLG mutations have been described. Clinical phenotypes include Alpers-Huttenlochner syndrome (early-onset hepatic failure with intractable epilepsy), ataxia and neuropathy with or without myopathy, and progressive external ophthalmoplegia with multiple mtDNA deletions. Some patients exhibit mtDNA depletion or multiple deletions in affected tissues, leading to a range of neuromuscular and hepatic manifestations.

Diagnosis typically involves genetic testing, including POLG sequencing or targeted mitochondrial gene panels. Muscle biopsy can reveal mtDNA depletion or multiple deletions, supporting the diagnosis in the appropriate clinical context. Management is supportive and multidisciplinary, as there is no cure for POLG-related disorders. Valproic acid is contraindicated in known POLG deficiency due to a high risk of fulminant hepatic failure. In severe Alpers cases, liver transplantation has been performed in selected patients, but outcomes vary. Ongoing research aims to improve genotype–phenotype correlations and develop targeted therapies.

Prognosis depends on the specific variant and clinical presentation; infantile-onset forms often have a poorer prognosis due to liver involvement, while later-onset forms may have a slower disease course.