Mitochondria are intracellular organelles essential for cellular energy production through oxidative phosphorylation, a process mediated by the mitochondrial respiratory chain (MRC). The MRC comprises more than 90 proteins encoded by both mitochondrial DNA (mtDNA) and nuclear DNA. The POLG gene encodes the catalytic subunit of mitochondrial DNA polymerase gamma, the enzyme responsible for mtDNA replication and repair. Pathogenic variants in POLG disrupt mtDNA maintenance, leading to quantitative defects (mtDNA depletion) and qualitative abnormalities (multiple mtDNA deletions). These defects impair adenosine triphosphate (ATP) production and result in multisystem organ dysfunction, most commonly affecting the central and peripheral nervous systems, liver, skeletal muscle, and gastrointestinal tract.

POLG-related disorders represent a clinical continuum with phenotypic overlap and age of onset ranging from infancy to late adulthood. Classically described syndromes include progressive external ophthalmoplegia (PEO), Alpers–Huttenlocher syndrome (AHS), childhood myocerebrohepatopathy spectrum (MCHS), ataxia-neuropathy spectrum (ANS), and myoclonic epilepsy, myopathy, and sensory ataxia (MEMSA). However, many affected individuals do not meet strict diagnostic criteria for a single defined syndrome, reflecting the broad and heterogeneous nature of POLG-associated disease.

Epilepsy is a prominent feature of POLG-related disorders, with generalized and focal seizures, status epilepticus (SE), and epilepsia partialis continua frequently observed. Importantly, patients with pathogenic POLG variants are at markedly increased risk of valproic acid–induced acute liver failure. The role of orthotopic liver transplantation (OLT) in mitochondrial hepatopathies remains controversial because of concerns regarding progressive extrahepatic disease and poor long-term outcomes.

In this report, we describe a case of successful OLT in a patient with epilepsy who developed fulminant liver failure after valproic acid exposure and was found to harbor pathogenic POLG mutations, highlighting important considerations for transplant candidacy in this complex patient population.