Background: Mitochondrial disorders result from primary defects in the mitochondrial DNA (mtDNA) or from defects in nuclear genes which cause disease by affecting the mtDNA. POLG1 is a nuclear gene which encodes for the catalytic subunit of the mtDNA polymerase gamma, essential for mtDNA replication. Less than a decade ago, POLG1 mutations were discovered in patients with progressive external ophthalmoplegia. Since then, it has emerged that POLG1 mutations can result in a spectrum of clinical manifestations, resulting in autosomal recessive or dominant mitochondrial diseases.
Review summary: Here we summarize the common clinical phenotypes associated with POLG1 mutations. Alpers syndrome, progressive external ophthalmoplegia with or without limb myopathy, ataxia-neuropathy syndrome, and epilepsy are frequent clinical manifestations of the POLG1-related disease. Childhood progressive encephalopathy, Parkinsonism, stroke-like events, and isolated exercise intolerance can occur in association with POLG1 mutations. Muscle biopsy can show signs of mitochondrial dysfunction by histologic and biochemical studies or it can be unrevealing. mtDNA analysis of affected tissues can reveal depletion, multiple deletions or point mutations, but it can be occasionally noninformative by routine analysis.
Conclusions: : POLG1 mutations result in extremely heterogenous phenotypes which often have overlapping clinical findings, making it difficult to categorize patients into syndromes. The lack of signs of mitochondrial dysfunction in the muscle biopsy does not exclude a POLG1-related disease. Analysis of mtDNA of clinically affected tissues is often informative, but not always. Molecular analysis of POLG1 is essential when POLG1-related disease is suspected. Sodium valproate should be avoided because of the risk of liver failure.