Mitochondrial DNA multiple deletion syndromes, autosomal dominant and recessive (POLG, POLG2, TWINKLE and ANT1)

Mitochondrial DNA (mtDNA) replicates continuously. The minimal mitochondrial replisome consists of the DNA polymerase gamma (pol g), the mtDNA helicase Twinkle, and the mitochondrial single-stranded binding protein, all encoded by nuclear genes. Pol g is responsible for mtDNA replication and repair and is composed by a catalytic subunit (POLG) and two identical accessory subunits, POLG2. Mutations in POLG, POLG2, and Twinkle result in multiple mtDNA deletions and/or mtDNA depletion, causing disease. Multiple mtDNA deletions accumulate along the years and usually give rise to late-onset disease. Autosomal-dominant mutations in POLG and POLG2 lead to progressive external ophthalmoplegia (PEO) that can occur as sole clinical manifestation of the disease or in association with other clinical features, such as myopathy, exercise intolerance, or predominantly axonal peripheral neuropathy. Autosomal-recessive POLG mutations lead to a broader spectrum of clinical phenotypes ranging from Alpers syndrome to ataxia-neuropathy syndrome with or without epilepsy to PEO. Heterozygous mutations in Twinkle cause PEO, while recessive mutations in this protein result in early-onset ataxia and epileptic encephalopathy, associated with mtDNA depletion. In addition to the genes encoding proteins involved in mtDNA replication, mutations in nucleotide translocator 1 (ANT1) also result in multiple mtDNA deletions responsible for PEO.