Disorders of oxidative phosphorylation and mitochondrial function can be caused from mutations involving both mitochondrial DNA (mtDNA) or mitochondrial-targeted nuclear DNA genes. Progressive depletion of mtDNA is one mechanism of mitochondrial dysfunction leading to human disease, which is the end result of loss of the sufficient mtDNA-encoded proteins for normal electron transport chain function. Mitochondrial DNA depletion is caused by germline deletions and duplications of segments within the mtDNA as well as germline mutations in the nuclear genes responsible for mtDNA duplication (the polymerase apparatus including POLG, POLG2 and PEO1) and mtDNA maintenance (those genes that regulate the deoxynucleotide triphosphate pools and other functions including TP1, TK2, DGUOK, SUCLA1, SUCLA2, ANT1, RRM2B and MPV17). This review will focus on the most common disorders that result from mutations with POLG, with some discussion of the other nuclear-encoded genes involved in mtDNA maintenance. Mutations in POLG can cause a wide range of disease, which vary in both age of onset and severity. These disorders comprise a continuous spectrum of overlapping symptoms and signs; and range from a rapidly fatal infantile cerebrohepatic disease to a progressive external ophthalmoplegia (PEO) that may not present until the sixth decade of life. Many of the disorders seem to have a more unique and restrictive clinical presentation, at least to date. Since the first disorders linked to mtDNA depletion were described in 2001, the nomenclature, methods of diagnosis, clinical evaluation and treatment of these disorders have been better defined. However, this remains a rapidly evolving field, with additional proteins and genes are being discovered as DNA testing becomes part of the standard of care in everyday medical practice.
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