Polg and Other Mitochondrial Disease Relevance for Psychiatry

ver the last decade, novel mitochondrial genetic diseases have been identified in which mutations in DNA polymerase γ (POLG [MIM 174763]) gene are involved. POLG1 is the only DNA polymerase in human mitochondria and is essential for mitochondrial (mt) DNA replication and repair. It has to be stressed that functional genetic variants of POLG are present in about 0.5 percent of the normal population. Defects in mtDNA replication lead to mitochondrial dysfunction and disease. Originally, primary mtDNA mutations were thought to be the major cause of human mitochondriopathies Nowadays, however, a great number of novel diseases have been described in which POLG mutations are causative through a secondary effect on mtDNA. These syndromes are thought to have a common European ancestry and may manifest from early infancy to late middle age. To date, POLG mutations have been found to be causal in a great number of mitochondrial diseases with a very heterogeneous clinical manifestation and affecting multiple systems About one decade ago, a mutation in POLG with progressive external ophthalmoplegia was identified. Subsequently,, mutations in POLG were found in a great variety of diseases like Alpers syndrome, SCA negative cerebellar ataxia and CharcotMarie-Tooth disease. POLG mutations cause an overlapping clinical spectrum of diseases with both dominant and recessive modes of inheritance. Autosomal recessive forms often present with external ophthalmoplegia, peripheral neuropathy, ataxia, and epilepsy. Autosomal dominant forms are mostly characterized by symptoms within the ataxia-neuropathy range and by progressive external ophthalmoplegia. In addition, these autosomal dominant syndromes are reported to be associated with an array of neuropsychiatric symptoms from the parkinson spectrum and from the psychotic and depressive domains of which major depression has the highest incidence.