Mitochondrial diseases of nuclear origin

Keywords Definition Etiology and related clinical characteristics Diagnostic methods Prevalence Inheritance Genetic counseling and prenatal diagnosis Management References Abstract Mitochondrial disorders of nuclear DNA (nDNA) origin include oxidative phosphorylation (OXPHOS) disorders (such as Leigh syndrome, paraganglioma); defects in nuclear-encoded mitochondrial proteins for mtDNA integrity (progressive external ophthalmoplegia (PEO) and mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) syndrome; and mitochondrial disorders with secondary effects on the OXPHOS system (Friedreich ataxia and hereditary spastic paraplegia). OXPHOS is a main function of mitochondria, that is, the oxidation of substrates to generate ATP produced by the cell. The large majority of the OXPHOS subunits are encoded in the nucleus. In addition, the nucleus also encodes a large number of proteins that are involved in OXPHOS complex assembly and maintenance, mtDNA replication, transcription, translation, and repair. OXPHOS disorders are associated with a diverse array of multisystem diseases often referred to as mitochondrial encephalomyopathies because of the prominent involvement of the central nervous system and the skeletal muscle. Once believed to be rare, it is now clear that OXPHOS deficiencies are an important cause of a wide range of neuromuscular, cardiac and endocrine disorders, and even some cancers. The prevalence of these diseases has been estimated at 1:11 000. In children most oxidative phosphorylation disorders are of nuclear origin, transmitted as autosomal recessive traits, usually with severe phenotypes and a fatal outcome. Mendelian oxidative phosphorylation disorders have also been described in adults, most of which result in a progressive loss of the integrity of mtDNA. Therapy is scarce and palliative in disorders associated with nuclear OXPHOS genes.