How are Mitochondrial Disorders Inherited?

Mitochondrial disorders are complex diseases that are due to defects in genes encoding for the respiratory chain. These genes are located not only in the maternally-inherited mitochondrial genome (mtDNA), but also in the nuclear genome as the majority of proteins that are important for respiratory chain function are encoded by nuclear DNA and subsequently imported into mitochondria. Thus, in addition to a maternal mode of inheritance, autosomal recessive and dominant traits are apparent while some cases are sporadic. Mitochondrial disorders encompass a wide spectrum of clinical presentations commonly affecting the muscle and nervous systems. One syndrome can be due to different gene defects. For example, a common clinical presentation is progressive external ophthalmoplegia (PEO) that is frequently associated with single, large-scale deletions of mtDNA that are generally sporadic. However, PEO can also be caused by defects in nuclear genes (POLG, C10Orf2, ANT1) that are important in mtDNA maintenance resulting in autosomal inheritance, or by maternally-inherited point mutations of mtDNA such as the 3243A>G mutation that was originally identified in patients with MELAS (mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes). MERRF syndrome (myoclonic epilepsy with ragged red fibers) is commonly due to the maternally-inherited 8344A>G mutation of mtDNA. The 3243A>G and 8344A>G mutations belong to the group of tRNA mutations that show remarkable phenotypical variability with occurrence of asymptomatic or oligosymptomatic maternal relatives with low levels of mutant DNA (heteroplasmy). Another common mitochondrial disorder is Leber's hereditary optic neuropathy (LHON) that is also due to point mutations of mtDNA. There are three common mutations (11778G>A, 14484T>C, 3460A>G) that are found in 95% of the LHON patients. Families with LHON also show a maternal mode of inheritance but women are rarely affected, thus an X-chromosomal modifier gene has been postulated. Finally, Leigh syndrome (subacute necrotizing encephalopathy) is a frequent presentation of mitochondrial disease in children that is genotypically heterogeneous. Mutations of mtDNA (e.g., 8993G>T/C, 9176T>C, 13513G>A) result in maternally-inherited Leigh syndrome, while many cases harbor mutations in nuclear genes that are inherited recessively, notably in structural subunits of respiratory chain complex I and assembly proteins required for the biosynthesis of complex IV.