Mitochondrial Inheritance

Mitochondrial inheritance follows a strictly maternal pattern because mitochondria are transmitted through the oocyte cytoplasm. Pathogenic variants cause disease primarily in tissues with high energy demands. For the genome itself, its organization, heteroplasmy mechanics, and the germline bottleneck, see Mitochondrial Genome.

• Maternal inheritance: All children of an affected mother are at risk; affected fathers do not transmit mtDNA to any children. This is the hallmark distinguishing mitochondrial from other inheritance patterns.
• Heteroplasmy: A cell can contain a mixture of normal and mutant mtDNA molecules. The proportion of mutant mtDNA varies between cells and tissues and can shift across generations.
• Threshold effect: Clinical symptoms appear only when the proportion of mutant mtDNA exceeds a critical threshold (typically 60-90%, varying by tissue and mutation). Tissues with high oxidative demands (brain, muscle, heart, retina) have lower thresholds.
• Mitotic segregation: During cell division, mitochondria are randomly distributed to daughter cells, so the proportion of mutant mtDNA can shift over time within tissues.
• Replicative segregation: Over successive generations, a heteroplasmic mother can have children ranging from mildly to severely affected depending on the bottleneck effect during oogenesis.
• Genetic bottleneck: During oocyte development, the number of mtDNA molecules is drastically reduced then re-expanded, causing random shifts in heteroplasmy levels among offspring.
• Homoplasmy: All mtDNA copies carry the same sequence (either all normal or all mutant). Homoplasmic pathogenic variants affect all maternal relatives equally (e.g., LHON: m.11778G>A).

• MELAS (m.3243A>G in MT-TL1): Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-like episodes. Onset typically in childhood/young adulthood. Ragged red fibers on muscle biopsy.
• MERRF (m.8344A>G in MT-TK): Myoclonic Epilepsy with Ragged Red Fibers. Progressive myoclonus, seizures, ataxia, and myopathy.
• Leigh syndrome: Subacute necrotizing encephalomyelopathy; can be caused by mtDNA or nuclear gene variants affecting complex I, IV, or V. Characteristic symmetric basal ganglia lesions on MRI.
• LHON (MT-ND4, MT-ND1, MT-ND6): Leber Hereditary Optic Neuropathy. Acute/subacute bilateral painless vision loss in young adults, predominantly males despite maternal inheritance (incomplete penetrance).
• NARP/MILS (m.8993T>G/C in MT-ATP6): Neuropathy, Ataxia, Retinitis Pigmentosa at lower heteroplasmy; Maternally Inherited Leigh Syndrome at higher heteroplasmy, demonstrating the threshold effect.