Mitochondrial Inheritance

Mitochondria contain their own circular DNA (mtDNA), which encodes 37 genes essential for oxidative phosphorylation and mitochondrial function. During fertilization, the sperm's mitochondria are typically destroyed, meaning all mitochondria in the zygote are maternal. Mitochondrial disorders show a unique maternal inheritance pattern: an affected mother can pass the condition to all her children, but an affected father will pass it to none. A complicating factor is heteroplasmy, where a cell contains a mixture of normal and mutated mtDNA. The severity of the disease depends on the proportion of mutated mtDNA (the 'threshold effect')—once a certain percentage of mutated mitochondria is reached, symptoms appear. This explains why mitochondrial diseases often have highly variable expressivity even within the same family. Organs with the highest ATP requirements, such as the central nervous system, retina, skeletal muscle, and heart, are most frequently affected. Common syndromes include Leber Hereditary Optic Neuropathy (LHON), Mitochondrial Encephalopathy with Lactic Acidosis and Stroke-like episodes (MELAS), and Myoclonic Epilepsy with Ragged Red Fibers (MERRF).

mtDNA is a small, 16.5kb circular molecule. Unlike nuclear DNA, it lacks histones and has minimal repair mechanisms, making it prone to oxidative damage and a high mutation rate. The 37 genes include 13 that code for polypeptides of the electron transport chain, plus tRNA and rRNA genes. Mitochondrial replication is independent of the cell cycle. When a cell divides, mitochondria are distributed randomly into daughter cells; if the mother has a mixture of mutant and wild-type mitochondria (heteroplasmy), different offspring can receive vastly different 'doses' of the mutation. This results in the clinical spectrum seen in mitochondrial pedigrees. Some mitochondrial diseases are actually caused by mutations in nuclear DNA that code for mitochondrial proteins; these follow Mendelian inheritance patterns (AD, AR, or X-linked) rather than the maternal pattern describe here.

Mitochondrial diseases are rare but should be suspected in 'multisystem' disorders that don't fit other patterns, especially when involving 'mitochondrial red flags' like ptosis, ophthalmoplegia, exercise intolerance, stroke-like episodes in the young, or unexplained lactic acidosis. LHON presents as subacute painless vision loss in young men. MELAS presents with seizures, headache, and stroke-like episodes. For the MLA, recognizing the maternal-only transmission pattern in a pedigree is the key diagnostic feature. Recent advancements include 'mitochondrial donation' (three-parent babies) to prevent transmission in families with known mtDNA mutations.

1. Lactic acid levels (serum and CSF) are often elevated. 2. Muscle biopsy showing 'ragged red fibers' on Gomori trichrome stain. 3. mtDNA sequencing (from blood, or more reliably from muscle/urinary sediment if heteroplasmy is suspected). 4. Brain MRI (e.g., basal ganglia lesions in Leigh syndrome).

Treatment is largely supportive as there is no cure. Management includes Coenzyme Q10 and riboflavin (the 'mito cocktail'), avoiding mitochondrial toxins (certain antibiotics like linezolid or valproate), and treating symptoms like seizures or diabetes. Genetic counseling is challenging due to heteroplasmy making the risk of severity in offspring difficult to predict.