Mitochondrial Genetics
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Direct answer
Mitochondrial DNA is a small circle of 16,569 base pairs inside the organelle — 37 genes coding 13 electron-transport-chain polypeptides, 22 transfer RNAs and 2 ribosomal RNAs — inherited exclusively from the mother, because the sperm's tail mitochondria are destroyed after fertilisation. It packs no introns, wears no histones, repairs itself poorly, and mutates roughly ten times faster than nuclear DNA. Two properties make the pedigrees behave strangely: heteroplasmy (each cell holds a mixture of normal and mutant genomes) and the threshold effect (disease appears only when the mutant fraction crosses a tissue-specific threshold), compounded by replicative segregation of mitochondria into daughter cells. The canonical syndromes are MELAS, MERRF, Leber hereditary optic neuropathy, Kearns-Sayre and Leigh disease.
What you must remember
- Pedigree signature: all children of an affected (or carrier) mother inherit, no child of an affected father does — a matrilineal line that mimics no Mendelian pattern.
- MELAS: mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes, most often from the m.3243A>G mutation in tRNA Leu — cortical blindness, seizures, diabetes, short stature; the strokes respect vascular territories poorly because they are metabolic, not embolic.
- MERRF: myoclonic epilepsy with ragged red fibres, typically m.8344A>G — myoclonus, ataxia, seizures and ragged red fibres on modified Gomori trichrome staining of muscle.
- Leber hereditary optic neuropathy: painless bilateral central vision loss in young adult males, commonly homoplasmic point mutations (m.11778G>A among the primary three) — yet incomplete penetrance and male bias via nuclear modifier genes.
- Kearns-Sayre syndrome: sporadic large-scale deletion — progressive external ophthalmoplegia, pigmentary retinopathy plus heart block, cerebellar ataxia, cerebrospinal fluid protein above 100 mg/dL, and short stature; cardiac pacing prevents sudden death.
- Leigh disease (subacute necrotising encephalomyelopathy): infancy or early childhood, basal ganglia and brainstem necrosis on imaging, often from ATP6 mutations or nuclear genes — hypotonia, ophthalmoplegia, respiratory drives failing.
- Diagnostic ladder: resting and post-exercise lactate, lactate-to-pyruvate ratio, muscle biopsy with cytochrome c oxidase-negative fibres, then targeted mitochondrial genome sequencing; many respiratory-chain proteins are nuclear-encoded, so autosomal recessive "mitochondrial" disease exists.
- Vulnerability logic: tissues with the highest energy demand — brain, retina, muscle, heart, renal tubule, endocrine pancreas — express mitochondrial disease first.
A worked case: the family in which every generation is affected
A 30-year-old woman with diabetes and deafness brings her son, who has had a stroke-like episode with cortical blindness at 12; her mother died of "kidney failure and dementia" in her forties; her brother has migraines and short stature. A first glance suggests an autosomal dominant trait, but the affected father transmits nothing — every affected person descends through women. The explanation: the mother's oocytes each sampled a different mutant load (the mitochondrial bottleneck), so the son received a high heteroplasmic fraction of the m.3243A>G MELAS mutation that crossed his brain's threshold, while an asymptomatic aunt carries a low fraction. Genetic testing of blood may miss low mutant loads in adulthood (blood levels fall with age, and muscle is more sensitive), which is why the workup pairs genotype with lactate studies and biopsy. Counselling is exact: all the woman's children inherit risk, none of her son's children do — the male transmits no mitochondria.
Where students slip
Two errors dominate. The first is forcing Mendelian labels onto mitochondrial pedigrees — calling the pattern X-linked dominant because it passes mother-to-child of both sexes; the giveaway is that affected fathers never transmit, which no X-linked pattern shows. The second is expecting uniform severity: heteroplasmy and the threshold effect mean one family can hold a deaf diabetic, a stroke victim and an asymptomatic carrier, and mutation load differs between blood and muscle even in one patient. Third, Leber optic neuropathy is assumed to be always penetrant; it is commonly homoplasmic yet incomplete penetrance with male predominance requires nuclear modifier genes and possibly environmental factors — a favourite discussion point. Fourth, Leigh and Kearns-Sayre are mixed up: deletion-based Kearns-Sayre is sporadic with ophthalmoplegia and heart block, whereas Leigh is usually point-mutation or nuclear, infantile, with basal ganglia necrosis.
Frequently asked questions
Why is mitochondrial inheritance exclusively maternal?
The sperm's mitochondria, located principally in the tail and midpiece, are ubiquitinated and destroyed after fertilisation, so only oocyte mitochondria populate the embryo.
What is heteroplasmy and how does it cause variable disease severity?
Cells contain a mixture of mutant and normal mitochondrial genomes; symptoms emerge only when the mutant fraction crosses a tissue-specific threshold, so relatives with different loads differ clinically.
Which mutation most commonly causes MELAS?
The m.3243A>G point mutation in the mitochondrial tRNA for leucine, producing stroke-like episodes, lactic acidosis, seizures and diabetes.
Which syndrome follows a large sporadic mitochondrial deletion?
Kearns-Sayre syndrome — progressive external ophthalmoplegia, pigmentary retinopathy, heart block, ataxia and high cerebrospinal fluid protein.
Can a mitochondrial disease be inherited autosomally?
Yes, when the defective protein is nuclear-encoded; many respiratory-chain subunits and assembly factors follow Mendelian inheritance despite a mitochondrial phenotype.