Mitochondrial Inheritance Disorders
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Direct answer
Mitochondrial DNA passes only from mothers, because the sperm contributes almost no mitochondria to the zygote: a woman with a mitochondrial mutation transmits it to all her children, yet none of her sons passes it further. Severity varies with heteroplasmy — the proportion of mutant to normal mitochondrial genomes within a tissue — and the threshold effect, so one mutation can mean migraine and diabetes in the grandmother but stroke-like episodes in the grandson. Brain, skeletal muscle, retina, heart, liver and renal tubules, the tissues with the highest adenosine triphosphate demand, fail first.
What you must remember
- Four hallmarks: maternal inheritance, heteroplasmy (mixed mutant and normal genomes), threshold effect, and replicative segregation — the mutation load shifts randomly between daughter cells, so expression varies even between siblings.
- MELAS: mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes; the m.3243A>G point mutation is the classic lesion; ragged red fibres on muscle biopsy.
- MERRF: myoclonic epilepsy with ragged red fibres, ataxia and sensorineural deafness; m.8344A>G is the exam mutation.
- LHON: Leber hereditary optic neuropathy — subacute painless bilateral visual loss in young adults, predominantly men, most often m.11778G>A; smoking and alcohol act as triggers.
- Kearns-Sayre syndrome: progressive external ophthalmoplegia, pigmentary retinopathy, heart block, cerebellar ataxia and short stature; usually sporadic large-scale mitochondrial deletions.
- NARP and Leigh syndrome: m.8993 in the ATP6 gene gives neuropathy, ataxia and retinitis pigmentosa at lower mutation loads, and necrotising basal ganglia disease of infancy (Leigh) at higher loads — threshold effect in one gene.
- Morphology: ragged red fibres on modified Gomori trichrome, cytochrome oxidase-negative fibres on enzyme histochemistry, and on electron microscopy mitochondria in increased number and abnormal shape.
A three-generation pedigree that misbehaves
A pedigree that looks Mendelian until you interrogate it. The grandmother has type 2 diabetes and deafness of uncertain cause; her daughter developed progressive external ophthalmoplegia in her thirties and went grey early; the grandson at twelve has an episode that reads like a stroke on imaging, though the affected regions cross vascular territories, and his lactate is raised. Every generation is affected, every transmission is through a woman, and the men are spared as transmitters — the shape on paper that should make an examinee say "mitochondrial" before any test is ordered.
The explanation is the meiotic bottleneck. Only a small sample of a woman's many mitochondrial genomes populates each oocyte, so a mother with 40 per cent mutant load can, by luck of sampling, produce one child with 10 per cent (healthy) and another with 90 per cent (devastating disease). Postnatally the same random partitioning continues as rapidly dividing tissues segregate their mitochondria, which is why muscle and brain, whose cells divide little, drift toward high mutant loads with age while blood can stay relatively clean — a reason muscle, not leucocytes, is the preferred biopsy when the blood test is negative. Counselling follows directly: an affected man's children are at no specific risk, while an affected or carrier woman cannot be given a clean recurrence figure, only risk ranges framed by her own mutation load.
Where students slip
Two errors dominate. First, Mendelian reflexes: candidates call maternal transmission "X-linked dominant" — but X-linked dominant disease passes from fathers to all daughters, which mitochondrial disease never does, and the male-transmission line is silent in both. Second, the muscle biopsy findings get shuffled: ragged red fibres are clumps of abnormal mitochondria staining red on Gomori trichrome at the fibre periphery, not glycogen (PAS) or lipid (oil red O). A quieter trap is LHON — students expect a degenerative retina, yet the fundus is often near-normal with subtle disc telangiectasia, and the male predominance, though incompletely explained, is a standard viva question.
Frequently asked questions
Why is mitochondrial inheritance exclusively maternal?
The sperm's few mitochondria are ubiquitinated and destroyed after fertilisation, so all embryonic mitochondria descend from the oocyte; sons inherit but do not transmit.
What is heteroplasmy and why does it matter clinically?
It is the coexistence of mutant and normal mitochondrial genomes within a cell; disease appears only when the mutant fraction crosses the tissue's threshold, which is why severity varies wildly within one family.
Which mutation is classic for MELAS?
The m.3243A>G point mutation in transfer RNA leucine, presenting with stroke-like episodes, lactic acidosis, seizures and short stature.
Which stain demonstrates ragged red fibres?
Modified Gomori trichrome on frozen muscle sections; cytochrome oxidase-negative fibres on enzyme histochemistry support a respiratory chain defect.
Why does Kearns-Sayre syndrome not follow maternal inheritance?
It usually results from large sporadic mitochondrial DNA deletions arising in the oocyte or early embryo, so there is typically no family history.
Which mitochondrial disease shows marked male predominance?
Leber hereditary optic neuropathy — young men are affected several-fold more often than women, an effect only partly explained by hormonal and nuclear modifiers.