Mitochondrial Disease MELAS and MERRF
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Direct answer
Mitochondrial disease results from defects in oxidative phosphorylation, caused either by mitochondrial DNA mutations, which are inherited through the maternal line, or by nuclear gene mutations. MELAS, mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes, is most often caused by the m.3243A>G mutation in MT-TL1, while MERRF, myoclonic epilepsy with ragged red fibres, usually carries m.8344A>G in MT-TK.
What you must remember
- Commonest MELAS mutation: m.3243A>G in MT-TL1, the gene encoding a mitochondrial tRNA for leucine, is found in most patients with MELAS.
- Commonest MERRF mutation: m.8344A>G in MT-TK, the tRNA lysine gene; myoclonus, ataxia and seizures dominate the picture.
- Maternal inheritance: mitochondrial DNA comes almost entirely from the ovum, so affected mothers can pass it to all their children, while affected fathers do not.
- Heteroplasmy: normal and mutant mitochondrial DNA coexist, and the proportion of mutant copies in each tissue determines severity, which explains variable expression within a family.
- Stroke-like episodes: MELAS episodes cross arterial territories, often occipitally, with headache, vomiting and seizures, and the lesions can partly resolve.
- Ragged red fibres: seen on Gomori trichrome staining of muscle biopsy as subsarcolemmal accumulation of abnormal mitochondria, usually with COX-negative fibres alongside.
- Kearns-Sayre syndrome: onset before age 20, progressive external ophthalmoplegia, pigmentary retinopathy and heart block, usually from a sporadic large-scale mtDNA deletion.
A diagnostic pathway for suspected mitochondrial disease
Mitochondrial disease is multisystem and mimics other conditions, so no single test settles it. Clinicians build the diagnosis from the family history, biochemistry, imaging, muscle biopsy and genetic testing, in that order of priority.
- Take a family pedigree: Map the maternal relatives, since deafness, diabetes and early seizures recurring down the maternal line suggest mtDNA inheritance.
- Measure lactate and pyruvate: Raised blood and CSF lactate supports a mitochondrial cause, but lactate can be normal between episodes, so a normal value does not exclude the diagnosis.
- Image the brain: MRI in MELAS shows stroke-like lesions that cross arterial territories, often parieto-occipital, and basal ganglia calcification may be present.
- Biopsy the muscle: Gomori trichrome shows ragged red fibres, and COX staining shows COX-negative fibres, while succinate dehydrogenase staining is intensely reactive in the abnormal fibres.
- Send molecular testing: Mutation analysis of blood and muscle is used, since heteroplasmy levels can differ between tissues and blood may underestimate the mutant load in affected organs.
- Start supportive care: Manage seizures, diabetes, hearing loss and cardiac conduction defects, and avoid drugs known to worsen the disease, such as valproate.
Where exam questions trip students
Each trap below turns on a fact about mitochondrial genetics or drug safety that the stem rarely states outright.
- Trap: Calling a MELAS stroke-like episode an ordinary infarct Correct: episodes cross arterial territories, often occipitally, and the lesions can resolve, so MELAS is suspected when lactate and biopsy features coexist.
- Trap: Assuming an affected father passes MELAS to his children Correct: mtDNA comes from the ovum, so only mothers transmit it, though sons and daughters of an affected mother can both be affected.
- Trap: Giving valproate for mitochondrial epilepsy without caution Correct: valproate is avoided in mitochondrial disease because of hepatotoxicity risk, especially in POLG-related disease, and other antiepileptics are chosen.
- Trap: Reading a normal blood lactate as exclusion Correct: lactate can be normal between episodes, so muscle biopsy and genetic testing decide the diagnosis.
Frequently asked questions
What is the commonest mutation in MELAS?
The m.3243A>G point mutation in the MT-TL1 gene, which encodes a mitochondrial tRNA for leucine, accounts for most cases of MELAS. It is a heteroplasmic mtDNA change, so severity depends on the proportion of mutant copies in each tissue. Genetic testing of blood and muscle is used to confirm the diagnosis.
Why does mitochondrial disease show maternal inheritance?
Paternal mitochondria are generally eliminated after fertilisation, so mitochondrial DNA comes almost entirely from the ovum. Mothers therefore transmit mtDNA mutations to all their children, while affected fathers do not pass them on. A maternal pattern in the pedigree points towards a mitochondrial cause.
Which muscle biopsy finding suggests mitochondrial myopathy?
Ragged red fibres seen on Gomori trichrome stain are the classic finding in mitochondrial myopathy. They reflect subsarcolemmal accumulation of abnormal mitochondria. COX-negative fibres and intense succinate dehydrogenase staining in the same biopsy add supporting evidence.
Why is valproate avoided in mitochondrial disease?
Valproate can cause severe hepatotoxicity, and this risk is particularly high in POLG-related mitochondrial disease. Clinicians therefore choose alternative antiepileptic drugs when treating seizures in these patients. Specialist neurology input is advisable for drug selection.
How does Kearns-Sayre syndrome differ from MELAS?
Kearns-Sayre syndrome begins before age 20 and combines progressive external ophthalmoplegia, pigmentary retinopathy and heart block. It is usually caused by a single large-scale mtDNA deletion and is typically sporadic. MELAS instead presents with stroke-like episodes, seizures and lactic acidosis, usually from the maternally inherited m.3243A>G mutation.