Mitochondrial Disorders: MELAS, MERRF, LHON & Kearns-Sayre
Maternal genes, mixed doses and energy-hungry tissues
Mitochondrial genetics
The mitochondrial genome. Each mitochondrion holds several copies of a 16.6-kb circular DNA with 37 genes: 13 respiratory-chain polypeptides (subunits of complexes I, III, IV and V), 22 tRNAs and 2 rRNAs. Complex II has no mtDNA-encoded subunits. Mitochondria reach the zygote only through the egg, so an affected woman can transmit to all of her children while an affected man transmits to none; maternal relatives such as a mother's brother share the same mtDNA.
Nuclear control. More than 1,000 mitochondrial proteins, including complex II, assembly factors, polymerase γ (POLG) and the pyruvate dehydrogenase (PDH) complex, are nuclear-encoded and imported. Their disorders are Mendelian: most Leigh syndrome and POLG disease are autosomal recessive, and PDHA1 deficiency is X-linked. A mitochondrial phenotype passed from father to son cannot come from an mtDNA variant.
Heteroplasmy and threshold. A cell carries hundreds to thousands of mtDNA copies. When mutant and normal genomes coexist (heteroplasmy), only a few copies repopulate each developing egg (the bottleneck) and copies segregate randomly at every division, so the mutant fraction differs between siblings and tissues. A tissue fails once its threshold is passed, so high-ATP organs (brain, skeletal muscle, heart, retina) suffer first.
Biochemical signature and diagnosis
Lactate. A failing respiratory chain cannot reoxidize NADH, so pyruvate is reduced to lactate: blood and CSF lactate rise, the lactate:pyruvate ratio exceeds about 25, and plasma alanine increases. In PDH deficiency lactate and pyruvate rise together, so the ratio stays normal.
Tissue and genetic testing. Muscle biopsy shows ragged-red fibers, subsarcolemmal aggregates of abnormal mitochondria that stain red with modified Gomori trichrome, and COX-negative fibers. Genetic testing covers mtDNA and nuclear mitochondrial genes; because heteroplasmy varies by tissue and the m.3243A>G load in blood falls with age, urine sediment or muscle can be more sensitive than blood.
Classic syndromes
| Syndrome | Genetic lesion | Hallmarks |
|---|---|---|
| MELAS | m.3243A>G in MT-TL1 (tRNA-Leu) | Stroke-like episodes before 40 with posterior lesions crossing arterial territories; lactic acidosis, seizures, migraine-like headache with vomiting, hearing loss, diabetes, short stature |
| MERRF | m.8344A>G in MT-TK (tRNA-Lys) | Myoclonic epilepsy, ataxia, myopathy, hearing loss; ragged-red fibers |
| LHON | Complex I (ND) variants, most often m.11778G>A in ND4 | Retinal ganglion cell loss: painless subacute central vision loss, one eye then the other, men aged 15–35; optic atrophy |
| Kearns-Sayre | Single large deletion, usually sporadic | Onset before 20: external ophthalmoplegia with ptosis, pigmentary retinopathy, plus heart block, CSF protein >100 mg/dL or ataxia |
| Leigh | Mostly nuclear (SURF1, PDH complex); some mtDNA (MT-ATP6 m.8993T>G) | Subacute necrotizing encephalomyelopathy: infant regression, hypotonia, dystonia, ophthalmoparesis, abnormal breathing, high blood and CSF lactate; symmetric basal ganglia, thalamic and brainstem lesions |
MELAS. Stroke-like lesions reflect mitochondrial failure in neurons and small vessels rather than large-artery occlusion, so they ignore vascular territories (contrast CADASIL, from NOTCH3 variants). At lower loads the same variant causes maternally inherited diabetes and deafness, so a patient's mother may show only those features.
LHON vs optic neuritis. Optic neuritis, typically in young women and often linked to multiple sclerosis, is usually unilateral, painful on eye movement and tends to recover. LHON is painless, involves both eyes within weeks to months, affects mainly young men in the maternal line and usually leaves permanent loss; penetrance is incomplete, and smoking and heavy alcohol use raise the risk.
Kearns-Sayre. Parents are usually unaffected because the deletion arises sporadically. Conduction disease can progress to complete heart block and sudden death, so serial ECGs and early pacing are standard. The same deletions cause Pearson syndrome in infancy (sideroblastic anemia, exocrine pancreatic failure), and survivors may evolve into Kearns-Sayre. Myotonic dystrophy (DMPK CTG expansion) also brings ptosis and conduction block, but not ophthalmoplegia with retinopathy.
Mitochondrial toxins and management
- NRTIs inhibit mitochondrial DNA polymerase γ and deplete mtDNA: lactic acidosis with hepatic steatosis, myopathy (zidovudine), peripheral neuropathy and pancreatitis (didanosine, stavudine); tenofovir and lamivudine carry much less risk.
- Linezolid given for weeks inhibits the bacterial-like mitochondrial ribosome: lactic acidosis, optic and peripheral neuropathy, myelosuppression.
- Aminoglycosides can cause permanent deafness after brief exposure in carriers of the m.1555A>G variant in the 12S rRNA gene.
- Valproate can precipitate fulminant liver failure in POLG disease (e.g., Alpers-Huttenlocher syndrome) and is contraindicated there.
Management. Care is supportive: non-valproate seizure control, treatment of diabetes and hearing loss, pacing for conduction block, and avoidance of mitochondrial toxins. Coenzyme Q10 and similar supplements are widely used but weakly supported. Mitochondrial replacement, which places the nuclear genome in a donor egg with healthy mitochondria, can prevent maternal transmission.
Stroke-like lesions that cross vascular territories plus high lactate in a young patient point to MELAS.
Avoid valproate when POLG disease is possible: it can cause fatal liver failure.