General characteristics of mitochondrial diseases. Leber hereditary optic neuropathy (LHON), MERRF syndrome, MELAS syndrome, NARP syndrome, Leigh syndrome, Kearns-Sayre syndrome.
Mitochondrial diseases are a heterogeneous group of inherited disorders caused by defects in oxidative phosphorylation, leading to impaired ATP production. They predominantly affect high-energy–demand tissues such as the brain, muscles, heart, retina, and endocrine organs.
These diseases can be caused by mutations in:
- Mitochondrial DNA (mtDNA)
- Nuclear DNA encoding mitochondrial proteins
Unique Features of Mitochondrial Genetics
1. Maternal Inheritance
- mtDNA is inherited exclusively from the mother.
- Affected mothers transmit mutations to all offspring.
- Affected fathers do not transmit the disease.
2. Heteroplasmy
- Cells contain a mixture of normal and mutant mtDNA.
- Proportion of mutant mtDNA varies between tissues.
3. Threshold Effect
- Clinical disease appears only when mutant mtDNA exceeds a critical threshold in a tissue.
- Explains variable severity and organ involvement.
4. Replicative Segregation
- mtDNA is randomly distributed during cell division.
- Leads to unpredictable disease expression among siblings.
General Pathophysiology
- Mutation affects components of the respiratory chain (Complexes I–V).
- Reduced electron transport → ↓ ATP production.
- Increased reliance on anaerobic glycolysis → lactic acidosis.
- Energy failure in high-demand tissues → progressive organ dysfunction.
- Oxidative stress and apoptosis contribute to cell loss.
Common Clinical Features of Mitochondrial Diseases
- Myopathy, muscle weakness
- Neurological dysfunction (seizures, ataxia, stroke-like episodes)
- Optic neuropathy, retinopathy
- Cardiomyopathy
- Sensorineural hearing loss
- Endocrine abnormalities (diabetes, growth failure)
- Lactic acidosis