Mitochondrial Diseases

Mitochondrial Diseases - Tiny Engines, Big Trouble

• Cellular powerhouses; ATP via oxidative phosphorylation (OXPHOS).
• Mitochondrial DNA (mtDNA):
  • Circular; encodes 13 OXPHOS proteins, tRNAs, rRNAs.
  • High mutation rate (no histones, poor repair).
  • 📌 Exclusively maternally inherited.
• Core Principles:
  • Heteroplasmy: Mix of normal/mutant mtDNA per cell.
  • Threshold Effect: Disease if mutant mtDNA % > critical level.
  • Replicative Segregation: Random mtDNA sorting at cell division.
• Affects high-energy organs: brain, muscle (ragged red fibers), heart, eye.
• Common Syndromes: MELAS, MERRF, LHON, KSS.

  ⭐ Mitochondrial DNA (mtDNA) is exclusively maternally inherited, a key concept for pedigree analysis.

Mitochondrial Diseases - Energy Drain Drama

• Genetic defects (mtDNA/nDNA) impairing oxidative phosphorylation (OXPHOS) $\rightarrow \downarrow ATP$ & $\uparrow$ ROS.
• Clinical Impact (High-Energy Demand Tissues):
  • Brain: Encephalopathy, seizures, stroke-like episodes (MELAS).
  • Muscle: Myopathy, ptosis, ophthalmoplegia (KSS); Ragged Red Fibers (RRF) on biopsy.
  • Heart: Cardiomyopathy.
  • Eye: Optic neuropathy (LHON).
• Diagnosis:
  • Clinical suspicion.
  • Elevated lactate (often > 2.2 mmol/L).
  • Muscle biopsy: RRFs (Gomori trichrome stain).
  • Genetic testing.
• Inheritance: Maternal (mtDNA defects); Mendelian (nDNA defects).

⭐ Tissues with high energy demand like the brain (encephalopathy), muscles (myopathy), and heart (cardiomyopathy) are most vulnerable in mitochondrial diseases.

Mitochondrial Diseases - The Usual Suspects

Mitochondrial diseases are maternally inherited disorders affecting energy-intensive organs. Key syndromes include:

⭐ 'Ragged Red Fibers' (RRF) on muscle biopsy (Gomori trichrome stain) are characteristic of mitochondrial myopathies like MERRF, KSS, and sometimes MELAS.

Mitochondrial Diseases - Clues & Care Plans

• Clinical Clues (Suspect if):
  • Multi-system involvement (neuro, muscle, cardiac, ophthalmic)
  • ↑ Lactate, ↑ Pyruvate; ↑ Lactate/Pyruvate ratio
  • Family history (maternal inheritance for mtDNA)
• Diagnostic Approach:
  • Metabolic screen: Blood (lactate, pyruvate, AAs), Urine (organic acids)
  • Muscle Biopsy: Ragged Red Fibers (RRF), COX-negative fibers
    • 
  • Genetic Testing: mtDNA (common deletions, point mutations), nDNA (e.g., POLG)
• Management Strategies:
  • Supportive Care: Symptom-specific (e.g., anti-epileptics, cardiac support)
  • Cofactor "Cocktail": CoQ10, L-carnitine, riboflavin, thiamine
  • Avoid Mitochondrial Toxins: Valproate, statins, aminoglycosides, metformin, linezolid ⚠️
  • Exercise: Aerobic, endurance training
  • Genetic Counseling

⭐ A diagnostic triad often includes clinical suspicion, biochemical markers (elevated lactate/pyruvate ratio), and confirmatory genetic testing or muscle biopsy findings.

High‑Yield Points - ⚡ Biggest Takeaways

• Mitochondrial diseases exhibit maternal inheritance due to mtDNA mutations.
• Primarily affect high-energy organs: brain, muscle, heart, and eyes.
• Heteroplasmy (mixed mtDNA) and threshold effect cause variable expressivity.
• Common examples: MELAS, MERRF, LHON, and Kearns-Sayre syndrome (KSS).
• "Ragged red fibers" on muscle biopsy (Gomori trichrome) are characteristic.
• Elevated lactate (lactic acidosis) is a common metabolic finding.
• Often present with multi-systemic involvement and progressive course.