Mitochondrial Disorders

Mitochondrial Disorders: Mito Basics - Tiny Powerhouse Troubles

• Mitochondria: "Cell's powerhouses"; generate ATP via Oxidative Phosphorylation (OXPHOS).
• Dual Genome:
  • mtDNA: Small, circular, maternally inherited. Encodes 13 essential OXPHOS protein subunits, tRNAs, rRNAs.
  • nDNA: Nuclear DNA; encodes vast majority (~1500) of mitochondrial proteins.
• Unique Genetic Principles:
  • Heteroplasmy: Presence of both mutant and wild-type mtDNA in cells/tissues.
  • Threshold Effect: Clinical disease manifests when mutant mtDNA proportion exceeds a critical level.
  • Replicative Segregation: Random distribution of mtDNA during cell division, affecting tissue involvement.

⭐ Maternal inheritance is a key characteristic for disorders caused by mtDNA defects.

Mitochondrial Disorders: Clinical Clues - Energy Crisis Manifestations

Mitochondrial dysfunction leads to impaired ATP production, causing an "energy crisis." This primarily affects organs with high energy requirements.

• Multi-systemic involvement is characteristic.
• Neurological: Encephalopathy, seizures, ataxia, stroke-like episodes, migraines, developmental delay/regression.
• Muscular: Myopathy, exercise intolerance, fatigue, ptosis, progressive external ophthalmoplegia (PEO).
• Cardiac: Cardiomyopathy (often hypertrophic), conduction defects.
• Ocular: Optic atrophy, pigmentary retinopathy, ophthalmoplegia.
• Auditory: Sensorineural hearing loss (SNHL).
• Endocrine: Diabetes mellitus, short stature, hypoparathyroidism.
• Renal: Fanconi syndrome, tubulopathy.
• Gastrointestinal: Dysmotility, pseudo-obstruction, liver dysfunction.
• Other: Persistent lactic acidosis, failure to thrive.

📌 Mnemonic: "My Brain Hates Exercise" - Myopathy - Brain: Encephalopathy, seizures, ataxia - Heart: Cardiomyopathy - Eyes: Ophthalmoplegia, optic atrophy - Endocrine: Diabetes mellitus - Ears: Sensorineural hearing loss (SNHL)

⭐ Tissues with high energy demand (brain, muscle, heart, retina, cochlea) are most severely affected.

Mitochondrial Disorders: Syndrome Showcase - Rogues' Gallery

⭐ MELAS often presents with stroke-like episodes, typically before age 40, not conforming to vascular territories.

• Other Notable Syndromes:
  • Pearson Syndrome: Infantile pancreatic exocrine dysfunction, sideroblastic anemia, pancytopenia. Large mtDNA deletions. May evolve to KSS.
  • LHON (Leber Hereditary Optic Neuropathy): Acute/subacute bilateral central vision loss. Primarily MT-ND gene mutations.

Mitochondrial Disorders: Diagnosis & Care - Unmasking & Managing

• Diagnosis: Suspect with unexplained multi-systemic disease (neuro, myopathy).
  • Initial tests: ↑ Plasma/CSF lactate, $L/P \text{ ratio} > \mathbf{20}$, urine organic acids, plasma amino acids.
  • Muscle biopsy: Key for histochemistry (Ragged-Red Fibers, COX-deficiency) & enzyme assays.
  • Genetic testing: mtDNA (e.g., MELAS, MERRF) & nDNA (e.g., Leigh syndrome) targeted panels or exome.
• Management:
  • Supportive: Symptomatic relief, avoid mitochondrial toxins (valproate, statins).
  • Mitochondrial cocktail (empirical): CoQ10, L-carnitine, riboflavin, thiamine.
  • Physiotherapy, genetic counseling.

⭐ Muscle biopsy showing ragged-red fibers (RRF) is a classic finding but not pathognomonic; may be absent in some disorders or early stages.

High‑Yield Points - ⚡ Biggest Takeaways

• Mitochondrial disorders typically show maternal inheritance (mtDNA); some from nuclear DNA.
• Primarily affect high-energy organs (brain, muscle, heart, eyes), causing varied symptoms.
• Clinical presentation is highly variable due to heteroplasmy (mixed mutant/normal mtDNA).
• Lactic acidosis, often with ↑ lactate/pyruvate ratio, is a key biochemical marker.
• Key syndromes: MELAS, MERRF, LHON, and Kearns-Sayre syndrome.
• Ragged red fibers on muscle biopsy (Gomori trichrome) are characteristic.
• Management is supportive; cofactor therapy (e.g., CoQ10) is often tried.