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EMERGENCY

Mitochondrial Diseases

High EvidenceUpdated: 2025-12-24

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Red Flags

  • Stroke-like episodes in young patient (MELAS)
  • Acute Metabolic Decompensation (Lactic Acidosis)
  • Cardiac Conduction Block (Kearns-Sayre)
  • Sudden visual loss (LHON)
  • Respiratory Failure (Leigh Syndrome)
Overview

Mitochondrial Diseases

1. Clinical Overview

Summary

Mitochondrial diseases are a heterogenous group of genetic disorders caused by defects in Oxidative Phosphorylation (Energy production). They can arise from mutations in Mitochondrial DNA (mtDNA) (Maternal inheritance) or Nuclear DNA (nDNA) (Mendelian inheritance). Since mitochondria are present in all cells, the phenotype is notoriously multi-systemic, typically affecting high-energy organs: Brain (Stroke, Seizures, Dementia), Muscle (Myopathy, Ptosis), Eye (Optic atrophy, Retinopathy), and Heart (Cardiomyopathy). Classic syndromes include MELAS, MERRF, and Kearns-Sayre Syndrome. Diagnosis involves Lactate levels, Muscle Biopsy ("Ragged Red Fibres"), and Genetic Sequencing. There is no cure, but "Mitochondrial Replacement Therapy" (Three-Parent Baby) offers hope for prevention. [1,2]

Key Facts

  • Prevalence: 1 in 4,000. One of the most common metabolic diseases.
  • Genetics:
    • mtDNA: Maternal inheritance. Heteroplasmy (variable mutant load).
    • nDNA: Autosomal Recessive/Dominant.
  • The "Any Symptom, Any Organ, Any Age" Rule: Suspect Mito in any complex multisystem disorder.
  • Biomarker: Elevated Lactate (Blood/CSF) and Pyruvate.
  • Pathology: Ragged Red Fibres on Gomori Trichrome stain.

Clinical Pearls

"The Stroke that isn't a Stroke": In MELAS, patients have stroke-like episodes that do NOT respect vascular territories. They are metabolic crises.

"Diabetes and Deafness": This specific combination (MIDD - Maternally Inherited Diabetes and Deafness) is a classic mitochondrial presentation (m.3243A>G mutation).

"The Heteroplasmy Threshold": A mother with 10% mutant mitochondria might be asymptomatic, but if she passes 80% to her child (Bottleneck effect), the child has severe disease. Phenotype depends on "Mutant Load".

"Ptosis + Ophthalmoplegia": CPEO (Chronic Progressive External Ophthalmoplegia). If this is present, ALWAYS check the heart (Kearns-Sayre Syndrome causes heart block).

2. Epidemiology

Incidence

  • mtDNA mutations: 1 in 200 people carry a mutation (often asymptomatic due to low heteroplasmy).
  • Clinical Disease: 1 in 4,300.
  • Age: can present from neonatal period (severe) to late adulthood (mild).
3. Pathophysiology

The Power Plant Failure

  1. The Mitochondria: Generates ATP via the Electron Transport Chain (ETC).
  2. The ETC: Composed of 5 complexes (I-V).
    • Complexes I, III, IV, V contain subunits encoded by mtDNA.
    • Complex II is purely nDNA.
  3. The Defect: Mutation leads to ETC failure -> ATP Deficiency.
  4. Energy Crisis: High-energy tissues fail first.
    • CNS: Seizures, Ataxia, Stroke-like episodes.
    • Muscle: Weakness, Fatigue.
    • Signalling: Calcium dysregulation, Apoptosis.
  5. Compensatory Mechanism: Glycolysis increases -> Lactic Acidosis.
    • Mitochondria proliferate to compensate -> Accumulation under sarcolemma -> Ragged Red Fibres.

Genetics: Unique Concepts

  1. Maternal Inheritance: Sperm mitochondria are destroyed at fertilization. Only the egg's mitochondria survive.
  2. Heteroplasmy: Each cell has hundreds of mitochondria. Some wild-type, some mutant. The ratio determines severity.
  3. Threshold Effect: Symptoms appear only when mutant load exceeds a threshold (e.g. 70%).
  4. Mitotic Segregation: During cell division, mitochondria are distributed randomly. One tissue may get high load, another low load.
4. Clinical Syndromes (The "Big 5")

1. MELAS

  • Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-like episodes.
  • Mutation: m.3243A>G (tRNA-Leu).
  • Features: Recurrent strokes (occipital/parietal), Seizures, Migraines, Diabetes.
  • Onset: Childhood/Adolescence.

2. MERRF

  • Myoclonic Epilepsy with Ragged Red Fibers.
  • Mutation: m.8344A>G (tRNA-Lys).
  • Features: Myoclonus (jerks), Ataxia, Seizures, Deafness.

3. Kearns-Sayre Syndrome (KSS)

  • Mutation: Large mtDNA Deletion (Sporadic).
  • Features:
    • Ptosis & Ophthalmoplegia (CPEO).
    • Pigmentary Retinopathy ("Salt and Pepper").
    • Cardiac Conduction Block (Pacemaker required).
    • Ataxia, High CSF Protein.
  • Onset: <20 years.

4. LHON (Leber's Hereditary Optic Neuropathy)

  • Mutation: Complex I genes (ND1, ND4, ND6).
  • Features: Subacute painless visual loss in young men (sequential eyes). Central scotoma.
  • Trigger: Smoking/Alcohol can precipitate blindness in carriers.

5. Leigh Syndrome (Subacute Necrotising Encephalomyelopathy)

  • Mutation: diverse (mtDNA or nDNA).
  • Features: Severe paediatric neurodegeneration. Brainstem/Basal Ganglia lesions on MRI. Respiratory failure.
  • Prognosis: Death often <2-3 years.
5. Clinical Presentation (By System)

"The Multi-System Checklist"

Neurological

  • Seizures (Myoclonic).
  • Ataxia.
  • Dementia / Regression.
  • Stroke-like episodes.
  • Peripheral Neuropathy.

Muscular

  • Proximal Myopathy (Exercise intolerance).
  • Ptosis (Droopy eyelids - very resistant to fatigue unlike Myasthenia).
  • Ophthalmoplegia (Frozen eyes).

Sensory

  • Sensorineural Deafness.
  • Retinopathy (Pigmentary).
  • Optic Atrophy.

Endocrine / Other

  • Diabetes Mellitus (often thin patients).
  • Short stature.
  • GI Dysmotility (Pseudo-obstruction).
  • Cardiomyopathy (Hypertrophic or Dilated).
6. Investigations

Biochemistry

  • Lactate:
    • Plasma Lactate: Elevated (especially post-exercise).
    • CSF Lactate: More sensitive for CNS disease.
    • Lactate/Pyruvate Ratio: High (>20).
  • CK: Usually normal or mildly elevated (unlike Dystrophies).

Imaging

  • MRI Brain:
    • Leigh: T2 hyperintensity in Putamen, Caudate, Brainstem.
    • MELAS: Cortical swelling (oedema) not respecting vascular territories.
    • MRS (Spectroscopy): Shows Lactate Peak.

Pathology (Muscle Biopsy)

  • Take from deltoid or vastus lateralis.
  • Histology:
    • Ragged Red Fibres (Gomori Trichrome): Abnormal subsarcolemmal mitochondria.
    • COX Negative Fibres: Cytochrome c Oxidase stain shows mosaic pattern (checkered flag).
  • Electron Microscopy: "Parking lot" inclusions (Crystalline).

Genetics

  • mtDNA Sequencing: For classic syndromes.
  • Whole Exome Sequencing (WES): For nuclear genes (e.g. POLG, SURF1).

1. Surgical Atlas: Muscle Biopsy Technique

"The Open Biopsy." While needle biopsies are common, for mitochondrial disease, an Open Biopsy is preferred to get enough tissue for enzymology.

  • Site: Vastus Lateralis (Thigh) or Deltoid (Shoulder). Must be a clinically affected muscle but NOT end-stage (fibrotic).
  • Technique:
    • Local Anaesthetic (Avoid adrenaline - it affects morphology).
    • Incision through skin and fascia.
    • Isolate muscle bundle. Do NOT use diathermy (burns artifacts). Clamp and cut.
    • Processing:
      • Fresh tissue -> Enzymology (ETC activity).
      • Frozen -> Histology (Ragged Red Fibres).
      • Glutaraldehyde -> Electron Microscopy.

2. Deep Dive: The Electron Transport Chain

"The Proton Pump." Oxidative Phosphorylation occurs on the Inner Mitochondrial Membrane.

  • Complex I (NADH Dehydrogenase): The largest. 45 subunits (7 mtDNA). Entry point for NADH. Pumping protons (H+).
  • Complex II (Succinate Dehydrogenase): Entry point for FADH2. Purely nDNA. Connects Krebs cycle. No pumping.
  • Co-Enzyme Q10 (Ubiquinone): The shuttle bus. Carries electrons from I/II to III.
  • Complex III: Pumps protons.
  • Cytochrome c: The second shuttle.
  • Complex IV (Cytochrome c Oxidase - COX): The final pump. Transfers electrons to Oxygen -> Water.
  • Complex V (ATP Synthase): Uses the H+ gradient (Proton Motive Force) to spin the turbine and make ATP.

Pathology Correlate:

  • LHON affects Complex I.
  • Leigh Syndrome often affects Complex I or IV.
  • "COX Negative Fibres" means Complex IV is missing in those cells (mtDNA mutation affecting COX subunits).
7. Management

(Renumbered)

3. Deep Dive: Managing the MELAS Stroke

"It's not Ischaemia."

  • Pathophysiology:
    1. Energy Failure: Neurons run out of ATP -> Ion pumps fail -> Cytotoxic Oedema.
    2. Angiopathy: Mitochondrial proliferation in vascular smooth muscle/endothelium impairs vasodilation (Nitric Oxide deficiency).
  • Acute Management:
    • IV Arginine: Nitric Oxide donor -> Vasodilation. Bolus + Infusion.
    • Treat Seizures: Aggressively. Seizures consume massive energy. Avoid Valproate.
    • Hydration: Flush out lactate.
  • Prophylaxis:
    • Oral Arginine + Citrulline.
    • CoQ10.

4. Case Studies

Case A: The "Migraineur".

  • 25-year-old woman. History of severe migraines and sensorineural deafness.
  • Presents with confusion and aphasia.
  • CT Head: "Infarct" in Left Temporal lobe.
  • Neurologist notes: "Why does a 25-year-old have a stroke? And why is she short/thin?"
  • Lactate: 4.5 mmol/L.
  • Diagnosis: MELAS.

Case B: The "Floppy" Baby.

  • 6-month-old infant. Evaluation for developmental delay.
  • Develops RSV bronchiolitis -> Rapid respiratory failure -> Intubated.
  • MRI Brain: Bilateral symmetrical hyperintensity in the Basal Ganglia.
  • Diagnosis: Leigh Syndrome.
  • Prognosis: Palliative.

Management Algorithm

(Renumbered)

        SUSPECTED MITO DISEASE
                ↓
    ┌───────────┴───────────────┐
  ACUTE CRISIS               CHRONIC
 (Stroke/Acidosis)          MANAGEMENT
    ↓                           ↓
- Hydration                - Exercise (Aerobic)
- Treat Infection          - "Mito Cocktail"?
- Seizure Mgmt             - Cardiac/Eye Screen
- Arginine (MELAS)         - Genetic Counselling

1. Supportive Care

  • Exercise: Aerobic exercise encourages mitochondrial biogenesis (and may select for wild-type mitochondria).
  • Nutrition: Avoid fasting (catabolic stress).
  • Infection: Aggressive treatment of fevers (metabolic demand).

2. Pharmacological

  • Mitochondrial Cocktail: (Evidence weak but widely used).
    • Co-Enzyme Q10 (Ubiquinol): Electron carrier.
    • Riboflavin (B2): Co-factor for Complex I/II.
    • L-Carnitine: Fatty acid transport.
    • Creatine: Energy buffer.
  • L-Arginine: Used in MELAS acute strokes. Nitric oxide donor -> Vasodilation.
  • Idebenone: Approved for LHON (may preserve vision).

3. Organ Specific

  • Heart: Pacemaker for KSS (essential).
  • Eyes: Ptosis props (Crutch glasses) or surgery.
  • Diabetes: Insulin (Metformin is CONTRAINDICATED as it causes lactic acidosis).
  • Epilepsy: Avoid Valproate (Mitochondrial toxicity - inhibits Beta-oxidation). Use Levetiracetam/Lamotrigine.
8. Prevention

Mitochondrial Replacement Therapy (MRT)

"The Three-Parent Baby."

  • Indication: Mother carries severe mtDNA mutation.
  • Technique:
    1. Mother's nuclear DNA is removed from her egg.
    2. Donor egg (Healthy mitochondria) has its nucleus removed.
    3. Mother's nucleus is inserted into Donor egg (enucleated).
    4. Resulting egg has Mother's nDNA + Donor's mtDNA.
  • Status: Legal in UK (HFEA approved).
9. References
  1. Gorman GS, et al. Mitochondrial diseases in adults. Nat Rev Dis Primers. 2016;2:16080.
  2. Chinnery PF. Mitochondrial Disorders Overview. GeneReviews. 2000 (Updated 2021).
10. Examination Focus

Common Exam Questions

1. Histology:

  • Q: What is the hallmark finding on muscle biopsy?
  • A: Ragged Red Fibres (Gomori Trichrome).

2. Inheritance:

  • Q: A mother has MELAS. What is the risk to her children?
  • A: All children inherit the mtDNA, but severity depends on heteroplasmy load.
  • Q: A father has MELAS. What is the risk?
  • A: 0%. (Paternal mitochondria are not transmitted).

3. Drugs:

  • Q: Which diabetic drug is contraindicated?
  • A: Metformin (Risk of Lactic Acidosis).
  • Q: Which antibiotic can cause deafness in mitochondrial patients?
  • A: Aminoglycosides (Gentamicin) - m.1555A>G mutation makes hair cells hypersensitive.
13. Technical Appendix: The "Big 5" Syndromes Detailed
SyndromeAcronymMutationKey Features
MELASMitochondrial Encephalopathy, Lactic Acidosis, Strokem.3243A>G (tRNA-Leu)Strokes (Occipital), Diabetes (MIDD), Short Stature, Migraine.
MERRFMyoclonic Epilepsy, Ragged Red Fibresm.8344A>G (tRNA-Lys)Myoclonus, Ataxia, Seizures, Deafness.
Kearns-SayreKSSLarge DeletionPtosis, Ophthalmoplegia, Pigmentary Retinopathy, Heart Block. Onset <20y.
PEOProgressive External OphthalmoplegiaDeletion or POLGPtosis + Ophthalmoplegia ONLY. (Restricted form of KSS).
NARPNeuropathy, Ataxia, Retinitis Pigmentosam.8993T>G (ATP6)Sensory neuropathy, Ataxia, Night blindness. (Milder form of Leigh).
LeighSubacute Necrotising EncephalomyelopathyManySevere regression, Brainstem lesions, Respiratory failure. Death <3y.
14. Postscript: Mitochondrial Donation Ethics

"The slippery slope?" Mitochondrial Replacement Therapy (MRT) involves using a donor egg to replace defective mitochondria.

  • The Argument For: It prevents horrific, fatal diseases (like Leigh Syndrome). The donor mtDNA gives no physical traits (hair/eye color) - it is just the "battery".
  • The Argument Against:
    • Germline modification: The change is passed to future generations.
    • Identity: The child has DNA from 3 people (Dad, Mum, Donor).
    • Safety: Nucleo-mitochondrial incompatibility?
  • Current Status: Approved in UK for specific severe cases.
15. Examination Focus (Expanded)

Advanced Viva Questions

1. Stroke:

  • Q: How does a MELAS stroke differ from an ischaemic stroke?
  • A: It does not follow a vascular territory (e.g. MCA). It is often cortical/occipital. It is caused by failure of oxidative metabolism in the neurons (energy crisis) rather than blocked blood flow. However, mitochondrial angiopathy is also a factor.

2. Cardiac:

  • Q: Why do KSS patients need a pacemaker?
  • A: They develop progressive AV block. It can lead to sudden cardiac death.

3. Genetics:

  • Q: What is the "Bottleneck Effect"?
  • A: During oogenesis, the number of mitochondria is reduced to a small number (the bottleneck) before expanding again. This sampling error means a mother with low heteroplasmy can produce an egg with very high heteroplasmy (random drift).

16. Patient and Layperson Explanation (Expanded)

  • What is Mito?: It is like a power cut in your body. The batteries (mitochondria) in your cells don't work properly, so organs that need lots of energy (brain, muscles) struggle.
  • Energy Management: Imagine you have a "spoonful" of energy for the day. Once it's gone, it's gone. Use it for what matters. Rest before you crash.
  • Sick Days: If you get a tummy bug, your body needs extra energy to fight it. Drink sugary drinks (Lucozade) to keep your energy up. Don't stop eating.

Medical Disclaimer: MedVellum content is for educational purposes and clinical reference. Clinical decisions should account for individual patient circumstances. Always consult appropriate specialists.

Last updated: 2025-12-24

At a Glance

EvidenceHigh
Last Updated2025-12-24
Emergency Protocol

Red Flags

  • Stroke-like episodes in young patient (MELAS)
  • Acute Metabolic Decompensation (Lactic Acidosis)
  • Cardiac Conduction Block (Kearns-Sayre)
  • Sudden visual loss (LHON)
  • Respiratory Failure (Leigh Syndrome)

Clinical Pearls

  • **"The Stroke that isn't a Stroke"**: In MELAS, patients have stroke-like episodes that do NOT respect vascular territories. They are metabolic crises.
  • **"Diabetes and Deafness"**: This specific combination (MIDD - Maternally Inherited Diabetes and Deafness) is a classic mitochondrial presentation (m.3243A
  • **"Ptosis + Ophthalmoplegia"**: CPEO (Chronic Progressive External Ophthalmoplegia). If this is present, ALWAYS check the heart (Kearns-Sayre Syndrome causes heart block).
  • Accumulation under sarcolemma -
  • **Ragged Red Fibres**.

Guidelines

  • NICE Guidelines
  • BTS Guidelines
  • RCUK Guidelines