Mitochondrial Disease

Heterogenous group of (hundreds of) genetic and environmental enzymatic mitochondrial defects.

Two major categories of defects:

Epidemiology and Risk Factors

Prevalance is estimated 1:8,500.

Disease (and inheritance) may occur:

  • De novo
    Spontaneous mutation (usually deletion) in mitochondrial DNA.
  • Mitochondrial DNA defect
    • Transmitted only by maternal inheritence
      Mother of affected patient will usually have detectable levels of the mutation.
    • Amount of affected mitochondria transmitted to the child is highly variable
      • Significant clinical variability in presentation, even amongst siblings in the same family
  • Nuclear gene defect
    May be autosomal dominant or recessive.

Pathophysiology

Mutation of genes either in nuclear DNA or in mitochondrial DNA.

Manifestations may be:

  • Single-organ
    e.g. Leber hereditary optic neuropathy.
  • Multi-organ
    Generally greatest effect on body systems with the highest metabolic requirements:
    • CNS
    • Cardiac
    • GI tract
    • Musculoskeletal

Clinical Manifestations

Clinical presentation:

  • May fall into a discrete syndrome
  • Can be highly variable
    Some common features include:
    • Cardiac effects:
      • Cardiomyopathy
    • CNS effects:
      • Seizures
      • Dementia
      • Migraine
      • Ataxia
      • Spasticity
      • Optic atrophy
      • Pigment retinopathy
      • Sensorineural deafness
      • External opthalmoplegia
    • MSK effects:
      • Ptosis
      • Proximal myopathy
      • Exercise intolerance
    • Metabolic effects
      • DM
      • Lactic acidosis

Diagnostic Approach and DDx

Investigations

Dependent on presentation:

  • Consistent with a defined mitochondrial disorder
    Specific mitochondrial DNA testing, usually on blood.
  • Not consistent with any particular disorder
    Testing includes:
    • Blood lactate
    • CSF lactate
    • Neuroimaging
    • Molecular genetic testing

Management

Medical therapy depends on underlying deficiency. General principles:

  • Supportive
    Treatment of other system manifestations (e.g. epilepsy).
  • Supplementation
    • Vitamins
    • Coenzyme Q
    • L-Carnitine

Anaesthetic Considerations

Most patients do well, although there may be an ↑ risk of perioperative complications including organ damage and death. * A * Airway obstruction
Secondary to hypotonia. * B * Respiratory failure * Pre-existing muscle weakness * Worsened by anaesthetic drugs * Post-operative monitoring for return of respiratory function * C * Conduction abnormalities * Reduced contractility * D * Anaesthetic technique * General anaesthesia usually required * Brief anaesthetics usually safe * Hypersensitive to volatile anaesthesia
* Complex I in the respiraory chain is affected by all halogenated anaesthetic agents
* Safe provided titrated to anaesthetic depth. Mitochondrial function returns as agent is washed-out. * Consider avoiding propofol for maintenance * Affects complexes I, II, IV: significant affect on electron transport chain function * Risk of propofol infusion syndrome may be ↑ with substantial doses * Avoid bupivacaine
Toxicity threshold lowered in carnitine-deficiency. * Use drugs which do not affect mitochondrial function * Opioids (except morphine) * NSAIDs * Benzodiazepines * Ketamine * Dexmedetomidine * E * Optimise temperature control
Minimise shivering. * F * Avoidance of lactated solutions
Lactate metagbolism may be impaired. * Avoid dextrose solutions for patients on ketogenic diets * G * Dysphagia * GORD * Avoid prolonged fasting
* Exacerbates metabolic burden
Fatty acid metabolism may be impaired. * Aim first on list

Marginal and Ineffective Therapies

Complications

Prognosis

Key Studies

References

  1. Hsieh VC, Krane EJ, Morgan PG. Mitochondrial Disease and Anesthesia. Journal of Inborn Errors of Metabolism and Screening. 2017 Jan;5:232640981770777.
  2. Chinnery PF. Mitochondrial Disorders Overview. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJ, Stephens K, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993 [cited 2019 Jun 16]. Available from: http://www.ncbi.nlm.nih.gov/books/NBK1224/