Home > D. Systemic pathology > Genetic and developmental anomalies > Genetic metabolic diseases > mitochondrial diseases

mitochondrial diseases

Wednesday 28 May 2003

Etiologies

- A. mitochondrial genome anomalies

  • whole mitochondrial proteome anomalies
    • tRNA gene anomalies
    • rRNA gene anomalies
    • deletions of the mitochondrial genome
  • specific protein of respiratory chain anomalies
    • punctual mutations of the mitochondrial genome
    • deletions of the mitochondrial genome

- B. nuclear gene anomalies

  • B-1. nuclear mutations of genes encoding electron transport proteins (structure genes of respiratory chain complex) - anomalies of the strucure of respiratory chain (mutations of 12 out of 38 subunits coded bu nuclear genes)
    • complex I deficiency
      • Leigh syndrome or Leigh-like syndromes (lethal and precocious necrotizing encephalopathy)
    • complex II deficiency
      • SDH-flavoprotein deficiency or SDHA deficiency
      • Leigh syndrome
    • complex III deficiency
    • complex IV deficiency
  • B-2. resipratory chain complex assembly anomalies (nuclear mutations of genes encoding mitochondrial enzymes - proteins of assembling of respiratory chain, incorporation of cofactors, heme, iron, copper)
    • complex I assembling (38 subunits coded by nDNA, 7 subunits coded by mtDNA)
      • NDUFAF1
      • NDUFAF2
      • C6orf66
      • C20orf7
      • ACAD9
    • complex II assembling
      • NDUFAF2
    • complex III assembling
      • SDHAF1
      • BCS1L (iron-sulfur protein assembly)
      • TTC19
    • complex IV assembling
      • SURF1
      • SCO1
      • COX10
      • SCO2
      • LRPPRC
      • FASTKD2
      • TACO1
    • complex V assembling
      • TMEM70
      • ATP12
    • iron-sulfur protein assembly
      • Friedreich ataxia
  • B-3. mtDNA maintenance anomalies (nuclear genes)
    • mtDNA multiple deletions (frequent autosomal dominant progressive external ophtalmoplegia - adPEO)
      • POLG1
      • POLG2
      • ANT1
      • OPA1
    • mtDNA depletion (hepatocerebral form, myopathic form, encephalomyopathic form, mitochondrial neurogastrointestinal encephalomyopathy/MNGIE)
      • POLG
      • PEO1
      • DGUOK
      • MPV17
      • RRM2B
      • TK2
  • TP
  • B-4. maturation and traduction of mitochondrial proteins
    • mtDNA mutations
      • tRNA mutations
        • tRNA-Leu(UUR) - 3243A>G (MT-TL1) (MELAS syndrome)
      • rRNA mutations
      • tRNA modifier genes
        • PUS1
        • TRMU
      • mitochondrial tRNA synthases
        • RARS2
        • DARS2
        • YARS2
        • HARS2
      • unknown function proteins
        • C12Orf65
  • B-5. mitochondrial protein importation
    • TIMM8A - Mohr-Tranebjaerg syndrome (X-linked deafness and dystonia)
    • DNAJC19 (dilated cardiomyopathy with ataxia)
  • B-6. mitochondrial lipid anomalies
    • ubiqinone (coenzyme Q10) anomalies
      • PDSS1
      • PDSS2
      • COQ2
      • COQ9
      • CABC1
      • tafzzine naomalies: Barth syndrome (cardiolipine synthesis deficiency)

Types

- mitochondrial respiratory chain anomalies - oxidative phosphorylation anomalies - OXPHOS disorders
- defects of transport through the mitochondrial membrane
- defects of substrates utilization
- defects of Krebs cycle
- fatty acid oxydation anomalies
- urea cycle anomalies
- carnitine palmityl-transferase pyruvate dehydrogenase
- mitochondrial DNA depletion syndrome

Localization

- mitochondrial hepatopathies
- mitochondrial myopathies
- mitochondrial encephalopathies
- mitochondrial encephalomyopathies
- multiple symmetrical lipomatosis
- Barth Syndrome

  • down-regulation of Bid protein in parallel to the genetic deficiency in cardiolipin remodeling

Classification (Mancuso, Filosto, 2007)

- mtDNA rearrangements

  • sporadical mtDNA rearrangements
    • Kearns-Sayre syndrome (KSS)
    • Pearson syndrome
    • sporadical chronic progressive external ophtalmoplegia (sporadical CPEO)
  • maternal transmitted mtDNA rearrangements
    • maternal transmitted chronic progressive external ophtalmoplegia (maternal transmitted CPEO)
    • systemic syndromes
    • diabetes mellitus and deafness (DAD)
      • this combination at an early age can be due to mitochondrial disease
      • Diabetes mellitus and deafness can also be found together for other reasons

- mtDNA punctual mutations

  • mtDNA punctual mutations of genes coding for proteins
  • mtDNA punctual mutations of genes coding for tRNA
    • mitochondrial myopathy, encephalomyopathy, lactic acidosis, stroke-like symptoms (MELAS syndrome)
    • myoclonic epilepsy with ragged red fibers (MERRF)
    • myoneurogenic gastrointestinal encephalopathy (MNGIE)
    • cardiomyopathy and myopathy
    • chronic progressive external ophtalmoplegia (CPEO)
    • isolated myopathy
    • diabetes mellitus and deafness (DAD)
    • sensorial deafness
    • hypertrophic cardiomyopathy
    • tubulopathy
    • massive hepatic necrosis
  • mtDNA punctual mutations of genes coding for rRNA
    • aminosid-induced non syndromal deafness
    • hypertrophic cardiomyopathy

Nota bene: Conditions such as Friedreich ataxia can affect the mitochondria, but are not associated with mitochondrial proteins.

See also

- mitochondrial protein synthesis diseases
- mitochondrial respiratory chain diseases

References

- Dimauro S, Schon EA. Mitochondrial Disorders in the Nervous System. Annu Rev Neurosci. 2008 Mar 10; PMID: 18333761

- Rotig A, Lebon S, Zinovieva E, Mollet J, Sarzi E, Bonnefont JP, Munnich A. Molecular diagnostics of mitochondrial disorders. Biochim Biophys Acta. 2004 Dec 6;1659(2-3):129-35. PMID: 15576044

- Taylor RW, Turnbull DM. Mitochondrial DNA mutations in human disease. Nat Rev Genet. 2005 May;6(5):389-402. PMID: 15861210

- Jacobs HT. Disorders of mitochondrial protein synthesis. Hum Mol Genet. 2003 Oct 15;12 Spec No 2:R293-301. PMID: 12928485

- Rotig A, Munnich A. Genetic features of mitochondrial respiratory chain disorders. J Am Soc Nephrol. 2003 Dec;14(12):2995-3007. PMID: 14638899