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A. Mitochondria and Mitochondrial DNA (mtDNA) [1,2,3]

  1. Main function of mitochondria is oxidative phosphorylation (OXPHOS)
    1. OXPHOS is carried out by electron transport chain
    2. Electron transport is carried out by five complexes on inner mitochondrial membrane
    3. Electron transport generates an electrochemical gradient of ~150mVolts
    4. This gradient is used to drive ATP generation via complex V (an ATPase)
  2. Electron Transport Process
    1. Complex I metabolizes glutamate, pyruvate, and ß-hydroxybutyrate (BHB)
    2. Complex II metabolizes succinate
    3. Complexes I and II donate electrons to ubiquinone (Coenzyme Q)
    4. Ubiquinone donates electrons to Complex III, which reduces cytochrome c
    5. Reduced cytochrome c passes electrons to Complex IV (cytochrome oxidase)
    6. Complex IV donates electrons to oxygen and complex V forming water
    7. Complex V is an ATPase which converts adenosine diphosphate (ADP) + Pi to ATP
  3. Each mitochondrion contains its own DNA called mtDNA
  4. mtDNA
    1. Circular molecule of 16,569 nucleotides containing 37 genes
    2. Both mtDNA and nuclear DNA genes are required for formation of mitochondria
    3. mtDNA codes for 13 protein subunits, 2 ribosomal RNAs, 22 transfer RNAs
    4. mtDNA is derived solely from the ovum (maternal)
  5. Some 2 to 10 mitochondrial DNA molecules are found in each mitochondrion
    1. Mutant and wild type mtDNA can coexist in the same cell
    2. Coexistant mutant and wild type mtDNA in the same cell is called heteroplasmy
    3. Single type of mtDNA in a cell is called homoplasmy
    4. Degree of heteroplasmy can affect symptoms and progression of disease
    5. When cells divide, relative levels of mutant and normal mtDNA can differ in daughter cells
    6. mtDNA is maternally inherited because the egg contributes all of the initial mitochondria
    7. Single report of paternally inherited mtDNA in skeletal muscle (but not other tissues) [9]
  6. Mutation rates ~10X higher than chromosomal DNA, but recombination does not occur

B. Characteristics of Mitochondrial Disease [6]

  1. Overall prevalence of 10-15 cases per 100,00 persons (similar to muscular dystrophy)
  2. MItochondrial diseases may be inherited with many patterns
    1. Mutations in mtDNA are typically inherited maternally
    2. However, many proteins and RNA required for mitochondria are coded by nuclear DNA
    3. Unaffected mothers are unlikely to have >1 offspring with mtDNA deletion disease [10]
    4. In mothers with mtDNA deletion disease, risk of offspring inheriting is ~4% [10]
  3. Generally progressive diseases with variable onset
  4. May affect any organ in the body but high energy requiring organs affected most severely
  5. Classical syndromes have skeletal muscle and neurological dysfunction
  6. Homoplasmy versus Heteroplasmy can affect the phenotype
  7. Classification
    1. Class Ia - mutations affecting mtDNA genes encoding OXPHOS proteins, tRNAs or rRNAs
    2. Class Ib - mutations of nuclear genes encoding OXPHOS proteins
    3. Class IIa - disease caused by nuclear encoding non-OXPHOS proteins
    4. Class IIb - diseases associated with OXPHOS defects caused by nuclear gene mutations encoding non-mitochondrial proteins
  8. Class Ia Diseases [2]
    1. Diseases of Giant Deletions in mtDNA
    2. Diseases of Mutant transfer RNA (tRNA)
    3. Diseases of Mutant ribosomal RNA (rRNA)
    4. Diseases of Mutant messenger RNA (mRNA)
  9. Diseases of Giant Deletions in mtDNA (Class Ia)
    1. Chronic progressive external ophthalmoplegia (CPEO): giant deletion in mtNDA
    2. Kearns-Sayre Syndrome (KSS)
    3. Pearson's Syndrome
  10. Diseases of Mutant tRNAs (Class Ia)
    1. MELAS
    2. MERRF
  11. Mutation in rRNA (Class Ia): aminoglycoside induced deafness (AID)
  12. Diseases of Mutant mRNA (Class Ia)
    1. Leber's hereditary optic neuropathy (LHON)
    2. Maternally inherited Leigh's Syndrome (MILS)
    3. NARP: Neuropathy, Ataxia, Retinitis Pigmentosa
  13. Class Ib Diseases
  14. Class IIa Diseases
    1. Friedreich's Ataxia - mutations in frataxin
    2. COX-deficiennt Leigh's Syndrome - Surf-1 mutations
    3. Hereditary spastic paraplegia - paraplegin mutations
    4. Wilson's Disease - ATP 7B mutations
    5. Sideroblastic Anemia - ATM-1 mutations
    6. Mohr-Tranebjaerg Syndrome - DPPI mutations
    7. MIDD - Leu-tRNA mutation (see below) [8]
  15. Class IIb Diseases
    1. Huntington's Disease - huntingtin mutations
    2. Autosomal recessive mitochondrial myopathy - thymidine phosphorylase mutations
  16. Acquired mitochondrial disease associated with various antiretroviral agents [7]

C. Systemic Manifestations of Mitochondrial Disease

  1. Cardiac: conduction disease, cardiomyopathy (dilated)
  2. Myopathy: proximal weakness usually occurs first; Myoclonus
  3. Ocular: Ophthalmoplegias, Pigmentary Retinopathy, Cataracts
  4. Endocrine: Hypoparathyroidism, Diabetes Mellitus, Short Stature
  5. Gastrointestinal: liver dysfunction, pancreatic exocrine insufficiency, pseudo-obstruction
  6. Other: lactic acidosis, pancytopenia, renal dysfunction, depression

D. Neurological Manifestations

  1. Ocular: ophthalmoplegias, optic neuropathy, pigmentary retinopathy
  2. Sensorineural hearing loss
  3. Seizures
  4. Basal Ganglia Calcification
  5. Stroke - particularly in young persons [13]
  6. Ataxia, Dementia
  7. Peripheral Neuropathy
  8. Headache (vascular type)

E. Mitochrondrial Myopathy

  1. Progressive loss of skeletal muscle function
  2. Elevation of muscle enzymes
  3. Biopsy required for diagnosis
  4. Isolated limb myopathy is frequent manifestation of various mtDNA mutations

F. Chronic Progressive External Ophthalmoplegia (CPEO)

  1. Most common clinical manifestation of OXPHOS mtDNA mutation
  2. Ptosis
  3. Ophthalmoplegia
  4. Limb Myopathy (± weakness)
  5. With or without retinitis pigmentosa
  6. Large, single deletions in mitochondrial DNA, usually sporadic
  7. Kearns Sayre Syndrome
    1. Subtype of CPEO
    2. Onset before age 20 with pigmentary retinopathy
    3. Cardiac conduction defect, ataxia, or raised cerebrospinal fluid protein

G. MELAS Syndrome [5,6]

  1. Syndrome of Mitochrondrial Encephalopathy, Lactic Acidosis and Seizures and/or Strokes
  2. Usually develops during childhood, with relapsing remitting course
  3. Age nearly always <40 years
  4. Etiology
    1. 80% of cases have point mutations in tRNA-Leu gene at position 3243
    2. Many other cases have other point mutations in the same gene
    3. There is considerable phenotypic variability in patients with these mutations
    4. Maternal inheritance is always observed
  5. Symptoms
    1. Stroke-Like Episodes: hemiparesism, hemianopia and/or cortical blindness may occur
    2. Focal or generalized seizures
    3. Recurrent migraine-like headaches
    4. Vomiting
    5. Short-stature
    6. Hearing loss
    7. Muscle weakness
    8. Ataxic gait
  6. Neuroimaging
    1. Radiolucent areas on CT scans
    2. Hyperintense signals on MRI scans
    3. Cortex and subcortical white matter usually affected
    4. Lesions may be transient
  7. Diagnosis
    1. Suspicion / Family History
    2. Mitrochondrial DNA sequencing
    3. Presence of "ragged red fibers" on muscle biopsy
  8. No current therapy

H. Myoclonic Epilepsy (MERRF)

  1. Called MERRF: myoclonic epilepsy with ragged-red fibers
  2. Usually presents in late adolescence or early adulthood
  3. Symptoms include myoclonus, ptosis, seizures, cerebellar ataxia, myopathy, deafness
  4. tRNA-Lys gene mutations

I. Leigh Syndrome

  1. A small proportion of Leigh syndrome is due to mtDNA mutations (maternal inheritance)
  2. These forms are due to missense mutations in the ATPase 6 gene
  3. Usually manifest in infancy with hypotonia, seizures, developmental delay, lactic acidosis

J. Leber's Hereditary Optic Neuropathy (LHON)

  1. First disease in humans linked to heritable point mutations in mDNA
  2. Most common form of blindness in otherwise healthy young men
    1. Males affected 4 to 1 over females
    2. Average onset at 23 years of age; 90% affected by age 40
  3. Painless, subacute, bilateral visual loss
  4. Central scotomas and abnormal color vision
  5. Visual recovery can occur, mainly in patients with T14484C mutation
  6. Dystonia may be present, usually with optic atrophy [14]
  7. Four different mutations have been identified

K. Ornithine Transcarbamylase Deficiency

  1. X-linked mitochrondrial enzyme (not truely a mitochondrial disease)
  2. Synthesis of citrulline, and therefore urea, is impaired
  3. Result is high ammonia, glutamine, low arginine and citrulline
  4. Clinical spectrum includes episodic encephalopathy, brain injury and death
  5. Fatal in homozygous males in newborn period
  6. Hemizygotes who survive have mental retardation, cerebral palsy, and seizures
  7. Girls with symptomatic deficiency can be treated with drugs which activate alternative waste nitrogen systems (eg. sodium phenylbutyrate) [12]

L. Maternal Inherited Diabetes with Deafness (MIDD) [8]

  1. Due to point mutation in miochondrial DNA at position 3243
  2. Type Ia disease, with mutation causing abnormal transfer RNA leucine
  3. Mainly due to defect in secretion of insulin, rather than insulin insensitivity
  4. Maternal family history of DM found in 73% of probands
  5. Average age of DM onset ~40 years
  6. Most patients progressed to insulin dependency within 10 years
  7. Symptoms
    1. Neurosensory hearing loss present in nearly all patients
    2. Muscle dysfunction common: 43% myopathy, 15% cardiomyopathy
    3. Macular pattern dystrophy found in most patients
    4. Prevalance of kidney disease 28%
  8. Treatment similar to diabetes mellitus with increased need for insulin

M. Mitochondrial DNA Polymerase Gamma Mutations [11]

  1. Can underlie multifunction disease including parkinsonism, premature menopause
  2. Progressive external ophthalmoplegia with muscle weakness and neuropathy
  3. Mutations in POLG gene leading to this unusual mitochondrial genetic syndrome

N. Bjornstad Syndrome [15]

  1. Sensorineural hearing loss (SNHL) with pili tori
  2. Caused by mutations in gene BCS1L on chr 2q34-36
    1. BCS1L encodes member of AAA family of ATPases
    2. BCS1L required for formation of mitochondrial complex III
  3. Mutations causing Bjornstad Syndrome occur in protein-protein interaction domains
  4. BCS1L mutations also cause complex III deficiency and GRACILE syndrome
    1. These are lethal conditions with multisystem and neurogical manifestations
    2. Similar to other severe mitochondrial disorders
    3. Mutations causing these syndromes occur in ATP binding domain
    4. Increased mitochondrial content and reactive oxygen species in these severe syndromes but not in Bjornstad syndrome

References

  1. Schapira AH. 2006. 2006. Lancet. 368(9529):70 abstract
  2. DiMauro S and Schon EA. 2003. NEJM. 348(26):2656 abstract
  3. Leonard JV and Schapira AH. 2000. Lancet. 355(9200):299 abstract
  4. Leonard JV and Schapira AH. 2000. Lancet. 355(9201):389 abstract
  5. Dashe JF and Boyer PJ. 1998. NEJM. 339(26):1914 (Case Record)
  6. Dickerson BC, Holtzman D, Grant E, Tian D. 2005. NEJM. 353(21):2271 (Case Record) abstract
  7. Carr A and Cooper DA. 2000. Lancet. 356(9239):1423 abstract
  8. Guillausseau PJ, Massin P, Dubois-LaForgue D, et al. 2001. Ann Intern Med. 134(9):721 abstract
  9. Schwartz M and Vissing J. 2002. NEJM. 347:576 abstract
  10. Chinnery PF, DiMauro S, Shanske S, et al. 2004. Lancet. 364(9434):592 abstract
  11. Luoma P, Melberg A, Rinne JO, et al. 2004. Lancet. 364(9437):875 abstract
  12. Maestri NE, Brusilow SW, Clissold DB, Bassett SS. 1996. NEJM. 335(12):855 abstract
  13. Chinnery PF, Turnbull DM, Walls TJ, Reading PJ. 1997. Lancet. 350:560 (Case Report) abstract
  14. Tarsy D and Simon DK. 2006. NEJM. 355(8):818 abstract
  15. Bagai A, Thavendiranathan P, Detsky AS. 2006. 295(4):416 abstract