Myoclonic Epilepsy and RaggedRed Fibers

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Myoclonic Epilepsy and Ragged-Red Fibers

• Presented by
• Diana Baek diana.baek_at_utoronto.ca
• Wendy Li wenndy.li_at_utoronto.ca
• Vickie Chang vickie.chang_at_utoronto.ca

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Myoclonic Epilepsy and Ragged-Red Fibres (MERRF)

• A multisystem disorder
• Characterized by myoclonus (involuntary twitching
  of a muscle), followed by generalized epilepsy,
  ataxia weakness and dementia.
• Onset childhood, occurs after normal early
  development.

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MERRF

• Maternally inherited
• Pathological changes in neurons of the
  dentato-rubral and the spinocerebellar pathways.
• Pathological changes also in the inferior olivary
  nuclei and in skeletal muscle.
• Generation of ragged red fibres is indicative of
  proliferation and subsarcolemmal accumulation of
  mitochondria.

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MERRF- Signs and Symptoms
Table 1. Signs and Symptoms seen in 62
individuals with MERRF
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MERRFClinical Diagnosis

• Based on the following four canonical features
• Myoclonus
• Generalized epilepsy
• Ataxia
• Ragged-red fibres in the muscle biopsy
• Other manifestations
• Hearing loss, peripheral neuropathy, dementia,
  short stature, exercise intolerance, optic
  atrophy

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Cause of MERRF

• An A to G transition mutation at nucleotide pair
  8344 in human mitochondrial DNA (mtDNA)
• Mutation alters the T?C loop of the tRNALys gene
• Mutations of tRNA sequence can affect the
  primary, secondary and tertiary folding of the
  structure
• Posttranscriptional modification in the wobble
  position at uridine was decreased in tRNALys
  mutation

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Diagrammatic presentation of tRNALYS, showing
position of A-to-G base substitution in
pseudouridine loop of tRNA. This
affects the mitochondrial protein synthesis.
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Modified Uridine
Uridine modification is important in the
codon-anticodon interaction
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The significance of the wobble position.

• MERRF-mutant tRNAlys will be unable to do its
  translational activity due to impaired
  codon-anticodon interaction of the unmodified
  uridine
• Unmodified anticodon UUU is unable to translate
  its codon AAR
• It is also unable to bind to the ribosome which
  ultimately leads to mitochondrial dysfunction

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Introduction to mtDNA

• Human mitochondrial DNA (mtDNA) contains genes
  required for mitochondrial protein biosynthesis
• Specifically, mtDNA has tRNA genes for each of
  the 20 amino acids and codes for subunits of the
  respiratory complex
• 7 subunits of complex 1
• 1 subunit of complex III
• 3 subunits of complex IV
• 2 subunits of complex V

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Introduction to mtDNA contd

• Defect of tRNA leads to defective oxidative
  complex production
• Associated with defects in oxidative
  phosphorylation complexes I and IV
• Severity of the defect varies due to heteroplasmy
  mtDNA mutation

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Possible cause of the mutation

• The side effect of oxidative phosphorylation
  generation of reactive oxygen species (ROS)
• MtDNA is located in the mitochondrial matrix and
  undergoes oxidative stress due to its close
  proximity to the respiratory chain complexes in
  the inner membrane ? high mutation rate

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A closer look at the mitochondria
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Treatment of MERRF

• No cure, treatment is symptomatic
• Valoproic acid, clonazepam, piracetam and
  levetiracetam for myoclonus and epilepsy
• Possible treatments to improve mitochondrial
  function include coenzyme Q10, vitamin B
  complexes, vitamin C, folate, vitamin E, and
  levo-carnitine

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Treatment of MERRF contd

• Co-enzyme Q 10 transfers electrons from complex I
  to complex II and generates a proton gradient
  that supports ATP synthesis.  It is also a potent
  free radical scavenger.  Theoretically, it can
  work in respiratory chain defects by bypassing
  the defective respiratory chain complexes, acting
  as pure electron acceptors, and by acting as free
  radical scavengers.  The suggested dosage is
  60-300mg/day
• Vitamin B complexes, particularly vitamin B1
  (thiamine) at 50-200mg/day and vitamin B2
  (riboflavin) at 50-600mg/day
• Vitamin C at 100-2000mg in divided doses

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Treatment of MERRF contd

• Folate at 1-10mg/day
• Vitamin E at 200-1200 IU/day in divided doses
• Levo-carnitine at 100-200mg/kg/day in divided
  doses, maximum 1000 mg tid
• The efficacy of these treatments are theoretical
  and require further research

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Summary

• Myoclonic Epilepsy and Ragged-Red Fiber (MERRF)
  is maternally inherited
• Characterized by myoclonus (involuntary twitching
  of a muscle), followed by generalized epilepsy,
  ataxia weakness and dementia
• Caused by an A to G transition mutation at
  nucleotide pair 8344 in human mitochondrial DNA
  (mtDNA)
• Mutation alters the T?C loop of the tRNALys gene

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Summary contd

• Posttranscriptional modification in the wobble
  position at uridine was decreased in tRNALys
  mutation
• Defect of tRNA leads to defective oxidative
  complex production, this is associated with
  defects in oxidative phosphorylation complexes I
  and IV
• No cure, treatment is symptomatic
• Valoproic acid, clonazepam, piracetam and
  levetiracetam for myoclonus and epilepsy
• Possible treatments to improve mitochondrial
  function include coenzyme Q10, vitamin B
  complexes, vitamin C, folate, vitamin E, and
  levo-carnitine

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References

• Fernando Scaglia, Lee-Jun C. Wong. Human
  mitochondrial transfer RNAs Role of pathogenic
  mutation in disease. 2008. Muscle Nerve 372
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• Yasukawa T, Suzuki T, Ishii N, Ueda T, Ohta S,
  Watanabe K 2000. Wobble modification defect in
  tRNA disturbs codonanticodon interaction in a
  mitochondrial disease. FEBS Lett 467175178.
• DiMauro S and Hirano M. MERRF. http//www.ncbi.nlm
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