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28. MERRF

Myoclonic Epilepsy with Ragged-Red Fibers. mitochondria. 28. MERRF. INDEX. Principles Physical Finding Background disease etiology and incidence pathogenesis phenotype and natural history Management Inheritance risk Small Group Discussion 1,2 / 3,4. Principles to physical finding.

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28. MERRF

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  1. Myoclonic Epilepsy with Ragged-Red Fibers mitochondria 28. MERRF

  2. INDEX • Principles • Physical Finding • Background • disease etiology and incidence • pathogenesis • phenotype and natural history • Management • Inheritance risk • Small Group Discussion 1,2 / 3,4

  3. Principles to physical finding 이재일

  4. pRINCIPLES • mtDNA mutations • Replicative segregation • Expression threshold • High mutation rate • Accumulation of mutation with age • Heteroplasmy

  5. Heteroplasmy • Heteroplasmy is the presence of a mixture of more than one type of an organellar genome (mitochondrial DNA (mtDNA) or plastid DNA) within a cell or individual.

  6. Major Phenotypic Features • Age at onset: childhood through adulthood • Myopathy • Dementia • Myoclonic seizures • Ataxia • Deafness

  7. Myopathy (근질환) • a neuromuscular disease in which the muscle fibers do not function for any one of many reasons • meaning "lack of order". It is a neurological sign and symptom consisting of gross incoordination of muscle movements. Ataxia (사지 불능)

  8. Major Phenotypic Features • Age at onset: childhood through adulthood • Myopathy • Dementia • Myoclonic seizures • Ataxia • Deafness

  9. HISTORY and PHYSICAL FINDINGS • R.S., Male, Age 15 • Well developed. • Clinic for myoclonic epilepsy. • EEG(Electroencephalogram) bursts of slow wave and spike complex

  10. FAMILY HISTORY [MATERNAL] Grand mother deafness, diabetes and renal dysfunction.(80yrs) Uncle died of an undiagnosed myophathic disorder.(53yrs) Aunt progressive dementia who had presented with ataxia.(37yrs) R.S.(Pt.)'s sibs and his mother's sibs were carriers of a mtDNA mutation.

  11. Examination • Muscle wasting and weakness • Myoclonus • Ataxia

  12. Myoclonus • is brief, involuntary twitching ofa muscle or a group of muscles.

  13. Examination • Muscle wasting and weakness • Myoclonus • Ataxia

  14. Initial evaluation • Sensorineural hearing loss • Slow nerve conduction • Mildy elevated blood • Cerebrospinal fluidlactate level

  15. Muscle biopsy • Abnormal mitochondria • Deficient staining for cytochromeoxidase • Ragged-red fibers

  16. Testing mutations within mtDNA • Heteroplsmic mutation (8344G>A, tRNAlys gene) • associated with Myoclonic Epilepsy with Ragged-Red fibers(MERRF)

  17. background 장준원

  18. Disease Etiology and Incidence • MERRF is caused by mutations within the mtDNA in the tRNAlysgene. • More than 90% of patients have one of three mutations within this gene • 8344G>A accounts for 80% • 8356T>C and 8363G>A together account for an additional 10% • Inherited maternally • MERRF patients are nearly always heteroplasmic for the mutant mitochondria.

  19. Pathogenesis • Mitochondria generate ATP energy through oxidative phosphorylation. • In MERRF, the activities of Com Iand IV are severely reduced. • Expression of the MERRF phenotype ultimately depends on the overall reduction in OXPHOS capacity. • The threshold for expression of a deleterious phenotype depends on the balance between oxidative supply and demand.

  20. Oxidative Phosphorylation Fig. OXPHOS takes place in Electron transport chain Com I (NADH dehydrogenase) accepts fuel from the citric acid cycle in the form of NADH, which donates electrons to the chain. Com II Succinatedehydrogenase) accepts electron from FADH2 and passes them to COM III via cytochrome C. Com III (cytochrome-c oxidase) Com V (ATP synthase) converts adenosine diphosphate (ADP) to adenosine triphosphate (ATP)

  21. Oxphos PATHWAY • Com I to Vcompose the OXPHOS pathway. • Except for Com II, each complex has some components encoded within the mtDNA and some in the nuclear genome. • The mtDNA encodes 13 of the polypeptides in the OXPHOS complexes as well as 2 rRNAs and 22 tRNAs

  22. Pathogenesis • Mitochondria generate ATP energy through oxidative phosphorylation. • In MERRF, the activities of Com Iand IV are severely reduced. • Expression of the MERRF phenotype ultimately depends on the overall reduction in OXPHOS capacity. • The threshold for expression of a deleterious phenotype depends on the balance between oxidative supply and demand.

  23. mtDNA has high mutation rate (10x nDNA) • mtDNA has no intron,random mutations affect coding sequences. • Mitochondrial efficiency declinesgradually with age • Increases in the proportion of mutant mtDNA can occur by a combination of inheritance, preferential replication of mutant mtDNA, and selection.

  24. Both intercellular and intergenerational mtDNA transmission follow the principles of population genetics. • The children of heteroplasmic mothers have widely varying proportions of mtDNA genotypes because of replicative segregation. • As heteroplasmic cells within an individual undergo mitosis, the proportion of mtDNA genotypes in daughter cells changes from that of the parent cell by replicative segregation. • The mtDNA is subject to strong selective pressures because changes in the proportion of mtDNA genotypes affect the cellular phenotype.

  25. Replicative segregation • Random partitioning of mitochondria during expansion of the oogonial population, particularly because of the mitochondrial “genetic bottleneck” that occurs during oogenesis

  26. Population Bottleneck (genetic bottleneck) • an evolutionary event in which a significant percentage of a population or species is killed or otherwise prevented from reproducing Sudden fall down Of population

  27. Both intercellular and intergenerational mtDNA transmission follow the principles of population genetics. • The children of heteroplasmic mothers have widely varying proportions of mtDNA genotypes because of replicative segregation. • As heteroplasmic cells within an individual undergo mitosis, the proportion of mtDNA genotypes in daughter cells changes from that of the parent cell by replicative segregation. • The mtDNA is subject to strong selective pressures because changes in the proportion of mtDNA genotypes affect the cellular phenotype.

  28. Phenotype to inheritance risk 조한철

  29. Phenotype and Natural history Clinical aspect variable in form and grade, cannot regulate progress easily. Some MERRF cases are not with Ragged-red fibers in muscular biopsy. So mtDNA test is preferred, and muscular biopsy is assistant.

  30. Management • No useful treatment. • Treatment must be temporarily expedient to symptoms. • Mostly prescribes vitamins to optimize OXPHOS activity.

  31. Inheritance Risk • Children of • Affected male : no risk • Affected female : risky • mtDNAinherits from mother.

  32. Inheritance Risk • 2 major problems in blood testing in at-risk family • Because of replicative segregation and tissue selection, the mutation may not be detectable in blood. • Because of Replicative segregation,(+) result inform us neither the proportion of mutant mtDNA nor the expected severity of disease.

  33. Small group discussion 1, 2 이지원

  34. Questions for small group discussion • 1. How does a mutant mtDNA molecule, arising de novo in a cell with hundreds of normal molecules, become such a significant fraction of the total that energy-generating capacity is compromised and symptoms develop? • 어떻게 수많은 정상의 molcule과 함께 발생한 mutant mtDNAmocule이 에너지 생성 능력이 손상되거나 증상이 유발되는 것처럼 전체에 있어서 중요한 영역이 될 수 있는가?

  35. Questionsfor small group discussion 1

  36. Questions for small group discussion • 2. How could mitochondrial mutations affecting oxidative phosphorylation accelerate the mutation rate of mtDNA? • Oxidative phosphorylation에 영향을 주는 미토콘드리아 돌연변이가 어떻게 mtDNA의 돌연변이 비율을 촉진시킬 수 있는가?

  37. Questionsfor small group discussion 2

  38. Small group discussion 3, 4 이정택

  39. Questions for small group discussion • 3. howcould mitochondrial mutations affecting oxidative phosphorylation accelerate aging? • 산화적 인산화에 영향을 주는 미토콘드리아 변이는 어떻게 노화에 영향을 주는가?

  40. Questionsfor small group discussion 3

  41. Questions for small group discussion • 4. In the fetus, oxygen tenion is low and the most energy is derived from glycolysis. How could this observation affect the prenatal expression of deleterious oxidative phosphorylation mutations? • 태아기엔 산소분압이 낮고 대부분의 에너지는 해당과정에 의해 얻어진다. 이러한 상황이 어떻게 유해한 산화적 인산화 이상의 태아적 표현형에 영향을 미칠까?

  42. Questionsfor small group discussion 4

  43. credits • 7조이재일 이정택 이지원 장준원정신석 조한철 진호 2007. 12. 6. College of medicine, Dankook Univ.

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