28. MERRFMyoclonic Epilepsy with Ragged-Red Fibers

mitochondria

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

이재일

pRINCIPLES

mtDNA mutations Replicative segregation Expression threshold High mutation rate Accumulation of mutation with age Heteroplasmy

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.

Major Phenotypic Features

Age at onset: childhood through adulthood

Myopathy Dementia Myoclonic seizures Ataxia Deafness

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 neuro-logical sign and symptom consisting of gross incoordination of muscle movements.

ATAXIA ( 사지 불능 )

Major Phenotypic Features

Age at onset: childhood through adulthood

Myopathy Dementia Myoclonic seizures Ataxia Deafness

HISTORY and PHYSICAL FINDINGS

R.S., Male, Age 15 Well developed. Clinic for myoclonic epilepsy. EEG(Electroencephalogram)

bursts of slow wave and spike complex

FAMILY HISTORY [MATERNAL]

Grand Mother

Mother

Pt. R. S.

MERRF

Uncle Aunt

G1

G2

G3

Grand motherdeafness, diabetes and renal dysfunction.(80yrs)

Uncledied of an undiagnosed myophathic disorder.(53yrs)

Auntprogressive dementia who had presented with ataxia.(37yrs)

R.S.(Pt.)'s sibs and his mother's sibs were carriers of a mtDNA mutation.

Examination

Muscle wasting and weakness Myoclonus Ataxia

Myoclonus

is brief, involuntary twitching of a muscle or a group of muscles.

Examination

Muscle wasting and weakness Myoclonus Ataxia

Initial evaluation

Sensorineural hearing loss Slow nerve conduction Mildy elevated blood Cerebrospinal fluid lactate level

Muscle biopsy

Abnormal mitochondria Deficient staining for cytochrome ox-

idase Ragged-red fibers

Testing mutations within mtDNA

Heteroplsmic mutation (8344G>A, tRNAlys gene)

associated with Myoclonic Epilepsy with Ragged-Red fibers(MERRF)

background

장준원

Disease Etiology and Incidence

MERRF is caused by mutations within the mtDNA in the tRNAlys gene.

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 het-

eroplasmic for the mutant mitochondria.

Pathogenesis

Mitochondria generate ATP energy through oxidative phosphorylation.

In MERRF, the activities of Com I and IV are severely reduced.

Expression of the MERRF phenotype ul-timately depends on the overall reduc-tion in OXPHOS capacity.

The threshold for expression of a delete-rious phenotype depends on the balance between oxidative supply and demand.

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 Succinate dehydrogenase) 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)

Com I to V compose 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 polypep-tides in the OXPHOS complexes as well as 2 rRNAs and 22 tRNAs

Oxphos PATHWAY

Pathogenesis

Mitochondria generate ATP energy through oxidative phosphorylation.

In MERRF, the activities of Com I and IV are severely reduced.

Expression of the MERRF phenotype ul-timately depends on the overall reduc-tion in OXPHOS capacity.

The threshold for expression of a delete-rious phenotype depends on the balance between oxidative supply and demand.

mtDNA has high mutation rate (10x nDNA)

mtDNA has no intron,random mutations affect coding se-quences.

Mitochondrial efficiency declines gradually with age

Increases in the proportion of mutant mtDNA can occur by a combination of in-heritance, preferential replication of mu-tant mtDNA, and selection.

Both intercellular and intergenerational mtDNA transmission follow the principles of population genetics.1. The children of heteroplasmic mothers

have widely varying proportions of mtDNA genotypes because of replicative segrega-tion.

2. 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 segrega-tion.

3. The mtDNA is subject to strong selective pressures because changes in the proportion of mtDNA genotypes affect the cellular pheno-type.

Replicative segregation

Random partitioning of mito-chondria during expansion of the oogonial population, par-ticularly because of the mito-chondrial “genetic bottleneck” that occurs during oogenesis

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 downOf population

Both intercellular and intergenerational mtDNA transmission follow the principles of population genetics.1. The children of heteroplasmic mothers

have widely varying proportions of mtDNA genotypes because of replicative segrega-tion.

2. 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 segrega-tion.

3. The mtDNA is subject to strong selective pressures because changes in the proportion of mtDNA genotypes affect the cellular pheno-type.

Phenotype to inheritance risk

조한철

Phenotype and Natural history

• Progressive myoclonus• Raggred red fiberClassical symp.

• Abnormal brainstem reaction,• Deafness /nephric failure, diabetes• Ataxia / cardiac myopathy• dementia

Continuous symp.

• Relation with mutant mtDNA ratio in mus-cular tissue must be considered with Pt.'s age

• OXPHOS capacity declines below organ ex-pression threshold with age

Phenotype

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.

Management

No useful treatment.

Treatment must be temporarily ex-pedient to symptoms.

Mostly prescribes vitamins to opti-mize OXPHOS activity.

Inheritance Risk

Children of Affected male : no risk Affected female : risky

mtDNA inherits from mother.

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 propor-tion of mutant mtDNA nor the expected severity of disease.

Small group discussion 1, 2

이지원

Questions for small group discussion

1. How does a mutant mtDNA molecule, arising de novo in a cell with hundreds of normal mol-ecules, become such a significant fraction of the total that energy-generating capacity is compromised and symptoms develop?

어떻게 수많은 정상의 molcule 과 함께 발생한 mutant mtDNA mocule 이 에너지 생성 능력이 손상되거나 증상이 유발되는 것처럼 전체에 있어서 중요한 영역이 될 수 있는가 ?

Questions for small group discussion 1

Questions for small group discussion

2. How could mitochondrial mutations affect-ing oxidative phosphorylation accelerate the mutation rate of mtDNA?

Oxidative phosphorylation 에 영향을 주는 미토콘드리아 돌연변이가 어떻게 mtDNA 의 돌연변이 비율을 촉진시킬 수 있는가 ?

Questions for small group discussion 2

Small group discussion 3, 4

이정택

Questions for small group discussion

3. how could mitochondrial mutations affect-ing oxidative phosphorylation accelerate ag-ing?

산화적 인산화에 영향을 주는 미토콘드리아 변이는 어떻게 노화에 영향을 주는가 ?

Questions for small group discussion 3

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 ex-pression of deleterious oxidative phosphoryla-tion mutations?

태아기엔 산소분압이 낮고 대부분의 에너지는 해당과정에 의해 얻어진다 . 이러한 상황이 어떻게 유해한 산화적 인산화 이상의 태아적 표현형에 영향을 미칠까 ?

Questions for small group discussion 4

credits

7 조이재일 이정택 이지원 장준원정신석 조한철 진호

2007. 12. 6.College of medicine, Dankook Univ.