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Module 104 - Nutrition, metabolism & excretion > T2 L4 Mitochondrial myopathies > Flashcards

T2 L4 Mitochondrial myopathies Flashcards

1
Q

How many copies of the genome in each mitochondria?

A

5-10

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2
Q

How many mitochondria are in a cell?

A

Between 2 and 2000

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3
Q

Describe maternal inheritance of mitochondria

A

Embryo derives all of its mitochondria from the egg
The mitochondria are in the tail of the sperm so aren’t absorbed on fertilisation
Any paternal mitochondria that do enter the egg are destroyed

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4
Q

What does the mitochondrial genome code for?

A

13 of the respiratory chain proteins
2 rNA
22 tRNA

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5
Q

What is the major producer of ROS?

A

The respiratory chain

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6
Q

Describe ROS

A

Reactive oxygen species

Highly reactive - sometimes due to the presence of unpaired valence shell electrons

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7
Q

What genome suffers the greatest exposure to & damage by ROS

A

Mitochondrial genome
Mitochondrial DNA is less effective at correcting mistakes & repairing mitochondrial DNA damage so defects can accumulate with age due to oxygen free radicals

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8
Q

What are some important electron carriers?

A

NAD+/NADH
NADP/NADPH
FAD+/FADH2

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9
Q

What are some reactive oxygen species?

A 
Superoxide anion
Hydroxyl radical
Peroxide ion
Hydrogen peroxide
Hydrochlorus acid
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10
Q

Why does the efficiency of oxidative phosphorylation decline with age?

A

Due to the accumulation of mutations to mitochondrial DNA by ROS
Oxidative phosphorylation enzyme defects are strongly implicated in Alzheimer’s, Parkinson’s & type II diabetes

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11
Q

What are mitochondrial diseases?

A

Diseases arriving from defects in mitochondrial enzymes & systems
Major defects are incompatible with life so the affected embryos rarely survive

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12
Q

What is a myopathy?

A

Muscle disease

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13
Q

What is encephalomyopathy?

A

Mitochondrial disease causing muscular & neurological problems

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14
Q

What tissues are less able to tolerate lowered ATP production?

A

Neurons
Myocytes
Skeletal muscle cells
Beta cells of the pancreas

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15
Q

What are mitochondrial myopathies?

A

Group of muscular diseases
Mostly occur before the age of 20
Often begin with exercise intolerance or muscle weakness

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16
Q

What are some other symptoms of mitochondrial myopathies?

A 
Heart failure / rhythm disturbances
Dementia
Deafness
Blindness
Seizures
17
Q

Describe the threshold effect

A

When the level of mutant mitochondrial exceeds a certain threshold the cell then expresses dysfunction

18
Q

What is homoplasmy?

A

The copies of mitochondrial DNA are all identical

19
Q

What is heteroplasny?

A

Both normal & mutant mitochondrial DNA are present

20
Q

What are the different types of mitochondrial myopathies?

A

Lebers hereditary optic neuropathy (LHON)
Myoclonus epilepsy with ragged-red fibre (MERRF)
Mitochondrial encephalomyopathy lactic acidosis & stroke-like episodes (MELAS)
Kearns-Sayre syndrome (KSS)

21
Q

What is Lebers hereditary optic neuropathy?

A

Single base change in mitochondrial gene ND4 from Arg to His in a polypeptide of complex I
Mitochondria are partially defective in electron transport from NADH to UQ
Some ATP is produced by electron transport from succinate but not enough to support the very active metabolism of neurons
Results in damage to optic nerve leading to blindness

Single base change in mitochondrial gene for cytochrome b in complex III also produces LHON

22
Q

What is myoclonus epilepsy with ragged-red fibre?

A

Caused by a point mutation in the mitochondrial gene encoding a tRNA specific for lysine. Usually at position 8344 in the mitochondrial genome for more than 80% of cases.
Many other genes are involved:
- Mt-TK
- Mt-TL1
-Mt-TH
-Mt-TF
Disrupts the synthesis of proteins that are essential for oxidative phosphorylation (ATP synthesis)
Skeletal muscle fibres have abnormally shaped mitochondria
Ragged red fibres due to clumps of mitochondrial that accumulate in aerobic skeletal muscle fibres.

23
Q

What stain is used for the ragged red fibres?

A

Gomori modified Trichrome

24
Q

What is mitochondrial encephalomyioathy lactic acidosis & stroke-like episodes (MELAS)?

A

Primarily affects the brain & skeletal muscle
Gene dysfunction involving Mt ND5 complex, Mt-TH, Mt-TL1, Mt-TV
Symptoms appear in childhood

25
Q

What are the symptoms of MELAS?

A 
Build up of lactic acid
Stroke-like episodes with muscle weakness
Seizures leading to loss of vision
Movement difficulties
Involuntary muscle spasms (myoclonus)
Dementia
26
Q

What is Kearns-Sayre syndrome (KSS)?

A

Results from a 5kb deletion of mitochondrial genome
Onset before the age of 20
Affected patients have a short status & often have multiple endocrinopathies including diabetes

27
Q

What are the symptoms of KSS?

A

Dementia
Retina pigmentosa - group of genetic eye conditions in which abnormalities of rods & cones or the retinal pigment epithelium eventually lead to blindness
Lactic acidosis
Heart conduction defects
Raised cerebrospinal fluid protein content

28
Q

What is the treatment for mitochondrial myopathies?

A

Prognosis is variable & dependent on the type of disease & the patient’s metabolism
Occupational / physical therapy may extend the range of muscle movement
Vitamin therapies may improve function - Rivoflavin, creatine, CoQ, C, K, carnitine
No specific treatments

29
Q

How do you prevent mitochondrial myopathies?

A

IVF strategy to replace defective mitochondria inherited from a mother
Merge DNA from 2 fertilised eggs
Mitochondrial gene replacement
Maternal spindle transfer

30
Q

What is the process of mitochondrial gene replacement (pronuclear stage)?

A

1) Patient’s egg with abnormal mitochondria is fertilised with the partner’s sperm
2) Patient’s zygote has abnormal mitochondria
3) Patient’s pronuclei is removed from the zygote & transferred to enucleated egg which has normal mitochondria
4) Cleaving embryo with normal mitochondria & maternal & paternal genome can be transferred to the uterus

31
Q

What is the process of maternal spindle transfer?

A

1) Unfertilised patient’s egg with abnormal mitochondria
2) Spindle & associated chromosomes are removed as karyoplast from patient’s egg & fused into enucleated donor egg
3) Reconstituted egg is fertilised with sperm from the patient’s partner

Module 104 - Nutrition, metabolism & excretion (31 decks)

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