Mitochondrial myopathies

Question 1

Origins of the mitochondrion

Answer 1

Endosymbiotic relationship

Many features of mitochondrial DNA resemble those found in prokaryotes

Strengthened the theory that mitochondria are the evolutionary descendants of a prokaryote

Result of an endosymbiotic relationship with ancestral eukaryotic cells early in the history of life on earth

Question 2

Mitochondrial DNA

Answer 2

Closed circular double stranded molecule

5-10 copies of the genome in each mitochondrion

Human mitochondrion genome is 16.5kb

> 900 different mt proteins are encoded by nDNA o cytosolic ribosomes, important and then assembled in the mitochondrion

Question 3

Maternal inheritance

Answer 3

The embryo essentially derives all its mitochondria from the egg

Most sperm mitochondria are in the tail- not absorbed on fertilisation

Any paternal mitochondria that do enter the egg are destroyed

Question 4

Mitochondrial genome

Answer 4

Many of the genes needed for mitochondrial function have moved from the mitochondrion into nuclear genome

Mt genome codes for:
13 of the respiratory chain proteins
2 rRNA
22 tRNA

Question 5

Mutation of mt DNA

Answer 5

Respiratory chain is the major producer of ROS

Mt genome suffers the greatest exposure to and damage by ROS

mtDNA less effective at correcting mistakes and repairing mt DNA damage

Defects in mtDNA accumulate with age and mtDNA mutates more rapidly than nDNA

Question 6

Reactive oxygen species

Answer 6

Superoxide anion

Hydroxyl radical

Peroxide ion

Hydrogen peroxide

Hypochlorous acid

Question 7

Efficiency of OXPHOS

Answer 7

Efficiency declines with age as a result of accumulation of mutation s to mtDNA due to ROS

OXPHOS enzyme defects strongly implicated in Alzheimer’s/ Parkinsion’s type II diabetes

Question 8

Defects in OXPHOS

Answer 8

Involve tissues most reliant on OXPHOS

Occurs later in life

Progressive with age

Show progressive enrichment in mutated mtDNA’s

Question 9

Mitochondrial diseases

Answer 9

Arise from defects in mt enzymes and systems

Major defects are incompatible with life and affect embryos very rarely survive

Over 150 different mitochondrial diseases, some linked to mtDNA

Often involve CNS and musculoskeletal system

Question 10

Mitochondrial myopathies

Answer 10

Number of human diseases attributed to mutations in mt genes in mtDNA, reduce capacity of cells to produce ATP

Some tissues/ cell types less able to tolerate lowered ATP production

Group of neuromuscular disease

Most occur before the age of 20, beginning with exercise intolerance or muscle weakness

Other symptoms

• heart failure/ rhythm disturbances
• dementia
• deafness
• blindness
• seizures

Question 11

Clinical features of mitochondrial diseases

Answer 11

Onset of symptoms, phenotypic variability and variable penetrance of mt diseases governed by:

• homoplasmy and heteroplasmy of mt
• mt genetic bottleneck

Question 12

Threshold effect

Answer 12

At cell division, mitochondria are distributed unequally and do not necessarily reflect the ration found in the progenitor cell

Above threshold causes disease

Question 13

Mt myopathies- biochemical classification

Answer 13

1. Defects of mitochondrial transport systems
2. Defects of substrate utilisation
3. Defects of TCA cycle
4. Defects of OCPHOS coupling
5. Defects of oxidative phosphorylation

Question 14

Defects of mitochondrial transport systems

Answer 14

Carnitine palmitoyltransferase (CPT I and II) deficiencies

Question 15

Defects of substrate utilisation

Answer 15

Pyruvate dehydrogenase complex deficiency

Fatty acid oxidation defects

Question 16

Defects of TCA cycle

Answer 16

Fumarase deficiency
or
Alpha ketoglutarate dehydrogenase deficiency

Question 17

Defects of OXPHOS coupling

Answer 17

Luft’s syndrome

Question 18

Defects of oxidative phosphorylation

Answer 18

Complexes I/II/III/IV/V deficiencies combined defects of respiratory chain components

Question 19

LHON

Answer 19

Lebers hereditary optic neuropathy

Single base change in mt gene ND4 (from Arg to His) in a polypeptide of complex I

Mt partially defective in e- transport from NADH to UQ

Not sufficient ATP produced to support neurones

Damage to optic nerve- blindness

Also causes by single base change in mt gene for cyt b in complex III

Question 20

MERRF

Answer 20

Myoclonus epilepsy with ragged red fibres

Caused by point mutation in mt gene encoding tRNA specific for lysine

Disrupts synthesis of proteins essential for oxidative phosphorylation

Caused by a mutation at position 8344 in mt genome in over 80% cases

Skeletal muscle fibres of MERRF patients have abnormally shaped mitochondria

Question 21

MELAS

Answer 21

Mitochondrial enxephalomyopathy lactic acidosis and stroke like episodes

Affect primarily the brain and skeletal muscle

Mt gene dysfunction involving mt ND5 (complex I) and mt-TH, mt-TL1 and mt-TV

Symptoms appear later in childhood

• build up of lactic acid
• stroke like episodes with muscle weakness, seizures, loss of visions, movement difficulties
• dementia

Question 22

KSS

Answer 22

Kearns-Sayre syndrome

Results from 5kb deletion of mt genome

Onset before age 20

Short stature and multiple endocrinopathies including diabetes

Dementia and retinitis pigmentosa

Lactic acidosis, heart conduction defects, raised cerebrospinal fluid protein content

Question 23

Ragged red fibres

Answer 23

Clumps of defective mitochondria accumulate in aerobic skeletal muscle fibres

Appear red after staining with Gomori modified Trichrome

Associated with mitochondrial disease

Question 24

Retinitis pigmentosa

Answer 24

Group of genetic eye conditions where abnormalities of rods and cones or retinal pigment epithelium of the retina lead eventually to blindness

Question 25

Mitochondrial myopathies prognosis

Answer 25

Variable and dependent on the type of disease and the patient’s metabolism

Varies greatly between individuals

Question 26

Occupational/ physical treatment

Answer 26

May extend the range of muscle movement

Question 27

Vitamin therapies

Answer 27

Riboflavin, creatine, CoQ, C, K and carnitine may improve function for some

Question 28

IVF strategy

Answer 28

Designed to replace defective mitochondria inherited from a mother

Merging DNA from two fertilised eggs- mother with defective mt, other from healthy donor

Malfunctioning mitochondria are replaced by donor healthy ones