Inherited muscle disorders Flashcards
What are the 6 ways muscle react to pathology?
-Atrophied fibres are very small and angular compared to normal fibres
What are the three origins of muscle pathologies?
- Upper motor neurons
- Lower motor neurons / neuromuscular junctions
- Skeletal muscle
What is the denervation/re-innervation cycle?
- Motor unit: One motor neuron and all the myofibres that it innervates
>Normally have a mosaic pattern of fibres
- Motor neuron dies, it loses its connection with the skeletal muscle and so the myofibres become atrophied (denervation)
- Neighbouring motor neuron is healthy, it can branch out and connect to the atrophied fibres, allowing them to survive.
> Fibre type switch as the motor neuron determines the properties of the fibres it innervates.
» Fibre Type grouping: big patches of one fibre type form next to clusters of another type (re-innervation) - More motor neurons are lost, leading to hypotrophied, atrophied and degenerating fibres, which the remaining motor neurons can no longer compensate for
At which stages of myogenesis do defects in important genes or proteins cause congenital muscular dystrophies?
-Later stages (Fusion and Maturation)
Name 4 ways dystrophies be identified on a histological slide?
Give 2 examples of muscular dystrophy.
- Duchenne Muscular Dystrophy (servere)
- Becker Muscular Dystrophy
What do inflammation myopathies cause?
- Loss of muscle fibre
What are ion channel myopathies?
- Myopathies caused by mutations or disfunctions that can occur in either: calcium, potassium, sodium or chloride ion channels
How do mitochondrial myopathies present?
How can mitochondrial myopathies be inherited?
-> Not evenly stained
- In a maternal germ cell with a mix of healthy and mutant mitochondria, random segregation during reproduction and subsequent proliferation of mitochondria can lead to a variety of outcomes for the gametes / daughter cells:
- Some cells will have only healthy mitochondria
- Some will have only mutant mitochondria
- Some will have a mixture
What are lipid storage myopathies?
- Presence of big lipid droplets
What are glycogen storage myopathies?
- Mutation in glycogen pathway
> Higher up in the pathway, as more of the downstream pathways are then impacted. Causes more severe pathology
Aside from biopsy, what information is required to diagnose a muscle dystrophy?
- Clinical and family history
- Physical examination
- Radiology
- Biochemistry
- Physiology
- Histopathology
- Genetic testing
What is DMD?
- A genetic disorder characterized by progressive muscle degeneration and weakness
What is DMD caused by?
-LOSS OF DYSTROPHIN
> The dystrophin gene leads to the production of the dystrophin protein, which acts as an anchor at the sarcolemma.
What does dystrophin anchor?
- Actin intracellularly
- Sarcoglycan complex in the sarcolemma
- Dystroglycan complex in the sarcolemma
- Laminin (bound to the dystroglycan complex) extraceullarly
What happens when there is a mutation in dystrophin?
- Mutations lead to a non-functional or non-existent dystrophin protein. This means that the anchoring functions are lost, along with the structural stability of the membrane.
Why are high levels of creatine kinase in the blood indicative of a muscular dystrophy?
> When the functional dystrophin protein is lost, membrane stability is also lost and the cell becomes more vulnerable to mechanical stress.
> This will lead to muscle damage and eventually necrosis of the skeletal muscle cells, which causes the release of creatine kinase into the blood.
> High levels of necrosis lead to high levels of creatine kinase
What is pseudohypertrophy? Why does it occur?
-
REPLACEMENT OF MUSCLE CELLS BY FIBROTIC (COLLAGEN) AND ADIPOSE TISSUE
> leads to the appearance of bigger muscles (particularly calf muscles) - Early stages of DMD, satellite cells are activated and can make new muscle > not sustainable. > Satellite cells cannot keep up with the extent of the damage and cannot produce new muscle quick enough > Absence of new muscle, the space is filled with adipose and collagen tissue.
( research: satellite cells can become defective with the absence of dystrophin)
What type of genetic disease is DMD?
Therefore how is it passed down?
- X-linked recessive disease, therefore the abnormal gene is passed down from a heterozygous carrier mother
Why can 1 in 50,000,000 girls have DMD?
> X-linked inactivation
If a female has inherited the mutant chromosome, there can be two outcomes:
- Cells that inactivate the mutant chromosome
- Cells that inactivate the healthy chromosome
In each cell of the early female embryo, there is random inactivation of one X chromosome to prevent the doubling of proteins from being expressed. The inactivated X chromosome forms a small, dense structure called a Barr body.
Random inactivation is followed by clonal expansion. Depending on the amounts and location of cells with the predominant mutant chromosome, there can be the rare occurrence of females being affected
What is variable penetrance and variable expressivity?
- The proportion of people with a given phenotype who exhibit the phenotype associated with that genotype. For instance, the percentage of carrier females who have DMD symptoms is the variable penetrance - in the figure below it would be 2/8
- A measure of the extent to which a given genotype is expressed at the phenotypic level. For instance with DMD, this is measured as the severity to which a female carrier expresses the symptoms of DMD. This is dependent on the amount and location of cells with the inactivated healthy X chromosome.
What is the difference between Becker Muscular Dystrophy and Duchenne Muscular Dystrophy? Describe this in terms of their mutations.
- Becker Muscular Dystrophy (BMD) is a milder version of DMD as it produces a partially functional protein, unlike DMD which produces a non-functional protein.
> This is due to the fact that in BMD, the deletions / duplications / mutations are in-frame and missense; whereas in DMD, they are out-of-frame and nonsense
How does Eteplirsen work as a therapy for DMD?
- Specifically recognises exon 51 and uses an antisense oligonucleotide (a short sequence of nucleotides) that binds to exon 51 and leads to it’s cutting out.
This leads to a semi-functional protein (from DMD to BMD)
*Success rate might be dependent on the state of the muscle - the more collagen / adipose tissue present, the less muscle available for the Eteplirsen to act on
