Myotonia Flashcards
What is myotonia?
- A condition caused by hyper-exciteable skeletal muscle, leading to stiff feeling muscles due to delayed relaxation within contraction cycle.
- Increased frequency of action potential
- The condition is faily rare, 1:23,000 to 1:50,000
- MYOTONIC SEIZURES: wise contraction of skeletal muscle causes incapacitation. They don’t last long but tend to happen in stressful conditions
What is the Myotonia congenita mutation?
A mutation in CLCN1, causing loss of function.
What is the Paramyotonia and the K+ Aggregation mutation?
A mutation in SCN4A, causing a gain of function.
The importance of the CLCN1 Chloride channels.
With normal muscle physiology, depolarisations are caused by ACh stimukating nicotinic receptors, which leads to Na+ channel activation. This further depolarises T tubules and activates Ca+ channels and further activated ryanodine receptors. This leads to a rise in IC Ca+ concentration, leading to muscle contraction.
CLCN1 channels work together with K+ channels to set a negative membrane potential to move it away from its threshold value. It’s main role is with resting potential rather than repolarisation (small openings when depolarisation happens allows for small help with repolarisation). A regular muscle action potential is around 1-2 ms long.
Myotonia congenita: Thomsen
An autosomal dominant condition which is prevelant in infancy and adulthood.
There is a “warm up phenomenon”, where the more they use muscles, it causes them to be less stiff. To aid stiffness, its recommended to do light movements involving muscle contractions like playing a musical instrument.
It leads to some muscle weakness, but also leads to some hypertrophy, as using muscles relieves stiffness and exercise is promoted, theyre prone to gain mass.
Myotonia congenita: Becker
An autosomal recessive condition that is more earlier onset. It is significantly more severe than Thomsen, and the warm up phenomenon leads to weakness and more hypertrophy than Thomsen also. It has more inappropriate contraction, which leads to more muscle usage.
Loss of function of CLC1
By losing the channels that help maintain resting potential, it leads to a more depolarised resting membrane potential compared to WT CLC1. This means its potential is closer to threshold, and is therefore easier to fire action potentials.
CLC1 also slightly regulates repolarisation with K+ channels also. Having delayed repolarisation by disallowing K+ ions to re-enter leads to more K+ efflux into T tubules’ space. Due to the changes in the gradient of K+ concentration, it changes the nernst potential to be more negative, allowing for more action potentials to pass and fire, due to it being so close to threshold.
Physiology of CLC1 channels
DOUBLE BARRELLED as it has 2 pore regions where Cl can move through. Each pore has its individual gate, and a supplementary gate which covers both pores. 50% of Cl pass through if one of the pores is blocked, 0% if both are blocked.
I290M dominant mutant.
- Mutation in the CLCN1 gene > alters structure of the protein, making it more active and increasing the flow of chloride ions into muscle cells > leads to the stiffness symtpom
- Dominant genetic mutation
Dominant mutations
Recessive mutations - Beckers’ mutation E291K
Paramyotonia
- Autosomal dominant seen neonatal to infancy
- Appears during exercise and WORSENS with activity, more muscle usage leads to increased stiffness.
- Cold sensitive > cold stimuli increases likelihood of inappropriate activity
- No hypertrophy as exercise worsens muscle condition
Nav1.4 mutations: Cluster of paramyotonia congenita mutations in the voltage sensor of 4th region. It leads to mutation dependant conditions in patients due to mutations in different places > multiple conditions can stem from mutation of the one gene.
PC - K+ aggregation
3 categories:
MYOTONIA FLUCTUANS
MYOTONIA PERMANENS
ACETAZOLOMIDE RESPONSIVE
+ Plasma potassium changes go up causing stiffness in the muslces.
+ Meziletine is a drug used for treatment.
PC - Nav1.4 Gain of Function mutation
- Having enhanced function of Nav leads to resting potential being at a depolarised state, meaning its closer to threshold, meaning that smaller stumili can cause action potentials.
- Longer action potentials as impaired inactivation. The delay leads for channels to be open for longer, and this can also lead to secondary action potentials due to the membrane being depolarised for longer than it should and other signals come through leading to secondary aps.
- K+ efflux into T tubular space leads to a larger concentration EC and different gradients than WT, leading to a depolarised Nernst of K+ and leads to membrane being closer to threshold.
