L7- myotonia Flashcards
what is myotonia + its symptoms?
- a condition where there is hyper excitability of the skeletal muscles
- due to delayed muscle relaxation
- muscle stiffness
- runs of action potentials (longer or more frequent)
- myotonic seizures
what is the incidence of myotonia?
1 in 23000 to 1 in 50000
what mutations causes myotonia congenita?
CLCN1 (CLC1) gene mutation - loss of function
what mutations cause paramyotonia and K+ aggrevated myotonia?
SCN4A (Nav1.4) mutation - gain of function
why do mutations in CLCN1 (CLC1 channel) cause myotonia congenita?
- CLC1 channel helps set resting potential
- when Cl channels open - potential more negative - drives towards nernst potential for Cl (negative)
- loss of function mutations in Cl channels mean the resting potential is not as negative as normal -so is closer to the threshold for an AP
- more likely to fire an AP
what causes muscle contraction?
- AP travels down T-tubule
- voltage gated L-type Ca2+ channels open via rianodine receptors in T-tubule
- increase in Ca2+ causes muscle contraction
what channel is important in AP firing?
Sodium channel - Nav1.4- causes depolarisation
what channels help keep resting potential away/more negative than threshold?
CLC1 channels and K+ channels
what happens in a muscle AP?
Nav1.4 channels open - causes more Na channels to open - if recahes threshold - depolarisation
- Nav1.4 channels close and Kv channels open - repolarsation
what are the two types of myotonia congenita?
thomsens and beckers
give the features of thomsens myotonia congenita
- autosomal dominant
- appears in infancy and adulthood
- mild
- warm up phenomenom - more they use muscles better it becomes - less stiff - encouraged to play musical instruments
- muscle weakness (changes in muscle structure)- less cross bridges?
- hypertrophy
give the features of beckers myotonia congenita
- autosomal recessive
- early onset
- more severe then thomsens
- warm up phenomenom
- muscle weakness
- more hypertrophy
what drug can be used to treat myotonia congenita?
mexiletene
- dependent Nav channel inhibitor (if block Nav channels - less likely to reach threshold for AP)
- don’t block all channels - given subthreshold dose - prevents excess contraction
- acetazolomide - carbonic anhydrase inhibitor (change in PH can be beneficial to muscle function)
what mutations are identified in CLCN1?
- are more recessive mutations (beckers?) identified than dominant mutations
- mutaitons are randomly scattered throughout protein (no pattern)
what is the structure of a CLC1 protein/channel?
is a double barrel - with 2 pores
- 4 subunits
- 3 different gates - 1 gates for each pore and one big gate to cover whole channel
How does the current change when different gates of the CLC1 channel are open/closed?
- all 3 gates open - max current
- large gate closed - no current
- one pore gate (one pore gate closed) and whole gate open - 1/2 max current
what is the dominant mutant of CLC1?
I290M - DOMINANT NEGATIVE
- mutant subunit inhibits other 3 subunits - channel non - functional as all subunits have to work for the channel to be functional
Why must effect of I290M be dominant negative?
- when 50% of mutated protein was used in mix - not majorly different to WT Po voltage curve
- mjust be dominant negative effect to have such a large effect
(there is slightly lower Cl- conductance)
what do dominant mutations in CLC1 do ? (thomsens)
- shift V1/2 more positive - so more positive potential is needed to open ClC1 channels - therefore there is more channels closed at rest - less negative resting potential - closer to AP threshold
- less Cl- selective
- dominant mutants effect WT subunits (DN effect)
what does V1/2 move to in CLCN1 I290M mutation?
- moves from -20 (WT) to +55 (mutant)
- so potential required for 1/2 of the channel to be open is more positive
- as resting potential is usually negative - less CLC1 channels are open
- less Cl- current into the cell as lower Po
- Resting membrane potential is more negative
- closer to threshold for AP
- AP fire more commonly/frequently
what is the recessive mutant in CLCN1?
E291K (glutamic acid to lysine)
-beckers?
why are carriers of the E291K mutations in CLCN1 asymptomatic for myotonia congenita and why is recessive condition more severe?
- because 50% of normal/WT protein ca produce high enough currents of Cl- for normal function
- but in full mutant there are no CLC1 currents - as there are no wt CLC1 channels - why recessive condition has more severe symtoms.
What effect does E291K have on voltage dependence/ v1/2?
there is no shift in voltage dependence so therefore - no change in v 1/2
- are only looking at what WT channels are present as mutant channels are not even made - are completely non - functional
give features of PARAmyotonia congenita
- autosomal dominant
- gain of function mutations in Nav1.4
- appears neonatally-infancy
- appears during exercise (worsens with activity)(NO warm up phenomenom)
- cold sensitive
- no hypertrophy
