Post on 14-Dec-2015
transcript
Understanding PPand
treatment of HypoPP
Biannual Meeting of the PPA Orlando, FL, 2011
Frank Lehmann-Horn, Senior Research Professor
Electrical potentials P of skeletal muscle fibers
P-values around -83 mV are most frequent (P1)
Second fraction around -60 mV (P2)
P is about 1/100 of the voltage of a car battery
K+ Battery
P1
-90 -80 -70 -60 (mV)
P2
Dis
trib
utio
n fr
eque
ncy
%
Muscle strength dependent on resting potential P
Muscle fibers
-90mV
-73 mV
-65 mV
-55 mVDepolarized fibers can´t develop force
Simple basis of PP weakness:Many fibers are episodically or permanently in the P2-state
prevalence: 1:100,000; dominant transmission
onset of disease: childhood or puberty
clinical features: weakness episodes (at younger age) and/orpermanent weakness, a progressive myopathy
weakness episodes: up to daily for several hours
Provocative factors: carbohydrates, sodium, resting periods after exercise, mental stress, cooling, fever, cortisol induce a drop in serum potassium
between episodes: blood potassium is normal
etiology: voltage sensor mutations (Na+, Ca2+ channels)
Hypokalemic Periodic Paralysis (HypoPP)
HypoPP mutations are situated in S4 only and cause Na+ leak
Due to the membrane leak of the accessory Na+ pore, the resting potential drops to approx. -58 mV at which fibers are paralyzed
VSD
III
III IV
Central pore
Accessory Na+ pore along mutant S4
S4
Calcium or sodium channelsituated in the cell membrane
Weak after carb-rich meal
-90 -80 -70 -60 -50 -400.00
0.04
0.08pr
obab
ility
den
sity
(m
V-1)
Em (mV)
P1
P2
P2
P1
-110 -100 -90 -80 -70 -60 -500.00
0.01
0.02
0.03
0.04
0.05
0.06
0.07
Em /mvUsually strongP2-fraction explains full-blown attack
hypokalemia opens Na+ pore
Periodic paralysis: permanent weakness
large P2-fraction explains perma-nent weakness
-90 -80 -70 -60 (mV)
P1
P2
Does the accessory pore really con-duct Na+? More Na+ in the fibers?
HypoPP with permanent weakness: dystrophy, edema and intracellular Na+ accumulation
1H-T1 23Na-IR1H-T2-STIR
NaCl solution
NaCl inagarose
Novel technique: 23Na-MRI IRControl: low muscle Na+
i content
P1
P2
-90 -80 -70 -60 (mV)
P1
P2
-90 -80 -70 -60
VolunteerStrength improved
by K+ and AA or CAI
(mV)-90 -80 -70 -60 (mV)
P1
P2
permanent weakness (large P2-fraction)
Therapy: shifting fibers from the P2- to the P1-state
control
untreated patient
Control
HypoPP before treatment
HypoPP during treatment
Jurkat-Rott et al. PNAS 2009
Therapy: reduction of edema and Na+ overload
Therapy also increases muscle strength
0,9
1
1,1
1,2
1,3
1,4
1,5
1,6
17 22 27 32
Na+ / mM
rela
tive
str
eng
th in
crea
se p
ost
/pre
tre
atm
ent
after therapy (acetazolamide)
before therapy
Jurkat-Rott et al. PNAS 2009
Hypothesis: development of muscle dystrophy
normalfull muscle strength
intracellular Na+ accumulation and edemareversible weakness
fibrosis and fatty replacementirreversible weakness
triggers CAI, aldosterone Antagonists, K+
25 y.
52 y.
80 y.
HypoPP family
with years
Drugs which stabilize muscle fibers in the P1 state
Potassium (fast & slow release)
Carbonic anhydrase inhibitors- Acetazolamide (Diamox)- Diclofenamide (Daranide)
Aldosterone antagonists- Spironolactone (Aldactone)- Eplerenone (Inspra)
Potassium-sparing diuretics- Triamterene (Dyrenium)- Amiloride (Midamor)
Potassium channel opener- Retigabine
Delayed K-channel blocker- 3,4-diaminopyridine; 3,4-DAP
At permanent weakness, continuous ingestion is required
Diet: high-K, low NaCl-saltlow carbohydrate
Similar MRI results for Duchenne muscular dystrophy as for PP – synergic therapeutical efforts
dystrophin deficiency
1:3,500 male births
rapid progression of skeletal muscle dystrophyand cardiomyopathy
corticoid treatment
T1w STIR
Na-IR: intracellular Na+
DMD boy at age of 7 years: minor degeneration, however: already severe edema and intracelluar Na accumulation
!
T1w STIR
[Na+]
DMD boy at age of 10 years: moderate degeneration and still severe edema and intracelluar Na accumulation
Na accumulation and edema preceed/cause degeneration
Na-IR: intracellular Na+