Biannual Meeting of the PPA
Orlando, FL, 2011
Understanding PP
and
treatment of HypoPP
Frank Lehmann-Horn, Senior Research Professor
Electrical potentials P of skeletal muscle fibers
Distribution frequency %
P1
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
P2
K+ Battery
(mV)
-90
-80
-70
-60
Muscle strength dependent on resting potential P
Muscle fibers
Depolarized fibers can´t
develop force
-55 mV
-65 mV
-73 mV
Simple basis of PP weakness:
Many fibers are episodically or
permanently in the P2-state
-90mV
Hypokalemic Periodic Paralysis (HypoPP)
prevalence:
1:100,000; dominant transmission
onset of disease:
childhood or puberty
clinical features:
weakness episodes (at younger age) and/or
permanent 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)
HypoPP mutations are situated in S4 only and cause Na+ leak
II
Central pore
Calcium or sodium channel
situated in the cell membrane
I
VSD
III
IV
S4
Accessory Na+ pore along mutant S4
Due to the membrane leak
of the accessory Na+ pore,
the resting potential drops
to approx. -58 mV at which
fibers are paralyzed
P1
0.07
0.06
0.05
0.04
0.03
P2
0.02
0.01
0.00
-110
-100
-90
-80
-70
-60
-50
Em /mv
Usually strong
P2-fraction explains full-blown attack
-1
probability density (mV )
Weak after carb-rich meal
P2
0.08
0.04
P1
0.00
-90
-80
-70
-60
-50
-40
E (mV) Na+ pore
hypokalemia opens
m
Periodic paralysis: permanent weakness
P1
large P2-fraction
explains permanent weakness
P2
-90
-80
-70
-60
(mV)
Does the accessory pore really conduct Na+? More Na+ in the fibers?
Novel technique: 23Na-MRI IR
Control: low muscle Na+i content
1H-T1
1H-T2-STIR
NaCl
solution
23Na-IR
NaCl in
agarose
HypoPP with permanent weakness:
dystrophy, edema and intracellular Na+ accumulation
Therapy: shifting fibers from the P2- to the P1-state
P1
P1
P1
P2
P2
P2
(mV)
-90
-80
-70
Volunteer
-60
-90
-80
-70
-60
(mV)
-90
-80
-70
-60
(mV)
permanent weakness Strength improved
(large P2-fraction) by K+ and AA or CAI
Therapy: reduction of edema and Na+ overload
Control
HypoPP
before
treatment
HypoPP
during
treatment
control
untreated patient
Jurkat-Rott et al. PNAS 2009
Therapy also increases muscle strength
1,6
relative strength increase post/pre treatment
after therapy (acetazolamide)
1,5
1,4
1,3
before therapy
1,2
1,1
1
0,9
17
22
27
Na+ / mM
Jurkat-Rott et al. PNAS 2009
32
Response to an aldosterone antagonist
before therapy
After 6 months of therapy
Hypothesis: development of muscle dystrophy
normal
full muscle strength
triggers
25 y.
CAI, aldosterone
Antagonists, K+
52 y.
intracellular Na+ accumulation and edema
reversible weakness
with years
fibrosis and fatty replacement
irreversible weakness
80 y.
HypoPP family
Drugs which stabilize muscle fibers in the P1 state
Diet: high-K,
low NaCl-salt
low carbohydrate
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
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 dystrophy
and cardiomyopathy
corticoid treatment
T1w
STIR
DMD boy at age of 7 years:
minor degeneration,
however: already severe
edema and intracelluar Na
accumulation
!
Na-IR: intracellular Na+
T1w
STIR
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+]
Na-IR: intracellular Na+
Thanks to
Karin Jurkat-Rott (Ulm), Marc-André Weber (Heidelberg), & Eva Luise Köhler
View from Ulm University of
Ulm Munster and the Alpes