1. Biannual Meeting of the PPA
Orlando, FL, 2011
Understanding PP
and
treatment of HypoPP
Frank Lehmann-Horn, Senior Research Professor

2. 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
Distribution frequency % P2
K+ Battery
(mV)
-90
-80
-70
-60

3. 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

4. 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)

5. HypoPP mutations are situated in S4 only and cause Na+ leak
Central pore
Calcium or sodium channel
situated in the cell membrane II I
VSD
III IV
Due to the membrane leak of the accessory Na+ pore, the resting potential drops to approx. -58 mV at which fibers are paralyzed S4
Accessory Na+ pore along mutant S4

6. P2-fraction explains full-blown attack
0.07
0.06
0.05
0.04
0.03 P2
0.02
0.01
0.00
-110
-100
-90
-80
-70
-60
-50
Usually strong E
/mv m
P2-fraction explains full-blown attack P2
Weak after carb-rich meal P1
hypokalemia opens Na+ pore

7. Periodic paralysis: permanent weakness
large P2-fraction
explains perma-
nent weakness P2
-90
-80
-70
-60
(mV)
Does the accessory pore really con-
duct Na+? More Na+ in the fibers?

8. Novel technique: 23Na-MRI IR Control: low muscle Na+i content
1H-T1
1H-T2-STIR
23Na-IR
NaCl
solution
NaCl in
agarose
HypoPP with permanent weakness: dystrophy, edema and intracellular Na+ accumulation

9. Therapy: shifting fibers from the P2- to the P1-state
(mV)
-90
-80
-70
-60
-90
-80
-70
-60
(mV)
-90
-80
-70
-60
(mV)
permanent weakness
(large P2-fraction)
Strength improved
by K+ and AA or CAI
Volunteer

10. Therapy: reduction of edema and Na+ overload
Control
HypoPP
before
treatment
during
control
untreated patient
Jurkat-Rott et al. PNAS 2009

11. Therapy also increases muscle strength
after therapy (acetazolamide)
before therapy
Jurkat-Rott et al. PNAS 2009

12. Response to an aldosterone antagonist After 6 months of therapy
before therapy
After 6 months of therapy

13. Hypothesis: development of muscle dystrophy
normal
full muscle strength
25 y.
CAI, aldosterone
Antagonists, K+
triggers
52 y.
intracellular Na+ accumulation and edema
reversible weakness
with years
80 y.
fibrosis and fatty replacement
irreversible weakness
HypoPP family

14. 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
Diet: high-K,
low NaCl-salt
low carbohydrate
At permanent weakness, continuous ingestion is required

15. 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

16. T1w
STIR
DMD boy at age of 7 years: minor degeneration, however: already severe edema and intracelluar Na accumulation !
Na-IR: intracellular Na+
Franzmann

17. Na accumulation and edema preceed/cause degeneration
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+
Sommer

18. Thanks to
Karin Jurkat-Rott (Ulm), Marc-André Weber (Heidelberg), & Eva Luise Köhler

19. View from Ulm University of Ulm Munster and the Alpes