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

After 6 months of therapybefore therapy

Response to an aldosterone antagonist

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+

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

View from Ulm University of Ulm Munster and the Alpes