Frank Lehmann-Horn, Senior Research Professor
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Frank Lehmann-Horn, Senior Research Professor. Biannual Meeting of the PPA Orlando, FL, 2011. Understanding PP and treatment of HypoPP. Electrical potentials P of skeletal muscle fibers. P1. K + Battery. P -values around -83 mV are most frequent (P1)

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Understanding PP and treatment of HypoPP

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Understanding pp and treatment of hypopp

Frank Lehmann-Horn, Senior Research Professor

Biannual Meeting of the PPA

Orlando, FL, 2011

Understanding PP

and

treatment of HypoPP


Understanding pp and treatment of hypopp

Electrical potentials P of skeletal muscle fibers

P1

K+ Battery

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

(mV)

-90

-80

-60

-70


Understanding pp and treatment of hypopp

Muscle fibers

-55 mV

-65 mV

-73 mV

-90mV

Muscle strength dependent on resting potential P

Depolarized fibers can´t

develop force

Simple basis of PP weakness:

Many fibers are episodically or

permanently in the P2-state


Understanding pp and treatment of hypopp

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)


Understanding pp and treatment of hypopp

HypoPP mutations are situated in S4 only and cause Na+ leak

Central pore

II

I

VSD

III

IV

S4

Accessory Na+ pore along mutant S4

Calcium or sodium channel

situated in the cell membrane

Due to the membrane leak of the accessory Na+ pore, the resting potential drops to approx. -58 mV at which fibers are paralyzed


Understanding pp and treatment of hypopp

0.07

0.06

0.05

0.04

0.03

0.02

0.01

0.00

-110

-100

-90

-80

-70

-60

-50

P1

P2

Usually strong

E

/mv

m

P2-fraction explains full-blown attack

P2

Weak after carb-rich meal

P1

hypokalemia opens Na+ pore


Understanding pp and treatment of hypopp

Periodic paralysis: permanent weakness

P1

P2

-90

-80

-70

-60

(mV)

large P2-fraction

explains perma-

nent weakness

Does the accessory pore really con-

duct Na+? More Na+ in the fibers?


Understanding pp and treatment of hypopp

1H-T2-STIR

23Na-IR

1H-T1

NaCl in

agarose

NaCl

solution

HypoPP with permanent weakness: dystrophy, edema and intracellular Na+ accumulation

Novel technique: 23Na-MRI IRControl: low muscle Na+i content


Understanding pp and treatment of hypopp

P1

P2

-90

-80

-60

-70

Therapy: shifting fibers from the P2- to the P1-state

P1

P1

P2

P2

(mV)

-90

-80

-70

-60

(mV)

-90

-80

-70

-60

(mV)

permanent weakness

(large P2-fraction)

Strength improved

by K+ and AA or CAI

Volunteer


Understanding pp and treatment of hypopp

Therapy: reduction of edema and Na+ overload

Control

HypoPP

before

treatment

HypoPP

during

treatment

control

untreated patient

Jurkat-Rott et al. PNAS 2009


Understanding pp and treatment of hypopp

Therapyalso increases muscle strength

after therapy (acetazolamide)

before therapy

Jurkat-Rott et al. PNAS 2009


Understanding pp and treatment of hypopp

Response to an aldosterone antagonist

before therapy

After 6 months of therapy


Understanding pp and treatment of hypopp

Hypothesis: development of muscle dystrophy

25 y.

52 y.

80 y.

HypoPP family

normal

full muscle strength

CAI, aldosterone

Antagonists, K+

triggers

intracellular Na+ accumulation and edema

reversible weakness

with years

fibrosisand fatty replacement

irreversible weakness


Understanding pp and treatment of hypopp

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


Understanding pp and treatment of hypopp

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


Understanding pp and treatment of hypopp

T1w

STIR

DMD boy at age of 7 years: minor degeneration, however: already severe edema and intracelluar Na accumulation

!

Na-IR: intracellular Na+

Franzmann


Understanding pp and treatment of hypopp

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-IR: intracellular Na+

[Na+]

Sommer


Understanding pp and treatment of hypopp

Thanks to

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


Understanding pp and treatment of hypopp

Thank you for your attention

View from Ulm University of

Ulm Munster and the Alpes


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