Understanding PP and 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 P (mV) P2 Distribution frequency %

Muscle strength dependent on resting potential P Muscle fibers -90mV -73 mV -65 mV -55 mV Depolarized 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/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 +, Ca 2+ 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 IIIIV Central pore Accessory Na + pore along mutant S4 S4 Calcium or sodium channel situated in the cell membrane

Weak after carb-rich meal P1 P2 P1 E m /mv Usually strong P2-fraction explains full-blown attack hypokalemia opens Na + pore

Periodic paralysis: permanent weakness large P2-fraction explains perma- nent weakness (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 1 H-T1 23 Na-IR 1 H-T2-STIR NaCl solution NaCl in agarose Novel technique: 23 Na-MRI IR Control: low muscle Na + i content

P1 P (mV) P1 P Volunteer Strength improved by K + and AA or CAI (mV) (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 after therapy (acetazolamide) before therapy Jurkat-Rott et al. PNAS 2009

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

Hypothesis: development of muscle dystrophy normal full muscle strength intracellular Na + accumulation and edema reversible weakness fibrosis and fatty replacement irreversible 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-salt low 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 dystrophy and cardiomyopathy corticoid treatment

T1wSTIR Na-IR: intracellular Na + Franzmann DMD boy at age of 7 years: minor degeneration, however: already severe edema and intracelluar Na accumulation !

T1wSTIR [Na + ] Sommer 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