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 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

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 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

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

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?

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

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

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

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

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

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

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

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+ Franzmann

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

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

View from Ulm University of Ulm Munster and the Alpes