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

  2. 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

  3. 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

  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 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

  6. 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

  7. 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?

  8. 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

  9. 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

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

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

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

  13. 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

  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. 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

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

  19. Thank you for your attention View from Ulm University of Ulm Munster and the Alpes

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