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Understanding HypoPP Treatment Through Muscle Potentials

Explore the prevalence, features, and treatment of Hypokalemic Periodic Paralysis (HypoPP). Learn about muscle fiber potentials, sodium channels mutations, and therapeutic approaches to manage permanent weakness. Dive into the innovative 23Na-MRI technique for muscle evaluation.

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Understanding HypoPP Treatment Through Muscle Potentials

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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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