Table 3.

Skeletal muscle channelopathies.

Disease	Gene (protein)	Pharmacotherapy	Pharmacological perspectives
Non-dystrophic myotonias including myotonia congenita (MC), paramyotonia congenita (PMC), and sodium channel myotonia (SCM)	CLCN1 (ClC-1) SCN4A (Nav1.4)	Symptomatic (MC) and targeted (PMC and SCM) therapy aims at reducing skeletal muscle hyperexcitability: – Mexiletine (first choice), carbamazepine, flecainide, propafenone are use-dependent Nav channels blockers – Charbonic anydrase inhibitors such as acetazolamide likely increase BK channels activity and ClC-1 channels open probability	– Enhancement of Nav slow inactivation with ranolazine and lacosamide – Repurposing of marketed Nav blockers, such as riluzole – Development of more selective and use-dependent Nav blockers – Development of ClC-1 channel activators and pharmacological chaperones for MC – Development of a pharmacogenetics approach
Periodic paralysis (PP) including hyperkalemic periodic paralysis (HyperPP), hypokalemic periodic paralysis types 1 and 2 (HypoPP1 and 2), Andersen-Tawil syndrome, tyreotoxic periodic paralysis	SCN4A (Nav1.4) CACNA1S (Cav1.1) KCNJ2 (Kir2.1) KCNJ6 (Kir2.6)	Symptomatic therapy aims at reducing frequency and severity of paralytic attacks and at restoring serum K+ levels: – Carbonic anhydrase inhibitors such as acetazolamide and dichlorphenamide (orphan drug for PP) likely increase BK channels activity and ClC-1 channels open probability – The β2-agonist salbutamol and glucose/insulin activate Na+/K+-ATPase and restore serum K+ levels in HyperPP – Potassium supplements or K+ sparing diuretics in HypoPP – Benzothiazide diuretics such as hydrochlorothiazide in HyperPP	– Development of guanidinium derivatives and other Igp blockers in HypoPP – Development of KATP openers selective for skeletal muscle channels – Bumetanide, a loop diuretic that inhibits the Na/K/2Cl co-transporter, was useful in a mouse model of HypoPP