The primary periodic paralyses: diagnosis, pathogenesis and treatment.
Periodic paralyses (PPs) are rare inherited channelopathies that manifest as abnormal, often potassium (K)-sensitive, muscle membrane excitability leading to episodic flaccid paralysis. Hypokalaemic (HypoPP) and hyperkalaemic PP and Andersen-Tawil syndrome are genetically heterogeneous. Over the past decade mutations in genes encoding three ion channels, CACN1AS, SCN4A and KCNJ2, have been identified and account for at least 70% of the identified cases of PP and several allelic disorders. No prospective clinical studies have followed sufficiently large cohorts with characterized molecular lesions to draw precise conclusions. We summarize current knowledge of the clinical diagnosis, molecular genetics, genotype-phenotype correlations, pathophysiology and treatment in the PPs. We focus on unresolved issues including (i) Are there additional ion channel defects in cases without defined mutations? (ii) What is the mechanism for depolarization-induced weakness in Hypo PP? and finally (iii) Will detailed electrophysiological studies be able to correctly identify specific channel mutations? Understanding the pathophysiology of the potassium-sensitive PPs ought to reduce genetic complexity, allow subjects to be stratified during future clinical trials and increase the likelihood of observing true clinical effects. Ideally, therapy for the PPs will prevent attacks, avoid permanent weakness and improve quality of life. Moreover, understanding the skeletal muscle channelopathies will hopefully lead to insights into the more common central nervous system channel diseases such as migraine and epilepsy.
Venance
S L
SL
Department of Clinical Neurological Sciences, London Health Sciences Centre, London, ON, Canada. shannon.venance@lhsc.on.ca
Cannon
S C
SC
Fialho
D
D
Fontaine
B
B
Hanna
M G
MG
Ptacek
L J
LJ
Tristani-Firouzi
M
M
Tawil
R
R
Griggs
R C
RC
D000818:Animals; D002257:Carbonic Anhydrase Inhibitors / Q000627:therapeutic use; D005838:Genotype; D006801:Humans; D015640:Ion Channel Gating; D051379:Mice; D018345:Mice, Knockout; D023421:Models, Animal; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology; D009154:Mutation; D010245:Paralyses, Familial Periodic / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics; D010641:Phenotype; D011188:Potassium / Q000378:metabolism / Q000627:therapeutic use; D015221:Potassium Channels / Q000235:genetics / Q000378:metabolism; D015222:Sodium Channels / Q000235:genetics / Q000378:metabolism
D002257:Carbonic Anhydrase Inhibitors; D015221:Potassium Channels; D015222:Sodium Channels; D011188:Potassium