TY - JOUR
T1 - The primary periodic paralyses
T2 - Diagnosis, pathogenesis and treatment
AU - Venance, S. L.
AU - Cannon, S. C.
AU - Fialho, D.
AU - Fontaine, B.
AU - Hanna, M. G.
AU - Ptacek, L. J.
AU - Tristani-Firouzi, M.
AU - Tawil, R.
AU - Griggs, R. C.
N1 - Funding Information:
This report is dedicated to the memory of Philip G. McManis (1953–2004). The authors thank Shirley Thomas for organizing the IPP conference and assisting in the preparation of this manuscript. The authors belong to the Consortium for Clinical Investigation of Neurological Channelopathies (CINCH) supported by NIH RU54 RR019482-03 (NINDS/ ORD).
Funding Information:
This report summarizes the findings of an International Conference on the Pathogenesis and Treatment of the PPs (Rochester NY, October 31, 2004). The conference was generously supported by an NIH conference grant 1R13 NS050966-01 as well as the Muscular Dystrophy Association and the Association Franc¸ aise contre les Myopathies.
PY - 2006/1
Y1 - 2006/1
N2 - 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.
AB - 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.
KW - Andersen-Tawil syndrome
KW - Channelopathy
KW - Episodic weakness
KW - Periodic paralysis
KW - Potassium-sensitive
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U2 - 10.1093/brain/awh639
DO - 10.1093/brain/awh639
M3 - Review article
C2 - 16195244
AN - SCOPUS:30344434616
SN - 0006-8950
VL - 129
SP - 8
EP - 17
JO - Brain
JF - Brain
IS - 1
ER -