Brain Advance Access published online on September 29, 2005
Brain, doi:10.1093/brain/awh639
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1 Department of Clinical Neurological Sciences, London Health Sciences Centre, London, ON, Canada
* To whom correspondence should be addressed. 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.
Received June 14, 2005
Revised August 22, 2005
Accepted August 26, 2005
Article
The primary periodic paralyses: diagnosis, pathogenesis and treatment
2 Department of Neurology, University of Texas Southwestern Medical Center, Dallas, TX, USA
3 Institute of Neurology, Queen Square, London, UK
4 UMR546, INSERM/UPMC, Pitié-Salpêtrière, Paris, France
5 UCSF Howard Hughes Medical Institute, San Francisco, CA, USA
6 University of Utah, Salt Lake City, UT, USA
7 University of Rochester, Rochester, NY, USA
S. L. Venance, E-mail: shannon.venance{at}lhsc.on.ca
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