title: Acetazolamide efficacy in hypokalemic periodic paralysis and the predictive role of genotype.
abstract: OBJECTIVE
  Acetazolamide has been the most commonly used treatment for hypokalemic periodic paralysis since 1968. However, its mechanism of efficacy is not fully understood, and it is not known whether therapy response relates to genotype. We undertook a clinical and genetic study to evaluate the response rate of patients treated with acetazolamide and to investigate possible correlations between response and genotype.
  
  
  METHODS
  We identified a total of 74 genotyped patients for this study. These included patients who were referred over a 15-year period to the only U.K. referral center or to a Chinese center and who underwent extensive clinical evaluation. For all genotyped patients, the response to acetazolamide therapy in terms of attack frequency and severity was documented. Direct DNA sequencing of CACNA1S and SCN4A was performed.
  
  
  RESULTS
  Only 46% of the total patient cohort (34 of 74) reported benefit from acetazolamide. There was a greater chance of benefit in patients with mutations in CACNA1S (31 responded of 55 total) than in those with mutations in SCN4A (3 responded of 19 total). Patients with mutations that resulted in amino acids being substituted by glycine in either gene were the least likely to report benefit.
  
  
  CONCLUSIONS
  This retrospective study indicates that only approximately 50% of genotyped patients with hypokalemic periodic paralysis respond to acetazolamide. We found evidence supporting a relationship between genotype and treatment response. Prospective randomized controlled trials are required to further evaluate this relationship. Development of alternative therapies is required.
authors.affiliation: Medical Research Council Centre for Neuromuscular Disease, Department of Molecular Neuroscience UCL, Institute of Neurology and National Hospital for Neurology and Neurosurgery Queen Square London, UK.
authors.forename: E
authors.initials: E
authors.lastname: Matthews
authors.forename: S
authors.initials: S
authors.lastname: Portaro
authors.forename: Q
authors.initials: Q
authors.lastname: Ke
authors.forename: R
authors.initials: R
authors.lastname: Sud
authors.forename: A
authors.initials: A
authors.lastname: Haworth
authors.forename: M B
authors.initials: MB
authors.lastname: Davis
authors.forename: R C
authors.initials: RC
authors.lastname: Griggs
authors.forename: M G
authors.initials: MG
authors.lastname: Hanna
mesh_terms: D000086:Acetazolamide / Q000494:pharmacology / Q000627:therapeutic use*; D002257:Carbonic Anhydrase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D015331:Cohort Studies; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D005838:Genotype; D006801:Humans; D020514:Hypokalemic Periodic Paralysis / Q000188:drug therapy* / Q000235:genetics*; D008297:Male; D011237:Predictive Value of Tests; D012189:Retrospective Studies
chemical_list: D002257:Carbonic Anhydrase Inhibitors; D000086:Acetazolamide
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