There are no consensus guidelines for the treatment of hypoPP. Current pharmacologic agents commonly used include potassium supplements, potassium-sparing diuretics, and carbonic anhydrase inhibitors (acetazolamide and dichlorphenamide). Dichlorphenamide is the only therapy for hypoPP to have undergone a randomized double-blind placebo-controlled crossover trial. This trial showed significant efficacy of dichlorphenamide in reducing attack frequency, but the inclusion criteria were based on a clinical diagnosis of hypoPP and not genetic confirmation.8,9
A second randomized controlled trial of the efficacy of dichlorphenamide in genotyped cases of both hypokalemic and hyperkalemic periodic paralysis is currently open (see www.clinicaltrials.gov
). Aside from these trials, there is very little trial evidence to support the use of any treatment in hypoPP and no randomized controlled trial evidence supporting the most common choice, acetazolamide.
The data presented here suggest that at least half the patients treated with acetazolamide do not get a satisfactory response. A tentative correlation between detrimental response and genotype does emerge, and those patients with substitutions to glycine of arginine residues situated toward the extracellular side of the voltage sensors of either Cav1.1 or Nav1.4 () may be predicted not to respond to acetazolamide. This observation is particularly noteworthy in light of experimental data indicating that the deleterious effects of the R672G substitution on channel gating are insensitive to reductions in pH in vitro, which is in contrast to the deleterious effects of the R669H mutation that were ameliorated by an acidic pH. These in vitro observations predict that such patients would not respond to acetazolamide, which produces a metabolic acidosis.10
The deleterious effects studied relate to the ion-selective α pore. More recent studies have identified an anomalous proton-selective gating pore due to R669H and R672H SCN4A
mutations and a less selective cation-conducting pore in the R672G SCN4A
Similar gating pores have yet to be identified in the CACNA1S
mutations but are proposed as a likely pathomechanism. An additional suggestion is that the R to H substitutions are likely to have a greater effect on pH concentration gradients, and, as a result, there is more likelihood of a beneficial response to acetazolamide therapy than with the R to G substitutions. Overall, these data support the view that it is important to achieve a genetic diagnosis in each patient to help guide treatment.
Without randomized controlled trials, the exact efficacy of acetazolamide is unknown. In addition, its mechanism of action is unclear,13
although it has become first-line therapy and has been suggested to have benefit for the majority of patients for almost half a century.14
Our data suggest, however, that the response rate may be more modest than generally considered at present.
This retrospective clinical and literature evaluation collates the single largest evaluation of genotyped hypoPP patients reported. Our observations indicate that acetazolamide has a benefit for at most only 50% of patients. However, we observed that the response rate improves to 60% if only those patients with common CACNA1S mutations are considered. Furthermore, there is a suggestion that patients with arginine substitutions to glycine in the residues of the voltage sensor near the extracellular side of the sarcolemma may be predicted to respond poorly, and this is supported by experimental observations.
Conclusive evidence for a unified approach to the treatment of hypoPP is lacking, and retrospective data as outlined here have limitations. However, the data reported here support the view that randomized controlled trials of available therapies are required. Furthermore, given that the response rate is on the order of 50%, we suggest that new therapies need to be developed for patients with hypoPP.