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Hyperkalemic periodic paralysis (hyperKPP) and paramyotonia congenita (PC) are genetic muscle disorders sharing the common features of myotonia and episodic weakness. In hyperKPP, patient symptoms and signs are worsened by elevated serum potassium, whereas in PC, muscle cooling exacerbates the condition. There are patients in whom features of both hyperKPP and PC are present. These diseases result from molecular alterations in the adult skeletal muscle sodium channel. This report summarizes our sodium channel mutation analysis in 25 families with hyperKPP and PC. We also report the putative disease-causing mutation in acetazolamide-responsive myotonia congenita, a related disease in which myotonia is worsened by potassium but in which episodic weakness does not occur. This missense mutation (I1160V) occurs at a very highly conserved position in the sodium channel, cosegregates with the disease, and was not present in any of a large panel of normal DNAs. Electrophysiologic characterization of specific mutations will lead to better understanding of the biophysics of this voltage-gated ion channel.

Carbonic anhydrase inhibitors can cause nephrolithiasis. We studied 20 patients receiving long-term carbonic anhydrase inhibitor treatment for periodic paralysis and myotonia. Three patients on acetazolamide (15%) developed renal calculi. Extracorporeal lithotripsy successfully removed a renal calculus in one patient and surgery removed a staghorn calculus in another, permitting continued treatment. Renal function remained normal in all patients. Nephrolithiasis is a complication of acetazolamide but does not preclude its use.

Treatment of paramyotonia congenita with acetazolamide has been shown to reduce myotonic symptoms but severe weakness has developed in some patients leading to a recommendation not to use the drug in this disorder. We studied a patient with the characteristic clinical and electrophysiological profile of paramyotonia congenita. Myotonia was effectively treated with a very low dose of acetazolamide and no weakness developed. We conclude that acetazolamide can be a safe and effective medication in paramyotonia congenita.

Acetazolamide has been shown to be effective prophylaxis for both hypokalemic and hyperkalemic paralysis. A patient with paramyotonia congenita, a related disorder with myotonia and episodic weakness, was studied during treatment with acetazolamide. Athough the patient's myotonia was virtually abolished, severe quadriparesis was produced during each trial of acetazolamide. This response distinguished this patient's condition from other forms of familial periodic paralysis and suggests that acetazolamide may be deleterious to some patients with periodic paralysis.

Myotonia can occur in the periodic paralyses, particularly the hyperkalemic form. The beneficial response to acetazolamide in hypokalemic and hyperkalemic periodic paralysis has led us to study the effect of acetazolamide in 9 patients with disorders having myotonia as the major problem, 7 with myotonia congenita and 2 with paramyotonia congenita. Patients were studied before acetazolamide administration with glucose and potassium loading tests. All patients had an increase in myotonia with potassium, but no weakness occurred with either test. Acetazolamide treatment decreased myotonia in all patients and in 3 proved the most satisfactory therapy. Side-effects during acetazolamide therapy included paresthesias in 5 patients and renal calculus in 1. Flaccid weakness occurred in a patient with paramyotonia congenita. Acetazolamide treatment was associated in all patients with partially compensated metabolic acidosis and lowering of serum potassium within the normal range. Kaliuresis was also noted during introduction of therapy. Acetazolamide appears to be an acceptable treatment for occasional patients with myotonia who are unresponsive to or intolerant of other therapies.

We have studied 14 patients from a kindred with an autosomal dominant form of myotonia, with features differing from most cases of autosomal dominant or recessive myotonia congenita. All patients had painful muscle stiffness that was provoked by fasting and oral potassium administration and was relieved by carbohydrate-containing foods. Muscle biopsies showed the presence of type 1, 2A, and 2B fibers, as opposed to the absence of type 2B fibers seen in some patients with myotonia congenita. Acetazolamide was dramatically effective in alleviating myotonia in all patients and was more effective than other antimyotonic agents.

Acetazolamide is effective treatment for myotonia in certain patients with myotonia congenita. Since potassium metabolism may be abnormal in myotonia congenita, we studied the effect of acetazolamide administration on potassium regulation and glucose disposal, using the euglycemic insulin clamp technique in patients with myotonic disorders and in normal subjects. Glucose disposal was normal in patients with myotonia congenita; administration of acetazolamide increased glucose disposal in normal subjects and in patients with myotonia congenita. By contrast, patients with myotonic dystrophy showed insulin resistance and decreased glucose disposal that was not improved by acetazolamide administration. Patients with myotonia congenita had elevated potassium levels in the basal state and a greater fall in potassium level during the insulin clamp procedure than controls. Patients with myotonic dystrophy had normal or low basal potassium levels and a subnormal decrease in potassium level during the insulin clamp procedure. Administration of acetazolamide did not alter these abnormalities in potassium metabolism in patients with either myotonia congenita or myotonic dystrophy.