• Information
  1. Clinical Classification
  2. Hyperkalemic Periodic Paralysis
  3. Paramyotonia Congenita
  4. Potassium-Activated Myotonia
  5. Hypokalemic Periodic Paralysis
  6. Thyrotoxic Periodic Paralysis
  7. Andersen's Syndrome
  8. Myotonia Congenita
  9. Episodic Ataxia

A. Clinical Classification

1. Hyperkalemic Periodic Paralysis
2. Paramyotonia Congenita
3. Potassium-Activated Myotonia
4. Hypokalemic Periodic Paralysis
5. Thyrotoxic Periodic Paralysis (acquired)
6. Andersen's Syndrome
7. Myotonia Congenita
8. Episodic Ataxia
9. The majority of these syndromes are familial except as indicated

B. Hyperkalemic Periodic Paralysis

1. Attacks of weakness occur during periods of hyperkalemia
2. Onset of symptoms in infancy or early childhood
3. Characteristics of Attacks
   1. Attacks are frequent, lasting 1-3 hours
   2. Precipitated by rest after exercise and by emotional stress
   3. Potassium (K+) levels may be normal or even low after onset of an attack
   4. Patients with "normokalemic periodic paralysis" actually have hyperkalemic form
   5. Exertion generally improves weakness
   6. Interattack weakness develops only after years of acute attacks
4. Evaluation
   1. Disease is defined by precipitation of attack after K+ loading
   2. Disease is NOT defined by level of potassium during or after an attack
   3. Creatine kinase levels (and other muscle enzymes) are elevated
   4. Electromyography (EMG) usually shows myotonia
   5. Muscle biopsy is usually abnormal, with vacuoles, degenerating, or atrophic fibers
5. Molecular Genetics
   1. Caused by various mutations in the sodium (Na+) channel gene SCN4A
   2. Majority of patients have either T704M or M1592 mutations in alpha gene
   3. These mutations are found in membrane spanning semgnets of Na+ channel
   4. Physiologic basis for these disease-causing mutations is under investigation
6. Treatment
   1. Responds to acetazolamide, as do all of the Na+ channel disorders
   2. Mechanism of action of carbonic anhydrase inhibitors is not clear
   3. Thiazide diuretics and low K+ diet are recommended
   4. Frequent monitoring of potassium levels is very important
7. Prognosis
   1. Initially, strength is normal between attacks
   2. Over years, in the absence of treatment, weakness develops between attacks

C. Paramyotonia Congenita

1. Characteristics
   1. Myotonia worsens with activity ("paradoxical myotonia")
   2. Cold provokes or exacerbates myotonia
   3. Interattack weakness develops after years of attacks
   4. Majority of patients are hyokalemic during attacks
2. Evaluation
   1. Careful history noting cold effects and changes in weakness with activity
   2. Creatine kinase levels (and other muscle enzymes) may be elevated
   3. Potassium loading may precipitate attacks in a minority of patients
   4. Diagnosis by cold-induced alterations in CMAP amplitude on EMG
3. Molecular Genetics
   1. Caused by various mutations in the sodium (Na+) channel gene SCN4A
   2. At least 6 different mutations have been found in these patients
   3. Three of the 6 involve mutations of R1448 to either H, C or P amino acids
   4. Majority of these 6 mutations are found in transmembrane segments
4. Treatment
   1. Responds to acetazolamide and other carbonic anhydrase inhibitors
   2. Mechanism of action of carbonic anhydrase inhibitors is not clear
   3. Mexilitine or tocainide is also used for adjunctive treatment
   4. Frequent monitoring of potassium levels is very important
5. Prognosis
   1. Initially, strength is normal between attacks
   2. Over years, in the absence of treatment, weakness develops between attacks

D. Potassium-Activated Myotonia

1. Episodic myotonia worsened by potassium loading
2. Paralysis does not occur, as it does in hyperkalemic periodic paralysis
3. Cold does not affect the attacks
4. Molecular Genetics
   1. Caused by various mutations in the Na+ channel gene SCN4A
   2. At least 2 mutations found in patients with K+ activated myotonia
   3. Other mutations found in patients with cold-sensitive and K+ activated myotonia
5. Treatment
   1. Low potassium diet
   2. Carbonic anhydrase inhibitors
   3. Thiazide diuretics may be useful
   4. Frequent monitoring of potassium levels is very important

E. Hypokalemic Periodic Paralysis

1. Attacks of weakness occur during periods of hypokalemia
   1. About 2/3 of patients have a family history of the disease
   2. The remainder likely due to spontaneous mutations
   3. Familial transmission occurs in an autosomal dominant fashion
2. Onset of symptoms usually before age 20, but as early as age 3-4
   1. Attacks always begin before age 30
   2. Appearance of attacks after age 30 usually indicates other condition
   3. Such conditions include either thyrotoxic periodic paralysis or secondary hypokalemia
3. Characteristics of Attacks
   1. Severe weakness of the limbs occurs spontaneously
   2. Paralysis occurs without pain or changes in level of consciousness
   3. Limbs are primarily affected; facial and respiratory muscles usually spared
   4. Patients may become temporarily quadraplegic
   5. Attacks typically last for 3-4 hours, but may persist up to 24 hours
   6. Attacks worse in males than females
   7. Attacks usually follow exercise (at rest), or during sleep
4. Evaluation
   1. Serum K+ level usually low, but may be low normal, during an attack
   2. Reducing K+ levels will precipitate an attack
   3. Weakness improves with gentle exercise
   4. Eyelid myotonia is often present even between attacks
   5. EMG is generally not helpful for diagnosis between attacks
   6. Muscle fibers in this disease are permantely depolarized by 10-15mV
   7. Muscle biopsy shows vacuoles and/or atrophic changes
5. Molecular Genetics
   1. Disorder of voltage-gated calcium (Ca2+) channel gene, CACNL1A3, chromosome 1q
   2. Dihydropyridine calcium blockers binds to the CACNL1A3 protein product
   3. More than 3 mutations causing this disease have been identified
   4. The physiologic basis for hypokalemic PP remains unclear, however
6. Treatment
   1. Oral potassium loading during attacks will shorten duration
   2. Intravenous K+ should be avoided (dextrose solutions will reduce serum K+ levels)
   3. Attacks are prevented by acetazolamide or other carbonic anhydrase inhibitors
   4. Acetazolamide will worsen condition in some patients
   5. Triampterene or spironolactone will usually be effective in such patients
   6. Low carbohydrate, low Na+ diet recommended
7. Prognosis
   1. Initially, strength is normal between attacks
   2. Over years, in the absence of treatment, weakness develops between attacks

F. Thyrotoxic Periodic Paralysis

1. Acquired, sporadic disease associated with underlying thyrotoxicosis
2. Resolves with treatment of thyrotoxicosis
3. Always associated with hypokalemia
4. About 95% of cases occur in men, more common in Asians
5. Evaluation
   1. Suspect diagnosis in persons developing periodic paralysis after age 30
   2. Typical signs and symptoms of thyrotoxicosis are often completely lacking
   3. Low TSH with increased radioiodine uptake by thyroid are diagnostic
6. Treatment
   1. Purely aimed at thyroid dysfunction
   2. ß-adrenergic blockers can be of some benefit prior to definitive therapy
   3. The periodic paralysis does not respond to acetazolamide
7. Prognosis is good if underlying thyrotoxicosis is treated

G. Andersen's Syndrome

1. Characteristics
   1. Potassium-sensitive periodic paralysis
   2. Frequent ectopic ventricular premature beats
   3. Bigemini or bidirectional tachycardias common
   4. Short stature, hypertelorism, low set ears, mandibular hypoplasia, clinodactyly
2. Evaluation
   1. Usually presents as arrhythmia detected on physical exam
   2. Raising serum K+ precipitates weakness, but normalizes electrocardiogram (ECG)
   3. Lowering serum K+ improves strength, but worsens ECG abnormalities
   4. Occasional patients can develop weakness with hypokalemia

H. Myotonia Congenita

1. Two forms: autosomal recessive (Becker) and autosomal dominant (Thomsen)
2. Both caused by mutations in the voltage gated chloride channel (CLCN1 gene)
3. Becker's Disease
   1. Autosomal recessive disorder
   2. Myotonia
   3. Transient weakness after initial muscle contraction, gradually returning to normal
   4. Often mistaken for muscular dystrophy or periodic paralysis
   5. Muscles are generally large or normal in size (contrast with muscular dystrophy)
   6. EMG shows myotonia
   7. Several different mutations in chloride channel gene CLCN1 can cause disease
   8. Responds to acetazolamide; mexilitine, tocainide may be useful
4. Thomsen's Disease
   1. Autosomal dominant disorder
   2. Painless myotonia
   3. Myotonia improves with exercise
   4. EMG shows myotonia
   5. Several different mutations in chloride channel gene CLCN1 can cause disease
   6. Does not respond to acetazolamide
   7. Quinidine, procainamide, or phenytoin are generally effective

I. Episodic Ataxia

1. Group of disorders resulting from hyperexcitabiity of central nervous system
2. Patients often feel weak or paralyzed during inability to perform motor activities
3. Usually, patients experience a sudden loss of balance

References

1. Ptacek L. 1998. Am J Med. 105(1):58