Genetics May Hold the Key to Decoding Periodic Paralysis

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Developing guidelines on management and prevention of primary periodic paralysis is difficult due to the rarity of the condition.
Developing guidelines on management and prevention of primary periodic paralysis is difficult due to the rarity of the condition.

Primary periodic paralysis, a rare genetic disorder, describes several disorders of spontaneous muscle weakness or paralysis that may last from minutes to days.1 Types of periodic paralysis include hypokalemic periodic paralysis (hypoPP, estimated prevalence 1 in 100,000 people), hyperkalemic periodic paralysis (hyperPP; estimated prevalence 1 in 200,000 people), and Anderson-Tawil syndrome (ATS; estimated prevalence 1 in 1,000,000 people). All are autosomal-dominant disorders in which genetic mutations cause skeletal muscle channelopathies.1

Hypokalemic Periodic Paralysis

This sudden muscle weakness or temporary paralysis, usually in the arms and legs, first appears during childhood or adolescence.2 More men are affected by this disorder than are women. The attacks can last for hours or days, and their frequency ranges from daily to monthly.1 There is usually no warning that precedes the attacks, though case reports mention high-carbohydrate diets and vigorous exercise.2 The attacks may be precipitated by a virus, menstruation, certain medications (eg, insulin, beta agonists, corticosteroids), lack of sleep, or rest after exercise.3 While people with the disorder eventually regain their muscle strength, they may experience muscle fatigue later in life.2

As the name implies, people with hypoPP have low levels of potassium in their blood during an episode of muscle weakness or paralysis.2 Researchers are still mystified about how hypokalemia affects the muscles.

Diagnosing hypoPP includes genetic testing. Mutations in the CACNA1S or SCN4A genes affect the flow of the sodium or calcium channels, which prevents the necessary contractions needed for muscle movement.1,2 While most people with these gene mutations have hypoPP, a small subset of patients with this condition do not have the mutation.2

Other criteria that support the diagnosis of hypoPP include more than 2 attacks of muscle weakness with reported serum potassium levels <3.5 mEq/L and an attack of muscle weakness in the proband and at least 1 attack in a relative with low potassium levels, and 3 of 6 clinical or laboratory findings1:

  • Onset occurring in the first or second decade
  • Attack lasting more than 2 hours (and involving at least 1 limb
  • Presence of triggers (eg, high-carbohydrate meal, stress, rest after exercise)
  • Improvement with potassium administration
  • Family history or confirmed skeletal sodium or calcium channel mutation
  • Positive McManis long exercise test

During an acute attack, nonpharmacologic treatment for hypoPP includes walking and shaking the arms. Paradoxically, the goal of replenishing potassium should not include total body potassium, but rather should restore the levels to the intracellular muscle compartment.1

To prevent future attacks, patients should avoid high-carbohydrate diets, high-salt meals, alcohol, and stress.1 Chronic treatment may include slow-release potassium, dichlorphenamide, acetazolamide, and potassium-sparing diuretics.1

Hyperkalemic Periodic Paralysis

HyperPP first manifests in infancy or early childhood.4 Attacks most often occur after eating potassium-rich food, fasting, stress, pregnancy, exposure to cold, or rest after exercise.1 Patients with the disorder frequently experience muscle stiffness between episodes of paralysis.1

Genetic tests are used to confirm hyperPP, which involves a mutation in the SCN4A gene.1,4 The supportive diagnostic criteria for the disorder include a serum potassium level >4.5 mEq/L during 2 or more attacks, an attack of muscle weakness in the proband, plus 1 attack in a relative with elevated potassium levels, and 3 of 6 features1:

  • Onset prior to the third decade
  • Attacks involve at least 1 limb
  • Triggers of exercise or stress
  • Myotonia
  • Family history or confirmed skeletal sodium channel mutation
  • Positive McManis long exercise test

Like hypoPP, attacks of hyperPP could be managed with mild exercise.1 Some episodes resolve with a carbohydrate meal.1 To lower potassium levels, beta agonists can be considered, as can inhaled salbutamol.

Preventing hyperPP can include adding more frequent carbohydrate snacks to the diet as well as avoiding potassium-rich foods.1 Chronic therapy may include dichlorphenamide or acetazolamide to reduce the severity and frequency of attacks.

Anderson-Tawil Syndrome

This disorder affects not only skeletal muscle but also causes cardiac arrhythmia and facial and skeletal abnormalities.1 Patients with ATS have distinct facial and skeletal characteristics that include a small jaw, low-set ears, ocular hypertelorism, short stature, clinodactyly, syndactyly, broad forehead, and scoliosis.1

Cardiac symptoms such as syncope or palpitations first present in the first or second decade of life.1 The syndrome can be fatal because mutations in the KCNJ2 gene can cause ventricular arrhythmias.

Like the other periodic paralyses, ATS can be confirmed with a genetic test.1 Supporting diagnostic criteria for the syndrome include 2 of the 3 characteristics: periodic paralysis; symptomatic or electrocardiographic evidence of cardiac arrhythmias; or anomalies in the face, jaw, digits, and placement of the eyes or ears. In addition to the criteria, having a relative who meets 2 of the 3 characteristics of the syndrome would confirm the diagnosis.1

Because attacks can be associated with all levels of potassium, it is important to test before administering supplements for hypokalemia.1 The therapies common to all periodic paralyses are acetazolamide and dichlorphenamide.

Neurologists and cardiologists should manage the patient with ATS collaboratively to address the arrhythmias and sudden muscle weakness. Drug-drug interactions are especially important in patients with this syndrome because thiazide diuretics could prolong the QT interval, and several antiarrhythmic drugs could trigger neuromuscular symptoms.1

References

  1. Statland JM, Fontaine B, Hanna MG, et al. Review of the diagnosis and treatment of periodic paralysis [published online November 10, 2017]. Muscle Nerve. doi: 10.1002/mus.26009
  2. Genetics Home Reference. Hypokalemic periodic paralysis. https://ghr.nlm.nih.gov/condition/hypokalemic-periodic-paralysis. Published February 27, 2018. Accessed February 27, 2018.
  3. Venance SL, Cannon SC, Fialho D, et al. The primary periodic paralyses: diagnosis, pathogenesis and treatment. Brain. 2006;129(Pt 1):8-17.
  4. Lister Hill National Center for Biomedical Communications. Hyperkalemic periodic paralysis. https://ghr.nlm.nih.gov/condition/hyperkalemic-periodic-paralysis. Accessed February 19, 2018.
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