Clinical Guidance

Large-scale studies of the natural history of primary hypokalemic periodic paralysis (hypoPP) have not been performed. Thus, knowledge of the natural history relies largely on personal observations and on individual cases that have been published with a retrospective description of the individual disease history. Pattern of attacks. The natural history and expressivity vary greatly over time. Frequency ranges from a single occurrence of a paralytic attack that may be triggered by exceptional circumstances (extreme physical effort, specific medical intervention) to spontaneous recurrent attacks of variable frequency (ranging from multiple attacks daily to less frequent attacks).

Source: GeneReviews — "Hypokalemic Periodic Paralysis"

Penetrance

In general, the penetrance of this disorder is high (≥90%) in males and reduced in females. An exception to this occurs with pathogenic variants with an arginine-to-glycine substitution for which high penetrance in males and females is noted .

Source: GeneReviews — "Hypokalemic Periodic Paralysis"

Differential Diagnosis

The following signs and symptoms suggest a diagnosis other than hypokalemic periodic paralysis (hypoPP): • Associated sensory symptoms, including pain or tenderness • Sensory loss could suggest polyneuropathy such as Guillain-Barr syndrome. • Pain could suggest myositis; however, some individuals with hypoPP report paralytic episodes as painful. • Urinary retention or constipation, which may be observed in other causes of acute or subacute paralysis, but can occur rarely in hypoPP • Associated symptoms that suggest myasthenia or involvement of the neuromuscular junction, including: • Ptosis • Diplopia • Dysphagia • Dysarthria • Alteration or loss of consciousness • Abnormal movement • History of fever days before an attack, which could suggest poliomyelitis or other virus-caused paralysis • History of back pain days before an attack, which could suggest acute transverse myelitis • History of tick bite, which could suggest tick paralysis HypoPP is the most common cause of periodic paralysis. The four major differential diagnoses are normokalemic potassium-sensitive periodic paralysis (normoPP), hyperkalemic periodic paralysis (hyperPP), thyrotoxic periodic paralysis (TPP), and Andersen-Tawil syndrome (ATS) . Table 3. The Different Categories of Periodic Paralyses (PP) with Membrane Excitability Disorder and Associated Findings

Source: GeneReviews — "Hypokalemic Periodic Paralysis"

Clinical Guidance

Avoid anything that can trigger paralytic attacks in the individual case, including the following:

• Unusually strenuous effort

• Excess of carbohydrate-rich meals or sweets

• Cold

• Stress/excitement/fear

• High salt intake

• Prolonged immobility

• Oral or intravenous glucosteroids

• Use of cooling, glucose and/or mannitol infusion, excessive sodium- containing fluids and certain anesthetics such as succinylcholine during anesthesia

• Use of alcohol

Source: GeneReviews — "Hypokalemic Periodic Paralysis"

Therapies Under Investigation

Recent studies in mouse models of hypoPP with both SCN4A pathogenic variants and CACNA1S pathogenic variants show that maneuvers to reduce the activity of the Na-K-2Cl (NKCC) co-transporter can reverse an acute attack of hypoPP and protect against an attack triggered by low K+ exposure . The beneficial effect is the result of biasing intracellular chloride to be low, which promotes hyperpolarization of the resting potential. The NKCC co-transporter is activated by hyperosmolarity (hence the importance of avoiding high sodium diet, dehydration, hyperglycemia and mannitol) and is inhibited by loop diuretics such as bumetanide . Search ClinicalTrials.

Source: GeneReviews — "Hypokalemic Periodic Paralysis"