Comparison of Five Forms of Periodic Paralysis

Introduction:

The major features found in all the periodic paralyses are:

1. Attacks almost always begin before the age of 25, though occasionally later in life. ATS patients can develop first symptoms at any age.

2. Serum potassium fluctuates shortly before an attack, but serum potassium level will normalize before the attacks resolves and will be within the normal range between attacks. This is not a disorder of the blood but one in which there is an inappropriate shift of fluid, K+ and NA+ during attacks. 

3. The attack may affect only one muscle or group of muscles, or it may affect the entire body. Paralysis may not follow nerve pathways.

4. When weakness is ongoing or affects only one group of muscles the change in the potassium level may be too small or temporary to measure.

5. Speech, swallowing and breathing are not usually affected, but may be in severe attacks.

6. Rest after exercise may provoke an attack, but mild attacks may sometimes be "walked off", that is, if the patient can keep moving a mild attack may simply go away.

7. Becoming chilled can provoke attacks.

8. Deep tendon reflexes diminish and may disappear altogether during attacks.

In addition these further features are found in some forms of periodic paralysis:

1. Muscle stiffness;

2. Weakness between attacks; and

3. Heart rhythm abnormalities.

4. Differences in facial appearance

In this article, the five types of periodic paralyses are classified according to triggers and characteristics:

1) Hypokalemic Periodic Paralysis (HypoKPP)

The mutations identified to date are: CACNA1S: Calcium channels mutations on chromosome 1, location 1q31-32: The most common mutations are: Arg528His and Arg1239His, Arg1239Gly, Arg1086Cys, Arg1086His. These five mutations are responsible for over half the genetically identified cases of HypoKPP; SCN4A: Sodium Channel mutations on chromosome 17, location 17q23.1-q25.3: Six mutations have been identified; Arg669His, Arg672His, Arg672Gly, Arg672Ser, ArgPhe1158Ser, Arg1132Gln, KCNJ18: Kir2.6 Potassium Channel mutations on chromosome 17, three mutations have been identified: Arg43Cys, Val168Met and Ala200Phe.    

Symptoms in HypoKPP are provoked by factors that cause potassium to move from the serum (blood) into the muscle cell, thus lowering the serum potassium level. Significant weakness between attacks is common, especially in patients over 35. While serum potassium does not fall below normal (3.5) during every attack, or in every patient, the name Hypokalemic Periodic Paralysis persists.

2) Thyrotoxic Periodic Paralysis(TPP)

KCNJ18: Kir2.6 Potassium Channel mutations on chromosome 17, mutations identified: Arg43Cys, Val168Met and Ala200Phe. A genetic predisposition is observed in Asians and Native Americans with Hyperthyroid Disease. Incidence in Caucasians with HD is 0.1%. The thyrotoxicosis may present subclinically, especially for the first several attacks. Between 80-90% of patients with TPP are male. TPP attacks are more common from May-October. Serum K+ usually falls to 2.0 and below during attacks. Except for the thyroid disease (Grave's Disease, thyroid adenoma) TPP symptoms are very much like genetic HypoKPP. Once patient's thyroid function returns to normal TPP disappears.

3) Hyperkalemic Periodic Paralysis(HyperKPP)

Mutations identified so far: SCN4A: Sodium Channel mutations on chromosome 17, location 17q23-q25.3; Thr704Met, Met1592Val, Phe1490Leu, Met1493Ile, Ala1156Thr, Met1360Val, Met1367Val, Ser906Thr, Ile639Thr, Ile1495Phe.

Patients with potassium-sensitive ("Hyper" KPP) respond to potassium-rich foods or potassium with weakness. Their potassium level may not rise above normal, (5.0) during an attack, though it usually rises by 1 to 1.5 mmol/L. Toward the end of an attack the HyperKPP patient's potassium level may drop below normal. This may result in a misdiagnosis of HypoKPP. The patient with HyperKPP may experience myotonia - muscle stiffness which disappears as the patient moves around or exercises lightly.

4) Paramyotonia Congenita (PMC) and Paramyotonia Syndromes

Mutations identified so far: SCN4A: Sodium Channel: chromosome 17 located at 17q23-q25.3 Mutations identified including Thr704Met, Gly1456E; Leu689Ile, Ile693Thr, Ala1156Thr, Met1360Val, Ile1495Phe, Met1592Val, Phe1490Leu; Met1493Ile, Arg1448Cys, Ser804Phe; Ile1160Val; Gly1306Ala; Gly1306Val; Gly1306Glu; Val1589Met, Val1293Ile; Thr1313Met; Leu1433Arg; Arg1448Cys; Arg1448His; Arg1448Pro; Val1458Phe; Phe1473Ser.

The most common form is Paramyotonia Congenita (PMC), which may exist alone, or in combination with HyperKPP. PMC attacks can be hyperkalemic or hypokalemic in nature. The patient with the hypokalemic version of PMC may have it in combination with HyperKPP. There is also a pure Paramyotonia (PPP) which does not cause weakness, plus several Paramyotonia syndromes. The hallmark of all these disorders is paradoxical myotonia; myotonia which develops and worsens with exercise. Chilling and cold is also a potent trigger in some forms, as is exercise or exertion. Management must be fine - tuned for each individual.

5) Andersen-Tawil Syndrome (ATS)

Mutations identified to date: KCNJ2: Potassium channel KCNJ2 located on chromosome 17; location 17q24.3; Asp71Val, Arg218Trp, Gly300Val, Arg67Trp, Pro186Leu, Val302Met, Asn216His , Asp172Asn, Thr75Arg, Cys54Phe, Thr305Pro, Val93Ile; plus in frame deletions: (meaning that part of the gene's coding is missing) 12-BP DEL, NT513, 6-BP DEL, NT1167.

In addition to attacks of weakness, ATS patients have a variety of heart rhythm disturbances, several of which may be life threatening. Some require defibrillators. It was thought until recently that all ATS patients had Long QTc intervals but new studies have shown that is not always the case. ATS patients may also have curvature of the spine, crooked fingers, and webbing between second and third fingers and/or toes. They also have facial features like low-set ears, widely spaced eyes, a small jaw and chin. These features may be very subtle and not apparent except to an experienced examiner. Some ATS patients are always hypokalemic or hyperkalemic during attacks; others are hypokalemic during one attack and hyperkalemic the next. Some have normal potassium levels during attacks.

 

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