Hypokalemic periodic paralysis is a group of genetically determined myoplegias characterized by paroxysmal muscle disorders accompanied by a decrease in potassium levels. Their symptoms are sudden attacks of muscle weakness up to almost complete paralysis, mainly the musculature of the extremities is affected, sometimes with the involvement of the respiratory muscles, which can pose a threat to life. Diagnosis is made on the basis of the clinical picture, measurement of potassium levels during seizures, study of the patient’s hereditary history and genetic studies. There is no specific treatment, it is possible to stop seizures with potassium preparations and prevent their development with potassium-sparing agents.
General information
Hypokalemic periodic paralysis (in some sources – Westphal’s disease) – several hereditary diseases similar in their clinical manifestations due to defects in the ion channels of muscle cells. For the first time, such a condition was described in 1884 by the Russian doctor I. V. Shakhnovich, who discovered the classic variant of the disease. Later, other forms of it were discovered, which, in addition to genetic and molecular parameters and clinical manifestations, differ in their geographical distribution. In general, hypokalemic periodic paralysis is about 3 times more common in men than in women, the total occurrence is approximately 1:100,000. It is believed that the mechanism of inheritance of all forms of this disease is autosomal dominant, but there are indications of the presence of recessive family forms. Usually, with a timely diagnosis, seizures can be easily stopped, but sometimes they can threaten the patient’s life due to the involvement of the respiratory muscles.
Causes
Common to all types of hypokalemic periodic paralysis is a violation of the functioning of the ion channels of skeletal muscle myocytes caused by various mutations. Using the methods of modern genetics, it was possible to identify three genes whose defects lead to such a condition. Mutations of the CACNL1A3 gene located on the 1st chromosome are responsible for the classic variant of the disease. It encodes a special protein of myocyte membranes – the alpha subunit of the dehydropterin-sensitive calcium channel, which is why the functioning of this ion pathway is disrupted. The pathogenesis of disorders in this form of hypokalemic periodic paralysis has not been sufficiently studied, it is assumed that a change in the permeability of cell membranes for calcium ions introduces an imbalance in the entire system of ion interactions of myocytes. As a result, the depolarization time of muscle cells is significantly prolonged, which can lead to attacks of weakness.
The second genetic and molecular type of the disease is caused by missense mutations of the SCN4A gene located on the 17th chromosome. Just like CACNL1A3, this gene encodes one of the components of the ion channel of myocytes, only of a different type – the alpha subunit of the sodium channel. This type of hypokalemic periodic paralysis is accompanied not only by attacks of weakness and a decrease in the level of potassium in the blood, but also in some cases by a low concentration of insulin and an abnormal reaction of myocytes to stimulation with this hormone. Perhaps this is due to the fact that the effects of insulin are largely due to the different types of transport of sodium ions through the cell membrane, and disruption of this process leads to various failures. Some researchers have described cases of autosomal recessive inheritance of SCN4A gene mutations.
The third clinical type of hypokalemic periodic paralysis is caused by mutations of the KCNE3 gene localized on the 11th chromosome. The product of its expression is the protein of potassium channels of skeletal muscle myocytes, therefore, when its structure is defective, disturbances in the transport of potassium ions directly occur. Interestingly, similar mutations in some families were accompanied by hyperkalemic periodic paralysis, which may indicate the allelicity of these conditions. Unlike other types of the disease, with mutations of the KCNE3 gene, the myocardium is often affected, which is expressed in a violation of the heart rhythm at the height of an attack of muscle weakness and paralysis.
The mechanism of hypokalemia development in all three forms of the disease is a change in the permeability of myocyte membranes, as a result of which potassium begins to penetrate into cells more easily than in healthy people, while disappearing from the intercellular space and blood plasma. As a result, the transmembrane potential changes (provided by different concentrations of sodium and potassium ions outside and inside the cell), and the process of membrane depolarization is greatly complicated and lengthened. Since depolarization plays a central role in the development of action potential and muscle contraction, violations of this process are clinically expressed in the development of an attack of hypokalemic periodic paralysis.
Classification
To date, there are three known forms of hypokalemic periodic paralysis, which differ in etiology, clinical picture, geographical distribution. The occurrence of each type is not determined separately, so an average value is used.
- The classic type of hypokalemic periodic paralysis is caused by a mutation of the CACNL1A3 gene and caused by this defect in one of the calcium channels. It is widespread everywhere, there is no clear link to a specific region of the planet in this form.
- Distal renal tubular acidosis is a form of hypokalemic periodic paralysis caused by a mutation of the SCN4A gene, most common in Southeast Asian countries (Thailand, Indonesia). A characteristic feature of this type, in addition to muscle damage, are pronounced metabolic disorders, pathologies of the bone system (osteomalacia) and kidneys.
- Periodic thyrotoxic paralysis – caused by a mutation of the KCNE3 gene, especially common in Asia and North America. At the height of the attack, cardiac arrhythmias may occur, but fatal cases are quite rare. Sometimes this type of disease is mistakenly considered a secondary pathology caused not by genetic disorders, but by a lesion of the thyroid gland.
According to some geneticists, the above classification with reference to a specific form of hypokalemic periodic paralysis to certain genes is not entirely correct. They point out that there are cases when, for example, mutations of the KCNE3 gene manifested themselves as the first clinical type of the disease. This theory requires a comprehensive study and confirmation, to date there is no clear evidence of its correctness.
Symptoms
The leading symptom of all forms of hypokalemic periodic paralysis are paroxysmal attacks of muscle weakness of varying duration, capable of affecting various muscle groups. The classic type of the disease is characterized by the onset at the age of 3 to 22 years and the involvement of a large amount of musculature at once – the lower and upper extremities, trunk, neck. Mimic and masticatory muscles, as a rule, are not affected, in severe cases, respiratory muscles may be involved – without timely medical care, this can lead to sudden death. Most often, attacks of classical hypokalemic periodic paralysis occur at night or in the morning, are accompanied by adynamia (due to the large volume of muscles involved), hypothermia, significant physical exertion the day before, infectious diseases, painful menstruation can be a provoking factor. There are also indications that taking excessive amounts of table salt (for example, salty foods) can also cause an attack of muscle weakness.
The duration and frequency of seizures may be different, even in one patient there is a strong variation in this regard – muscle mobility may return in one case after an hour, and in another – after a day. In addition, during an attack, vegetative disorders can also be observed – hyperhidrosis (palmar, foot), nausea, vomiting. Fluctuations in blood pressure are characteristic, which can aggravate the patient’s condition. With age, episodes of classical hypokalemic periodic paralysis become less frequent, many clinical cases have been described when after 50-55 years they disappeared from the patient at all.
The second type of hypokalemic periodic paralysis – distal renal tubular acidosis – is an allelic type of hemolytic anemia and spherocytosis. Attacks of muscle weakness mainly affect the extremities (mainly the proximal parts), sometimes there may be involvement of the respiratory muscles. The duration of episodes is small – about an hour, but their development is absolutely spontaneous, since it has not yet been possible to identify reliable provoking factors. In addition to muscle disorders, this type of hypokalemic periodic paralysis often develops acidosis, the symptoms of which may be headache, nausea. Osteomalacia are also characteristic, which lead to frequent bone fractures – this serves as an additional symptom of this particular form of the disease.
The third form of hypokalemic periodic paralysis, or periodic thyrotoxic paralysis, manifests itself at the age of 20 to 40 years, the duration of attacks of muscle weakness is from 1 to 20 hours. The musculature of the legs is mainly affected, to a lesser extent the arms; it is noted that the more intensively one or another muscle group works, the greater the risk of its involvement in this form of the disease. For this reason, the development of an episode of paralysis is preceded by physical activity, after which the symptoms of the disease begin to manifest. In addition, with respect to this type of hypokalemic periodic paralysis, a clear seasonality has been revealed – most seizures develop between May and October. There are no reliable explanations for this, it is assumed that the development of muscle weakness is facilitated by the loss of potassium with sweat in the summer months. Also, at the height of the episode, a violation of the heart rhythm may occur, the respiratory muscles are almost never involved in the pathological process. There are also thyroid disorders with the development of symptoms of thyrotoxicosis – tremor, weight loss, exophthalmos.
In addition to the above provoking factors for each form, other circumstances may lead to the development of an attack – especially those that contribute to a decrease in the level of potassium in blood plasma. These include some endocrine diseases, the intake of carbohydrate-rich foods, insulin injections. Among other drugs that can provoke an attack of hypokalemic periodic paralysis, adrenocorticotropic hormone (ACTH), mineralocorticoids, potassium-sparing diuretics can be distinguished. Therefore, persons suffering from this disease should be cautiously prescribed these drugs and, when using them, constantly monitor the concentration of potassium ions in blood plasma.
Diagnostics
Detection of hypokalemic periodic paralysis is performed by examining the patient during seizures, electromyographic studies, biochemical blood analysis, genetic techniques and, in some cases, muscle biopsy. The results of all these studies may differ somewhat depending on the clinical form of the disease, which makes it possible to identify them even without the use of molecular genetic diagnostics. The manifestations common to all forms of pathology are muscle weakness, a sharp decrease or complete absence of tendon reflexes at the height of the attack, the lack of muscle reaction to any stimuli, including electric current. In the period between episodes of muscle weakness, hypokalemic periodic paralysis can often be diagnosed only by genetic studies, since no other signs of the disease will be detected. Even histological examination of a biopsy of muscle tissue in some cases does not detect any pathological changes.
With an attack of muscle weakness, a biochemical blood test reveals pronounced hypokalemia, with the second form of the disease it can also be accompanied by a decrease in insulin levels, acidosis and hyperchloremia. There is also a slight increase in the level of creatine phosphokinase, but this is an unstable sign, often manifested only at the very peak of an attack of hypokalemic periodic paralysis. A urine test performed during an episode of muscle weakness often shows a significant decrease in pH. An electrocardiogram may reveal cardiac arrhythmias (extrasystoles, arrhythmias), as well as other signs of hypokalemia – ST segment depression and smoothing of the T wave. When examining the patient, difficulty breathing may be detected – the cause of this may be either involvement in the pathological process of respiratory muscles, or hyperventilation with acidosis (with the second type of hypokalemic periodic paralysis).
A muscle biopsy performed between bouts of the disease may not reveal any changes – only with frequent and severe episodes, signs of atrophy and degeneration of muscle fibers may develop. Histological examination of tissues obtained during an attack can reveal the development of vacuoles in myocytes, the presence of enlarged areas of the endoplasmic network, and unequal thickness of muscle fibers. Genetic diagnosis is reduced to sequencing sequences of genes associated with hypokalemic periodic paralysis to identify defects and mutations. Prenatal diagnosis is possible by amniocentesis or chorionic villus biopsy. This disease should be differentiated with acquired forms of hypokalemia, some myopathies.
Treatment
There is no specific or etiotropic therapy for hypokalemic periodic paralysis, all therapeutic measures are reduced to relieving attacks of muscle weakness by restoring the ion balance of the body and preventing further episodes. With the development of paralysis, potassium chloride or another salt of this element is prescribed, depending on the severity of symptoms, it can be prescribed both orally and parenterally (jet or drip). It is advisable to avoid the introduction of potassium salts together with glucose, especially at a low concentration of the solution – this can further lower the level of this ion in the plasma and aggravate the patient’s condition. When administering medications, it is necessary to constantly monitor the heart (ECG) and the concentration of potassium in plasma in order to avoid hyperkalemia.
Preventive treatment includes the appointment of potassium preparations with acetazolamide – in some cases, this significantly reduces the frequency and severity of attacks of hypokalemic periodic paralysis. In this case, it is necessary to monitor the concentration of potassium ions in the blood plasma, as well as the work of the kidneys, since acetazolamide can cause the formation of kidney stones. Some patients have no reaction to the use of this drug, in such a situation it can be replaced with spironolactone or triamterene. An important role in the treatment of hypokalemic periodic paralysis is played by following a low-carbohydrate diet, eating potassium-rich foods, performing special physical exercises to prevent chronic muscle weakness.
Prognosis and prevention
The prognosis of hypokalemic periodic paralysis largely depends on the severity of symptoms. With the involvement of the respiratory muscles and cardiac arrhythmias, sudden death at the height of the attack is possible. But in most cases, the prognosis for life is favorable, with age, the frequency and strength of episodes decreases. It is possible to develop chronic muscle weakness due to frequent seizures, so it is necessary to stop them in a timely manner, as well as fulfill all the requirements for the prevention of their development. In addition to medicinal measures, prevention is carried out by a properly balanced diet with a low carbohydrate content and the inclusion of potassium-rich foods in it. It is advisable to avoid significant physical exertion, as well as the use of hormonal or diuretics without the appointment and supervision of a doctor.
