Paramyotonia Congenita

Disease Overview

Summary

Paramyotonia congenita (PMC) is a rare non-progressive genetic disorder that affects the skeletal muscles. The disorder typically begins in infancy or early childhood. Affected individuals experience spells of muscle stiffness or when the muscles do not relax after contracting (myotonia). Symptoms can be triggered by exposure to the cold or after physical activity. The stiffness most commonly affects the muscles in the neck, face, arms and hands, however it can occur in the lower back and the muscles used for breathing. The stiffness of the muscles can get worse with repeated movements. There are also intermittent periods of a type of muscle weakness in which there is no muscle tone (flaccid paresis). This condition does not necessarily coincide with exposure to cold temperatures or myotonia. There is generally no wasting (atrophy) of muscles; however, there is often increase in bulk (hypertrophy) of muscles with this disorder. There is no cure to PMC; however, with the proper management of diet, lifestyle and medication, patients can lead normal lives. PMC is an autosomal dominant genetic condition caused by a mutation in the muscle sodium channel gene SCN4A.

Introduction

PMC is classified as a form of periodic paralyses, a group of muscle disorders characterized by irregular episodes of muscle weakness or stiffness. PMC was first discussed in 1886 by von Eulenburg. It is considered the first recognized temperature-sensitive condition in humans.

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Synonyms

Eulenburg disease
paralysis periodica paramyotonica
paramyotonia congenita of von Eulenburg
PMC
Von Eulenburg's disease

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Signs & Symptoms

Muscle stiffness in PMC is the inability for the muscles to relax in a timely manner after contracting (myotonia). The muscles most commonly affected are located in the face, neck and upper extremities, although it can affect the muscles used for breathing and swallowing, as well as muscles in the lower back. PMC is usually apparent during infancy and always presents by teenage years. Symptoms do not progress with age. Individuals with this disorder do not have wasting of muscles (atrophy) but often have an increase of muscle bulk (hypertrophy).

The severity of the muscle stiffness depends on the individual; some patients experience painful myotonia, while others experience painless myotonia. This condition becomes worse with exposure to cold and alleviated by warm temperatures. In addition, it can become more severe with exercise. Sudden overexertion can trigger muscle stiffness and overall weakness that can take several days to completely resolve. PMC can make small everyday activities difficult, such as letting go of small objects (e.g. pens or door knobs).

Some episodes of muscle stiffness can coincide with potassium intake; affected individuals are instructed to avoid certain food products rich in potassium.

Some patients with more severe PMC can experience shortness of breath or tightness in their chest muscles.

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Causes

PMC is an autosomal dominant genetic condition caused by a change (mutation) in the SCN4A gene which codes for a sodium channel specific for skeletal muscles.

Dominant genetic disorders occur when only a single copy of a non-working gene is necessary to cause a particular disease. The non-working gene can be inherited from either parent or can be the result of a mutated gene in the affected individual. The risk of passing the non-working gene from an affected parent to an offspring is 50% for each pregnancy. The risk is the same for males and females.

In some individuals, the disorder is due to a spontaneous (de novo) genetic mutation that occurs in the egg or sperm cell. In such situations, the disorder is not inherited from the parents.

Skeletal muscles move the body; muscle contractions pull on tendons, which are attached to the bones and causes the body to move. Muscle contractions are triggered by the flow of positively charged atoms (e.g. potassium and sodium) through channels into the skeletal muscles. These atoms carry electrical impulses necessary for normal function of the muscle cells. However, a mutation of the SCN4A gene alters the structure of the sodium channels. The sodium channels fail to regulate the flow of atoms into the muscles cells, and the ratio of sodium and potassium becomes unbalanced. The abnormal ratio interferes with normal muscle contraction and relaxation, causing bouts of muscle weakness and stiffness.

Most individuals with a SCN4A gene mutation have symptoms; however, there are a few who remain unaffected and are known as “carriers”.

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Affected populations

PMC is a very rare disorder that affects males and females in equal numbers. The symptoms can begin during infancy, and are always apparent by the teenage years. It is estimated to affect fewer than 1 in 100,000 people.

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Disorders with Similar Symptoms

Symptoms of the following disorders can be similar to those of paramyotonia congenita. Comparisons may be useful for a differential diagnosis.

PMC needs to be distinguished from other forms of myotonic disorders such as myotonia congenita and myotonic dystrophy as well as other forms of periodic paralysis including hyperkalemic periodic paralysis, hypokalemic periodic paralysis, and Andersen-Tawil syndrome.

Myotonia congenita is a rare genetic disorder in which an abnormality of voluntary (skeletal) muscle fiber membranes causes an unusually exaggerated response to stimulation (hyperexcitability). As a result, affected individuals complain of muscle stiffness due to difficulty relaxing certain muscles after contracting them (myotonia) Such symptoms tend to occur when attempting to move certain muscles after rest and the myotonia improves with repeat use of the muscle. Many individuals with myotonia congenita also have abnormal enlargement of the muscles (hypertrophy), resulting in a “herculean” or “body-builder like” appearance. Two main forms of myotonia congenita have been described: Thomsen disease and Becker disease. Individuals with Thomsen disease may have myotonia, associated muscle rigidity, and abnormal muscle enlargement that becomes apparent from infancy to approximately two to three years of age. In many cases, muscles of the eyelids, hands, and legs may be most affected. Thomsen disease is an autosomal dominant condition. People with Becker disease develop symptoms most commonly between the ages of four and 12 years. As in Thomsen type myotonia congenita, affected individuals develop myotonia, associated muscle rigidity, and abnormal muscle enlargement (hypertrophy). The symptoms tend to remain constant, with little progression. Becker disease is inherited as an autosomal recessive condition. (For more information on this disorder, choose “myotonia congenita” as your search term in the Rare Disease Database.) PMC can be distinguished from myotonia congenita by its exquisite sensitivity to cold.

Myotonic dystrophy is a rare disorder inherited as an autosomal dominant trait. This disorder involves the muscles, vision, and endocrine glands. Myotonic dystrophy usually begins during young adulthood and is marked initially by an inability to relax muscles after contraction (myotonia). Loss of muscle strength, mental deficiency, cataracts, reduction of testicular function, and frontal baldness are also symptomatic of this disorder. (For more information on this disorder, choose “myotonic dystrophy” as your search term in the Rare Disease Database.)

Hyperkalemic periodic paralysis is an autosomal dominant genetic condition typically detected during infancy. It is caused by my mutations in the same gene that causes PMC. Whereas in PMC the main symptoms is muscle stiffness, the major symptom in hyperkalemic periodic paralysis is periodic muscle weakness with or without muscles that do not relax after contracting (myotonia). Patients may have attacks from once every few months to several times a day. Typically the periods of muscle weakness last from one half an hour to an hour. This weakness may be found in the calves or thighs of the legs, lower back, arms, neck and/or eyelids. Periods of muscle weakness usually follow rest after exercise, hunger, infection, exposure to the cold and/or emotional stress. Permanent weakness and wasting of muscles may develop later on.

Hypokalemic periodic paralysis is an autosomal dominant genetic condition typically detected in the first decade of life. The major symptom in hypokalemic periodic paralysis is periodic muscle weakness without muscle stiffness. Patients may have attacks once a week or once a day. Typically the periods of muscle weakness last from hours to a couple days. This weakness may affect muscles of the arms and legs but typically not the speech, swallow or breathing muscles. Periods of muscle weakness are associated with low blood potassium levels and usually follow rest after exercise, large carbohydrate meals, infection, and/or emotional stress. Permanent weakness and wasting of muscles may develop later on.

Andersen-Tawil syndrome is a rare disorder that causes muscle weakness and paralysis, as well as affecting the electrical system of the heart causing abnormal rhythms. This disorder is caused by a mutation in the KCNJ2 gene that disrupts the flow of protein to the muscles. (For more information on this disorder, choose “Andersen- Tawil Syndrome” as your search term in the Rare Disease Database.)

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Diagnosis

When PMC is suspected, a test is administered to test the capacity of muscles to conduct electricity (electromyography). During the test, the muscles are chilled and electrical signals are recorded before and after the muscle is cooled. The electromyography (EMG) will show rapid repetitive electrical discharges. EMG cannot always diagnose PMC definitively, and further testing may be necessary.

Genetic testing on a blood sample will result in a definitive diagnosis by showing the presence of a characteristic mutation in the SCN4A gene.

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Standard Therapies

Treatment

The treatment of PMC is based on the individual’s symptoms; PMC can be handled on a day-to-day basis and many patients can lead normal lives. Individuals must be cautious to sudden exposures to very cold weather, as well as avoiding sudden heavy physical activity.

Muscle stiffness could also be triggered or enhanced by potassium-rich foods. Patients will need to learn how to manage their potassium-intake. They should avoid potassium-rich foods, avoid skipping meals and take carbohydrate rich snacks in between meals.

The aim of treatment is to reduce the intensity of acute symptoms and to prevent, as far as possible, further attacks. Some attacks are so mild that treatment is not necessary. However, in other instances drug therapy is required.

Treatment with medications that block the sodium channels such as mexiletine and lamotrigine may help reduce the stiffness related to myotonia. Some patients with PMC may benefit from acetazolamide or thiazide diuretic drugs to reduce the number of paralytic attacks.

Genetic counseling is recommended for patients and their families.

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Clinical Trials and Studies

Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.

For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:

Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]

Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/

For information about clinical trials sponsored by private sources, contact:
www.centerwatch.com

For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/

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References

TEXTBOOKS
Ciafaloni, E, Chinnery PF, Griggs, RC, eds. Evaluation and Treatment of Myopathies. 2nd edition. Oxford University Press; Oxford. 2014:218-253.

Kasper, DL, Fauci AS, Longo DL, et al., eds. Harrison’s Principles of Internal Medicine. 16th ed. McGraw-Hill Companies. New York, NY; 2005:2526; 2537.

Rimoin D, Connor JM, Pyeritz RP, Korf BR, eds. Emory and Rimoin’s Principles and Practice of Medical Genetics. 4th ed. Churchill Livingstone. New York, NY; 2002:3377-82.

JOURNAL ARTICLES
Weber MA, Nielles-Vallespin S, Huttner HB, Worhle JC, et al. Radiology. 2006;240:489-500.

Kurihara T. New classification and treatment for myotonic disorders. Intern Med. 2005;44:1027-32.

Vicart S, Sternberg D, Fontaine B, Meola G. Human skeletal muscle sodium channelopathies. Neurol Sci. 2005;26:194-202

Fredericson M, Kim BJ, Date ES. Disabling foot cramping in a runner secondary to paramyotonia congenita: a case report. Foot Ankle Int. 2004; Jul;25(7):510-2.

Kuntzer T.[Electrophysiological testing in muscle channelopathies] Rev Neurol (Paris). 2004;160 (5 Pt 2):S49-54. French.

Phillips L, Trivedi JR. Skeletal Muscle Channelopathies. Neurotherapeutics. 2018;15(4):954-965.

INTERNET
McKusick VA, ed. Online Mendelian Inheritance in Man (OMIM). Baltimore, MD: The Johns Hopkins University Press; Paramyotonia Congenita of Von Eulenburg; PMC. Entry No: 168300; Last Edit: 07/14/2016. https://www.omim.org/entry/168300 Accessed August 20, 2019.

Latif W. Hyperkalemic periodic paralysis. Medical Encyclopedia. MedlinePlus. Review Date 10/26/2017. www.nlm.nih.gov/medlineplus/ency/article/000316.htm Accessed August 20, 2019.

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