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Hyperkalemic periodic paralysis and Paramyotonia congenita

This is part of Rare diseases.

Diagnosis: Hyperkalemic periodic paralysis and Paramyotonia congenita

Synonyms: HyperPP, Eulenburg disease

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Date of publication: 2011-04-13
Version: 3.0

ICD 10 code

G72.3B Hyperkalemic periodic paralysis
G71.1 Paramyotonia congenita

The disease

Hyperkalemic periodic paralysis (HyperPP) is associated with elevated levels of potassium in the blood and temporary episodes of paralysis. Paramyotonia congenita (also called von Eulenburg disease) is an inherited condition characterised by stiffness aggravated by physical activity. Both belong to a group of diseases which cause periodic episodes of paralysis. Hyperkalemic periodic paralysis and paramytonia congenita have been described as two separate diseases. However, it is now established that these two, similar, conditions are caused by mutations in the same gene. In both disorders, stiffness and paralysis result from malfunctioning sodium ion channels in the muscle fibres. (See under “Causes.”)

The first description of hyperkalemic periodic paralysis was in a 1956 dissertation entitled Adynamia episodica hereditaria, written by Swedish paediatric neurologist Ingrid Gamstorp. Paramyotonia congenita was first described in 1886 by German physician Albert von Eulenburg.

Occurrence

The exact incidence of the condition is unknown. It is estimated that in Sweden a maximum of one person per 100,000 has hyperkalemic periodic paralysis or paramyotonia congenita. This means that fewer than 100 individuals are affected by the two conditions. Hyperkalemic periodic paralysis is somewhat more common than paramyotonia congenita.

Cause

The cause of hyperkalemic periodic paralysis and paramyotonia congenita is a mutation in the gene which controls the production of (codes for) protein SCN4A, which forms part of a sodium ion channel in skeletal musculature. The gene is located on chromosome17q23 and is also called SCN4A. To date, nine different mutations in gene SCN4A have been linked to hyperkalemic periodic paralysis. Paramyotonia congenita, a similar condition, is the results of seven other mutations in the same region of SCN4A.

The sodium ion channel is a large molecule in the cell membrane of muscle fibre. It consists of four subunits arranged in pairs around a central opening. See figure below.

Figure: The sodium ion channel

Figure: The sodium ion channel

When muscle receptors bind neurotransmitter released from a nerve, normally the sodium channel opens to allow sodium to pass through the muscle cell. This initiates a chain of reactions causing the muscle to contract. In the recovery phase that follows muscle contractions the sodium channel closes.

In hyperkalemic periodic paralysis and paramyotonia congenita, the sodium channel closes too slowly and thus sodium ions continue to flow into the muscle. This leads to oversensitivity and stiffness in the muscle (myotonia). If the sodium channel remains open, the muscle will become desensitized and finally paralysed. At the same time, potassium ions are released from the muscle and the concentration of potassium in the blood rises.

Heredity

Both hyperkalemic periodic paralysis and paramyotonia congenita follow the autosomal dominant pattern of inheritance. This means that one of the parents has the disease, and so has one normal gene and one mutated gene. Sons and daughters of this parent have a 50 per cent risk of inheriting the disease. Children who do not inherit the mutated gene do not have the disorder and do not pass it down.

Figure: Autosomal dominant inheritance

Symptoms

Both hyperkalemic periodic paralysis and paramyotonia congenita are disorders associated with muscle stiffness and muscle weakness.

In hyperkalemic periodic paralysis symptoms usually manifest during early childhood, although onset sometimes occurs when the individual is over twenty years of age. The onset of the disease can occur at different ages, even among members of the same family. The condition is characterised by sudden episodes of muscle weakness, which develop into a transient period of paralysis. The episodes last from ten minutes up to a few hours, ending spontaneously. Their frequency varies, from every day to a few times a week. Muscle weakness is triggered by rest after strenuous exercise, fasting, stress, infections or exposure to cold. Episodes often occur early in the morning, before breakfast. The severity of the episode varies. Occasionally it may be necessary to sit or lie down until the paralysis disappears. Respiratory function is not affected.

Early symptoms of an episode often include muscle pain, numbness, tingling and stiffness (myotonia). Stiffness is usually most pronounced in the muscles of the eyelid, face, tongue, and hands. This may occur without the muscle weakness normally associated with the disease, and is easily triggered by exposure to cold.

The frequency of the episodes tends to decline after the age of fifty. However, with time the individual often develops mild, chronic muscle weakness. Men and women are affected in different ways. During pregnancy symptoms are often temporarily aggravated and episodes may be more frequent.

Although the heart is a muscle, its conduction system is not affected. However, heart arrhythmias and other irregularities visible in an electrocardiogram (ECG) may occur during episodes of muscle weakness. These are caused by elevated potassium levels in the blood.

In the more unusual form of the disease, paramyotonia congenital, symptoms are largely the same. Paradoxal myotonia is a typical characteristic symptom of paramyotonia congenita, and means that muscle stiffness is exacerbated when a movement is repeated. This differs from muscle stiffness in hyperkalemic periodic paralysis and certain other muscle diseases where stiffness decreases when a movement is repeated. Myotonia is most pronounced in the hands and face. The symptoms are easily triggered by low temperatures, for example by cold water. This form of the disease can also be characterised by temporary episodes of muscle weakness and paralysis. The onset of paramyotonia congenita may occur from early infancy.

Diagnosis

Eyelid myotonia triggered by exposure to cold strengthens a suspected diagnosis. During these episodes, the cold causes the muscles of the affected eyelid to become stiff, and the lid cannot open. The diagnosis is strengthened if potassium medication induces muscle weakness.

During an episode of muscle weakness the level of potassium in the blood rises, sometimes to very high levels. An attack can often be provoked by having the patient exercise on a bicycle ergometer. While the patient is resting immediately after this exercise, both muscle strength and the concentration of potassium in the blood are measured.

A neurophysiological test of muscle function (EMG, electromyogram) shows mytonia in approximately half of those affected, especially if the muscle is first cooled with ice. A special neurophysiological technique (an “exercise test”) can be used to measure typical changes in muscle response to repeated electrical stimulation of nerves before, during, and after exercise. Changes are more evident if the muscle is cooled first.

As a rule, DNA-based diagnosis is possible. Pre-natal diagnosis is possible if the mutation has been identified in the family.

Treatment/interventions

There is currently no cure for the disorder, and efforts are directed at relieving symptoms. However, a great deal can be done to help compensate for functional limitations. All interventions should be adapted to suit the situation and needs of the individual.

While growing up, children with hyperkalemic periodic paralysis or paramyotonia congenita should be in contact with a paediatric neurologist, a dietician and a specialist paediatrician as well as other caregivers. For children with the disease it is important that monitoring and treatment are coordinated by a paediatrician who has an overview of the child’s condition. Adults with the disease require corresponding contact with the medical services.

Medications that reduce potassium levels in the blood prevent attacks of paralysis and often reduce their severity. Examples of substances prescribed include thiazide diuretics, acetazolamide and dichlorphenamide. Small doses of the asthma medication salbutamol may alleviate muscle weakness, although unfortunately the effect is transient. In cases of severe muscle stiffness mexiletine may be prescribed. In Sweden, the use of some of these substances requires authorization from the Swedish Medical Products Agency.

General anaesthesia may trigger episodes of paralysis lasting for hours, in individuals with hyperkalemic periodic paralysis or paramyotonia congenita. For this reason, depolarizing muscle relaxants and acetylcholinesterase inhibitors are particularly unsuitable. In order to avoid complications the anaesthetist must be informed about the disorder in advance of surgery.

A basic element in treatment is to provide information on what can trigger attacks and what can be done when symptoms manifest. Frequently the risk of attacks can be minimised, or stopped, by avoiding known precipitating factors. As certain forms of medication contain potassium, it is important to consult a physician about suitable substitutes.

Changes in diet may prevent episodes of paralysis. If consumed at the onset, high carbohydrate food rich in sugar often suspends the episode. Many, frequent, carbohydrate-rich small meals are preferable to a few big meals. Fasting should be avoided, and any attempt to lose weight should be supervised by a dietician. Caution is warranted in the consumption of alcohol, as an attack of paralysis may be triggered by the body’s reaction to alcohol. For detailed information about suitable food a dietician with knowledge of the disorder should be consulted.

It is important to have a good degree of general physical fitness. It is also important for the individual not to rest completely, directly after strenuous muscle activity. Instead, the intensity of activity should be reduced slowly. A physiotherapist can provide advice on suitable forms of exercise and an exercise programme adapted to individual needs. School and preschool staff should be informed about the disorder so that the physical activities undertaken are suitable for the child.

To a greater or lesser degree, symptoms affect the individual’s ability to participate in certain daily activities at home or in the workplace, and may also impact on leisure activities. Changes in work routines, adjustments to the working environment and technical aids can enable the individual to lead an active life. An occupational therapist can analyse the need for assistance.

Knowledge of the disease makes it easier to make choices about education, training and suitable sporting activities. When deciding on a suitable career it is important to avoid factors which can trigger symptoms including cold environments, intense physical exertion, and physical or mental stress. Career guidance and occupational assessment are provided by the Swedish National Labour Market Administration. They also assist in finding suitable workplaces.

It is important that psychological and social support are readily available when needed. These services may be provided by a psychologist and/or a habilitation counsellor in the paediatric or adult health care services.

Medical warning card

In order to avoid misdiagnosis and inappropriate treatments, individuals with confirmed hyperkalemic periodic paralysis or paramyotonia congenita can carry a medical warning card, issued by NHR, The Swedish Association of Persons with Neurological Disabilities (see under “Organizations for the disabled/patient associations”) to be shown to all health care providers. The card confirms the diagnosis and provides information about potential risks, including those associated with anaesthesia.

Practical advice

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National and regional resources in Sweden

Expertise in hyperkalemic periodic paralysis and paramyotonia congenita is available at neuromuscular units at Sweden’s university hospitals.

Resource personnel

Associate professor Christopher Lindberg, Neuromuscular Centre, Sahlgrenska University Hospital/Sahlgrenska, SE-413 45 Gothenburg, Sweden. Tel: +46 31 342 10 00, email.christopher.lindberg@vgregion.se.

Senior physician Björn Lindvall, Muscle Centre, University Hospital, SE-701 85 Örebro, Sweden. Tel: +46 19 602 10 00, email: bjorn.lindvall@orebroll.se.

Associate professor Göran Solders, Neurology Clinic, Karolinska University Hospital, SE-141 86 Stockholm, Sweden. Tel: +46 8 585 800 00, email: goran.solders@karolinska.se.

Courses, exchanges of experience, recreation

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Organizations for the disabled/patient associations

NHR, The Swedish Association for Persons with Neurological Disabilities, St Eriksgatan 44, Stockholm. Sweden. Mailing address: Box 49084, SE-100 28 Stockholm, Sweden. Tel: +46 8 677 70 10, fax: +46 8 677 13 15, email: nhr@nhr.se, www.nhr.se.

Courses, exchanges of experience for personnel

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Research and development (R&D)

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Information material

An information leaflet on hyperkalemic periodic paralysis and paramyotonia congenita that summarises the information in this database text is available free of charge from the customer service department of the Swedish National Board of Health and Welfare (in Swedish only, article number 2010-10-11.) Address: SE-120 88 Stockholm, Sweden. Tel: +46 75 247 38 80, fax: +46 35 19 75 29, email: publikationsservice@socialstyrelsen.se. Postage will be charged for bulk orders.

Literature

Brancati F, Valente EM, Davies NP, Sarkozy A, Sweeney MG, LoMonaco M et al. Severe infantile hyperkalemic periodic paralysis and paramyotonia congenita: broadening the clinical spectrum associated with the T704M mutation in SCN4A. J Neurol Neurosurg Psychiatry 2003; 74: 1339-1341.

Cannon SC. An expanding view for the molecular basis of familial periodic paralysis. Neuromusc Disord 2002; 12: 533-543.

Eulenburg A. Über eine familiare, durch 6 generationen verfolgbare Form congenitaler Paramyotonie. Neurologischer Centralblatt 1886; 12: 265-272.

Finsterer J. Primary periodic paralysis. Acta Neurol Scand 2008; 117: 145-158.

Fournier E, Viala K, Gervais H, Sternberg D, Arzel-Hezode M, Laforet P et al. Cold extends electromyography distinction between ion channel mutations causing myotonia. Ann Neurol 2006; 60: 356-365.

Gamstorp I. Adynamia episodica hereditaria. Acta Paediat (suppl. 108) 1956; 45: 1-126.

Hayward LJ, Sandoval GM, Cannon SC. Defective slow inactivation of sodium channels contributes to familial periodic paralysis. Neurology 1999; 52: 1447-1453.

Jurkat-Rott K, Lehmann-Horn F. Genotype-phenotype correlation and therapeutic rationale in hyperkalemic periodic paralysis. Neurotherapeutics 2007; 4: 216-224.

Klingler W, Lehmann-Horn F, Jurkat-Rott K. Complications of anaesthesia in neuromuscular disorders. Neuromuscul Disord 2005; 15: 195-206.

Kuntzer T, Flocard F, Vial C, Kohler A, Magistris M, Labarre-Vila A et al. Exercise test in muscle channelopathies and other muscular disorders. Muscle Nerve 2000; 23: 1089-1094.

Lehmann-Horn F. The basics of the familial periodic paralysis. Acta Myologica 2002; 21: 106-113.

Lehman-Horn F, Jurkat-Rott, Rudel R. Periodic paralysis: understanding channelopathies. Curr Neurol Neurosci Rep 2002; 2: 61-69.

Miller TM, Dias da Silva MR, Miller HA, Kwiecinski H, Mendell JR, Tawil R et al. Correlating phenotype and genotype in the periodic paralysis. Neurology 2004; 63: 1647-1655.

Ptacek LJ, Tawil R, Griggs RC, Meola G, McManis P, Barohn RJ et al. Sodium channel mutations in azetazolamide-responsive myotonia congenita, paramyotonia congenita, and hyperkalemic periodic paralysis. Neurology 1994; 44: 1500-1503.

Rudel R, Ricker K, Lehmann-Horn F. Genotype-phenotype correlations in human skeletal muscle sodium channel diseases. Arch Neurol 1993; 50: 1241-1248.

Sansone V, Meola G, Links TP, Panzeri M, Rose MR. Treatment for periodic paralysis. Cochrane Database Syst Rev 2008; 1: CD005045.

Sillén A, Wadelius C, Sundvall M, Ahlsten G, Gustavson KH. Hyperkalemic periodic paralysis caused by recurring mutation in the adult muscle sodium channel alpha-subunit gene. Genetic Couns 1996; 7: 267-275.

Tawill R, McDermott MP, Brown R Jr, Shapiro BC, Ptacek LJ. McManis PG et al. Randomized trials of dichlorphenamide in the periodic paralysis. Ann Neurol 2000; 47: 46-53.

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

Database references

OMIM (Online Mendelian Inheritance in Man)
www.ncbi.nlm.nih.gov/omim 
Search: hyperkalemic periodic paralysis, gamstorp disease, hypp, paramyotonia congenita, von eulenburg

GeneReviews (University of Washington),
www.genetests.org (select GeneReviews, then Titles)
Search: hyperkalemic periodic paralysis

Document information

The Swedish Information Centre for Rare Diseases produced and edited this information material.

The medical expert who wrote the draft of this information material is Associate Professor Göran Solders, Karolinska University Hospital, Stockholm,Sweden.

The relevant organisations for the disabled/patient associations have been given the opportunity to comment on the content of the text.

An expert group on rare diseases, affiliated with the University of Gothenburg, approved the material prior to publication.

Date of publication: 2011-04-13
Version: 3.0
Publication date of the Swedish version: 2010-11-16

For enquiries contact The Swedish Information Centre for Rare Diseases, The Sahlgrenska Academy at the University of Gothenburg, Box 400, SE-405 30 Gothenburg, Sweden. Tel: +46 31 786 55 90, email: ovanligadiagnoser@gu.se.

 

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