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Disease Descriptions
Date: 3/14/2004

Descriptions of Disorders Addressed by the PPRL.

This section provides descriptions of each of the primary diseases addressed by the Periodic Paralysis Research Library. If you are registered with the PPRL you can gain full access by logging in to the site and then selecting the Reading Room option to the left of this page. The following brief descriptions are provided for the convenience of the public.
 
What is Periodic Paralysis?

The term Periodic Paralysis describes a collection of disorders now known to be associated with mutations in genes that code for ion channels in the muscle membrane. Ion channels are important in controlling the movement of ions across the cell membrane and in the shift of ions from one cell compartment to another. Mutations in the genes that map the structure of these channels result in the disruption of muscle contraction mechanisms inhibiting the proper function of muscles (Cannon, 2002).

According to Brooke (2000), rather than resulting in permanent malfunction, some mutations produce intermittent symptoms, which is the case in periodic paralysis. It has been suggested that episodic, rather than periodic paralysis may be a more accurate description for this class of disorders, but established convention retains its hold.

The primary forms of periodic paralysis are transmitted by autosomal dominant inheritance. Individuals with autosomal dominant diseases have a 50-50 chance of passing the mutation on to their children. Genetic diagnostic resources are available for most known variants; however, access to genetic testing is still limited primarily to research centers. In the research environment, the diagnostic process can take several months to years to establish confirmation.

While positive genetic results can generally be considered dependable, false negatives are still known to occur at a relatively high rate. Many research protocols do not allow the researcher to report the results to the individual patient. As a consequence, for the majority of cases, diagnosis is still dependent on clinical evaluation.

Mutations have now been characterized in four voltage-gated skeletal muscle ion channels —calcium (Ca), sodium (Na), chloride (Cl), and potassium (K). Due to this association with abnormalities in ion channels, the periodic paralyses belong to the class of disorders referred to as "channelopathies." Rüdel, Hanna, and Lehmann-Horn (1999) list the periodic paralyses along with paramyotonia congenita, the non-dystrophic myotonias, and malignant hyperthermia, in this expanding class of primary skeletal muscle disorders.

General Description of Symptoms:

Although Hartwig provided “the first unmistakable account” in 1874 (Adams, Victor & Ropper, 1997), the periodic paralyses remain relatively obscure in our present time. Ruff and Gordon (1986), A. G. Engel (1988), and T. P. Links (1992) list a number of characteristics considered common to this group of disorders.

Common Characteristics
Associated with the Periodic Paralyses

Attacks may last from minutes to days, and occur sporadically.

Weakness can be local or generalized.

The deep tendon reflexes become depressed, diminished, or lost in the course of the attacks.

The muscle fibers become unresponsive to either direct or indirect electrical stimulation during attacks.

The generalized attacks usually begin in proximal muscles and then spread to distal ones.

Respiratory and cranial muscles tend to be spared but eventually may also be paralyzed.

Rest after exercise tends to provoke weakness of the muscles that had been exercised, but continued mild exercise may abort attacks.

Exercise restricted to a single muscle or a small group of muscles can induce weakness of the exercised muscles without a detectable change of the potassium level in systemic circulation.

Exposure to cold may provoke weakness in the primary forms of the disease.

Complete recovery usually occurs after initial attacks.

Permanent weakness and irreversible pathological changes in muscle can develop after repeated attacks.

The symptoms listed in the table above are representative of the description used by clinicians for at least the last three decades. As more knowledge is gained about the periodic paralyses, both the molecular and clinical descriptions have taken on new dimensions and our understanding is becoming more complete.

While the periodic paralyses are commonly grouped with the non-dystrophic myotonias, the classic forms of periodic paralysis traditionally include: Hypokalemic Periodic Paralysis, Hyperkalemic Periodic Paralysis, and Normokalemic Periodic Paralysis. Today Normokalemic Periodic Paralysis is rarely listed, and Andersen’s Syndrome is included.

Click here to view a chart of the molecular spectrum of the periodic paralyses and the nondystrophic myotonias.

The Primary Variants:

The traditional naming of the classic forms of Periodic Paralysis, based on varying levels of serum potassium, has led to some confusion in understanding these diseases. This confusion is exemplified in the case of the variant described as Normokalemic Periodic Paralysis.

Normokalemic Periodic Paralysis(NormoKPP): Prior to the advent of more effective diagnostic methodologies, cases of apparent periodic paralysis, in which blood serum potassium levels were reported to be within normal limits, were given the designation Normokalemic Periodic Paralysis. It is known that variants of the sodium and calcium channel disorders do present with serum potassium levels considered well within the normal range. In some individuals the potassium level may consistently be at the high or low ends of normal even though random testing may show periodic fluctuations. It has been suggested that relatively small shifts in serum potassium levels can induce symptoms in sensitive individuals.

The disease concept of NormoKPP was proposed by Poskanzer and Kerr in 1961 (Am J Med 1961;31:328-342), and was described as normokalemic sodium responsive periodic paralysis. Despite the reports by Fumio, et al. (Fumio Otsuka, Toshio Ogura, Takayoshi Yamauchi, Hirofumi Makino, Department of Medicine III, Okayama University Medical School, Japan, 1998), of new SCN4A mutations in Hyperkalemic Periodic Paralysis (HyperKPP), doubts remained as to whether NormoKPP existed as a discrete entity. Chinnery PF, Walls TJ, Hanna MG, Bates D, Fawcett PR (Ann Neurol 2002 Aug;52(2):251-2) report that they have identified the Met1592Val mutation of SCN4A in an affected descendent of the original NormoKPP family, stating emphatically, “This is the final piece in the puzzle: normoKPP is actually a variant of hyperKPP and is not a distinct disorder.” One hesitates to accept anything with such finality in today’s environment of rapid discovery and reevaluation. Designations can be confounded at the next opportunity for characterization.

Hyperkalemic (HyperKPP): Rüdel, Hana, and Lehmann-Horn (1999), identify at least four mutation variants in the SCN4A (sodium channel gene) that have been associated with the classical clinical picture of Hyperkalemic Periodic Paralysis (HyperKPP). As with other types of Periodic Paralysis, HyperKPP is transmitted by autosomal dominant inheritance. Attacks of weakness, according to the literature, usually occur in the morning, lasting from 10 minutes to as long as an hour or more. Attacks of weakness have been reported to last as long as a day or two. Ashcroft (2000) describes the myotonia (muscle stiffness) associated with HyperKPP as resulting from enhanced muscle excitability. According to Ashcroft, HyperKPP is known to “occur spontaneously, but attacks are usually precipitated by exercise, stress, fasting or eating potassium-rich foods.”

Rüdel, et al. report that some patients may experience only a few attacks of weakness in their lifetime, while others have reported near daily attacks of generalized weakness. During attacks of HyperKPP, serum potassium is mildly elevated to the high end of normal (4.5 mEq/l). Ashcroft (2000) describes potassium levels of between 5 and 7 mM, noting that since plasma potassium levels in non affected individuals can rise to as high as 8mM during strenuous exercise, “it seems possible that potassium may also be a precipitating factor in exercise-induced attacks: if this is the case, however, some additional factor must protect the muscle during the activity itself because the attack is only initiated on cessation of exercise.” Rüdel, et al. (1999) also report that rest following exercise, fasting, and the oral intake of potassium are very efficient in precipitating attacks in provocative testing.

Rüdel, et al., also offer the observation that “some patients always show slight signs of myotonia between and at the beginning of attacks; others show signs of paramyotonia, and in a third category myotonic signs are absent.” The additional observation that serum potassium can fall below normal at the end of an attack suggests that to avoid the misdiagnosis of hypokalemic periodic paralysis, interpretation of blood samples taken during this time should be carefully considered and confirmed by follow-up samples taken at the onset or during the initial stages of an attack.

Paramyotonia Congenita (PMC): Cannon (2002), reports that PMC shares significant clinical features with HyperKPP. These two disorders are both associated with mutations in the same gene (SCN4A sodium channel). PMC often results in episodic attacks of weakness with duration, severity, and serum potassium fluctuations similar to those seen in patients with HyperKPP. The hallmark symptoms in PMC are muscle stiffness that worsens with continued activity (paradoxical myotonia, or paramyotonia), severe worsening of myotonia when exposed to cold, and in most cases weakness will result from longer exposure to cold (Mitrovic and Lerche, 2000).

Hypokalemic Periodic Paralysis (HypoKPP): HypoKPP, the most prevalent form of periodic paralysis, has been associated with mutations in the CACNL1A3 (calcium channel) gene, the SCN4A (sodium channel) gene, which is also a known site of mutations causing hyperkalemic periodic paralysis, and the KCNE3 (potassium channel) gene.

In her work with a large multi-generation family in the Netherlands, T. P. Links (1992) provided standard criteria for the preliminary diagnosis of Familial Hypokalemic Periodic Paralysis:

Observation of paralytic attacks by a physician or a typical history of paralytic attacks.

Hypokalemia during attacks was often observed, but not prerequisite.

Characteristic histological findings in muscle biopsy.

Reduced muscle fiber conduction velocity (MFCV) in surface electromyographic EMG measurements, plus presence of first degree relatives with proven diagnosis.

Progressive proximal muscle weakness plus first line relatives with HOPP (HypoKPP).

Among the conclusions reached by Links in her work with this family is that Familial HypoKPP is characterized by: 1)permanent muscle weakness at older age, often independent of paralytic attacks, and 2) attacks occur in about 60% of the patients, with a ratio of 3 (men) to 2 (women). Variability of muscle strength was present in 80% of the patients. Twenty percent of the patients, all without paralytic attacks, did not have complaints until permanent muscle weakness developed. Others, including Sternberg, et al. (Sternberg D, Maisonobe T, Jurkat-Rott K, Nicole S, Launay E, Chauveau D, Tabti N, Lehmann-Horn F, Hainque B, Fontaine B., Brain 2001 Jun;124 (Pt 6):1091-9), have also described HypoKPP as a muscle disorder characterized by episodic attacks of muscle weakness associated with a decrease in blood potassium levels.

Interestingly, Links reported that a diagnosis could only be made in 50% of the subjects by applying a number of supplementary diagnostic steps. Diagnosis, according to Links, could be made in the majority of the studied cases if (besides a positive family history) at least one of the following characteristics was present: 1) hypokalemia during paralytic attacks, without other detectable causes, 2) characteristic histological finding in muscle biopsy, without the presence of chronic hypokalemia, and 3) reduced muscle fiber conduction velocity and a low frequency content of the power spectra, without the interfering use of steroids or the presence of poly- or dermatomyositis.

The above provides an excellent example of how much variability can be found even within the limits of a single family. Others have confirmed Links’ general findings. Mendell, Griggs, and Ptacek (1998), describe HypoKPP as causing episodic weakness and flaccid paralysis, with the distinction of distal limb muscles being more effected than proximal, and “rarely, ocular, bulbar, or respiratory muscles are affected.” The latter is especially fortuitous as respiratory muscle weakness can prove to be fatal.

Ptacek and Griggs (1996) report the important characteristic that there “is no alteration of consciousness during these attacks and patients are often unable to walk and at times may be totally quadriplegic.” Ptacek and Griggs add that while the weakness that occurs during attacks of paralysis is usually confined to the limbs, it is not uncommon to find some facial and respiratory muscle weakness, and, “during attacks of severe weakness, patients may have subjective sensory symptoms but tests of sensation are invariably normal.” Mitrovic and Lerche (2000) add that “reflexes become hypoactive, and cardiac arrhythmias may occur during attacks owing to low serum potassium.”

Andersen–Tawil Syndrome (ATS, also known as Andersen’s Syndrome, or AS): ATS is the most recently characterized variant of periodic paralysis and is unique among the periodic paralyses because, in addition to skeletal muscle, other tissues are also affected (Cannon, 2002). Mutations in KCNJ2 (potassium channel gene) cause the cardiac, skeletal muscle, and developmental phenotypes of ATS (M. R. Donaldson, BA, J. L. Jensen, MS, M. Tristani–Firouzi, MD, R. Tawil, MD, S. Bendahhou, PhD, W. A. Suarez, et al., 2003 and Nikki M. Plaster, Rabi Tawil, Martin Tristani-Firouzi, Sonia Canun, Saýd Bendahhou, Akiko Tsunoda, Matthew R. Donaldson, et al., 2001).

The first reports of AS were provided by Andersen (1971), describing a family with periodic paralysis, ventricular ectopy, and developmental abnormalities. Tawil R, Ptacek LJ, Pavlakis SG, et al. (1994), identified 15 similar cases from eight different kindreds, forming the basis for the current definition of ATS as a triad of potassium-sensitive periodic paralysis, ventricular arrhythmia and dysmorphic features. Similar to other periodic paralyses, ATS inheritance is autosomal dominant, however, penetrance is highly variable. Cannon (2002), provides the following summary of clinical features:

Affected family members (proven genetically) often have only two or even one of the clinical features of AS. The skeletal muscle dysfunction in AS is similar to other forms of periodic paralysis. Attacks of weakness begin in the first or second decade. Serum potassium during a spontaneous attack is often low, but may be normal and in some cases has even been high. Mild permanent weakness is another common feature of AS that was observed in 50% of patients. Myotonia is not present symptomatically or by EMG. The CK is usually normal, and the muscle biopsy typically shows mild chronic myopathy with tubular aggregates. Cardiac involvement in AS spans a wide spectrum of ventricular arrhythmias from asymptomatic long QT (LQT) to life-threatening ventricular tachycardia. In a series of 15 patients, the QT interval was prolonged in 12. Other cardiac defects observed in AS patients include ventricular ectopy, bi-directional ventricular tachycardia, and recurrent torsades de pointe. A constellation of distinctive dysmorphic features has been observed in AS. The most commonly involved structure is the face, which in AS may show low-set ears, broad nose, hypertelorism (wide-set eyes), and micrognathia (small mandible). Deformity of the digits also occurs with clinodactyly of the fingers or syndactyly of the toes. Less commonly occurring physical features include short stature, scoliosis, and high-arched palate.

Therapeutic Management:

The periodic paralyses are commonly managed through dietary manipulation designed to avoid fluctuations in serum potassium. This includes avoidance of excessive sodium and carbohydrate (sweets, sweetened beverages, pasta, starchy foods) in HypoKPP, and avoidance of high potassium foods in HyperKPP. It is important to recognize that individuals exhibit significant variability in sensitivity to dietary components and other triggers.

A dependable standard for all individuals has not been established. For example, in HypoKPP, some individuals report the inability to consume even very low levels of sodium without inducing weakness, while in a very few individuals salt has been shown to abort weakness. Management approaches include life-style changes to minimize sources of stress and exposure to other identified triggers. For improved control, individuals must work diligently to identify appropriate and effective management practices based on their own unique requirements.

In many cases, individuals require supplemental potassium, or the additional assistance of drugs. The most commonly used drugs are the carbonic anhydrase inhibitors.

Acetazolamide, still the most commonly prescribed, has been reported as ineffective in as many as thirty percent of individuals trying it. However, Acetazolamide has been the standard drug prescribed for periodic paralysis for over three decades, with a positive history of successful reduction of symptoms in the majority of patients.

Dichlorphenamide is the second most commonly used drug and is frequently interchanged with Acetazolamide when, or if, Acetazolamide becomes less effective.

Methazolamide is infrequently prescribed, but reported anecdotally by some patients to exhibit fewer side effects.

The principle side effects of these drugs are the formation of kidney stones, and various sensations including transient tingling and numbness in the extremities. Clinical trials must be accomplished to demonstrate the effectiveness of these and other potentially effective therapies for the growing list of periodic paralysis variants.

Periodic paralysis patients who exhibit cardiac dysrhythmias should be evaluated by an experienced clinician to insure effective follow-up and management of this potentially fatal status. In the case of Andersen’s-Tawil Syndrome, with the involvement of multiple tissues and organ systems, and the established risk associated with long QT and other cardiac irregularities, Tawil and others have advised that the patient be followed by a team that includes a cardiologist and a neurologist to maintain close monitoring of the patient's progress and insure effective management of the affected individual.

Resources:

The Periodic Paralysis Research Library.

References:

Adams RD, Victor M, and Ropper AH. Principles of Neurology, 6th ed. McGraw-Hill, New York, NY.

Andersen ED, Krasilnikoff PA, Overvad H. Intermittent muscular weakness, extrasystoles, and multiple developmental anomalies. A new syndrome? Acta Paediatr Scand 1971; 60:559–564.

Ashcroft FM. (2000). Ion Channels and Disease. Academic Press, San Diego, CA.

Brook MH. (2000). Disorders of Skeletal Muscle. In WG Bradley, RB Daroff, GM Fenichel, and CD Marsden (eds.). Neurology in Clinical Practice, Third (ed.), Volume II, (p 2187-2235).

Cannon, S. (2002). An expanding view for the molecular basis of familial periodic paralysis. Neuromuscular Disorders 12 (2002) Pergamom, pp. 533–543.

Links TP. (1992). Familial Hypokalemic Periodic Paralysis. Gronengen, The Netherlands: CIP-Gegevens Koninklijke Bibliotheek, Den Haag.

M. R. Donaldson, BA, J. L. Jensen, MS, M. Tristani–Firouzi, MD, R. Tawil, MD, S. Bendahhou, PhD, W. A. Suarez, MD FACC, A. M. Cobo, PhD, J. J. Poza, MD PhD, E. Behr, MA MBBS, MRCP, J. Wagstaff, MD PhD, P. Szepetowski, MD PhD, S. Pereira, MSc, T. Mozaffar, MD, D. M. Escolar, MD, Y.-H. Fu, PhD and L. J. Ptácek, MD (2003). PIP2 binding residues of Kir2.1 are common targets of mutations causing Andersen syndrome. Neurology 2003;60:1811-1816.

Engle AG. Periodic Paralysis. In AG Engle and BQ Banker, Myology: Basic and Clinical. New York: McGraw-Hill (p 1843-1870).

Mendel JR, Griggs RC, Ptacek LJ. (1998). Disease of Muscle. In AS Fauci, EB Braunwald, KJ Isselbacher, JD Wilson, JB Martin, DL Kasper, SL Hauser, and DL Longo (eds.), Harrison’s 14th Ed., Mc Graw-Hill, New York, NY. (p. 2473-2485).

Mitrovic N and Lerche H. Sodium and calcium channelopathies of sarcolemma: periodic paralyses, paramyotonia congenita and potassium-aggravated myotonia. In Frank Lehmann-Horn and K. Jurkat-Rott (eds.) Channelopathies – Common Mechanisms in Aura, Arrythmia and Alkalosis. Amsterdam, The Netherlands. Elsevier Science B. V. (p. 3-32).

Nikki M. Plaster, Rabi Tawil, Martin Tristani-Firouzi, Sonia Canun, Saýd Bendahhou, Akiko Tsunoda, Matthew R. Donaldson, Susan T. Iannaccone, Ewout Brunt, Richard Barohn, John Clark, Feza Deymeer, Alfred L. George, Jr., Frank A. Fish, Angelika Hahn, Alexandru Nitu, Coskun Ozdemir, Piraye Serdaroglu, S.H. Subramony, Gil Wolfe, Ying-Hui Fu, and Louis J. Ptacek. Mutations in Kir2.1 Cause the Developmental and Episodic Electrical Phenotypes of Andersen’s Syndrome. Cell, Vol. 105, 511–519, May 18, 2001,

Ptacek L, and Griggs RC, (1996). Familial Periodic Paralysis. In S. G. Schultz, T. E. Andrioli, A. M. Brown, D. M. Fambrough, J. F. Hoffman, and M. J. Welsh (eds). Molecular Biology of Membrane Transport Disorders. Plenum Press, New York (p 625-642) .

Poskanzer DC, Kerr DNS. A third type of periodic paralysis with normokalemic and favorable response to sodium chloride. Am J Med. 1961; 31:328.

Rüdel R, Hana MG, and Lehmann-Horn F. Muscle Channelopathies: Malignant Hyperthermia, (1999), Periodic Paralyses, Paramyotonia, and Myotonia. In A. H. V. Schapira and R. C. Griggs (eds.), Muscle Diseases, Butterworth and Heinmann, Boston. MA.

Ruff RL and Gordon AM. (1986). Disorders of Muscle, The periodic paralyses (p 825-839). In T. E. Andreoli, J. F. Hoffman, D. D. Fanestil and S. G. Schultz (eds.). Physiology of Membrane Disorders (2nd Ed.). Plenum Publishing Corporation, New York, NY.

Tawil R, Ptacek LJ, Pavlakis SG, et al. Andersen’s syndrome: potassium-sensitive periodic paralysis, ventricular ectopy, and dysmorphic features. Ann Neurol 1994;35:326–330.

  
Section Last Modified:
11/6/2011 10:55 PT
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