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PHYSICIAN'S INFORMATION SHEET

Paramyotonia Congenita and Paramyotonia Syndromes

Genetics and Inheritance

Sodium Channel - Voltage-Gated, Type IV, Alpha Polypeptide
SCN4A; Gene map locus: 17q23-q25.3
Mutations identified to date:

Pure Paramyotonia:

Mutations: G1456E; L1433R

Paramyotonia ± Episodic weakness with exercise: Mutation: R1448C

Poor inactivation of Na+ channel: Prolongs action potential and reduces membrane repolarization. Mild depolarization produces paramyotonia. Paradoxical myotonia: worsens with exercise. More severe depolarization produces weakness. Weakness or stiffness may occur alone. Worse in face, neck & upper extremities. Onset in infancy. May be associated with HyperKPP. Onset by adolescence or never. Some patients worse after K+ load.

Potassium aggravated myotonias (PAM):

PAM Mutations: S804P; I1160V; G1306A; G1306V; G1306Glu; V1589M

The PAMs include attacks of myotonia which are precipitated by K+. None include weakness. The PAMs are:

Myotonia fluctuans;

Mild myotonia that varies in severity from day to day, no weakness or cold sensitivity, stiffness develops during rest 1/2 hour after exercise; lasts for ~1 hour, worsens with K+, depolarizing agents, may interfere with respiration.

Myotonia permanens;

Severe continuous myotonia (may interfere with respiration) Marked muscle hypertrophy.

Acetazolamide responsive myotonia;

Paradoxical myotonia, Muscle hypertrophy, muscle pain, Symptoms improve with acetazolamide treatment.

Paramyotonia Congenita (PMC):

PMC Mutations: SCN4A Mutations: V1293I; T1313M; L1433A; A1448C; A1448H; A1448P; G1456E; V1458P; P1473S
CLCN1 Mutation: F428S

Weakness in PMC is precipitated by hypokalemia.

Paramyotonia congenita without cold paralysis: Mutation: V1293I

Reference: OMIM Number: 603967 Citation MUID: 91377747 IV,

Paramyotonia Congenita was first described by von Eulenburg in 1886. PMC's characteristics are (1) dominantly inherited with high penetrance; (2) myotonia, increased by exposure to cold; (3) intermittent flaccid weakness/paralysis, not necessarily dependent on cold or myotonia; (4) potassium level during attacks may be increased, decreased or normal; (5) nonprogressive; and (6) lack of atrophy or hypertrophy of muscles, though patients with overlap of PMC with hyperkalemic periodic paralysis may have hypertrophy and progressive myopathy associated with that form.

Lajoie described a family with many affected members. (1) Hudson reported that in 17 affected persons in five generations of one family, symptoms of PMC overlapped with hypokalemic, eukalemic and hyperkalemic periodic paralysis, with myotonia congenita and with myotonic dystrophy. (2) Six and possibly nine generations of the French-Canadian family reported by Samaha had affected members. Eating ice cream or swimming in cold water was dangerous to affected members. Serum potassium levels were only moderately increased and the patients were sensitive to administered potassium. (3)

McClatchey et al. confirmed the involvement of SCN4A in both hyperKPP and PMC (and) suggested that these are the first known examples of molecular definition of temperature-sensitive mutations in the human... At normal temperatures, this mutation may have minimal clinical significance; however, even a minor drop in temperature may impede movement of the loop enough to allow an abnormal Na+ flux. The mutations associated with PMC result in temperature-exacerbated, uncontrollable muscle tension after contraction. This tension is due to muscle fibre membrane hyperexcitability that produces long bursts of action potentials ('myotonic runs') rather than one or only a few spikes in response to a motor neuron discharge. (4, 5)

The demonstration of mutations in the SCN4A gene in both hyperKPP and PMC settles the long-standing question as to whether these two diseases are directly related. Lehmann-Horn et al. suggested the term 'sodium channel disease' to encompass the different allelic syndromes caused by SCN4A mutations. (6)

Variability of Signs

There are families where affected members present with the classical symptoms of PMC (muscle rigidity and weakness precipitated by cold and activity) and also experience attacks of hyperKPP. The presentation of both sets of symptoms in severe form was termed paralysis periodica paramyotonica (PPP) by P.E. Becker; however, a continuum seems to exist, with PPP families and families having 'pure' PMC presenting the two extremes. The fact that families, or even individuals within families, with the same mutation, present distinct phenotypes indicates that other factors, genetic or environmental, may modulate the expression of the disease in sodium channel disorders.

Diagnosis

Patients may describe paramyotonia as muscle stiffness which can be painful or painless, exacerbated by activity and cold. (i.e. a walk in the park on a cool windy day) Some patients develop a characteristic 'grimace' when exposed to cold.Characteristic grimace of a patient with PMC 65-year-old PMC patient attempting to smile on cool, windy day. Note narrowing of eyes.Patient may move stiffly or appear 'tense'. Some describe problems letting go of objects like pens, doorknobs or beverage containers. Exertion (carrying a heavy object, pushing a stalled car, lifting weights) may trigger weakness which takes weeks (even months) to resolve. Patients with severe PMC may develop contracture during attacks or experience s.o.b. due to intercostal tightness.

Exposure to cold not only worsens the myotonia but may provoke muscle weakness. When the muscle is sufficiently chilled, the paramyotonia disappears, and the muscle is flaccid and paralyzed. The weakness may far outlast the exposure to cold. Immersing the forearm in ice water may also produce weakness which is lacking at room temperature. Strong voluntary contraction also may be associated with a long-lasting decrease in strength, which is not clearly due to an increase in myotonia. (7)

Electrodiagnostic myotonia is characteristic and is readily distinguished from complex repetitive discharges. In complex repetitive discharges, the recurrent waveform is typically suggestive of a complex motor unit potential, has a fairly constant frequency of discharge, does not wax and wane, and has abrupt onset and offset. Sometimes, a change in discharge frequency or potential morphology occurs, but the transitions are always abrupt.

In myotonia, the primary subunits of the discharge are of positive wave or fibrillation potential configuration, wax and wane in frequency and amplitude (usually in an inverse fashion), and have characteristic variations in pitch and loudness different from the homogeneous whine of a complex repetitive discharge. However, like improper Victorian children, both myotonia and complex repetitive discharges are sometimes heard, but not seen until carefully sought, so patient searching is sometimes helpful. The biggest electrodiagnostic pitfall in the myotonias comes from failure to recognize the clinical features of the disorder. (8,9)

In contrast to myotonia, during the delayed muscle relaxation of paramyotonia, electrical activity of the muscle is not prominent . In patients with paramyotonia the EMG of the resting muscles at room temperature may show myotonia that is present on percussion or with movement of the limb. The most remarkable finding is the appearance of spontaneous activity on cooling the limb. Low-amplitude fibrillation activity appears as the muscle is cooled and is most intense when the muscle temperature is around 30 degrees C. This spontaneous activity completely disappears as cooling continues. EMG studies may also be useful in demonstrating the worsening of the myotonic discharges with exposure to cold. Since exercise may worsen the symptoms, a brief exercise test has been proposed, searching for a decrease in the muscle compound action potential. (7,8,9)

Pharmacology and Therapy

Aggravated by:

Each patient has to be treated on an individual basis. Patients with hyperKPP episodes need to be treated with traditionally proven therapies for HyperKPP, with the proviso that acetazolomide provokes weakness in a large number of PMC patients. However some PMC patients benefit from acetazolomide (125 to 1000 mg day) or Dichlorphenamide (50 to 150 mg/day). Some may take acetazolomide in an on/off pattern with benefit. Care needs to be taken not to treat hyperkalemic episodes too aggressively, in order not to trigger PMC episodes. In some patients with HyperKPP potassium levels drop below normal at the end of episodes, triggering PMC attacks. Controlling the HyperKPP often helps control the PMC in such patients. It has been demonstrated that potassium uptake in skeletal muscle is enhanced during episodes of PMC, a phenomenon which also occurs during episodes of hypoKPP. Serum potassium levels drop during this enhanced uptake and while it may seem contradictory in the extreme PMC patients may require potassium to control episodes of PMC weakness. This therapy should be introduced with some caution, and is best done with water soluble K+ which can be diluted, but experience has proven that a dose of 5-10 mEq K+ is often sufficient to stop an episode of PMC weakness without triggering hyperkalemia. (7, 11, 12, 13)

Paramyotonia may be lessened or controlled with lidocaine derivatives, i.e. Mexiletine 150 to 1,000 mg/day. We have had numerous reports that low dose Serontonin re-uptake inhibitors (i.e. Paxil 10-20 mg daily) have proven helpful in reducing myotonia in PMC, especially in combination with Mexiletine, and may allow for smaller doses of that drug. (7, 14)

References:

  1. Lajoie, W.J. : Paramyotonia congenita, clinical features and electromyographic findings. Arch. Phys. Med. 42: 507-512, 1961.
  2. Hudson, A.J. :Progressive neurological disorder and myotonia congenita associated with paramyotonia. Brain 86: 811-826, 1963.
  3. Samaha, F.J. : Von Eulenburg's paramyotonia. Trans. Am. Neurol. Assoc. 89: 87-91, 1964. !PubMed ID : 5828532
  4. McClatchey, A.I.; et al. : Temperature-sensitive mutations in the III-IV cytoplasmic loop region of the skeletal muscle sodium channel gene in paramyotonia congenita. Cell 68: 769-774, 1992. !PubMed ID : 1310898
  5. Lehmann-Horn, F.; et al.: Adynamia episodica hereditaria with myotonia: a non-inactivating sodium current and the effect of extracellular pH. Muscle Nerve 10: 363-374, 1987. !PubMed ID : 3587272
  6. Lehmann-Horn, F.; Rudel, R.; Ricker, K.: Non-dystrophic myotonias and periodic paralyses. Neuromusc. Disord. 3: 161-168, 1993.!PubMed ID : 7689382
  7. Brooke M. H.; Disorders of Skeletal Muscle. Neurology in Clinical Practice, Third Ed, 2000: Bradley, W.G. et al. Eds. Boston, MA: Butterworth/Heinemann.
  8. Kimura J. Electrodiagnosis in Diseases of Nerve and Muscle: Principles and Practices. Philadelphia, PA: FA Davis, 1983
  9. Subramony SH, Malhotra CP, Mishra SK. : Distinguishing paramyotonia congenita and myotonia congenita by electromyography. Muscle Nerve 1983;6:374-379.
  10. Neuromuscular Disease Center, Washington Univ school of Medicine, St. Louis, Mo.1999
  11. Riggs J.E. ; Neurology Clinics; Muscle Disease; The Periodic Paralyses: Vol. 6, No 3 Aug 1988 pp. 485-493
  12. Benstead T.J.; Camfield P.R.; King D.B.; Can J Neurol Sci, 1987 May, 14:2, 156-8)
  13. Moxley RT; et al. : Neurology, 1989 Jul, 39:7, 952-5)
  14. ackson CE, Barohn RJ, Ptacek LJ. : Paramyotonia congenita: Abnormal short exercise test, and improvement after mexiletine therapy. Muscle Nerve 1994;17:763

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