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PHYSICIAN'S INFORMATION SHEET

Andersen-Tawil Syndrome

Genetics

Potassium Channel KCNJ2 (Kir2.1) ; Gene Map Locus 17q23;
Dominant; Most mutations are missense; Some are inframe deletions. Mutated protein expression produces reduced inwardly rectifying K+ current. (16)
The R67W mutation: Phenotype - Ventricular arrhythmia in females (81%); Periodic paralysis in males (40%) Some carriers exhibited the dysmorphic features of ATS (hypertelorism, small mandible, syndactyly, clinodactyly, cleft palate, and scoliosis) however, no one individual had all features of ATS, and ATS was not considered in the proband until other family members were examined. Other features seen in this kindred included unilateral dysplastic kidney and a variety of cardiovascular malformations. Nonspecific electrocardiographic abnormalities were identified in some individuals, but none had a prolonged QT interval. Female subjects with the R67W mutation typically noted onset of ventricular arrhythmia after age 10 years. An increased incidence is usually reported during pregnancy, but female subjects with R67W reported reduced ventricular arrhythmias during pregnancy and after menopause. (17)

Tristani-Firouzi et al identified three mutations in the KCNJ2 channel; P186L; which alters binding of the signaling phospholipid PIP2.
V302M; which lies in a region that may be responsible for channel subunit assembly.
N216H; which lies within a region thought to be involved in PIP2 interactions. (18)

Lu et al. identified mutation T75R, which causes a non-functional channel in the cytoplasmic N-terminal portion of Kir2.1. Transgenic T75R mice had bidirectional ventricular tachycardia after induction and longer QT intervals. (19)

Andersen-Tawil syndrome (ATS) is a distinct periodic paralysis. Patients may have normo, hypo or hyper kalemia, or serum potassium may be labile during attacks. ATS may include severe cardiac involvement and skeletal anomalies. ATS is not genetically linked to other currently identified periodic paralyses or Long QT syndromes (1). Electrocardiographic (EKG) findings in ATS frequently, but not always, includes a prolonged QTc interval, which predisposes to sudden cardiac death (8,13, 17), and a variety of rhythm disturbances, including ventricular bigeminy, nonsustained ventricular tachycardia, bidirectional ventricular tachydysrhythmia, and frequent ventricular ectopy (13). A recently described mutation included cardiovascular malformations in affected females (i.e., bicuspid aortic valve, bicuspid aortic valve with coarctation of the aorta, or valvular pulmonary stenosis), which have not been previously associated with ATS. (17)

Clinical Description

The clinical description of ATS continues to evolve as more affected families come to light (7,8,17). Both Sansone and Katz noted that, in ATS, potassium shifts during attacks of weakness are inconsistent. A patient may experience an attack of paralysis accompanied by hypokalemia one time and by hyperkalemia (or normokalemia) the next. Therefore, traditional classifications of hypo-, normo-, or hyper- kalemic PP cannot be applied (6,11). Potassium sensitive ATS patients may become weak and develop QTc prolongation when hypokalemic (13). Partial manifestations of ATS are common. The subtle nature of the cardiac and dysmorphic features may delay diagnosis, but clinical recognition of ATS is vital given the predisposition for dysrhythmias and sudden death. Cardiac evaluations using serial EKGs with measurements of the QTc interval are essential and should be performed early on all patients undergoing workup for periodic paralysis. As alterations in serum K+ may aggravate cardiac arrhythmias in ATS, provocative testing for hypo- or hyperkalemic periodic paralysis in ATS patients is a relative, if not absolute, contraindication (3,4,13,17).

Every patient who has been diagnosed with periodic paralysis should be screened for ATS, with special emphasis on screening for a prolonged QTc interval. PP patients who manifest clinical signs consistent with ATS should be referred to a clinical team experienced in ATS (13).

A prolonged QTc was observed in almost every case of ATS that Sansone described (11), suggesting this to be a minimal diagnostic sign; however, Canun described a family with ATS in which only three of the eight affected members studied had a prolonged QTc (3). Canun presented facial photographs of 10 affected members of the family he studied. Degree of facial involvement did not correlate with the severity of heart or muscle involvement. This family was not of short stature; however, low weight and a slender constitution were found in several relatives (3). Andelfinger et. al. described a large family where no individual had all three characteristics (paralysis, dysmorphic features, cardiac affects) common to ATS, and furthermore, where only males had weakness and females had cardiac arrhythmias (17)

Clinical Signs Summary:

QT Features:

Normal QTc interval is 0.39 sec for men and 0.44 sec for women (as per Bazett's Formula: QT/(R-R)^1/2) (2). In AS there is frequently, but not always, a variable prolongation of QT interval. (3,6,11,13) See discussion of Long QT by Dr. Michael Vincent below.

Arrhythmias:

Ventricular ectopy; bigeminy (a ventricular premature beat follows each normal beat); bidirectional tachycardia (tachycardia in which QRS contours vary in alternate complexes) (6,13).

Weakness:

Timing: episodic, lasting 1 hour to days; attacks may be rare though some patients may have persistent generalized background weakness. Onset: from early childhood to anytime in adulthood.

Precipitants for attacks: hypokalemia, K+ administration, exercise, or idiopathic.

Permanent weakness: observed in some patients; proximal and distal muscles can be involved (6,10,11,13).

Dysmorphic Features:

May be very subtle, partial or seen in 'unaffected' family members

Skeletal:

Hands/Feet:

webbed foot, second and third toes joined, viewed from topwebbed foot, second and third toes joined, viewed from bottomAn example of webbed toes sometimes seen in ATS.

Facial:

Laboratory:

May have labile serum K+ during attack (6,11,13).

Muscle Pathology:

Tubular aggregates (10,13).

Treatment

Must be individualized to patient, may require periodic readjustment. Treatment for ATS remains empirical and is frustrated by a paradoxical response of cardiac and skeletal muscle to changes in potassium levels, unpredictable responses to drugs (5,13), and an overall refractoriness to antiarrhythmic agents (5,9,13,15).

Oral K+ may improve weakness in patients with low serum K+. In some families, raising serum K+ improves arrhythmia but exacerbates weakness. In addition to the standard pharmacologic therapies for the periodic paralyses, (i.e. acetazolamide, diclorphenamide, diuretics) beta-blockers (esp. Atenolol) have been used successfully in some patients (6,13). Patients who have experienced a cardiac arrest or who continue to have syncope in spite of medication are candidates for an implantable defibrillator or pacemaker (6). Patients must avoid hypokalemia (caused by vomiting, diarrhea, or iatrogenically by diuretic use) and drugs that cause prolongation of the QT interval (14).

Drugs Which Patients With Prolonged QT Interval Should Avoid:

Note: Use this list as a starting point only Clinicians should consult a reliable pharmacology source for authoritative information. One such source is found at: The University of Arizona Center for Education and Research on Therapeutics

BETA-AGONISTS: Epinephrine a.k.a. adrenaline (many trade names) (found in local anaesthetics and asthma medications)

ANTIHISTAMINES: Seldane, Hismanal, Benadryl, Terfenadine, Astemizole, Diphenhydramine

ANTIBIOTICS: E-Mycin, EES, Erypeds, PCE, etc., Bactrim, Septra, Erythromycins, Trimethoprim, Sulfamethoxazole, Pentamidine, Pentam IV

HEART MEDICATIONS: Amiodarone HCI, Quinidine, Quinidex, Duraquin, Quiniqlute, Pronestyl, Norpace, Betapace, Lorelco, Vascor, Procainamide, Disopyramide, Sotalol, Probucol, Bepridil

GASTROINTESTINAL: Propulsid, Cisapride

ANTIFUNGALS: Nizoral, Diflucan, Sporanox, Ketoconazole, Fluconazole, Itraconazole

PSYCHOTROPICS: Norpramine, Viractil, Compazine, Stelazine, Thorazine, Mellaril, Etrafon, Trilafon, Haldol, Risperdal, ORAP, Amitriptyline, tricyclics, phenothiazine derivatives, Haloperidol, Risperidone, Pimozide

DIURETICS: Lozol, Indapamide. Many diuretics cause potassium wasting, and hypokalemia lengthens the QT interval.

LONG QT SYNDROME - G. Michael Vincent, M.D.

Sudden Arrhythmia Death Society

Long QT Syndrome (LQTS) is a disorder of the electrical system of the heart. The duration of the QT interval is the measure of the time required for repolarization to occur after a heartbeat. Prolongation of the QT interval renders patients vulnerable to an arrhythmia known as torsades de pointes. When this rhythm occurs, no blood is pumped out from the heart, and the brain quickly becomes deprived of blood, causing syncope and sudden death. The flow of ions in and out of the cells produces the electrical activity of muscle. In LQTS, the channel abnormalities can be acquired or inherited. The inherited form occurs when a mutation develops in one of the genes which encode an ion channel. These mutations cause the electrical recovery of the heart to be slowed, and this slower recovery is manifest on the ECG by a prolonged QT interval.

Symptoms

Syncope and sudden death are the common symptoms of LQTS. Syncope usually occurs during (or seconds to minutes following) physical exertion or emotional excitement. Sudden death may also occur during sleep or arousal from sleep. In patients with syncope, the heart rhythm reverts spontaneously to normal. With syncope, the patient regains consciousness within a minute or two. When the abnormal rhythm persists, the outcome is death. It is uncommon for syncope or sudden death to occur when the person is awake and at rest. About one-third of LQTS patients are asymptomatic. In the other two-thirds, some have one or two syncopal spells as children, and none thereafter. Others have many episodes over a number of years. Symptoms may begin in the first days or weeks of life, or as late as middle age. The absence of syncope or sudden death in a family does not guarantee the absence of this condition in the family.

Diagnosing LQTS

The primary finding is a prolonged QT interval on the ECG. A clearly long QT interval is present in about 60% to 70% of affected persons. Sometimes the QT prolongation is overlooked by medical professionals even when present, so when a patient is concerned about LQTS it is appropriate for them to ask the Doctor to specifically evaluate the QT interval. About 12% of affected patients actually have a normal QT interval on their resting ECG. In another 30% the QT interval is only borderline prolonged, not prolonged enough to clearly make the diagnosis.

In these cases, an exercise ECG will usually assist in clarifying the diagnosis. The exercise test is preferably a low level, somewhat protracted exercise test, which allows the individual to exercise for 10 or more minutes without reaching a heart rate much in excess of 150-160 beats per minute. This prevents the T wave from merging with the P wave in normal subjects and simplifies the measurement of the QT interval. The principle abnormality to be identified is a prolonged QT interval relative to the heart rate, determined by an increase in the calculated QTc interval, and the appearance of bifid T-waves.

Electrical heart catheterization (EPS testing) is not helpful in identifying LQTS. Also helpful is examination of ECGs of parents and siblings. Since this is a genetic disorder, one parent and other siblings may be affected and their QT may be diagnostically prolonged.

References

  1. Andersen, ED; et al: Intermittent muscular weakness, extrasystoles, and multiple developmental anomalies: a new syndrome? Acta Paediat. Scand. 60: 559-564, 1971.
  2. Bazett H. An analysis of the time-relations of electrocardiograms. Heart 7:353-370, 1920.
  3. Canun, S; Perez, N; Beirana, LG: Andersen syndrome autosomal dominant in three generations. Am. J. Med. Genet. 85: 147-156, 1999.
  4. Chalak, W; Taha, A; Araoya, M; Rifaat, M: Torsade de pointes. Reportof 18 cases. J. Med. Liban. 41(2):62-8, 1993; disc. 68-9 Middle East Hospital, Beirut, Lebanon.
  5. Gould, RJ; Steeg, CN; Eastwood, AB; Penn, AS; Rowland, LP; De Vivo, DC: Potential fatal cardiac dysrhythmia and hyperkalemic periodic paralysis. Neurology. 35:1208-1212, 1985.
  6. Katz, JS; Wolf, GI; Iannaccone, S; Bryan, WW; Barohn, RJ: The Exercise Test in Andersen Syndrome. Arch. Neurol. 56:352-356, 1999.
  7. Kramer, LD; Cole, JP; Messenger, JC; Ellestad, MH: Cardiac dysfunction in a patient with familial hypokalemic periodic paralysis. Chest. 75: 189-192, 1979.
  8. Levitt, LP; Rose, LI; Dawson, DM: Hypokalemic periodic paralysis with arrhythmia. New Eng. J. Med. 286: 253-254, 1972.
  9. Lisak, RP; Lebeau, J; Tucker, SH; Rowland, LP: Hyperkalemic periodic paralysis with cardiac arrhythmia. Neurology. 20:386, 1970.
  10. Neuromuscular Disease Center, Washington Univ School of Medicine, St. Louis, Mo. 1999.
  11. Sansone, V; Griggs, RC; Meola, G; Ptacek, LJ; Barohn, R; Iannaccone, S; Bryan, W; Baker, N; Janas, SJ; Scott, W; Ririe, D; Tawil, R: Andersen's syndrome: a distinct periodic paralysis. Ann. Neurol. 42:305-312, 1997.
  12. Stubbs, WA: Bidirectional ventricular tachycardia in familial hypokalaemic periodic paralysis. Proc. Roy. Soc. Med. 69: 223-224, 1976.
  13. Tawil, R; Ptacek, LJ; Pavlakis, SG; De Vivo, DC; Penn, AS; Ozdemir, C; Griggs, RC: Andersen's syndrome: potassium-sensitive periodic paralysis, ventricular ectopy, and dysmorphic features. Ann. Neurol. 35:326-330, 1994.
  14. Vincent, GM: Sudden Arrthymia Death Society
  15. Yoshimura, T; Kaneuji, M; Okuno, T: Periodic paralysis with cardiac arrhythmia. Eur. J. Pediatr. 1 0:338-343, 1983.
  16. Plaster, N.M.; Tawil, R. Tristani-Firouzi, M.; et. az; Mutations in Kiru.1 Cause the Developmental and Episodic Electric l Phentoypes in Andersen's Syndrome. Cell Vol 105, 511-519, May 18, 2001.
  17. Andelfinger G, Tapper AR, Welch RC; et. al; KCNJ2 Mutation Results in Andersen Syndrome with Sex-Specific Cardiac and Skeletal Muscle Phenotypes; Am J Hum Genet 2002 Sep;71(3):663-8
  18. Tristani-Firouzi, M.; Jensen, J. L.; Donaldson, M. R.; et. al. Functional and clinical characterization of KCNJ2 mutations associated with LQT7 (Andersen syndrome). J. Clin. Invest. 110: 381-388, 2002. PMID: 12163457
  19. Lu, C.-W.; Lin, J.-H.; Rajawat, Y. S. et. al. Functional and clinical characterization of a mutation in KCNJ2 associated with Andersen-Tawil syndrome. J. Med. Genet. 43: 653-659, 2006. PubMed ID:16571646

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