Clinical Diagnosis

The diagnosis of Andersen-Tawil syndrome (ATS) is suspected in individuals with either:

• Two of the following three criteria:

  • Periodic paralysis

  • Symptomatic cardiac arrhythmias or electrocardiographic (ECG) evidence of enlarged U-waves, ventricular ectopy, or a prolonged QTc or QUc interval

  • Characteristic facies, dental anomalies, small hands and feet, and at least two of the following:

    • Low-set ears

    • Ocular hypertelorism

    • Small mandible

    • Fifth-digit clinodactyly

    • Syndactyly
      
      or

• One of the above three in addition to at least one other family member who meets two of the three criteria [Tawil et al 1994, Sansone et al 1997, Tristani-Firouzi et al 2002].

The presence of a pathogenic KCNJ2 sequence variant confirms the diagnosis of Andersen-Tawil syndrome type 1 (ATS1).

Testing

Serum potassium concentration during episodes of weakness may be elevated, normal, or, most commonly, reduced (<3.5 mmol/U) [Tawil et al 1994, Sansone et al 1997, Canun et al 1999, Tristani-Firouzi et al 2002].

Routine nerve conduction electrophysiology is normal between episodes. A more sensitive electrophysiologic study, the long exercise protocol, may reveal an immediate post-exercise increment followed by an abnormal decrement in the compound motor action potential (CMAP) amplitude (>40%) [Katz et al 1999] or area (>50%) 20-40 minutes post-exercise [Kuntzer et al 2000, Fournier et al 2004].

Electrocardiogram may reveal characteristic abnormalities including prominent U waves, prolonged Q-U intervals, premature ventricular contractions, polymorphic ventricular tachycardia, and bidirectional ventricular tachycardia [Zhang et al 2005].

24-hour Holter monitoring is important to document the presence, frequency, and duration of ventricular tachycardia (VT) and the presence or absence of associated symptoms.

Molecular Genetic Testing

Gene. KCNJ2, encoding the inward rectifier potassium channel 2 protein (Kir2.1), is the only gene known to be associated with Andersen syndrome type 1 (ATS1).

Locus heterogeneity. To date, no other loci have been identified to account for ATS (termed Andersen syndrome type 2, or ATS2) in the 40% of kindreds not linked to KCNJ2.

Clinical testing

• Sequencing of the entire coding region. Approximately 60% of individuals with ATS have a missense mutation or a small deletion in KCNJ2; more than 20 missense mutations have been described to date [Plaster et al 2001, Ai et al 2002, Andelfinger et al 2002, Tristani-Firouzi et al 2002, Donaldson et al 2003, Hosaka et al 2003]. The mutation Arg218Trp is considered a potential hotspot for disease-causing mutations [Davies et al 2005].

• Mutation scanning. The detection rate for mutation scanning remains unknown.

• Deletion/duplication analysis is available clinically. However, no partial- or whole-gene deletions or duplications involving KCNJ2 as causative of ATS1 have been reported.

Table 1. Molecular Genetic Testing Used in Andersen Syndrome Type 1

View in own window

Gene Symbol	Test Method	Mutations Detected	Mutation Detection Frequency by Test Method 1	Test Availability
KCNJ2	Sequence analysis	Sequence variants 2	~60%	Clinical
	Mutation scanning		Unknown
	Deletion / duplication analysis 3	Partial- or whole-gene deletions/duplications	Unknown

Test Availability refers to availability in the GeneTests™ Laboratory Directory. GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests™ Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.

1. The ability of the test method used to detect a mutation that is present in the indicated gene

2. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations.

3. Testing that identifies deletions/duplications not readily detectable by sequence analysis of genomic DNA; a variety of methods including quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), or targeted array GH analysis (gene/segment-specific) may be used. A full array GH analysis that detects deletions/duplications across the genome may also include this gene/segment. See array GH.

Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.

Testing Strategy

To confirm/establish the diagnosis in a proband

• Individuals with either episodic weakness or cardiac symptoms require careful evaluation by a neurologist and/or cardiologist as well as measurement of serum potassium concentration (baseline and during attacks of flaccid paralysis), a 12-lead ECG, a 24-hour Holter monitor, and possibly the long exercise protocol.

• In approximately 60% of individuals, molecular genetic testing confirms the clinical diagnosis. To date there is no known role for routine deletion/duplication analysis.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family.

Note: It is the policy of GeneReviews to include in GeneReviews™ chapters any clinical uses of testing available from laboratories listed in the GeneTests™ Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Genetically Related (Allelic) Disorders

No other phenotypes have been associated with mutations in KCNJ2.

Natural History

Andersen-Tawil syndrome (ATS) is characterized by the triad of episodic flaccid muscle weakness, distinctive dysmorphic features, and ventricular arrhythmias and prolonged QT interval. Affected individuals present initially with either periodic paralysis or cardiac symptoms (palpitations and/or syncope) in the first or second decade [Tawil et al 1994, Tristani-Firouzi et al 2002]; however, prospective standardized natural history data are not yet available.

Intermittent weakness occurs spontaneously, or alternatively may be triggered by prolonged rest or rest following exertion. The attack frequency, duration, and severity are variable between and within affected individuals. Mild permanent weakness is common [Tawil et al 1994, Sansone et al 1997, Canun et al 1999, Tristani-Firouzi et al 2002].

Ventricular arrhythmias, including bidirectional ventricular tachycardia (VT), polymorphic VT, and multifocal premature ventricular contractions may be asymptomatic or manifest as palpitations most commonly. Less common symptomatic presentations include syncope, cardiac arrest, or sudden death [Andelfinger et al 2002, Tristani-Firouzi et al 2002, Donaldson et al 2003]. While the ECG may reveal a long QTc interval (LQT), characteristic T-U patterns including enlarged U waves, a wide T-U junction, and prolonged terminal T-wave downslope distinguish ATS1 from other LQT syndromes [Zhang et al 2005, Haruna et al 2007].

Dilated cardiomyopathy was observed in two of three affected individuals in a single kindred with the Arg218Trp mutation [Schoonderwoerd et al 2006]; whether this is an uncommon phenotypic manifestation or a consequence of chronic tachycardia remains to be seen [Tristani-Firouzi 2006].

Distinctive physical features recognized initially included low-set ears, ocular hypertelorism, small mandible, fifth-digit clinodactyly, syndactyly, short stature, broad nasal root, and scoliosis [Andersen et al 1971, Tristani-Firouzi et al 2002, Donaldson et al 2003]. Dental enamel discoloration was noted in two kindreds with the Gly300Asp and Arg218Trp mutations [Davies et al 2005].

Detailed, prospectively collected data in ten individuals with confirmed KCNJ2 mutations have expanded the phenotype to include a characteristic facies and dental and skeletal anomalies [Yoon et al 2006a].

• Characteristic facies include broad forehead, short palpebral fissures, full nasal bridge with bulbous tip, hypoplasia of maxilla and mandible, thin upper lip, and a triangular shape.

• Dental findings include (among others) persistent primary dentition, multiple missing teeth (oligodontia), and dental crowding.

• Skeletal findings include mild syndactyly of toes 2 and 3 as well as fifth-digit clinodactyly.

• Novel findings include small hands and feet (<10th centile for age) and joint laxity.

Isolated reports of renal anomalies include unilateral hypoplastic kidney [Andelfinger et al 2002] and renal tubular defect [Davies et al 2005].

Mild learning difficulties have been described [Davies et al 2005]. A distinct neurocognitive phenotype (i.e., deficits in executive function and abstract reasoning) has been recognized in individuals with a KCNJ2 mutation despite IQ levels similar to those of their unaffected sibs [Yoon et al 2006b].

Afebrile seizures occurring only in infancy were reported in 4/23 (17%) of a Japanese cohort with ATS1 [Haruna et al 2007].

Genotype-Phenotype Correlations

Individuals with clinically defined ATS are phenotypically indistinguishable, regardless of the presence of a KCNJ2 mutation (ATS1) or absence of a KCNJ2 mutation (ATS2) [Tristani-Firouzi et al 2002, Donaldson et al 2003].

In a single large kindred with the KCNJ2 Arg67Trp mutation, periodic paralysis was observed only in men, cardiac symptoms only in women, and congenital anomalies in both [Andelfinger et al 2002]. However, this apparent sex-limited bias in clinical presentation has not been confirmed [Donaldson et al 2003, Davies et al 2005].

Penetrance

The phenotype is highly variable. Approximately 60% of affected individuals manifest the complete triad of cardinal features and up to 80% express two of the three cardinal features [Tristani-Firouzi et al 2002, Haruna et al 2007]. Non-penetrance is evident in 6%-20% of individuals with an identifiable mutation [Andelfinger et al 2002, Tristani-Firouzi et al 2002, Donaldson et al 2003].

Anticipation

Anticipation is not observed.

Nomenclature

Although listed in OMIM, the following names for ATS are no longer in clinical use:

• Periodic paralysis, potassium-sensitive cardiodysrhythmic type

• Andersen cardiodysrhythmic periodic paralysis

Prevalence

The prevalence is not known. ATS represents fewer than 10% of cases of primary periodic paralysis. The incidence of periodic paralysis is also unknown and estimated to be at most 1:100,000.

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with Andersen-Tawil syndrome (ATS), the following evaluations are recommended:

• Baseline assessments by a neurologist and cardiologist familiar with periodic paralysis and LQT respectively

• Serum potassium concentrations at baseline and during attacks of weakness

• 12-lead ECG and 24-hour Holter monitor

• Electrophysiologic studies including the long exercise protocol [Kuntzer et al 2000, Fournier et al 2004]

• Verification that serum concentration of thyroid-stimulating hormone (TSH) is within normal limits

Treatment of Manifestations

Management of individuals with ATS requires the coordinated input of a neurologist familiar with the treatment of periodic paralysis and a cardiologist familiar with the treatment of cardiac arrhythmias. To date, no randomized clinical therapeutic trials have been conducted on ATS.

Management of attacks of episodic weakness depends on the associated serum potassium concentration:

• If the serum potassium concentration is low (<3.0 mmol/L), administration of oral potassium (20-30 mEq/L) every 15-30 minutes until the serum concentration normalizes often shortens the attack. Monitoring of serum potassium concentrations and the ECG in the emergency department may be useful during potassium replacement therapy to avoid secondary hyperkalemia.

• Attacks of weakness when the serum potassium concentration is high usually resolve within 60 minutes. Episodes may be shortened by ingesting carbohydrates or continuing mild exercise. Intravenous calcium gluconate is rarely necessary for management in an individual seen in the emergency department.

Vasovagal syncope in individuals with ATS mandates a careful cardiology assessment [Airey et al 2009].

Prevention of Primary Manifestations

Prophylactic treatment aimed at reduction of attack frequency and severity can be achieved, as in other forms of periodic paralysis, with the following:

• Lifestyle and dietary modification to avoid known triggers

• The use of carbonic anhydrase inhibitors (acetazolamide 250-500 mg/1-2x/day or dichlorphenamide 50-100 mg/1-2x/day)

• The daily use of slow-release potassium supplements, which may also be helpful in controlling attack rates in individuals with a tendency to become hypokalemic. Elevating the serum potassium concentration (>4 mEq/L) has the added benefit of narrowing the QT interval, thus reducing the risk of LQT-associated arrhythmias.

• An implantable cardioverter-defibrillator (ICD) in individuals with tachycardia-induced syncope [Chun et al 2004]

• Empiric treatment with flecainide [Bökenkamp et al 2007, Pellizzón et al 2008, Fox et al 2008] should be considered for significant, frequent ventricular arrhythmias in the setting of reduced left ventricular function [Tristani-Firouzi & Etheridge 2010].

Prevention of Secondary Complications

Cardiologists should be aware that some antiarrhythmic drugs, particularly class I drugs, may paradoxically exacerbate the neuromuscular symptoms and should be used cautiously in individuals with ATS.

Although malignant hyperthermia has not been reported in ATS, appropriate anesthetic precautions should be undertaken as with individuals with other forms of periodic paralysis.

Surveillance

Screening of an asymptomatic individual with a pathogenic KCNJ2 mutation with an annual 12-lead ECG and 24-hour Holter monitoring is desirable, followed by referral to a cardiologist if abnormalities are identified.

Agents/Circumstances to Avoid

Affected individuals should avoid medications known to prolong QT intervals. See www.azcert.org [Woosley 2001] for a complete and updated list.

Salbutamol inhalers, which may be used in the treatment of primary hyperkalemic periodic paralysis, should be avoided because of the potential for exacerbation of cardiac arrhythmias.

Thiazide and other potassium-wasting diuretics may provoke drug-induced hypokalemia and could aggravate the QT interval.

Evaluation of Relatives at Risk

It is appropriate to offer molecular genetic testing to at-risk relatives if the disease-causing mutation is identified in an affected family member, so that morbidity and mortality can be reduced by early diagnosis and treatment.

If the disease-causing mutation in the family is not known, it is appropriate to offer clinical diagnostic evaluations to at-risk family members in order to permit early diagnosis and treatment.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Registries

Contact information for voluntary patient registries is provided by GeneReviews staff

Consortium for Clinical Investigation of Neurologic Channelopathies Contact Registry
Web: rarediseasesnetwork.epi.usf.edu

Other

Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.

See Consumer Resources for disease-specific and/or umbrella support organizations for this disorder. These organizations have been established for individuals and families to provide information, support, and contact with other affected individuals.

Mode of Inheritance

Andersen-Tawil syndrome (ATS) is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

• At least 50% of individuals diagnosed with ATS have an affected parent.

• A proband with ATS may have the disorder as the result of a de novo gene mutation. The proportion of cases caused by de novo mutations may be as high as 50%.

• Recommendations for the evaluation of parents of a proband with an apparent de novo mutation include a detailed neurologic and cardiologic evaluation, 12-lead ECG, 24-hour Holter monitoring, and molecular genetic testing for the KCNJ2 mutation identified in the proband.

Note: Although at least 50% of individuals diagnosed with ATS have an affected parent, the family history may appear to be negative because of failure to recognize the disorder in family members, early death of the parent not attributed to the disease, or reduced penetrance.

Sibs of a proband

• The risk to the sibs of the proband depends on the genetic status of the proband's parents.

• If a parent of the proband is affected and does not have the KCNJ2 mutation identified in the proband, the risk to the sibs is 50%.

• When the parents are clinically unaffected, the risk to the sibs of a proband appears to be low.

• If a disease-causing mutation cannot be detected in the DNA extracted from the leukocytes of either parent, two possible explanations are germline mosaicism in a parent or a de novo mutation in the proband. Although no instances of germline mosaicism have been reported, it remains a possibility.

Offspring of a proband. Each child of an individual with ATS has a 50% chance of inheriting the mutation.

Other family members of a proband. The risk to other family members depends on the status of the proband's parents. If a parent is affected, his or her family members are at risk.

Related Genetic Counseling Issues

Considerations in families with an apparent de novo mutation. When neither parent of a proband with an autosomal dominant condition has the disease-causing mutation or clinical evidence of the disorder, it is likely that the proband has a de novo mutation. However, possible non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) or undisclosed adoption could also be explored.

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.

• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals. See for a list of laboratories offering DNA banking.

Prenatal Testing

Prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at about 15 to 18 weeks' gestation or chorionic villus sampling (CVS) at about ten to 12 weeks' gestation. The disease-causing allele of an affected family member must be identified before prenatal testing can be performed.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Requests for prenatal testing for conditions such as ATS are not common. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. Although most centers would consider decisions about prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

Preimplantation genetic diagnosis (PGD) may be available for families in which the disease-causing mutation has been identified in an affected family member. For laboratories offering PGD, see .

Note: It is the policy of GeneReviews to include in GeneReviews™ chapters any clinical uses of testing available from laboratories listed in the GeneTests™ Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Molecular Genetic Pathogenesis

KCNJ2 encodes the inward rectifier potassium channel 2, or Kir2.1 [Plaster et al 2001], expressed primarily in skeletal muscle, heart, and brain. Kir2.1 is involved in setting and stabilizing the resting membrane potential in skeletal and cardiac muscle and has a major role in the terminal repolarization phase of the cardiac action potential [Plaster et al 2001, Tristani-Firouzi et al 2002]. The majority of mutations exert a dominant-negative effect on channel current [Lange et al 2003, Donaldson et al 2004, Davies et al 2005, Ballester et al 2006]. Several mutations affect trafficking of the mutant channel to the cell surface for reasons that are not clear [Ballester et al 2006] while the majority traffick normally to the cell surface but fail to conduct normally [Bendahhou et al 2003]. Phosphatidylinositol 4,5 bisphosphate (PIP₂) is an important regulator of Kir2.1 channel function; many KCNJ2 mutations alter PIP₂ binding [Lopes et al 2002, Donaldson et al 2003].

Flaccid paralysis results from failure to propagate action potentials in the muscle membrane as a result of sustained membrane depolarization [Cannon 2002]. The modestly prolonged QT interval and ventricular arrhythmias are caused by impaired cardiac ventricular repolarization; the reduced inward rectifying potassium current results in distinct T-U wave morphology [Tristani-Firouzi et al 2001, Zhang et al 2005].

While the role of Kir2.1 in skeletal development remains to be clarified, consistent craniofacial, dental, and skeletal anomalies are present [Yoon et al 2006a]. Targeted disruption of Kir2.1 in a knockout mouse is fatal with complete cleft of the secondary palate [Zaritsky et al 2000].

Normal allelic variants. KCNJ2 has two exons spanning 5.4 kb.

Pathologic allelic variants. The 31 mutations described reside in exon 2. They include: Arg67Trp/Gln,Tyr68Asp, Asp71Val/Asn, Thr74Ala, Thr75Arg/Met, Asp78Gly, Arg82Gln, del95-98, Cys101Arg, Val123Gly, Ser136Phe, Gly144Ala/Ser, Gly146Asp/Ser, Pro186Leu, Arg189Ile, Thr192Ala, Asn216His, Leu217Pro, Arg218Trp/Gln, Gly300Asp/Val, Val302Met, Glu303Lys, Arg312Cys, and del314-315. For more information, see Table A.

Normal gene product. KCNJ2 encodes the inward rectifier potassium channel 2 protein (Kir2.1), with 427 amino acid residues and 48-kd molecular weight.

Abnormal gene product. Mutations in KCNJ2 cause dominant-negative suppression of Kir2.1 current [Plaster et al 2001, Tristani-Firouzi et al 2002] and affect channel-PIP₂ interactions [Donaldson et al 2003].

Literature Cited

1. Ai T, Fujiwara Y, Tsuji K, Otani H, Nakano S, Kubo Y, Horie M. Novel KCNJ2 mutation in familial periodic paralysis with ventricular dysrhythmia. Circulation. 2002;105:2592–4. [PubMed: 12045162]
2. Airey KJ, Etheridge SP, Tawil R, Tristani-Firouzi M. Resuscitated sudden cardiac death in Andersen-Tawil syndrome. Heart Rhythm. 2009;6:1814–7. [PMC free article: PMC2789273] [PubMed: 19959136]
3. Andelfinger G, Tapper AR, Welch RC, Vanoye CG, George AL, Benson DW. KCNJ2 mutation results in Andersen syndrome with sex-specific cardiac and skeletal muscle phenotypes. Am J Hum Genet. 2002;71:663–8. [PMC free article: PMC379203] [PubMed: 12148092]
4. Andersen ED, Krasilnikoff PA, Overvad H. Intermittent muscular weakness, extrasystoles, and multiple developmental anomalies. A new syndrome? Acta Paediatr Scand. 1971;60:559–64. [PubMed: 4106724]
5. Ballester LY, Benson DW, Wong G, Law IH, Mathews KD, Vanoye CG, George AL. Trafficking-competent and trafficking-defective KCNJ2 mutations in Andersen syndrome. Hum Mutat. 2006;27:388. [PubMed: 16541386]
6. Bendahhou S, Donaldson MR, Plaster NM, Tristani-Firouzi M, Fu YH, Ptacek LJ. Defective potassium channel Kir2.1 trafficking underlies Andersen-Tawil syndrome. J Biol Chem. 2003;278:51779–85. [PubMed: 14522976]
7. Bökenkamp R, Wilde AA, Schalij MJ, Blom NA. Flecainide for recurrent malignant ventricular arrhythmias in two siblings with Andersen-Tawil syndrome. Heart Rhythm. 2007;4:508–11. [PubMed: 17399642]
8. Cannon SC. An expanding view for the molecular basis of familial periodic paralysis. Neuromuscul Disord. 2002;12:533–43. [PubMed: 12117476]
9. Canun S, Perez N, Beirana LG. Andersen syndrome autosomal dominant in three generations. Am J Med Genet. 1999;85:147–56. [PubMed: 10406668]
10. Chun TU, Epstein MR, Dick M, Andelfinger G, Ballester L, Vanoye CG, George AL, Benson DW. Polymorphic ventricular tachycardia and KCNJ2 mutations. Heart Rhythm. 2004;1:235–41. [PubMed: 15851159]
11. Davies NP, Imbrici P, Fialho D, Herd C, Bilsland LG, Weber A, Mueller R, Hilton-Jones D, Ealing J, Boothman BR, Giunti P, Parsons LM, Thomas M, Manzur AY, Jurkat-Rott K, Lehmann-Horn F, Chinnery PF, Rose M, Kullmann DM, Hanna MG. Andersen-Tawil syndrome: new potassium channel mutations and possible phenotypic variation. Neurology. 2005;65:1083–9. [PubMed: 16217063]
12. Donaldson MR, Jensen JL, Tristani-Firouzi M, Tawil R, Bendahhou S, Suarez WA, Cobo AM, Poza JJ, Behr E, Wagstaff J, Szepetowski P, Pereira S, Mozaffar T, Escolar DM, Fu YH, Ptacek LJ. PIP2 binding residues of Kir2.1 are common targets of mutations causing Andersen syndrome. Neurology. 2003;60:1811–6. [PubMed: 12796536]
13. Donaldson MR, Yoon G, Fu YH, Ptacek LJ. Andersen-Tawil syndrome: a model of clinical variability, pleiotropy, and genetic heterogeneity. Ann Med. 2004;36 Suppl 1:92–7. [PubMed: 15176430]
14. Fournier E, Arzel M, Sternberg D, Vicart S, Laforet P, Eymard B, Willer JC, Tabti N, Fontaine B. Electromyography guides toward subgroups of mutations in muscle channelopathies. Ann Neurol. 2004;56:650–61. [PubMed: 15389891]
15. Fox DJ, Klein GJ, Hahn A, Skanes AC, Gula LJ, Yee RK, Subbiah RN, Krahn AD. Reduction of ventricular ectopy and improvement in exercise capacity with flecanide therapy in Andersen-Tawil syndrome. Europace. 2008;10:1006–08. [PubMed: 18621769]
16. Haruna Y, Kobori A, Makiyama T, Yoshida H, Akao M, Doi T, Tsuji K, Ono S, Nishio Y, Shimizu W, Inoue T, Murakami T, Tsuboi N, Yamanouchi H, Ushinohama H, Nakamura Y, Yoshinaga M, Horigome H, Aizawa Y, Kita T, Horie M. Genotype-phenotype correlations of KCNJ2 mutations in Japanese patients with Andersen-Tawil syndrome. Hum Mutat. 2007;28:208. [PubMed: 17221872]
17. Hosaka Y, Hanawa H, Washizuka T, Chinushi M, Yamashita F, Yoshida T, Komura S, Watanabe H, Aizawa Y. Function, subcellular localization and assembly of a novel mutation of KCNJ2 in Andersen's syndrome. J Mol Cell Cardiol. 2003;35:409–15. [PubMed: 12689820]
18. Katz JS, Wolfe GI, Iannaccone S, Bryan WW, Barohn RJ. The exercise test in Andersen syndrome. Arch Neurol. 1999;56:352–6. [PubMed: 10190827]
19. Kuntzer T, Flocard F, Vial C, Kohler A, Magistris M, Labarre-Vila A, Gonnaud PM, Ochsner F, Soichot P, Chan V, Monnier G. Exercise test in muscle channelopathies and other muscle disorders. Muscle Nerve. 2000;23:1089–94. [PubMed: 10883004]
20. Lange PS, Er F, Gassanov N, Hoppe UC. Andersen mutations of KCNJ2 suppress the native inward rectifier current IK1 in a dominant-negative fashion. Cardiovasc Res. 2003;59:321–7. [PubMed: 12909315]
21. Lopes CM, Zhang H, Rohacs T, Jin T, Yang J, Logothetis DE. Alterations in conserved Kir channel-PIP2 interactions underlie channelopathies. Neuron. 2002;34:933–44. [PubMed: 12086641]
22. Pellizzón OA, Kalaizich L, Ptácek LJ, Tristani-Firouzi M, Gonzalez MD. Flecainide suppresses bidirectional ventricular tachycardia and reverses tachycardia-induced cardiomyopathy in Andersen-Tawil syndrome. J Cardiovasc Electrophysiol. 2008;19:95–7. [PubMed: 17655675]
23. Plaster NM, Tawil R, Tristani-Firouzi M, Canun S, Bendahhou S, Tsunoda A, Donaldson MR, Iannaccone ST, Brunt E, Barohn R, Clark J, Deymeer F, George AL, Fish FA, Hahn A, Nitu A, Ozdemir C, Serdaroglu P, Subramony SH, Wolfe G, Fu YH, Ptacek LJ. Mutations in Kir2.1 cause the developmental and episodic electrical phenotypes of Andersen's syndrome. Cell. 2001;105:511–9. [PubMed: 11371347]
24. 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. 1997;42:305–12. [PubMed: 9307251]
25. Schoonderwoerd BA, Wiesfeld AC, Wilde AA, van den Heuvel F, Van Tintelen JP, van den Berg MP, Van Veldhuisen DJ, Van Gelder IC. A family with Andersen-Tawil syndrome and dilated cardiomyopathy. Heart Rhythm. 2006;3:1346–50. [PubMed: 17074642]
26. Tawil R, Ptacek LJ, Pavlakis SG, DeVivo DC, Penn AS, Ozdemir C, Griggs RC. Andersen's syndrome: potassium-sensitive periodic paralysis, ventricular ectopy, and dysmorphic features. Ann Neurol. 1994;35:326–30. [PubMed: 8080508]
27. Tristani-Firouzi M. Andersen-Tawil syndrome: an ever-expanding phenotype? Heart Rhythm. 2006;3:1351–2. [PubMed: 17074643]
28. Tristani-Firouzi M, Etheridge SP (2010) Kir 2.1 channelopathies: the Andersen-Tawil syndrome. Pflugers Arch. [Epub ahead of print]
29. Tristani-Firouzi M, Chen J, Mitcheson JS, Sanguinetti MC. Molecular biology of K(+) channels and their role in cardiac arrhythmias. Am J Med. 2001;110:50–9. [PubMed: 11152866]
30. Tristani-Firouzi M, Jensen JL, Donaldson MR, Sansone V, Meola G, Hahn A, Bendahhou S, Kwiecinski H, Fidzianska A, Plaster N, Fu YH, Ptacek LJ, Tawil R. Functional and clinical characterization of KCNJ2 mutations associated with LQT7 (Andersen syndrome). J Clin Invest. 2002;110:381–8. [PMC free article: PMC151085] [PubMed: 12163457]
31. Woosley RL (2001) Drugs that prolong the QT interval and/or induce torsades de pointes. Online database [www.qtdrugs.org]
32. Yoon G, Oberoi S, Tristani-Firouzi M, Etheridge SP, Quitania L, Kramer JH, Miller BL, Fu YH, Ptacek LJ. Andersen-Tawil syndrome: prospective cohort analysis and expansion of the phenotype. Am J Med Genet A. 2006a;140:312–21. [PubMed: 16419128]
33. Yoon G, Quitania L, Kramer JH, Fu YH, Miller BL, Ptacek LJ. Andersen-Tawil syndrome: definition of a neurocognitive phenotype. Neurology. 2006b;66:1703–10. [PubMed: 16769944]
34. Zaritsky JJ, Eckman DM, Wellman GC, Nelson MT, Schwarz TL. Targeted disruption of Kir2.1 and Kir2.2 genes reveals the essential role of the inwardly rectifying K(+) current in K(+)-mediated vasodilation. Circ Res. 2000;87:160–6. [PubMed: 10904001]
35. Zhang L, Benson DW, Tristani-Firouzi M, Ptacek LJ, Tawil R, Schwartz PJ, George AL, Horie M, Andelfinger G, Snow GL, Fu YH, Ackerman MJ, Vincent GM. Electrocardiographic features in Andersen-Tawil syndrome patients with KCNJ2 mutations: characteristic T-U-wave patterns predict the KCNJ2 genotype. Circulation. 2005;111:2720–6. [PubMed: 15911703]

Suggested Reading

1. Venance SL, Cannon SC, Fialho D, Fontaine B, Hanna MG, Ptacek LJ, Tristani-Firouzi M, Tawil R, Griggs RC. The primary periodic paralyses: diagnosis, pathogenesis and treatment. Brain. 2006;129:8–17. [PubMed: 16195244]

Acknowledgments

The authors are funded in part by the Consortium for Clinical Investigation of Neurological Channelopathies (CINCH) supported by NIH 8 U54 NS59065 (NINDS/ORD).

Revision History

• 13 May 2010 (me) Comprehensive update posted live

• 19 March 2007 (me) Comprehensive update posted to live Web site

• 27 April 2005 (cd) Revision: prenatal diagnosis available

• 22 November 2004 (me) Review posted to live Web site

• 1 June 2004 (rt) Original submission