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Andersen-Tawil Syndrome

Synonyms: Anderson Syndrome, LQT7, Long QT Syndrome 7

, MD, , MD, and , MD, PhD.

Author Information
, MD
Department of Neurology
University of Rochester Medical Center
Rochester, New York
, MD
Department of Neurology
University of Rochester Medical Center
Rochester, New York
, MD, PhD
Department of Clinical Neurological Sciences
London Health Sciences Centre
University of Western Ontario
London, Ontario

Initial Posting: ; Last Update: January 3, 2013.

Summary

Disease characteristics. Andersen-Tawil syndrome (referred to as ATS in this entry) is characterized by a triad of episodic flaccid muscle weakness (i.e., periodic paralysis), ventricular arrhythmias and prolonged QT interval, and anomalies including low-set ears, widely spaced eyes, small mandible, fifth-digit clinodactyly, syndactyly, short stature, and scoliosis. Affected individuals present in the first or second decade with either cardiac symptoms (palpitations and/or syncope) or weakness that occurs spontaneously following prolonged rest or following rest after exertion. Mild permanent weakness is common. Mild learning difficulties and a distinct neurocognitive phenotype (i.e., deficits in executive function and abstract reasoning) have been described.

Diagnosis/testing. The diagnosis of ATS is suspected in an individual with characteristic clinical and ECG findings. KCNJ2, encoding the inward rectifier potassium channel 2 protein (Kir2.1), is the only gene in which mutations are known to cause ATS. Approximately 60% of individuals with ATS have a detectable mutation in KCNJ2. The presence of a pathogenic KCNJ2 mutation confirms the diagnosis.

Management. Treatment of manifestations: For episodic weakness: if 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; if serum potassium concentration is high, ingesting carbohydrates or continuing mild exercise may shorten the attack.

Prevention of primary manifestations: Reduction in frequency and severity of episodic attacks of weakness with lifestyle/dietary modification to avoid known triggers; use of carbonic anhydrase inhibitors; daily use of slow-release potassium supplements; implantable cardioverter-defibrillator for those with tachycardia-induced syncope.

Prevention of secondary complications: Cautious use of antiarrhythmic drugs (particularly class I drugs) that may paradoxically exacerbate the neuromuscular symptoms.

Surveillance: Annual screening of asymptomatic individuals with a pathogenic KCNJ2 mutation with a 12-lead ECG and 24-hour Holter monitoring.

Agents/circumstances to avoid: Medications known to prolong QT intervals; salbutamol inhalers (may exacerbate cardiac arrhythmias); thiazide and other potassium-wasting diuretics (may provoke drug-induced hypokalemia and could aggravate the QT interval).

Evaluation of relatives at risk: Molecular genetic testing if the disease-causing mutation is known, otherwise clinical diagnostic evaluations to reduce morbidity and mortality through early diagnosis and treatment.

Genetic counseling. ATS is inherited in an autosomal dominant manner. At least 50% of individuals diagnosed with ATS have an affected parent. Up to 50% of cases are caused by de novo mutations. Each child of an individual with ATS has a 50% chance of inheriting the disorder. Prenatal diagnosis for pregnancies at increased risk is possible if the disease-causing mutation has been identified in an affected family member.

Diagnosis

Clinical Diagnosis

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

A.

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
    • Widely spaced eyes
    • Small mandible
    • Fifth-digit clinodactyly
    • Syndactyly
B.

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, Canún 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 amplitude (>40%) [Katz et al 1999] or area (>50%) 20-40 minutes post-exercise [Kuntzer et al 2000, Fournier et al 2004]. In a study of 11 individuals with ATS, 82% met long-exercise amplitude decrement criteria for abnormal testing [Tan et al 2011].

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 in which mutations are known to cause Andersen syndrome type 1 (ATS1).

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

Clinical testing

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

Gene 1Test MethodMutations Detected 2Mutation Detection Frequency by Test Method 3
KCNJ2Sequence analysis 4Sequence variants~60% 5
Mutation scanning 6Unknown
Deletion/duplication analysis 7Partial- or whole-gene deletions/duplicationsUnknown; none reported

1. See Table A. Genes and Databases for chromosome locus and protein name.

2. See Molecular Genetics for information on allelic variants.

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

4. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

5. Approximately 60% of individuals with ATS have a missense mutation or a small intragenic 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 p.Arg218Trp is considered a potential hotspot for disease-causing mutations [Davies et al 2005].

6. Sequence analysis and mutation scanning of the entire gene can have similar mutation detection frequencies; however, mutation detection rates for mutation scanning may vary considerably among laboratories depending on the specific protocol used.

7. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.

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 (see Genotype-Phenotype Correlations). 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.

Clinical Description

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, Canún 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 (LQT) interval, 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]. A large case series found no significant difference in the incidence of ventricular tachyarrhythmias between individuals with typical and atypical presentations of ATS [Kimura et al 2012].

Dilated cardiomyopathy was observed in two of three affected individuals in a single kindred with the p.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, widely spaced eyes, 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 p.Gly300Asp and p.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 case series that evaluated for KCNJ2 mutations in typical (>2 ATS features) and atypical (only 1 ATS feature or catecholaminergic polymorphic ventricular tachycardia) individuals with ATS, mutation-positive rates were 75% (15/20) in those with typical ATS, 71% (5/7) in those with the cardiac phenotype alone, 100% (2/2) in those with periodic paralysis, and 7% (2/28) in those with CPVT [Kimura et al 2012].

In a single large kindred with the KCNJ2 p.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.

Differential Diagnosis

See Long QT Syndrome: OMIM Phenotypic Series, a table of similar phenotypes that are genetically diverse.

Andersen-Tawil syndrome (ATS) should be considered in any individual presenting with periodic paralysis and ventricular arrhythmias or enlarged U waves. 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. The differential diagnosis depends on the initial presentation and includes the primary and secondary periodic paralyses and thyrotoxic periodic paralysis.

Episodes of flaccid paralysis

  • Hypokalemic periodic paralysis is the most common periodic paralysis. Affected individuals have episodes of reversible, flaccid paralysis associated with reduced serum potassium concentrations (<3.5 mmol/U) and/or slowly progressive proximal weakness. The onset, duration, and severity of attacks, with the associated triggers, are similar to those in individuals with ATS. Respiratory muscles are spared. Weakness is improved with oral potassium ingestion. The cardiac and dysmorphic features of ATS are, however, absent in hypokalemic periodic paralysis. Molecular testing identifies mutations in CACNA1S or SCN4A in approximately 80% of affected individuals after secondary causes such as thyrotoxicosis, diuretic use, and renal (e.g., hyperaldosteronism, distal tubular acidosis) or gastrointestinal (e.g., vomiting, diarrheal illness) causes have been ruled out. Inheritance is autosomal dominant.
  • Hyperkalemic periodic paralysis is characterized by episodes of flaccid paralysis associated with normal or elevated ictal serum potassium concentrations (>5.0 mmol/U) and aggravated by potassium ingestion. Onset is in the first decade; episodes are briefer than those that occur in individuals with hypokalemic periodic paralysis. Electrical myotonia is evident in 50% of affected individuals. The cardiac and dysmorphic features of ATS are absent. Molecular testing reveals one of seven common mutations in SCN4A in approximately 50% of individuals. Secondary forms of hyperkalemic periodic paralysis to rule out include adrenal insufficiency, hypoaldosteronism, and adverse effects of certain medications (e.g., ACE inhibitors, spironolactone, nonsteroidal anti-inflammatory drugs). Inheritance is autosomal dominant.
  • Thyrotoxic periodic paralysis is a consideration in any individual with severe weakness and marked hypokalemia. Men, particularly Asians, are affected in greater numbers; however, thyrotoxic periodic paralysis may be seen in all races. Diagnosis is established by measurement of serum TSH, T4, and T3 concentrations. A mutation in an inwardly rectifying potassium (Kir) channel (encoded by KCNJ18) has been identified in approximately one third of affected individuals in one series [Ryan et al 2010].

Palpitations, syncope, or cardiac arrest. Syncopal episodes are often interpreted as a neurologic problem rather than arrhythmia. Physical examination and ECG should be part of the evaluation of syncope. Bidirectional ventricular tachycardia demonstrated on ECG may be seen with ATS, digitalis toxicity, and catecholaminergic polymorphic ventricular tachycardia (CPVT). A normal resting ECG with exercise-induced polymorphic arrhythmias is a clue to CPVT. Mutations in RYR2 and CASQ2 are causative. Inheritance is autosomal dominant [Tristani-Firouzi & Etheridge 2010].

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

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
  • Medical genetics consultation

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 ECG may be useful during potassium replacement therapy in an emergency setting to avoid secondary hyperkalemia.
  • Attacks of weakness when 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 an emergency setting.

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
  • Use of carbonic anhydrase inhibitors (acetazolamide 250-500 mg/1-2x/day or dichlorphenamide 50-100 mg/1-2x/day)
  • Daily use of slow-release potassium supplements, which may also be helpful in controlling attack rates in individuals prone to hypokalemia. 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 in individuals with tachycardia-induced syncope [Chun et al 2004]
  • Empiric treatment with flecainide [Bökenkamp et al 2007, Fox et al 2008, Pellizzón 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

For asymptomatic individuals with a pathogenic KCNJ2 mutation, annual screening including a 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.crediblemeds.org [Woosley 2014] 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.

Pregnancy Management

The rarity of ATS and the paucity of reports pertaining to pregnancy in women with ATS make an evidence-based approach to pregnancy management difficult to formulate. One case study reported an uneventful pregnancy, with increased episodes of weakness but reduced ventricular ectopy compared to the pre-pregnancy period [Subbiah et al 2008]. However, as data are limited, a multidisciplinary approach to patient care and anticipation of increased risk (as can be seen in those with long QT syndrome) seems reasonable.

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.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

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: At least 50% of individuals diagnosed with ATS have an affected parent; however, 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/or has the KCNJ2 mutation identified in the proband, the risk to the sibs of inheriting the mutation 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

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

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, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

If the disease-causing mutation has been identified in the family, prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis (usually performed at ~15-18 weeks’ gestation) or chorionic villus sampling (usually performed at ~10-12 weeks’ gestation).

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 an option for some families in which the disease-causing mutation has been identified in an affected family member.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • National Library of Medicine Genetics Home Reference
  • Muscular Dystrophy Association - USA (MDA)
    3300 East Sunrise Drive
    Tucson AZ 85718
    Phone: 800-572-1717
    Email: mda@mdausa.org
  • Periodic Paralysis Association (PPA)
    155 West 68th Street
    Suite 1732
    New York NY 10023
    Phone: 407-339-9499
    Email: lfeld@cfl.rr.com
  • Sudden Arrhythmia Death Syndromes (SADS) Foundation
    508 East South Temple
    Suite #20
    Salt Lake City UT 84102
    Phone: 800-786-7723 (toll-free); 801-531-0937
    Email: sads@sads.org
  • Consortium for Clinical Investigation of Neurologic Channelopathies Contact Registry
  • Long QT Syndrome (LQTS) Registry
    An ongoing research study with the goal of contributing to a better understanding of the genetics, natural history, and treatment of LQTS. Currently enrolling families in which a mutation has already been identified.
    University of Rochester Medical Center
    265 Crittenden Boulevard
    CU 420653
    Rochester NY 14642-0653
    Phone: 585-276-0016
    Fax: 585-273-5283

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A. Andersen-Tawil Syndrome: Genes and Databases

Gene SymbolChromosomal LocusProtein NameHGMD
KCNJ217q24​.3Inward rectifier potassium channel 2

Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B. OMIM Entries for Andersen-Tawil Syndrome (View All in OMIM)

170390ANDERSEN CARDIODYSRHYTHMIC PERIODIC PARALYSIS
600681POTASSIUM CHANNEL, INWARDLY RECTIFYING, SUBFAMILY J, MEMBER 2; KCNJ2

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, Barajas-Martinez et al 2011, Marrus et al 2011]. Several mutations affect trafficking of the mutant channel to the cell surface for reasons that are not clear [Ballester et al 2006]. One study identified loss of an endoplasmic reticulum export motif [Doi et al 2011]. The majority traffic 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].

Gene structure. KCNJ2 has two exons spanning 5.4 kb. For a detailed summary of gene and protein information, see Table A, Gene Symbol.

Pathogenic allelic variants. See Table A, Locus Specific and HGMD.

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].

References

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 B, 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]
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Suggested Reading

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

Chapter Notes

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

  • 3 January 2013 (me) Comprehensive update posted live
  • 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
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